COR) genes, and the regulatory pathways in response to cold stress. Cold-tolerant QTLs were found to be overlapped with the genomic region of maturity loci of E1, E3, E4, pubescence color locus of T, stem growth habit gene locus of Dt1, and leaf shape locus of Ln, indicating that pleiotropic loci may control multiple traits, including cold tolerance. The C-repeat responsive element binding factors (CBFs) are evolutionarily conserved across species. The expression of most GmDREB1s was upregulated by cold stress and overexpression of GmDREB1B;1 in soybean protoplast, and transgenic Arabidopsis plants can increase the expression of genes with the DRE core motif in their promoter regions under cold stress. Other soybean cold-responsive regulators, such as GmMYBJ1, GmNEK1, GmZF1, GmbZIP, GmTCF1a, SCOF-1 and so on, enhance cold tolerance by regulating the expression of COR genes in transgenic Arabidopsis. CBF-dependent and CBF-independent pathways are cross-talking and work together to activate cold stress gene expression. Even though it requires further dissection for precise understanding, the function of soybean cold-responsive transcription factors and associated COR genes studied in Arabidopsis shed light on the molecular mechanism of cold responses in soybeans and other crops. Furthermore, the findings may also provide practical applications for breeding cold-tolerant soybean varieties in high-latitude and high-altitude regions.Cold stress is a major factor influencing the geographical distribution of soybean growth and causes immense losses in productivity. Understanding the molecular mechanisms that the soybean has undergone to survive cold temperatures will have immense value in improving soybean cold tolerance. This review focuses on the molecular mechanisms involved in soybean response to cold. We summarized the recent studies on soybean cold-tolerant quantitative trait loci (QTLs), transcription factors, associated cold-regulated ( Glycine max (L.) Merr.) is an important food crop and a valuable source of protein and oil in human and animal diets worldwide [http://www.soybeancouncil.ca, accessed on 20 January 2022). Because of the cold temperatures in these regions, a lack of cold tolerance imposes prominent negative influences on soybean nodulation, yield, and seed quality [The soybean  has been studied most intensively. Cultivars and lines with the T allele at the T locus, which controls the color of pubescence, have repeatedly been demonstrated to exhibit better chilling tolerance than those with the alternative allele, t [Src2) transcript accumulation and chilling tolerance in soybean seedlings [apx1 locus and the previously reported loci associated with chilling tolerance, further experiments may be needed to verify its linkage relationship with recently identified QTLs [E1, E3, and E4 were also found to be associated with chilling tolerance for both seed yield and quality [E1 allele was found to be more important than the e1 allele in chilling tolerance [qCTTSW1, qCTTSW2, and qCTTSW3, were detected for chilling tolerance in seed-yielding ability. The two QTLs, qCTTSW1 and qCTTSW2, were mapped near the QTLs for flowering time [Dt1), regulators of leaf shape (Ln), and pubescence density (P1) loci have been associated with chilling tolerance in soybeans [fd2 and fd4, are believed to correspond to maturity genes E1 and E3, respectively.The exploitation of stress-tolerant genes and quantitative trait loci (QTLs) are effective ways to generate stress-tolerant crops . Chen etllele, t ,21,29. Teedlings . Howeveried QTLs . Maturit quality . The E1 olerance . Moreoveing time . Stem grsoybeans . Out of soybeans , two of GmIRCHS) showed that GmIRCHS or a region located very close to it was responsible for cold tolerance [Twelve QTLs were detected for tolerance to chilling temperature during germination by one-way ANOVA. More than 28 QTLs related to cold acclimatization were identified from genome-wide studies in soybeans during germination and seedling stages . Of thesolerance .qCS8-1, and qCS11-1, for seed coat cracking tolerance under chilling stress at the reproductive stage. The qCS8-1 and qCS11-1 loci were found to have no negative influence on flowering time or other agronomic traits. Recently, Yamaguchi et al. [I locus associated with cold-induced seed coat discoloration (CD). Likewise, Jähne et al. [qCS11-1) identified by Yamaguchi et al. [Additionally, some of the QTLs, listed in i et al.  identifie et al.  also idei et al. .2+, plant hormones, and reactive oxygen species (ROS) which triggers the expression of key transcription factors like CBF and other regulators. In turn, CBF and other regulators activate the expression of downstream COR genes, such as RD29A, RD17, COR6.6, COR15A, ERD10, KIN1, KIN2, and others in response to cold [When plants are exposed to cold stress, there will be a perception of a cold signal and a rise in Ca to cold ,43,44,45 to cold . While t to cold ,47, GmDR to cold , GmDREB1 to cold , soybean to cold , GmEIN3  to cold , KS dehy to cold , and soy to cold . Thus, uAtCBFs can function as transcriptional activators that bind to the CRT/DRE regulatory element of cold-regulated genes in Arabidopsis [CBF genes are conserved in plants that can or cannot acclimate to cold temperatures, including rice (Oryza sativa), tomato (Solanum lycopersicum), rapeseed (Brassica napus), wheat (Triticum aestivum), barley (Hordeum vulgare), maize (Zea mays), and soybean (Glycine max) [The C-repeat binding factor/dehydration-responsive element binding factor (CBF/DREB) belonging to AP2/ERF family transcription factors plays important roles in cold temperature response in plants . The CBFbidopsis . It has ine max) ,57,58. Aine max) . Unlike ine max) .GmDREB1s was upregulated by abiotic stresses, such as cold, salt, drought and heat stresses [GmDREB1s, GmDREB1A;1, GmDREB1A;2, GmDREB1B;1, GmDREB1B;2, GmDREB1C;1, GmDREB1D;1, and GmDREB1D;2 were significantly upregulated after an hour and remained elevated at 24 h under cold stress [DREB gene, GmDREB3, was upregulated after 0.5 h of cold treatment and was not detected in 3 h after cold treatment. Overexpression of GmDREB3 improved drought, high salt, and cold stress tolerance in transgenic Arabidopsis [GmDREB1B;1 in soybean protoplast can increase the expression of genes with the DRE core motif in their promoter regions under abiotic stress conditions. GmDREB1B;1 can activate many soybean-specific cold-responsive genes including GmPYL21, an ABA receptor family gene, which could activate the downstream ABRE-mediated gene expression in an ABA-independent way. Soybean DREB1s were demonstrated to upregulate the transcription of downstream COR genes AtCOR47 and AtRD29a and increase cold tolerance in transgenic Arabidopsis [DREB1 genes, GmVRN1 is strongly accumulated in the AtDREB1A-overexpressing soybean [GmVRN1 is responsive to low temperatures and is believed to participate in the vernalization pathway in transgenic Arabidopsis to regulate flowering time. This feature of GmVRN1 in soybeans is different from its role in transgenic Arabidopsis [VRN1, the homolog of GmVRN1, causes early flowering in Arabidopsis [AtDREB1A could bind to the DRE motif, which is 157 to 186 bp upstream of GmVRN1, indicating that the effect of GmVRN1 may be mediated by a CBF-dependent cold-responsive pathway [GmVRN1 will help uncover its role in downstream COR gene regulation.The expression of most stresses . Seven Gd stress ,49. Anotbidopsis . Overexpbidopsis . Regulat soybean . GmVRN1 bidopsis . Moreovebidopsis . AtDREB1 pathway . FurtherDREB1A;1 and DREB1B;1 was found to be upregulated by the cold, and their levels were consistently increased and decreased by ethylene pathway inhibitors and stimulators, respectively. Further studies would be required to determine whether GmEIN3 negatively regulates GmDREB1A;1 by binding to the DRE motif in the GmDREB1A;1 promoter during cold stress.The soybean ethylene pathway is found to regulate the soybean CBF/DREB1 cold-responsive pathway by the accumulation of transcripts encoding the transcription factor GmEIN3 in response to the cold . GmEIN3 COR genes like RD29A. Similarly, GmDREB1B;1 directly activates GmPYL21 expression and enhances ABRE-mediated gene expression in soybeans [Besides the CBF-dependent (DRE-mediated) pathway, the CBF-independent pathway, which is activated by other transcription factors rather than CBF/DREB, such as MYB, bZIP, WRKY, and Zinc Finger-type transcription factors ,62,63,64soybeans .GmMYBJ1 (R2R3-type MYB genes), GmZF1 and SCOF-1 (C2H2 zinc finger gene), GmbZIP44, GmbZIP62 and GmbZIP78 , GmTCF1a (regulator of chromosome condensation 1 (RCC1) family genes), GmNEK1 (NEK family gene), and GmWRKY21 (WRKY-type transcription factor) in Arabidopsis can enhance cold tolerance [COR genes in a CBF-independent pathway. Different regulators induce different target COR genes in transgenic Arabidopsis, e.g., GmMYBJ1 , GmZF1 (AtCOR6.6), GmbZIPs , GmTCF1a (AtCOR15a), and SCOF-1 .Several soybean genes have been shown to mediate cold tolerance . Soybeanolerance ,64,67,68AtDREB2A in the GmMYBJ1 transgenic Arabidopsis, suggesting the expression of stress-responsive COR genes may be regulated independently of CBFs [GmZF1 mRNA induced by exogenous ABA suggested that GmZF1 was also involved in a CBF-independent signal transduction pathway in transgenic Arabidopsis [GmTCF1a does not alter the expression of CBFs in Arabidopsis, suggesting that the impact of GmTCF1a in overexpressing Arabidopsis is independent of the CBF pathway [AtTCF1, regulates freezing tolerance through a CBF-independent pathway [In a CBF-independent pathway, there is a slight downregulation in the expression of  of CBFs . A high bidopsis . The ect pathway . Its ort pathway .SCOF-1, a novel cold regulator specific to soybeans, functions as a positive regulator of COR gene expression to enhance cold tolerance in transgenic Arabidopsis and tobacco [SCOF-1 did not bind directly to CRT/DRE or ABRE in the promoter of COR genes; instead, it greatly enhanced the DNA binding activity of a soybean G-box binding bZIP transcription factor, SGBF-1 [SGBF-1 by SCOF-1 is CBF-independent in transgenic Arabidopsis. Soybean SCOF-1 has a considerable sequence similarity with Arabidopsis AZF and STZ, which act as negative regulators of COR gene expression in Arabidopsis [SCOF1-like proteins are negative or positive regulators of soybean COR genes following cold treatments. No data was provided on the COR genes regulated by GmWRKY21 - and MicroRNA (miRNA)-based gene regulation were also involved in coordinating soybean responses to cold stress in post-transcriptional regulation ,76,77,78ectively . HoweverCOR gene expression in CBF-dependent manner. Some of them  have positive effects, while other  have negative effects on CBF expression [GmEIN3, a homolog of Arabidopsis EIN3, was identified to be involved in soybean cold response in a CBF-dependent manner and negatively regulate GmDREB1 expression in transgenic Arabidopsis. Moreover, Arabidopsis regulators such as SAG12, WRKY33, ERF5, CZF1, RAV1, CZF2, MYB73, ZAT10, HSFC1, NPR1, HSFA1, RCF1, STA1, HOS15, GCN5, and HD2C were involved in cold stress response through CBF-independent pathway [COR genes studied in Arabidopsis shed light on the molecular mechanism of the cold response in soybeans and other crops.As indicated above, homolog regulators identified in the soybeans exhibited a typical function of cold responsiveness in transgenic Arabidopsis. Nevertheless, it remains to be determined whether the regulators interacted with CBF and whether they are involved in the DRE-mediated or ABRE-mediated pathways. Arabidopsis cold responsive regulators including ICE1/2, CAMATA1-5, CESTA, BZR1/BES1, CCA1/LHY, SIZ1, CRLK1/2, OST1, EBF1/2, BTF3s, PIF3/4/7, 14-3-3s, CRPK1, EIN3, PRRs, MYB15, MPK3/6, phyB, and HOS1 regulate pression . GmEIN3, pathway . SimilarCBF/DREB1, which is differentially expressed in response to cold stress, were detected by transcriptomic studies [2 tends to compensate for low-temperature stress fully or partially without other abiotic stress. Utilizing the omics and non-omics data, an advanced framework in molecular biology was constructed for detecting cold tolerance genes [Recent advancements in omics have provided us with access to genomic, transcriptomic, proteomic, and