Colorectal cancer (CRC) ranks third in terms of global incidence and second in terms of death toll among malignant tumors. Gut microbiota are involved in the formation, development, and responses to different treatments of CRC. Under normal physiological conditions, intestinal microorganisms protect the intestinal mucosa, resist pathogen invasion, and regulate the proliferation of intestinal mucosal cells via a barrier effect and inhibition of DNA damage. The composition of gut microbiota and the influences of diet, drugs, and gender on the composition of the intestinal flora are important factors in the early detection of CRC and prediction of the results of CRC treatment. Regulation of gut microbiota is one of the most promising new strategies for CRC treatment, and it is essential to clarify the effect of gut microbiota on CRC and its possible mechanisms to facilitate the prevention and treatment of CRC. This review discusses the role of gut microbiota in the pathogenesis of CRC, the potential of gut microbiota as biomarkers for CRC, and therapeutic approaches to CRC based on the regulation of gut microbiota. It might provide new ideas for the use of gut microbiota in the prevention and treatment of CRC in the near future and thus reduce the incidence of CRC. Colorectal cancer (CRC) is a malignant tumor occurring in the colon or rectum in the lower gastrointestinal tract. According to data from a 2020 survey by the World Health Organization, CRC ranks third and second in terms of incidence and mortality among all cancers and third and second in terms of incidence among men and women, respectively . The latThe evolution of CRC is a complex multistep process. With the continuous developments and changes in people’s lifestyles toward Western lifestyles, the incidence and mortality rates of CRC are rising , which sClostridium, Enterobacter, and other pathogenic bacteria result in microecological imbalances and thereby disrupt cell DNA, activate carcinogenic signaling pathways, and ultimately affect the development of CRC -17+ T cells and inhibit proliferation and tumor formation, which may be achieved via a change in the intestinal microflora  demonstrated that fermented milk weakened intestinal inflammatory responses by increasing the number of IL-10-secreting cells, promoting apoptosis, and reducing the activity of procarcinogenic enzymes. These effects put gut microbiota into an ideal state and reduced the risk of cancer. Lactobacillus rhamnosus Probio-m9 that it can inhibit the expression of p-signal transducer and activator of transcription-3 and p-Akt, improve the balance of the intestinal flora, especially Akkermansia, Bifidobacterium, and Blautia, and suppress effects leading to CRC-related carcinogenesis. In particular, the study indicated that L. rhamnosus Probio-m9 can affect the metabolism of microbiota, especially glucose metabolism, and pointed out that glucose metabolism plays a far-reaching role as a driving force in the occurrence of tumors. Pediococcus pentosaceus, which carried a promoter that enabled the accurate expression of a fused protein containing P8, which is a small protein obtained from L. rhamnosus CBT LR5. This system significantly reduced the volume of tumors and inhibited the growth of CRC.Bifidobacterium bifidum inhibits the development and progression of CRC in multiple ways, including antibacterial activity, improving vitamin metabolism, and enhancing immunity  blockade, via lymphocyte-mediated immune responses.immunity , and alsimmunity . Bifidobr growth . BifidobIn vitro research also discovered -induced inflammatory signatures and the activation of mitogen-activated protein kinase (MAPK) in RAW264.7 macrophages, HT-29 intestinal cells, and NCM460 cells. Ziziphus jujuba cv. Muzao can not only improve the intestinal flora of the host but also maintain metabolic function. Lactobacillus, Bacteroides, butyrate-producing bacteria, and acetic acid-producing bacteria. It