metabolomic data that can shed light on soybean cold tolerance . Accordi studies ,81,82. T studies . Metabol studies  showed tce genes . PathwayCOR gene expression during cold stress could be a little information to conclude as soybeans are cold-intolerant given the evidence that soybeans are grown in the Beijicun  Village of Mohe, Heilongjiang Province China. Hence, more work is needed to unravel the molecular machinery in soybean cold response.Using genetic and molecular approaches, a number of relevant genes have been identified and new information has been continually discovered to enrich the cold-responsive pathway in soybeans. Elucidation of the mechanism regulating these complex and interactive signal transduction pathways is an important goal in achieving a full understanding of cold acclimation in soybeans. We believe that the inability of soybeans to increase GmWRKY21, GmbZIPs, GmTCF1a, GmVRN1, GmZF1, GmMYBJ1, GmNEK1, GmDREB3, GmDREB1s, SCOF-1, and so on. Experiments could be replicated in soybeans to verify whether the results were the same for soybeans. Moreover, orthologous genes of the upstream and downstream regulators that have been extensively described in Arabidopsis, must be further explored in soybeans. Our review indicated the involvement of both CBF-dependent and CBF-independent signaling pathways in soybean cold signal transduction. It is possible to confirm that the CBF cold-responsive pathway is not the only pathway in soybeans. More interestingly, an increased expression of GmPYL21 mediated by GmDREB1 under cold stress and the possible activation of downstream ABRE-mediated gene expression may be an interesting point of intersection between the two signaling pathways in soybean signal transduction.Even though several studies have been done on soybean cold-responsive genes, most of the experiments were conducted using Arabidopsis host, e.g., E1, E2 E3, and E4 loci, major contributors in flowering and maturity, in high-latitude regions and Gm ELF3 in high-altitude and low-latitude regions, are important target loci for genetic improvement related to growth periods. In addition, GmVRN1, described in the current review, can also be utilized as a cold-responsive gene to improve flowering time in the specific cold region. QTLs and molecular markers discussed in this review can be used for marker-assisted selection for soybean cold-tolerance. Regulators of cold response can be determined as target sites and be introduced by transformation or by precise modifications into the genome through genome editing. To create cold tolerate soybean cultivars, breeders always pyramid multiple genes into one line. Since cold tolerance is a multigenic trait controlled by many regulatory factors, future research on molecular mechanisms and regulatory pathways will facilitate the design of cold-tolerant varieties.Originating from the temperate regions, the soybean planting area has been moved northward to high-latitude regions in recent decades in China. It will continue to expand to high-altitude regions in the southwest of China. Thus, new varieties with cold tolerance are needed to adapt to low temperatures and short frost-free periods in high-latitude and high-altitude regions. Under the circumstance of these regions, soybeans are characterized by photoperiod insensitivity, early flowering, and early maturity for completing the life cycle before frost occurs.


Nevertheless, the most active platinum (Pt) metal-based catalysts for the HER are subject to high cost and substandard stability. Therefore, a highly efficient, low-cost, and stable HER electrocatalyst is urgently desired to substitute Pt-based catalysts. Due to their low cost, outstanding stability, low overpotential, strong electronic interactions, excellent conductivity, more active sites, and abundance, transition metal tellurides (TMTs) and transition metal phosphides (TMPs) have emerged as promising electrocatalysts. This brief review focuses on the progress made over the past decade in the use of TMTs and TMPs for efficient green hydrogen production. Combining experimental and theoretical results, a detailed summary of their development is described. This review article aspires to provide the state-of-the-art guidelines and strategies for the design and development of new highly performing electrocatalysts for the upcoming energy conversion and storage electrochemical technologies. The hydrogen evolution reaction (HER) is a developing and promising technology to deliver clean energy using renewable sources. Presently, electrocatalytic water (H Thus, renewable energy source usage has become increasingly important ,2,3,4. Df carbon . Hydrogef carbon . Currentrs (bm3) ,8. The Hel cells ,10,11,12eforming ,14,15, meforming ,17,18, beforming ,20,21, ceforming ,23,24, beforming ,26,27,28eforming ,30,31.2 production derives from non-renewable sources such as fossil fuels, specifically from methane [2 and more harmful greenhouse gases are produced from fossil fuels [The different hydrogen production methods are comprehensively represented in  methane ,33. Furtil fuels ,35,36.2-production approaches, high purity and eco-friendly H2 (99.999%) can be achieved from water electrolysis. The reaction is defined by Equation (1) [Further, the limited fossil fuel reserves and the constantly increasing global energy demand require new energy methods with no carbon footprint. Hydrogen energy has recently gained attention due to its production from environmentally friendly methods such as electrocatalysis and photocatalysis, which can replace fossil fuel-based energy production . Hydrogetion (1) ,2H2O + 2 production by H2O electrolysis is not sufficiently economically competitive, because of the high-energy utilization and the low-H2 evolution rate. Many researchers have been working on developing low-cost electrocatalysts to enhance performance and reduce energy consumption.The efficiency of HTo boost the hydrogen evolution reaction (HER), transition metal (TM)-based catalysts are being increasingly used instead of the scarce and costly platinum group metals (PGMs). A variety of TM-related electrocatalysts, such as phosphides , nitride2O redox potential, and by boosting the TMT-center redox reactions. Additionally, TMT-based electrocatalysts own outstanding stability, abundant active sites, excellent conductivity, low overpotential, and strong electronic interactions between the components of the material, resulting in catalytic performance enhancement [6X8  nanocatalysts for hydrogen evolution were studied [H). Interestingly, they identified that as the electronegativity of X-chalcogenide increases in Mo6X8, so does the hydrogen adsorption strength increase [2, TiTe2, and ZrTe2) are placed high on the volcano plot, facilitating the stronger hydrogen bond and thus promoting HER activity [Compared with other chalcogens (oxygen (O), sulfur (S), and selenium(Se)  which maancement ,47,48,49 studied , utiliziincrease . Lee et activity .2O electrolysis. Liu and coworkers [xP/NF catalysts showed 290 mV overpotential at 10 mA cm−2 for HER with good long-term stability in natural water conditions.Transition metal phosphides (TMPs) have gained great scientific interest for their high corrosion resistance, good conductivity, and superior HER-electrocatalytic performance. The latest studies have shown that TMPs showed outstanding stability and activity in Howorkers  recently2 NFs) through chemical deposition at the gas phase, which displayed a huge current density at 1.8 V (800 mA cm−2) and constancy for more than 8 days. Moreover, Wu and colleagues [2P-Fe2P catalysts that showed outstanding stability and activity, achieving current densities of 100 and 500 mA cm−2, with only 1.682 and 1.865 V required, in 1.0 M KOH-containing water, and the CoPx@FeOOH catalyst that exhibited good stability for 80 h at a current density of 500 mA cm−2 and an overpotential of 283 mV at 100 mA cm−2 in 1.0 M KOH-containing water.Chang et al.  synthesilleagues ,55 prepa2P@Cu nanostructure [2P/Ni2P/CNT [x/NiMoO4/NF [2P@NC/NF [2P/NPC [2/Ti3C2Tx [2O4/NiTe [2/g-C3N4 [2 [2P@Co(OH)2 [There are examples of TMP- and TMT-based materials that showed outstanding performance related to HER activity in both acidic and alkaline media; some examples are mentioned here: Cotructure , Co2P/NiNi2P/CNT , FeNiP/MiMoO4/NF , Ni2P@NC2P@NC/NF , MoP-Ru2 [2P/NPC , CoTe2/T/Ti3C2Tx , NiFe2O42O4/NiTe , NiTe-Hf2/g-C3N4 , Co,Ni-M-C3N4 [2 , and CoP@Co(OH)2  - and transition metal phosphide (TMP)-based electrocatalysts for HER .2O) is an emerging method for H2 production because it utilizes renewable H2O, releasing only pure O2 as a side product. In addition, the electrolysis process uses DC power from renewable energy sources such as biomass, solar, and wind. Currently only 4% of H2 can be attained by electrolysis of H2O, mainly because of the high cost [2O electrolysis has significant advantages, such as high hydrogen evolution rate, high purity, and good cell performance. The hydrogen purity is beneficial for its further transformation into electricity in low-temperature fuel cells (FCs) [2O molecule serves as the reactant, which under the effect of electricity dissociates into oxygen (O2) and hydrogen (H2). Water electrolysis, is divided into four types, depending on the operating conditions, electrolyte, and ionic agents . The usual water electrolysis approaches that will be analyzed, are; (i) alkaline water electrolysis (AWE), (ii) proton-exchange membrane water electrolysis (PEMWE), (iii) solid oxide electrolysis (SOE) [The electrolysis of water  . In an eis (SOE) ,70,71,72is (SOE) ,74.2O electrolysis, which is a well-known approach up to the megawatt range; it is reported [2O electrolysis procedure, at the cathode side, the alkaline solution of two molecules (KOH/NaOH) is reduced to a single molecule of H2 and two OH− ions. The produced H2 is eliminated from the cathode surface, while OH− is transferred from the cathode to anode through the porous diaphragm and converted into one molecule of water and a half (½) molecule of oxygen. The mechanism of alkaline water electrolysis is illustrated in Hydrogen can be synthesized from alkaline Hreported  that thi2O electrolysis procedure, nickel materials and asbestos diaphragms are used [Alkaline electrolysis can occur at lower temperatures (30–80 °C), employing a KOH/NaOH aqueous solution as an electrolyte, whose concentration ranges from 30 to 20% ,76,77,78are used . The dia−2), and low operating pressures [2O electrolysis in an alkaline medium [However, there are some disadvantages concerning the alkaline water electrolysis process: low energy efficiency, lower current densities , lower gas permeability, higher-pressure operation ability, and lower thickness. Given the environmental impact and sustainability, PEMWE is one of the most suitable and favorable processes for hydrogen production. Furthermore, other outstanding characteristics of PEMWE are: high current densities (over 2 A cm−2), compact design, good efficiency, small footprint, quick response, low operation temperature (20–80 °C), releasing only oxygen as a byproduct [The PEMWE was first introduced in 1959 by Grubb and the general electric company was established in 1966 to eliminate the problems associated with Htrolysis ,87,88,89trolysis ,91,92. Typroduct ,94,95. Myproduct . The sch2 with high performance [2O and oxygen anion (O2−) conductors [2− conductors at 500–700 °C [Solid oxide electrolysis (SOE) was invented in the 1980s by Donitz and Erdle [formance ,99. It onductors ; its wor0–700 °C . SOE tec0–700 °C ,102,103.2, and protons are produced. As electrons are transferred to the cathode by an external circuit and the protons reach the cathode through the electrolyte, the electrons combine with protons and produce H2. The MEC operation principle is schematically shown in 2 production [2 production rate, and the complicated design that has to be simplified before its use on a large scale [Microbial electrolysis cells (MECs) can produce hydrogen from wastewater containing organic matter and renewable biomass. The operating principle of an MEC is the reverse of microbial fuel cells (MFCs) . The MECoduction . Howeverge scale .2 nanosheets (NSs) synthesized through a liquid exfoliation strategy demonstrated a notably improved HER performance in 0.5 M H2SO4 instead of bulk MoTe2 [2 nanotubes (NTs) [2 nanowires (NWs) [2@NC nanoparticles (NPs) [2 with two different morphologies, for example, nanoflakes (NFs) and nanowires (NWs) that were obtained by hydrothermally treating Ni foam with NaHTe and Te powders, respectively. The NiTe2 NWs presented excellent HER performance as compared to NiTe2 NFs in both alkaline and acidic environments and, temporarily, demonstrated values of Tafel slope similar to (for 0.5 M H2SO4) or lower (for 1 M KOH) than those of the Pt/C parameters, illuminating adequate reaction kinetics [2 NWs.The electrocatalytic performance of bulk transition metal tellurides (TMTs) was found to be quite mediocre based on prior research ,108,109.es (NTs) , hierarces (NWs)  and corees (NPs) . Ananthaes (NPs)  preparedkinetics . A large2 thin films prepared by chemical vapor deposition (CVD) exhibited good HER performance. However, after ion-beam etching, the 1T-MoTe2 films presented clearly improved HER activity, achieving 100 mA cm−2 current density at a Tafel slope value of 44 mV dec−1 in 0.5 M H2SO4 solution and an overpotential of 296 mV [2 films showed the improved stability of the catalytic operation, maintaining 87% of its initial current density, in contrast to the 40% achieved for the pristine sample after 3600 s of successive electrolysis [Nanostructuring can efficiently enhance the catalytic activity of exposed active sites by improving their efficiency. Zhuang et al.  observedf 296 mV . Furthertrolysis . The imptrolysis .2 NPs composite in N-doped carbon nanotube frameworks, denoted as CoTe2@NCNTFs, by employing a template of ZIF (zeolitic imidazolate framework)-67 [2. Subsequently, CoTe2@NCNTFs exhibited excellent catalytic activity, requiring an overpotential of 208 mV to attain 10 mA cm−2 for HER in a 1.0 M KOH solution. The CoTe2@NCNTF provided 10 mA cm−2 when used as a bi-functional electrocatalyst for water splitting at a cell voltage of 1.67 V [1.11Te2/C electrocatalyst exhibited a high surface distribution of Co-ions and more reducible Co species than CoTe2/C and CoTe/C, which contributed to HER activity improvement (178 mV@10 mA cm−2 in 1 M KOH). The higher performance of Co1.11Te2/C was elucidated through DFT calculations, illustrating a perfect Gibbs free energy, as seen in Metal-organic frameworks (MOFs) are broadly utilized to synthesize catalysts, due to their (i) large specific surface area, (ii) spatially ordered microstructure, and (iii) high nanoporosity. Wang and coworkers  developework)-67 . This MOf 1.67 V . Wang etf 1.67 V . The attx NSs on Fe foam [2 NPs on Co foam [2 NWs on Ni foam [7Te4 arrays on Cu foil [2 NS array anchored on Ti mesh [2 NW array on Ti mesh [The in situ development of the electrocatalysts on the surface of electrodes has attracted considerable interest in recent years. According to the literature, such a structure can prevent the agglomeration and collapse of nanostructured electrocatalysts, enhancing the long-term durability of the electrodes ,123,124. Fe foam , CoTe2 N Co foam , NiTe2 N Ni foam , Cu7Te4  Cu foil , an NiTe Ti mesh , and a C Ti mesh , which w Ti mesh  and conf Ti mesh .Nanostructure engineering can improve electrocatalytic performance by tuning the morphology and structure to provide more catalytic active sites. The latter could locally modify the coordination conditions and chemical characteristics, improving the electrocatalytic performance by the ensemble effects or ligands. Doping with heteroatoms to control the electronic structure is now widely accepted, and various nonmetals such as S, and P ,130,131 1.11Te2@NCNTF catalytic activity. He and colleagues [1.11Te2@NCNTF catalyst, obtained through tellurization (under Ar/H2 atmosphere) of Fe-etched ZIF-67 gas, which presented a blue shift in the XPS spectrum of the binding energy of Co2p, comparative to the pristine Co1.11Te2@NCNTF, as shown in 3+, which can enhance OER performance. This accurately characterized the excellent HER activity of Fe-Co1.11Te2@NCNTF which offered TOF values 10-fold higher than the un-doped Co1.11Te2 [2 facilitated the stabilization of the 1T-phase and developed a nanosheet-like morphology with high porosity and an enhanced surface area, thus improving the HER activity, compared to that of the un-doped 1T-VTe2 [2 NSs (denoted as NiNCs-1T-Mn-VTe2 NS), compared to all other electrocatalysts studied.He et al. , confirmlleagues  developeo1.11Te2 . In cont 1T-VTe2 . Further2 can effectively activate the phase transition of 2H to 1T, in contrast with the mono-atom doping. The experiments demonstrated that the Ni/Co co-doped MoTe2 markedly improved HER activity. Apart from anion doping, the cation combination can also efficiently boost the electrocatalyst performance. Wang and his partners [2 from an inactive to an active electrocatalyst, due to the modification of the electronic structure, whereby electrons accumulated on the surface of S atoms, acting like active sites, adsorbed more rapidly the intermediate (H*), boosting the HER performance. Moreover, mixed anion-doped TMTs and tellurides, such as freestanding CoNiTe2 NSs [1−xFexTe2 hierarchical nanoflake arrays [0.12Te1.79 and MoSxTey/Gr [Dopants can affect electrocatalytic activity . This wapartners  describeiTe2 NSs , Ni1−xFee arrays , MoSe0.1SxTey/Gr  solid soSxTey/Gr  were recSxTey/Gr ,143.3Te2-CoTe hybrids, which were developed in a single-step on carbon cloth by a hydrothermal procedure, and their electrocatalytic activity was compared to every individual component (Ni3Te2 and CoTe). Ni3Te2-CoTe hybrids delivered a current density of 100 mA cm−2 at 392 mV overpotential, with a smaller Tafel slope value of 68 mV dec−1. Based on these findings, the hydroxyl group chemisorption into the electrocatalytic surface was a defined rate-measuring step. The investigators suggested that the enhanced activity stemmed from the incorporation of CoTe into the electrocatalyst, exposing more Ni3Te2 active sites, also confirmed by the double-layer capacitance and the denser states close to the Fermi level, using DFT analysis.A number of TMT-related heterostructured electrocatalysts have been freshly reported to illustrate enhanced HER activity, such as TMT nanostructures composited with a secondary TMT ,145,146,−2 and exhibited a Tafel slope of 49 mV dec−1 in 1.0 M KOH, which was significantly less than that of pure NiS and pure NiTe. In addition, the electrocatalyst displayed over 50 h stability at 50 mA cm−2, and a potential boost of approximately 6%.Xue et al.  presente2-layered double-hydroxides (NiFe-LDH and RuO2-LDH) on NiTe NR surfaces, synthesizing NiTe@NiFe-LDH and Ni-Te@RuO2 heterostructures, which served, respectively, as anodic and cathodic electrocatalysts for water splitting. At 1.63 V, the fabricated device delivered a current density of 200 mA cm−2 and was powered by a 1.5 V solar cell for the continuous electrolysis of water [−2).Instead, Sun et al.  successfof water . This ouof water . They em2 NWs with many interfaces that showed excellent HER activity in alkaline/acidic solutions. CoP-CoTe2 NWs was employed as a bi-functional electrocatalyst (HER and OER) in a bipolar water electrolysis membrane (BPWEM). The use of BPWEM permits HER to occur simultaneously in kinetically favorable acidic and alkaline solutions. In the ‘forward bias’ operation, the anion-exchange membrane (AEM) is at the cathode, while the cation-exchange membrane (CEM) is on the anode side. The electrochemical neutralization between H+ and OH− ions occurs when these ions cross the bipolar membrane and recombine to form water molecules. This can facilitate the electrolysis of H2O by reducing the external electrical energy requirements. Using the CoP-CoTe2 electrocatalyst in a BPWEM could transport 10 mA cm−2 at 1.01 V cell voltage (in the ‘forward bias’ operation), and it provided 100 h of stable operation without prominent degradation, superior to that of the anion-exchange H2O electrolysis membrane (AEWEM), using the same electrode pair, CoP-CoTe2. Furthermore, CoP-CoTe2 exhibited good stability, thus improving the catalytic performance. The results of the catalytic performance are mentioned in 2 evolution with low electrical energy consumption.Another research group  recently1,a2. Furthermore, after the tellurization, the material retained its cubic shape .The synthesized Te/FeNiOOH-NCs and FeNiOOH-NCs catalysts were characterized with SEM . The FeNic shape b1,b2.The Te/FeNiOOH-NCs catalyst showed better electrochemical results as compared to the FeNiOOH-NCs due to following reasons: (1) the surface area increased after tellurization, retaining the nanocubic structure, so improving the number of active sites for electrocatalysis. In addition, the Te-tailored nanocubic structure may have enriched edge active centers . (2) The−2 for the HER process. This overpotential is better than the commercially used Pt/C electrocatalyst (199 mV vs. RHE) or pure FeNiOOH-NCs (279 mV vs. RHE), suggesting the excellent HER performance of the Te/FeNiOOH-NC electrode [Furthermore, the synthesized FeNiOOH-NC and Te/FeNiOOH-NC nanocomposites were tested for HER in 1.0 M KOH. As depicted in the linear sweep voltammograms displayed in lectrode .−1) than the commercial Pt/C (20%) (108 mV dec−1). The durability of the electrocatalyst (Te/FeNiOOH-NCs) for HER was also explored by applying 1000 cycles of CV scans. As seen from the LSV curves of −2 current density was reported for the potential after 10 h of operation, as illustrated in Post-characterizations (XRD and FESEM images ) reveale2 may be created; consequently, efficiency will fast decline. Investigators, to address these issues, have synthesized an attractive HER electrocatalyst—by rational design in structure and composition—that can directly electrolyze H2O. Currently, H2O splitting normally employs three types of electrolysis: (i) an alkaline solution and seawater, (ii) an alkaline solution with NaCl (which replaces the seawater), (iii) and seawater.One of the primary design challenges is to improve the corrosion resistance and selective oxidation of TMPs. As a result of the corrosion phenomenon, the electrocatalyst may be affected, and hypochlorite/Cl2O electrolysis, and the activity of the added electrolyte  is significantly higher than in the H2O solution. To enhance the electrolysis performance of H2O, an interesting approach would be to alter the active site and electronic structure by utilizing heteroatoms (dopants or promoters), facilitating the interaction of the bulk solution and electrocatalyst surface. Thus, gas adsorption and desorption can be accelerated, electrolyte diffusion can be controlled, and electrocatalysis can be improved.TMPs present outstanding activity toward H2 nanoporous films following a procedure consisting of three steps, namely, anodic treatment, chemical-vapor deposition, and electrodeposition. The as-prepared nanocatalyst displayed outstanding electrocatalytic performance. 2. The four elements  coexist, presenting homogeneous distributions, as observed in Chang et al.  prepared−2, respectively, in a 0.5 M KOH aqueous solution, with 90% infrared correction. The NFs of the Fe, P-NiSe2 electrocatalyst demonstrated superior activity in the seawater electrolyte compared to that of non-PGM electrocatalysts. At the same time, the electrocatalyst delivered about 800 mA cm−2 with a voltage of 1.8 V and maintained stable operation for 200 h in an electrolytic cell with a seawater electrolyte.Overpotentials of about 120 and 180 mV were required to provide current densities of 100 and 500 mA cmThe Fe-doping provided the main active sites for the HER procedure, while P-doping formed a passivation layer that maintained the phosphorus–oxygen bonds, enhancing in this way the electronic conductivity and hindering Se dissolution. Moreover, bi-metal phosphides enhance electrocatalytic activity and long-term stability, by the simultaneous influence of the different metals. Thus, the development of an ion-exchange phosphorylation electrocatalyst, in situ into a nickel-foam (NF) substrate, was discussed, that could efficiently alter the distribution of electrons locally for the central metal, thus promoting the synthesis of low-cost and highly active seawater-electrolytic catalysts.2P-Fe2P/NF electrocatalyst with a 2D nanosheet structure, using a phosphidation and acidification method  with a 3D structure and high conductivity was first synthesized, followed by the synthesis of CoNiP/CoxP/NF via chemical vapor deposition and the formation of CoNi alloy/NF through electrodeposition. The overpotential of the designed CoNiP/CoxP/NF electrocatalyst at 10 mA cm−2 was 290 mV for HER and showed stability up to 500 h in clean water. This structure had a high concentration of exposed active sites and high corrosion resistance, resulting in superior performance and long-term stability during water electrolysis. DFT-simulation findings showed that the electrocatalyst (CoNiP) possessed an appropriate thermodynamic activity for the desorption/adsorption of H2 [The transformation of the electrocatalyst’s structure into a heterostructure has subsequently been identified as an appealing source for the enhancement of the active sites’ density and mass transfer rate, hence enabling the improvement of the activity. Liu et al.  developeon of H2 .x@FeOOH/NF electrocatalyst through a three-step process, which included hydrothermal treatment, phosphidation, and electrodeposition. CoPx precursors demonstrated linear smooth NWs and heterogeneous CoP2 distributions. As seen from the SAED and HR-TEM images . This may be due to a greater number of P atoms or defective phase interfaces [x) has a nanowire mesh structure that provides beneficial features to the catalyst for H2 production through water electrolysis. Some of those features are mentioned below; every catalytic nanowire is exposed to react, providing a broad contact with the electrolyte molecules, and enhancing mechanical strength.It is widely believed that phosphide-related electrocatalysts usually exhibit excellent HER performance due to the P atoms that can easily break down Hmediates ,159,160.terfaces ,163,164.x catalyst showed greater HER activity compared to other self-supported catalysts since it required low overpotential for attaining the required current densities. More precisely, 117, 190, 248, and 269 mV overpotentials were needed to attain 10, 100, 500, and 800 mA cm−2 current densities, respectively, with a 71.1 mV dec−1 Tafel slope value  by having both corrosion-resistance and active layers, demonstrating the important role structural morphology plays. Furthermore, at an industrial-scale current density of 500 mA cmof water .2 as an emerging energy carrier and illustrated the techniques used for this purpose. By using renewable energy sources, the electrolysis of water is the most competent technology to mitigate both energy demands and environmental pollution. Furthermore, different water electrolysis methods for H2 production  were discussed. Additionally, electrocatalysts play a key role in H2 production by water electrolysis. In this regard, from the various types of electrocatalysts, only the recent developments in transition metal tellurides and transition metal phosphides have been discussed in this review, due to their promising features, such as enhanced H2 production rate, stability, durability, high efficiency, and low cost requirements as compared to precious commercial electrocatalysts, such as the platinum group metals (PGMs). Although the development of metal-based tellurides and phosphides is competing with PGMs, more effort is still required to enable the commercialization of water-splitting technology.In this review article, we have discussed the production of HTherefore, an enhancement of the catalytic activity, as well as long-term operational stability, are highly required.There are some points to be considered for the future research in the field.−2) and long-term stability.Transition metal-based catalysts require some improvements for industrial-scale water electrolysis in terms of current density (greater than 500 mA cmTMT-based electrocatalysts have high electrical conductivity, due to their metallic character, but conductivity is not the only characteristic needed for enhancing the HER performance of the electrocatalysts. Therefore, improvements of the electronic structure of electrocatalysts are still required to change the composition; and of the structural engineering to achieve binding energy regulation of the reaction intermediates and lower the reaction energy barrier.The development of novel and advanced synthesis methods is required for large-scale production with suitable structural properties.More research is needed to explain the self-construction mechanism in the transition metal tellurides and phosphides. Furthermore, to understand the self-construction mechanisms and intrinsic properties, tests under different conditions should be performed for the self-constructions of TMT and TMP. By controlling the construction mechanism of the electrocatalysts, HER performance can be boosted.Development of simple but more accurate characterization techniques for the structural elucidation of the material may be beneficial for designing efficient electrocatalysts for HER performance.Transition metal telluride and phosphide electrocatalysts have greater electrical conductivity than other electrocatalysts due to the metallic character of transition metals.TMT and TMP electrocatalysts are better than conventional platinum-group electrocatalysts, due to their low cost.


The clinical data of patients with double-positive for leucine-rich glioma-inactivated protein 1 (LGI1) and contactin-associated protein-like 2 (CASPR2) antibodies is limited, particularly for children. This study aimed to investigate and summarize the clinical features and long-term prognosis of children’s LGI1 and CASPR2 antibodies related to neurological disorders.We collected the clinical data and prognosis of patients with dual positive antibodies of CASPR2 and LGI1, hospitalized in the Department of Neurology, Children’s Hospital of Chongqing Medical University. Furthermore, we summarized the clinical phenotypes of this disorder in children by reviewing the published literature.n = 7), the combination of IVIG, IVMP, oral prednisolone and methotrexate (n = 1), the combination of IVIG, IVMP, and mycophenolate mofetil (n = 1), the combination of IVIG, IVMP, oral prednisolone, and rituximab (n = 1), IVIG only (n = 2), IVMP only (n = 1). Median modified Rankin Scale (mRS) scores in the acute phase were 3 (range 1–4) and improved gradually. Over the follow-up , 52.9% (9/17) of the patients recovered completely; one patient relapsed and showed immunotherapy-dependent.Two patients presenting with variable neurological symptoms including pain, hypertension, profuse sweating, irritability, and dyssomnia from Children’s Hospital of Chongqing Medical University were enrolled in this study. Together with the two patients, we identified 17 children with dual CASPR2 and LGI1 antibodies, including 12 males and 5 females. At the onset, the median age was 4.1 years , with 9 children younger than 5 years and 6 adolescents. Of the 17 patients, 11 were diagnosed with Morvan syndrome, 4 with acquired neuromyotonia, 1 with Guillain-Barré syndrome, and 1 with Guillain-Barré syndrome combined with Morvan syndrome. Dysautonomia , pain , sleep disorders , encephalopathy , and weight loss  were the most frequently described symptoms overall. No tumors were identified. Of the 17 patients, 13 received immunotherapy comprising IVIG combination of IVMP during the acute symptomatic phase followed by oral prednisolone to maintain remission (LGI1 and CASPR2 double-positive antibodies associated with the neurological diseases can occur in children of all ages and involve multiple nervous systems. Morvan syndrome is the most common phenotype of this disorder. The long-term outcomes are mostly favorable upon immunotherapy. Leucine-rich glioma-inactivated protein 1 (LGI1) and contactin-associated protein-like 2 (CASPR2), parts of the voltage-gated potassium channel complex (VGKC-complex), are widely expressed in the central nervous system (CNS) and peripheral nervous system (PNS). LGI1 and CASPR2 antibodies have been identified in various neurological syndromes . While a1 and the search deadline was 1 October 2021, with the keys words: “(LGI1 or leucine-rich glioma-inactivated protein 1)” and “(CASPR2 or contactin-associated protein 2),” “Morvan syndrome,” “Neuromyotonia.” Articles were manually searched to select pediatric patients (0–18 years of age) with dual positive antibodies to LGI1 and CASPR2 and to extract relevant information focusing on clinical data, follow-up time, and prognosis. Relapse was defined as recurrence after complete or partial recovery, with sustained improvement for at least 2 months  showed slow-wave background, while magnetic resonance imaging (MRI) of the brain and spine were normal. No cardiovascular, renal, and endocrine system diseases causing arterial hypertension were found. Comprehensive screening for infectious and neoplastic disease on blood and CSF was unremarkable. CSF analysis was acellular with the average level of glucose and protein. Antineuronal antibodies screening revealed LGI1 antibodies  and CASPR2 antibodies , done by a commercial cell-based assay CBA, . The patIntravenous hydration and three antihypertensive drugs  were used as supportive treatment. Encephalopathy and dysautonomia had not been effectively improved. Immunotherapy was started immediately after diagnosis, 2 months after the onset of the disease. The patient received immunoglobulin intravenously , methylprednisolone intravenously , and oral prednisolone .The patient started to improve gradually 1 week after immunotherapy. Both CNS and autonomic symptoms were significantly resolved at discharge 3 months after onset, except for mild hyperhidrosis and irritability resolved entirely about 1 month after discharge. The mRS score at discharge was 2 and was 0 2 months later. The patient had typical developmental milestones and no relapse 7 months after discharge.A previously healthy 3-year-8-month-old male presented with severe abdominal pain without vomiting and diarrhea for 2 weeks, followed by decreased appetite, fatigue, skin rash, pruritus, and excessive sweating. One month after the onset of abdominal pain, he developed behavioral change, manifested by shouting, episodes of crying, and irritability. The patient gradually showed sleep disorders, manifested by difficulty falling asleep and easy to wake up. He refused to walk because of lower limb pain. Within 2 months before admission, his weight lost 1.5 kg. Physical examination revealed skin rash, mainly in the lower limbs, tachycardia, arterial hypertension, and regular power in all limbs. The mRS score at admission was 4.Blood and CSF samples screening showed no evidence for infectious and neoplastic disease. Neuroimaging (brain and spine MRI), computed tomography scans of the chest and abdomen, EEG, and electromyography were normal. There was acellular CSF with normal protein and glucose. Neural antibodies screening in serum detected positive LGI1 antibody (1:100) and CASPR2 antibody (1:100) by a commercial CBA. However, antibodies in CSF were negative. The diagnosis of Morvan syndrome was based on the combination of CNS , PNS (pain), and dysautonomia nervous system symptoms  as well as serum LGI1 and CASPR2 antibodies.The case received symptomatic therapy with risperidone and two antihypertensives (captopril and nifedipine). However, the clinical manifestations were not improved. Immune therapy was started 2 months after the onset of symptoms. IVIG (1 g/kg once daily for 2 days) and IVMP (20 mg/kg/day for 5 days) followed by oral prednisone  were administrated. Behavioral abnormalities and dysautonomia were slowly improved 2 weeks after immunotherapy. The mRS score 2 months after discharge was 0.Fifteen patients were collected from seven publications , 12–15. Of the 12 patients with manifestations of Morvan syndrome (11 with Morvan syndrome and 1 with combined Morvan syndrome with Guillain-Barré syndrome), dysautonomia and sleep disorders occurred in all patients. Tachycardia, hypertension, and hyperhidrosis were the main manifestations of dysautonomia. Sleep disturbances and insomnia were common manifestations of sleep disorders. Encephalopathy occurred in 12 patients , primarily presenting behavioral changes . Seizures only appeared in two patients . Pain, as the primary manifestation of peripheral nerve involvement, occurred in 10 patients , while 2 patients  also exhibited muscle cramps.Four patients with acquired neuromyotonia were male and presented mainly with muscle cramps and neuromyotonia without CNS involvement, only one patient (patient 4) presented with sleep disturbances. One patient presented with classical Guillain-Barré syndrome with albuminocytologic dissociation and progressive limb weakness. One patient presented with Guillain-Barré syndrome combined with Morvan syndrome, with typical Guillain-Barré syndrome combined with encephalopathy and sleep disorders.All patients were positive for LGI1 and CASPR2 antibodies in serum. Eight patients were tested for both LGI1 and CASPR2 antibodies in CSF, and one patient only was tested for CASPR2 antibodies in CSF, four of whom had double-positive antibodies in CSF, two had CASPR2 antibodies only in CSF. A total of 13.3% (2/15) brain MRI was abnormal. Spinal MRI was abnormal in 14.2% (2/14) of patients. Five of the 10 patients with CSF testing were abnormal, including three with high protein levels and two with mild pleocytosis. No tumors were identified.n = 7), the combination of IVIG, IVMP, oral prednisolone, and methotrexate (n = 1), the combination of IVIG, IVMP, and mycophenolate mofetil (n = 1), the combination of IVIG, IVMP, oral prednisolone, and rituximab (n = 1), IVIG only (n = 2), IVMP only (n = 1). A total of 91.6% (11/12) of patients presenting with Morvan syndrome received immunotherapy. In contrast, 1 of 4 patients present with acquired neuromyotonia received immunotherapy. Four patients did not receive immunotherapy, three received supportive treatment, and one patient (patient 4) had spontaneous remission without any treatment. Median mRS scores in the acute phase were 3  and improved gradually. A total of 52.9% (9/17) patients recovered completely . One patient (patient 6) relapsed over the follow-up period and was immunotherapy-dependent. No patient showed clinical signs of myasthenia gravis during disease and follow-up.A total of 76.5% (13/17) of patients received immune therapy, including IVIG combination of IVMP during the acute symptomatic phase followed by oral prednisolone to maintain  in the previous reports . This isImmunotherapy is currently widely used in antibody-mediated CNS disorders. For VGKC-related diseases, the limited available data are mainly retrospective and observational. Immunotherapies are the mainstay of treatment across all LGI1 and CASPR2 antibodies-associated syndromes. Immunotherapy is particularly effective than antiseizure medications in treating LGI1-antibodies-associated seizures . A totalOur study delineates the clinical phenotype of pediatric patients with LGI1-CASPR2 double-positive, presenting multiple CNS, autonomic nervous system, and PNS symptoms. Morvan syndrome is the most common phenotypic spectrum. Although some patients do not achieve complete remission, immunotherapy can have a favorable prognosis. In acquired neuromyotonia, immunotherapy is not mandatory. Although the incidence of tumors in children is extremely low, screening is still necessary.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.YJ, CT, TL, XS, JM, ZY, SH, XL, LJ, and YL contributed to the analysis and interpretation of data and references. YJ, CT, and YL participated in the conception and writing of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted versionThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


TFL1, SOC1, and GAI-like, was further verified by qRT-PCR. Therefore, we used this time-course transcriptome data for a preliminary exploration of the regulatory network of floral induction and to provide potential candidate genes for future studies of flowering in strawberries.The initiation and quality of flowering directly affect the time to market and economic benefit of cultivated strawberries, but the underlying mechanisms of these processes are largely unknown. To investigate the gene activity during the key period of floral induction in strawberries, time-course transcriptome analysis was performed on the shoot apex of the strawberry cultivar ‘Benihoppe.’ A total of 7177 differentially expressed genes (DEGs) were identified through pairwise comparisons. These DEGs were grouped into four clusters with dynamic expression patterns. By analyzing the key genes in the potential flowering pathways and the development of the leaf and flower, at least 73 DEGs that may be involved in the regulatory network of floral induction in strawberries were identified, some of which belong to the NAC, MYB, MADS, and SEB families. A variety of eight hormone signaling pathway genes that might play important roles in floral induction were analyzed. In particular, the gene encoding DELLA, a key inhibitor of the gibberellin signaling pathway, was found to be significantly differentially expressed during the floral induction. Furthermore, the differential expression of some important candidate genes, such as  Fragaria sp.) belong to the large botanical family Rosaceae which contains many species with high economic value worldwide [Strawberries  is a central activator that mediates the photoperiodic pathway. FLOWERING LOCUS C (FLC) acts as a central suppressor to regulate the vernalization and autonomous pathways. The concentrations of SQUAMOSA PROMOTER BINDING LIKE (SPL) transcription factors increase with plant age. All of these genes regulate the downstream floral pathway integrator transcription factors FLOWERING LOCUS T (FT), SUPPRESSOR OF OVEREXPRESSION OF CONSTANS 1 (SOC1), and AGAMOUS LIKE24 (AGL24), which activate the expression of the meristem identity genes LEAFY (LFY), APETALA1 (AP1), SEPALLATA3 (SEP3), and FRUITFULL (FUL) [A major ecological trait of perennial plants is the timing of the transition to flowering, which determines the transition from vegetative to reproductive growth. The genetic, epigenetic, hormonal, and environmental factors for the transition from the vegetative to reproductive stage are best understood in the annual long-day (LD) plant Arabidopsis thaliana ,12. At lLL (FUL) ,14,15. ILL (FUL) . The funTERMINAL FLOWER 1 (TFL1) functions to maintain the vegetative meristem in both the woodland strawberry (Fragria vesca) and Arabidopsis, it has been shown to be the major floral suppressor in the strawberry, whereas it plays only a minor role in flowering time in Arabidopsis [FvTFL1 integrates both photoperiodic and temperature signals to control floral induction in strawberries. Weak expression of FvTFL1 in cool temperatures below 13 °C or SDs at temperatures of 13–20 °C allows floral induction to occur [F. vesca. The activation of FvCO is affected by light, and CO plays a major role in activating FvFT1 in leaves. FT acts as a florigen, moving to the shoot apex to form leaves, and SOC1 acts as the hub for multiple flowing times in Arabidopsis. However, the leaf-expressed FvFT1 in strawberries represses flowering by activating FvTFL1 at SAM through FvSOC1 in LDs [FvAP1 and FvFUL1, which were considered a floral marker gene and have been used many times in the studies of strawberry flowering [FvSPL10, the ortholog of AtSPL9 in Arabidopsis, activates FvAP1 by directly binding to its promoter and ectopic expression of FvSPL10 in Arabidopsis promotes early flowering and increases organ size. However, whether FvSPL10 is involved in regulating the age pathway in strawberry flowering is unknown at present.Flowering has always been the focus of strawberry crop research. The induction of flowers generally takes three steps: the vegetative stage, in which vegetative SAM gives rise to leaf primordia; then SAM shifts to the reproductive stage, where the initiation of flower meristem occurs from SAM and the entire shoot apex looks fat; followed by the next stage, the development of flower primordia ,18. Althbidopsis ,20,21,22to occur ,24. Phot1 in LDs . Whereaslowering ,26,27,28lowering  reportedGA20ox4 in the GA biosynthetic pathway result in a runner-free phenotype. Additionally, a mutation in a DELLA growth inhibitor gene that regulates the GA signaling pathway caused a runner-less phenotype [Axillary buds (AXBs) fate is closely related to SAM fate in strawberries. AXBs mainly differentiate into runners (a type of elongated branch) during vegetative growth. In contrast, in reproductive growth, runner induction ceases, and the number of branch crowns increases with floral induction ,7,8,9,10henotype ,33,34. Ihenotype . Howeverhenotype ,36.Although several genes that control flowering in strawberries have been identified and functionally characterized, more details of the floral induction of this important berry crop have not been explored. In this study, we generated time-course RNA-seq data of the three floral induction stages in the cultivated strawberry ‘Benihoppe.’ Many genes potentially related to the floral induction process were investigated, such as the genes for seven potential flower-time control pathways, leaf development, and flower development during floral induction. In addition, the MADS family and SEB family genes, closely related to flowering, and eight hormone signaling pathway genes were investigated. These transcription factors and a variety of hormone signals form a regulatory network to regulate floral induction. These results will provide new ideas for future functional studies and shed light on the genetic control of floral induction in strawberries.FaAP1 during 8 w–16 w, the results showed that expression gradually increased from 13 w, suggesting that FaAP1 expression is up-regulated prior to the morphological change  . In ordel change F.FaAP1, samples at 9 w (vegetative stage), 13 w (shifts to the reproductive stage at gene level), and 15 w (reproductive stage) were selected for transcriptome sequencing. A total of 9 cDNA libraries were prepared from the RNA extracted from the shoot apex. After Illumina sequencing, the data were filtered to remove low-quality reads and adapters. A total of 441,229,076 clean reads were obtained, of which the clean base was 66.18 G, and the average GC content was 47.61%. An average of 98.36% of the sequenced bases had quality scores (Q-scores) of Q30 or higher (Fragaria × ananassa ‘Camarosa’ Genome (Version 1.0).Considering the results of the morphological observations and the expression profile of r higher . Clean rSpearman correlation coefficient analysis showed that the correlation coefficients of the three replicates were greater than 0.925, indicating that the RNA-seq data could be used for further analysis .p value < 0.05 were used as the critical thresholds to define the differentially expressed genes (DEGs). When compared with plants at 9 w, 3719 DEGs were significantly changed at 13 w, and of these, 2368 DEGs were up-regulated, and 1351 DEGs were down-regulated. Compared with plants at 13 w, 4525 genes showed significant differential expression at 15 w; 2174 DEGs were up-regulated, and 2351 DEGs were down-regulated . The functions of unknown genes or the unknown functions of known genes can be identified by clustering genes with the same or similar expression patterns. Hierarchical clustering of the HDEGs, which were clustered by the log2 of the FPKM values, is shown in |Log2 fold-change| (|Log2 FC|) ≥1, and egulated A. Based egulated B,C, and egulated B,D. The egulated B,E, and egulated B,F. To eegulated G. The DEegulated H. The geegulated I, and thegulated J. These To fully identify candidate genes in the flowering time pathway in the strawberries, we retrieved 68 homologs of important Arabidopsis flower induction genes from the transcriptome data and analyzed their FPKM values. These genes are roughly classified as participating in the photoperiod, vernalization, autonomous, gibberellin, age, and carbohydrate pathways based on the known flowering pathways in Arabidopsis ,11,13.FLAVIN BINDING KELCH REPEAT F-BOX 1 (FKF1) [GIGANTEA (GI) [PSEUDO-RESPONSE REGULATOR 5 (APRR5), and APRR7 [CO and FKF1 were both promoted in the leaves during the blue light-induced floral induction of strawberry [LUX ARRHYTHMO (LUX) [NUCLEAR FACTOR Y, SUBUNIT B2 (NF-YB2) [CONSTITUTIVE PHOTOMORPHOGENIC 1-like (COP1-like) [The FPKM values of some genes that are involved in the photoperiod pathway can be detected in the shoot apex. Surprisingly, some DEGs in this pathway that appear to have inconsistent functions were identified in short-day strawberries as compared with long-day Arabidopsis . For exa1 (FKF1) , GIGANTETEA (GI) , PSEUDO-nd APRR7  play posrawberry . HoweverMO (LUX) , NUCLEAR(NF-YB2) , and CONP1-like)  showed sFLOWERING LOCUS C (FLC) [ARABIDOPSIS TRITHORAX 1 (ATX1) [FLC and ATX1 act repressors during flowering in Arabidopsis, our results show that the expression of FLC at 15 w was significantly increased compared to 9 w, and the expression of ATX1 was increased at 13 w and decreased at 15 w. It is speculated that in addition to the factors of the expression locations of some genes, changes in seedling status and environment may also be significant factors.In addition to the photoperiod pathway, the vernalization pathway is also an important flowering pathway in Arabidopsis. In this transcriptome data, only  C (FLC)  and ARAB1 (ATX1)  were ideFLOWERING PROMOTING FACTOR 1 (FPF1) [DWARF AND DELAYED FLOWERING 1 (DDF1) [DDF2 showed a declining trend in general, while they are promoters of flowering in Arabidopsis. In addition, GAIP [TREHALOSE-6-PHOSPHATE SYNTHASE 1 (TPS1) [TPS10 was upregulated at 13 w and was down-regulated at 15 w. In other pathways, we detected continuous down-regulation of HYPERSENSITIVE TO RED AND BLUE 1 (HRB1) [GAIP encoding the DELLA protein, which can be further discussed.We did not find DEGs in the autonomous and age-related pathways in the strawberries B. Althou1 (FPF1) , DWARF A1 (DDF1) , and DDFon, GAIP , an inhi1 (TPS1) , but TPS1 (HRB1)  , adaxial-adaxial gene PHAVOLUTA (PHV) and some active family members, such as REGULATOR OF AXILLARY MERISTEMS 3 (RAX3), KNOTTED-LIKE FROM ARABIDOPSIS THALIANA 2 (KNAT2), and LATERAL ORGAN FUSION 1 (LOF) genes of MYB family, CUC1/2/3 of NAC family, and YAB1/5 and YAB4-like genes of YABBY family (LATERAL SUPPRESSOR (LAS), CUC2/3, FASCIATED EAR (FEA), etc. [Compared with the sample containing only SAM and a young leaf at 9 w, the sample at 13 w consists of SAM, a young leaf, and the flower meristem in the beginning, and the sample at 15 w consists of SAM and flower primordia A–E. ThusY family A. ComparA), etc. , which cFvTFL1 during the floral induction in short-day strawberries [SOC1 and TFL1 in our transcriptome at 13 w further verified the repressor role of SOC1 , NAC29, and NAC89 of NAC family; bHLH63, DYSFUNCTIONAL TAPETUM 1 (DYT1), SPATULA (SPT), and SPT-like of bHLH family; DIVARICATA 1 (DIV1) and MYB6 of MYB family. Besides, primordia-specific gene such as JAGGED (JAG) was also explored. These genes can also be considered candidate genes for studying flower development in strawberries.Floral induction is a prerequisite for flower development. It has been shown that the floral integrator FvSOC1 acts as a repressor by promoting wberries . In this of SOC1 B. The hod leaves ,21. Howerawberry ,21,25. FAP1, FLC, SOC1, and SVP (Chimonanthus praecox), peach, pear, and Arabidopsis were also found to be involved in several plant growth and development processes, such as flower morphogenesis, floral induction, gibberellin synthesis, and delay of senescence [AGAMOUS-LIKE 1 (AGL1), AGL14, MADS57, AGL15, CMB1, PISTILLATA (PI), MADS6-like, MADS2, and MADS14. Except for AGL14 and AGL15, which were significantly up-regulated at 13 w, the other genes, such as MADS57 and CMB1, mainly showed significant changes in expression at 15 w , the changes in the expression of key genes in various hormone signal transduction pathways during strawberry floral induction were explored. In the RNA-seq data, most of the key genes in the auxin signal transduction pathway were up-regulated , abscisic acid (ABA), GA, ethylene, brassinosteroids, jasmonic acid (JA), and salicylic acid (SA), play a synergistic role in floral induction in response to external stimulation and the local environment . KEGG enegulated A,B. AUX1DELLA, was significantly up-regulated at 13 w. At the same time, GID1B-like, the gibberellin receptor and the inhibitor of DELLA, was decreased at 13 w /ERF1 protein family and its evolutionary relatives, and there is a link between ethylene signaling and DELLA, that the inhibition of EIN3-ERF1 is mainly attributed to the decreased GA level and the accumulation of DELLA protein [EBF1-like was up-regulated at the early stage of floral induction. Correspondingly, EIN3-like1 was down-regulated at 13 w, and the expression of ERF1B was significantly decreased at 15 w  plays an important role in a variety of plant diseases and is involved in a variety of developmental processes, including flowering time in Arabidopsis . DELLA pMYC2 . Here, swberries D,E.PYRABACTIN RESISTANCE 1-LIKE/PYRABACTIN RESISTANCE (PYL/PYR) and other key genes were significantly up-regulated at 13 w. In contrast, the expression of the negative regulator of the ABA pathway, PROTEIN PHOSPHATASE 2C (PP2C), was decreased at 13 w. Although PP2C indirectly inhibits the expression of ABA-responsive genes by inhibiting SNF1-RELATED PROTEIN KINASE 2 (SnRK2), the expression of SAPK2-like, belonging to SnRK2 proteins, was consistent with that of PP2C. However, the expression level of SRK2I was increased at the early stage of floral induction and decreased at 15 w -like2 was significantly up-regulated at 13 w, and the expression of CYCLIN-D3-1 (CYCD3.1) and CYCD3.3 was increased at 15 w. The surprise is that although XYLOGLUCAN ENDOTRANSGLUCOSYLASE/HYDROLASE (XTH23) is positively regulated by BZR1  are thought to promote flowering in Arabidopsis . We foun by BZR1 B,D, it w at 15 w C,D, suggFKF1 in the photoperiodic pathway  in the auxin signaling pathway (AHK4 the ARR1-like) in the cytokinin signaling pathway  were grown in the greenhouse in Shangzhuang Experimental Station , Beijing , China. The daughter plants of ‘Benihoppe’ were rooted on 6 June 2018, which we marked as the 0 week (0 w) (Strawberry plants (ek (0 w) . The sho−ΔΔCT method was used to analyze the qRT-PCR expression data [FaACTIN was used as the internal control for the normalization of gene expression in strawberries. The name and sequences of gene-specific primers are given in Total RNA samples were isolated from strawberry shoot apices using the E.Z.N.A. Total RNA Kit  according to the manufacturer’s protocol. First-strand cDNAs were synthesized from total RNA using HIScript II Reverse Transcriptase . The qRT-PCR reactions were performed in 10 μL volumes containing 1 μL cDNA as a template using ChamQ Universal SYBR qPCR Master Mix  on an ABI Q6 Real-Time PCR System . The 2ion data . FaACTINhttps://ccb.jhu.edu/software/hisat/index.shtml accessed on 2 March 2022) was used for alignment, and valid reads were aligned to the reference octoploid strawberry genome (https://datadryad.org/stash/dataset/doi:10.5061/dryad.b2c58pc accessed on 2 March 2022) [https://ccb.jhu.edu/software/stringtie/ accessed on 2 March 2022); FPKM was used to estimate the quantification of gene expression levels. A corrected p-value of <0.05 and |log2foldchange| ≥1 were set as the thresholds for significant differential expression. The raw sequence data have been submitted to the NCBI Sequence Read Archive under accession number PRJNA746082.All RNA samples were delivered to Hangzhou Lianchuan Biotechnology Co. Ltd.  to prepare cDNA libraries and high-throughput RNA sequencing on the Illumina 4000 sequencing instrument. HISAT2 software (ch 2022) . Splicinhttps://bioconductor.org/packages/release/bioc/html/edgeR.html accessed on 2 March 2022), was used for transcript quantification, difference comparison, and visualization, and the differential expression results were graphically displayed using R (https://www.r-project.org/ accessed on 2 March 2022) and Tbtools (https://github.com/CJ-Chen/TBtools accessed on 2 March 2022). The GOseq R package (http://www.bioconductor.org/packages/release/bioc/html/goseq.html accessed on 2 March 2022) was used for Gene Ontology (GO) enrichment analysis, and KOBAS software was used for the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis (http://kobas.cbi.pku.edu.cn/kobas3/ accessed on 2 March 2022).EdgeR software  equipped with a RisingCam industrial digital camera .https://bioedit.software.informer.com/7.0/) and ClustalW . Phylogenetic analyses were performed using MEGA 7.0 (https://www.megasoftware.net/ accessed on 2 March 2022). The CDS sequences of MADS family and SEB family members from Arabidopsis were downloaded from TAIR (https://www.arabidopsis.org/ accessed on 2 March 2022). The primers are listed in Alignments were performed using BioEdit 7.0 (


We investigated the association between the levels of NPY-LA and single nucleotide polymorphisms (SNP) to better understand the genetic regulatory mechanisms of autoimmunity in T1D and the functional impacts of increased NPY-LA levels. (2) NPY-LA measurements from serum and SNP genotyping were done on 560 newly diagnosed individuals with T1D. SNP imputation with the 1000 Genomes reference panel was followed by an association analysis between the SNPs and measured NPY-LA levels. Additionally, functional enrichment and pathway analyses were done. (3) Three loci  were associated with NPY-LA levels , which indicates an association with neurologic and vascular disorders. SNPs associated with variations in expression levels were found in six genes (including DCAF5). The pathway analysis showed that NPY-LA was associated with changes in gene transcription, protein modification, immunological functions, and the MAPK pathway. (4) Conclusively, we found NPY-LA to be significantly associated with three loci , and based on our findings we hypothesize that the presence of NPY-LA is associated with the regulation of the immune system and possibly neurologic and vascular disorders. HLA-DR3-DQ2 is associated with autoantibodies to glutamic acid decarboxylase (GADA) as the first appearing islet autoantibody [HLA-DR4-DQ8 [HLA-DQ2 [Type 1 diabetes (T1D) is an autoimmune disease caused by the destruction of pancreatic islet β cells . More thantibody . Additio-DR4-DQ8 ,6,8 but [HLA-DQ2 .IFIH1 [ERBB3, SH2B3, RBFOX1, BACH2 [PTPN22, CTLA4, CCR7, TNFAIP3, and CD226 [HLA-DR3-DQ2/HLA-DR3-DQ2 individuals [LPP is associated with persistent GADA [Other loci, identified by genome-wide association studies (GWAS), have minor individual effects on the total genetic risk for T1D, but for most, their biological functions are still unknown . Fine-maIFIH1 , ERBB3, 1, BACH2 , PTPN22,nd CD226 , are assnd CD226 , most ofividuals . In addient GADA .FCRL3 and 11q13/RELA are assumed as candidates for early screening of clinical onset of T1D [IFIH1 is negatively associated with IA-2A [Individuals with IA-2A are at increased risk for T1D progression , and thet of T1D ,14, whilth IA-2A .The known T1D autoantibodies represent only one part of the multifaceted autoimmune response towards β cells . There aNeuropeptide Y (NPY) is a vesicle cargo peptide , and antHLA-DQ8 positive individuals with T1D who are diagnosed over 10 years of age, while associations between NPY-LA and HLA-DRB or -DP have not yet been investigated [Autoantibodies to NPY-L (NPY-LA) are present in both individuals with T1D and type 2 diabetes (T2D)  but alsostigated .In the present study, we aimed to characterize associations between NPY-LA levels and GWAS data, including their functional annotation. This was done to better understand the genetic regulatory mechanisms of autoimmunity and the functional impacts of having increased levels of the minor autoantibody, NPY-LA.Participants: A total of 569 newly diagnosed individuals with T1D were available from three sub-cohorts, all part of The Danish Childhood Diabetes Register (DanDiabKids), described elsewhere [lsewhere ,27,28. DThe first sub-cohort, Steno 2007, consisted of 500 individuals with T1D, of which 77 were excluded due to insufficient material. The second sub-cohort included 129 consecutively enrolled individuals with T1D from the Danish Remission Phase Study, where 58 individuals were excluded due to insufficient material, co-participation in Steno 2007, or missing data. Both the first and second sub-cohorts had previously been genotyped with the ImmunoChip array. The third sub-cohort included 79 individuals with T1D from the CPH remission phase 2015 cohort [Participant demographics of all the 560 individuals with T1D are shown in Autoantibody measurements: Serum samples from the 560 individuals, taken within 3 months from clinical onset of T1D, have been stored at −80 °C and were analyzed for NPY-LA using a radioligand binding assay (RBA), described elsewhere [35S-methionine radiolabeled autoantigens incorporated into an overnight immunoprecipitation/filtration assay. A polyclonal rabbit IgG antibody to NPY , in seven-doubling dilution steps, was used for converting Protein A Sepharose-bound radioactivity into in-house units. Analyses for NPY-LA were done in duplicates. The mean value of the intra-assay coefficient of variation (CV) for duplicates was 13%. The NPY-LA assay has not been part of the international standardization workshops [lsewhere ,26,30. Iorkshops ,32.GADA and IA-2A were analyzed within 3 months from the clinical onset of T1D and were analyzed in a standard RBA, previously described in detail elsewhere ,32. LeveSNP genotyping of the three sub-cohorts: A total of 560 individuals had genotyping data available, of which 486 were previously genotyped on the ImmunoChip array described elsewhere [lsewhere , and 74 The two datasets were merged using PLINK v1.90 before proceeding with the imputation. A total of 13,066 SNP markers overlapped between the two platforms. Before merging, we made sure that both datasets had the same strand and build concordance. After QC and strand alignment, 402,410 SNPs remained in the merged dataset. After removing duplicate variants, 397,929 SNPs remained for imputation analysis.Imputation with 1000 genomes: To explore regions not well covered by the ImmunoChip, imputation was performed on the merged dataset using the 1000 Genomes haplotype reference panel. Chromosome strand and allele order in the merged dataset were adjusted to match the reference 1000 Genome Phase 3 dataset (excluding non-European samples) using the conform-gt program. Pre-phasing was performed using SHAPEIT v2 [APEIT v2   and the imputed SNPs . The linear model was adjusted for the following covariates: sex, age at clinical onset of T1D, ethnicity, log2 of GADA, and IA-2A measurements. Ethnicity was coded as a factor with two levels . The age at clinical onset of T1D was grouped into four levels: below 5, 5–10 or 10–15 years, and above 15 years. The value of genomic inflation-estimate (lambda), a measure of inflated p-values (based on median chisq), was 1. Lambda statistic should be close to 1 if the points fall within the expected range or greater than 1 if the observed p-values are more significant than expected. Manhattan plot and QQ-plots before and after adjustment for genomic control were created using the qqman package in R version 4.1.0. A p-value cutoff of p < 1.0 × 10−4 was used to identify the top signals from the association analysis.p-values and normalized effect sizes (NES). The NES of eQTLs is defined as the slope of the linear regression. It is computed as the effect of the alternative allele relative to the reference allele in the human genome reference GRCh38/hg38. A p-value cutoff of p < 0.05 was used as the threshold for the eQTL analysis.Variant Effect Predictor (VEP) in Genome Reference Consortium Human Build 38 Ensembl release 104 (GRCh38) was used to annotate the top variants. Expression quantitative trait loci (eQTLs) in whole blood were extracted for the top variants using the GTEx portal (The Genotype-Tissue Expression Project), hereby retrieving Pathway analysis and network establishment were performed on the annotated top variants using Ingenuity Pathway Analysis .Of the 560 individuals with T1D, 0.5% had missing NPY-LA values (3/560). For GADA, 53% and 21% were positive and negative, respectively. IA-2A was detected in 51% of individuals, while 23% were negative. The measurements were missing in 26% for both GADA and IA-2A, and the missing values of the two variables were set to zero. The ethnic distribution of the genotyped samples is shown in p-values. A Manhattan plot illustrates chromosomes with significant SNPs  resulted in 348 SNPs .Expression quantitative trait loci (eQTLs) for the selected 348 SNPs in whole blood were retrieved from GTEx, and the analysis identified several eQTLs of DCAF5 . Only 24ABCC2 and SNP rs3746583 from gene DCAF5, of which eQTL was identified , mapping to 52 genes . We highentified .Finally, the IPA analysis generated two networks that illustrate the influence of the NPY-LA associated genes on the p38 mitogen-activated protein kinases (MAPK) pathway, where one network includes JNK, Akt, and PI3K a and theDGKH, DCAF5, and LINC02261, which had SNPs significantly associated with NPY-LA levels. When including GADA and/or IA-2A levels in the model, the associations did not change, indicating that the three loci are not important for the known association between NPY-LA and the islet autoantibodies [DCAF5, ABCC2, CCDC6, PABPC1L, DENND2C, and TTF2, suggesting potential interactions between these genetic factors and NPY-LA levels. The top molecules of the pathway analysis included DGKH, DCAF5, PABPC1L, and ABCC2.This observational study of 569 children with T1D was designed to examine genetic loci associated with levels of NPY-L autoantibodies at the clinical onset of T1D. Association analysis identified three loci DGKH, encodes a member of the diacylglycerol kinase enzyme family [DCAF5 encodes DDB1 and CUL4-associated factor 5 [LINC02261 is a non-protein-coding lncRNA. None of the genes are known susceptibility loci for T1D or islet autoimmunity. However, DCAF5 has previously been linked with T2D [ABCC2 is part of the adenosine triphosphate-binding cassette family (ABC transporters) located in the plasma membrane that enables an active transport of various compounds across the cell membrane [The gene, e family , while Dfactor 5 , and LINwith T2D , and NPYmembrane ,41. BothMAPK-signaling pathway: Several identified genes affect cell transcription and apoptosis signaling. DGKH is known to regulate intracellular concentrations of phosphatidic acid and diacylglycerol and has a key role in promoting cell growth by activating the MAPK-signaling pathway [DGKH as a hub node directly or indirectly activating several kinase signaling pathways, e.g., Akt, JNK, PI3K, and LYN. Akt affects glucose uptake and utilization, glycogen, fatty acid, and protein syntheses, and has been implicated in several diseases, including diabetes, autoimmunity, and insulin resistance [LYN is a member of the Src family of tyrosine kinases and plays an important role in regulating innate and adaptive immune responses, responses to growth factors, and cytokines [LYN was recently identified as a novel T1D susceptibility locus [DCAF5 indirectly interacts with Akt. Other genes from the pathway analysis and eQTLs support an association with the MAPK-signaling pathway . This suggests that NPY may impact the T1D phenotype by complex regulation of pro- and anti-apoptotic signaling pathways. pathway . MAPKs a pathway ,43. The sistance ,45. The sistance . The Phosistance . LYN is ytokines . InteresDCAF5 is assumed to function as a substrate receptor for the CUL4-DDB1 E3 ubiquitin-protein ligase complex helping ubiquitination [DGKH [DCAF5 influence neutrophiles of the innate immune system. Studies have shown that increasing NPY levels in mice lead to hyperglycemia, impaired glucose tolerance, hyperphagia, and obesity. On the contrary, NPY knockdown in rats leads to the development of brown adipose tissue and elevated thermogenic activity [Furthermore, the MAPK pathway is regulated by enzymatic post-translational modification of ubiquitination ,50, a prtination . Ubiquittination , and inton [DGKH  and DCAFactivity ,53,54,55activity .The findings suggest that NPY-LA plays a role in post-translational modification and regulation of the MAPK signaling pathway via ubiquitination, and through that influence survival of β cells or activation of inflammatory cells, thus influencing the autoimmune response in T1D and glucose regulation. Interestingly, NPY acts through the Y1 receptor to increase neuronal proliferation, mediated through activation of the MAPK pathway .Neurological disorders: DCAF5 has been associated with neurogenic bowel disease [DCAF5, and the function of ABCC2. Although, a previous study including few participants with T1D and T2D found no relation between peripheral or cardiac autonomic neuropathy and NPY autoantibodies [DCAF5, ABCC2, NPY-LA, and neuropathies. disease , which i disease . Further disease . Moreove disease . Since w disease , we hypotibodies . StudiesDGKH, a gene that has previously been reported in bipolar disorders [LINC02261 has previously been found in schizophrenia and autism spectrum disorder [The present study identified a significant association between NPY-LA and isorders . Also, tdisorder ,64. Intedisorder . Moreovedisorder .PRKG1 [2+-channels in the neuronal system [2+ in β cells [2+ is involved in the vesicular trafficking of ABC transporters to the membrane [Additionally, our pathway analysis identified genes affecting calcium channels (PRKG1 ). NPY acl system , and, in β cells . Voltagemembrane .In T1D, persistent hyperglycemia has previously been found to promote neurovascular dysfunction, leading to endothelial cell dysfunction, oxidative stress, increased neuronal cell apoptosis, and inflammation ,66. The The strength of the present study involves the large number of samples at the clinical onset of T1D with genetic information to identify loci associated with NPY-LA levels in individuals with T1D. Though the lack of replication sample/data is a limitation, as well as the use of whole blood for functional annotation in the absence of follow-up experiments in relevant cells/models, an important strength is the combination of analyses identifying associations with SNPs, expressions, and pathway analyses. Finally, there may be limitations to using publicly available databases as study design and demographic data vary.DGKH, DCAF5, and LINC02261. It is hypothesized that the presence of NPY-LA is associated with activation of the innate immune system, where NPY-LA may interact with the MAPK pathway in the regulation of glucose homeostasis, inflammation, cell survival, ABC transporter, and Ca2+ levels in β cells, leukocytes, endothelial cells, and neurons in the development of T1D and possibly in T2D neuropathies or vascular disorders.In conclusion, NPY-LA is significantly associated with three loci:


Ambient air pollution has become a common problem worldwide. Exposure to pollutant particles causes many health conditions, having a particular impact on pulmonary and cardiovascular disease. Increased understanding of the pathological processes related to these conditions may facilitate the prevention of the adverse impact of air pollution on our physical health. Evidence from in vitro, in vivo, and clinical studies has consistently shown that exposure to particulate matter could induce the inflammatory responses such as IL-6, TNF-α, IL-1β, as well as enhancing the oxidative stress. These result in vascular injury, adhesion molecule release, platelet activation, and thrombin generation, ultimately leading to a prothrombotic state. In this review, evidence on the effects of particulate matter on inflammation, oxidative stress, adhesion molecules, and coagulation pathways in enhancing the risk of thrombosis is comprehensively summarized and discussed. The currently available outcomes of interventional studies at a cellular level and clinical reports are also presented and discussed. Air pollution has recently become a major concern worldwide. It has been proposed that exposure to high ambient pollutant particles leads to adverse health impacts which may contribute to as many as three million premature deaths per year ,2. There10 has an aerodynamic diameter of between 2.5 to 10 microns. Fine particulate matter, PM2.5 has a particle size of more than 0.1 micron, but less than 2.5 microns in aerodynamic diameter. Ultrafine particulate matter (UFP) has an aerodynamic diameter of less than 0.1 micron [Particulate matter (PM) can consist of a variety of components depending on the source ,16. PM i1 micron ,18. Dies1 micron . These p1 micron ,18. Past1 micron ,25,26,271 micron ,29, and 1 micron ,25,26,301 micron , increas1 micron ,32. VCAM1 micron ,32. Incr1 micron ,34.Normal hemostasis is a complex system mainly maintaining stable physiology in the body and protecting against pathological processes. The generation of thrombin is the key mechanism that links blood clot formation and the fibrinolytic system, the counterbalance that controls the thrombotic process ,35. In g2AR: beta-2 adrenergic receptor, DNA: deoxyribonucleic acid, ICAM-1: intercellular adhesion molecules-1, IFN-γ. interferon- γ, IL-1β: interleukin-1β, IL-6: interleukin-6, MCP-1: monocyte chemoattractant protein-1, NOS: nitric oxide synthase, PAI-1: plasminogen activator inhibitor-1, ROS: reactive oxygen species, SOD: superoxide dismutase, TF: tissue factor, TNF-α: tumor necrosis factor-α, tPA: tissue plasminogen activator, VCAM-1: vascular adhesion molecule-1.Inhalation exposure to PM induces pulmonary and systemic inflammation and oxidative stress. It increases the expression of adhesion molecules resulting in the recruitment of inflammatory cells and the activation of the vascular endothelium, platelets, and coagulation cascade, causing fibrin clots, while hampering fibrinolytic activity, and eventually contributing to thrombosis. βCurrently, knowledge surrounding the outcomes of PM-mediated coagulation and fibrinolysis is still inconclusive. In this review, the effects of PM on the inflammatory responses, oxidative stress, adhesion molecules, and coagulation factors related to thrombosis from in vitro, in vivo, and clinical studies are comprehensively summarized and discussed. The understanding accrued from this overview of the pathological process of PM-mediated thrombosis will help in limiting or preventing the damaging effects of PM exposure on our health.2O5) is one of the toxic substances, a consequence of burning fuel oil and fly ash. An in vitro study showed that V2O5 could directly affect the human umbilical vein endothelial cells (HUVECs), by enhancing oxidative stress, and increasing expression of adhesion molecules, which resulted in shape changes, decreased cell proliferation, and increased apoptosis [Over the past decade, it has been shown that polluted air particles can activate inflammation, and oxidative stress and cause cell death ,37. In vpoptosis . A reporpoptosis . Other rpoptosis ,41, whicpoptosis ,41,42,432AR agonist, enhanced PM-induced IL-6 release in human alveolar macrophages and MH-S cell lines, while the alveolar macrophages from Adrb2−/− mice incubated with albuterol showed a decreased PM-mediated IL-6 response [2AR, encoded by the Adrb2 gene. Moreover, PM was also shown to activate the microparticles and cause intracellular calcium release, and to enhance tissue factor function in HUVECs and peripheral blood mononuclear cells (PBMCs) [PM could also induce cAMP secretion and activate further downstream pathways, resulting in the enhancement of PM-mediated IL-6 release in murine alveolar macrophages (MH-S) and human alveolar macrophages . In addiresponse . These f (PBMCs) . The actIn in vitro studies of venous blood from rodent models, incubation with DEP rapidly induced platelet activation and platelet aggregation in a dose-dependent manner ,47,48,49The different types of particles also had differing effects on outcomes. Positively-charged amine-particles could enhance platelet function, as indicated by the shortening of PFA100 closure time in both 60-nm UFP and 400-nm amine-polystyrene particles. In contrast, negatively-charged carboxylated UFP and unmodified UFP did not affect platelet function . This me2-adrenergic receptor (β2AR) in the macrophages encoded for by the Adrb2 gene was the key receptor that modulates PM-induced inflammation and thrombosis [flox/flox mice together with a decrease in thrombus formation and tissue factors [flox/flox mice pretreated with a β2AR agonist, Formoterol, showed that these mice which lack the Adrb2 gene in the macrophages had blunted IL-6 and TF response, in comparison to Adrb2flox/flox mice after PM exposure [2AR signaling in the macrophages. This further activated the release of IL-6, TNF-α, and TF leading to the thrombus formation [Consistent with in vitro reports, in vivo studies showed that the βrombosis . Adrb2-k factors . In addiexposure . Furtherexposure . These formation ,55,56,572.5 [2AR, resulting in IL-6 release, systemic inflammation, and thrombosis, these processes being regulated by Sirt1. In addition, PM also induced oxidative stress in the rodent models. An increase in nitric oxide synthase (NOS) and heme oxygenase-1 (HO-1), and a decrease in catalase function in response to PM exposure were observed, together with an increase in the antioxidative response indicated by increase in glutathione (GSH) and a decrease in ascorbate level [PM may also induce oxidative stress, resulting in DNA damage ,57. Sirt2.5 , whereas2.5 ,56. Theste level ,57. This2.5 may induce alveolar wall thickening and also enhance adhesion molecule and TF function [2.5 also damaged vascular endothelial cells, resulting in TF release, which further activated the coagulation cascade and enhanced thrombus formation [PMfunction . PM2.5 aormation ,54,55,56ormation . These f2.5 exposure showed lower vWF levels, despite higher markers of vascular injury and vascular adhesion molecules [2.5 on the prothrombotic state including evidence of extensive microvascular thrombi, decreased vWF, decreased coagulation factor levels, and prolonged clotting time, which resulted from a combination of the action of many clotting factors and vWF [2.5 and PM10, no significant changes in vWF secretion and white blood cell (WBC) influx in the lungs and plasma were observed [A study in hamsters revealed that PMolecules . This co and vWF . Howeverobserved . Althougobserved ,60, and observed ,54. Actiobserved ,58,60. OThe effect of PM on the fibrinolytic system remains controversial. Most studies reported that PM exposure alleviated fibrinolysis as a result of increased PAI-1 and decreased tPA mRNA expression, which caused the suppression of fibrinolytic activity and ultimately promoted a prothrombotic state ,55,56. AThe effect of PM exposure on the blood cell count was inconclusive due to the conflicting data. Although PM was shown to increase the number of red blood cells (RBC) and hemoglobin (Hb) levels in mice , anotherPrevious studies into acute and prolonged DEP exposure showed adverse cardiopulmonary impact ,63,64,65As regards the coagulation and fibrinolytic systems, DEP exposure did not affect vWF in normal hamsters and mice ,66,68. HDEP exposure had some impact on blood cell count, including RBC, Hb, hematocrit (Hct), WBC, and platelets. Some studies reported an elevated number of red cells, Hb, Hct, and WBC ,48. Foll2.5 [2.5 and other inflammatory cytokines including IL-6, IL-10, and IL-1β [The cumulative evidence from clinical studies demonstrates that inhalation of ambient PM could activate systemic inflammation ,70,71,722.5 ,70. In cnd IL-1β ,71. ThesCurrently, knowledge around the effect of PM on CRP remains inconclusive. Studies in short-term exposure to ambient PM in young and elderly patients with coronary arterial disease (CAD) showed a significant association between CRP and elevated PM . However2.5 in Boston showed that elevated ICAM-1 and VCAM-1 were significantly directly associated with the level of PM2.5 at many time courses from the four hour to 28 days moving average [Fine PM may affect endothelial cells, resulting in vascular endothelial injury and release of adhesion molecules. A study in healthy elderly individuals exposed to ambient PM average . However average . The posPM exposure could induce many aspects of the prothrombotic state. Several studies reported that P-selectin and platelet factor 4 (PF4), reflecting platelet activation, had a positive association with PM exposure in healthy young adults and patients with coronary arterial disease ,72,76. EThere is limited data regarding the effect of PM on platelet counts in clinical studies. One study reported increased platelet counts in healthy adults and metabolic syndrome patients after inhalation of DEP for two hours . AnotherIn terms of the coagulation pathway, there are only a few clinical studies which have investigated the PM-affected coagulation test. One report in young healthy adults and another report in elderly patients with coronary arterial disease described elevated fibrinogen levels in association with high ambient PM in Beijing and New York, respectively ,76, whilAnother study revealed that PM was significantly associated with the increased fibrin degradation product (FDP), reflecting the occurrence of a blood clot and clot degeneration . ConversThere are only a few clinical studies which have focused on the impact of PM on blood cell parameters. Two reports revealed no significant changes in the RBC and Hb levels in association with exposure to PM ,77, but 2AR encoded for by the Adrb2 gene plays a significant role in the PM-induced inflammation and thrombosis [2AR blocker had beneficial effects on reduction of the PM-induced adverse inflammatory response.A previous in vitro and in vivo study demonstrated that βrombosis . Consistrombosis . These fPrevious reports also stated that PM exposure induced oxidative injury, which further activates the inflammatory response ,85,86. TIn mouse models, a study using either Reserpine, a chemical sympathectomy agent, or Propranolol, a βAR antagonist, demonstrated that blocking sympathetic effects could alleviate the PM-induced IL-6 response and reduce thrombus formation . These fTNF-α was identified as being the key mediator that regulates PM-mediated fibrinolytic changes . Adminis2AR-agonist, while these effects could be lessened by adding either a β2AR antagonist, TNF-α blocker, an antihistamine, or an anti-inflammatory/antioxidative agent. The summary of intervention reports on the effect of PM on the inflammation, oxidative stress, and thrombosis following PM exposure in in vivo and clinical studies is shown in Findings from both in vivo and clinical studies supported the findings from in vitro studies that PM-mediated inflammation, oxidative stress, and thrombosis could be enhanced by administration of a βAlthough many previous studies explained the pathological effects of PM on inflammatory and oxidative stress responses associated with thrombosis, there were several gaps of knowledge to be explored. In the past decades, some reports directly focused on the effects of certain toxic components. However, most of the studies mainly evaluated the composite outcomes of PM that had different compositions of various organic and inorganic compounds. The different substances and the characteristics such as size, positive- or negative-charge properties, dose, and time-dependent effects had shown different outcomes. Additional in vitro and in vivo research should be done to determine which specific toxic components have certain characteristics, especially the dose-effects (transient or cumulative effects). Moreover, both in vitro and in vivo studies have shown PM-induced platelet aggregation and thrombosis, but there have been only a few studies on the coagulation- and adhesion-associated molecules, necessitating further study to fully comprehend the pathological effects of PM on the coagulation system. With this knowledge, the pathology of PM-induced blood clotting may be comprehended, and it may be possible to reduce the negative effects of the harmful components and halt the production and use of these poisonous substances.2AR, IL-6, and the TNF-α signaling pathway. Lung injury together with the release of IL-6 would further enhance TF, activate platelets, vWF, and coagulation factor function, resulting in the generation of thrombi. PM has also been shown to inhibit the fibrinolytic pathway via TNF-α signaling. These processes would make blood clots more robust, and they may therefore eventually occlude the luminal vessels. The effects of PM exposure on inflammation, oxidative stress, adhesion molecules, and thrombus formation are summarized in 2AR antagonists in the prevention of PM-mediated adverse clinical outcomes. However, to eradicate or attenuate the air pollution problem seems to be currently more important and challenging. Global intervention and social movements may be required to reduce the air pollution, protect fresh air, and alleviate the impact of inhaling ambient air pollution on our health.Inhalation of ambient air pollution consisting of various toxic substances may induce pulmonary inflammation, and an oxidative stress response and induce the prothrombotic state through β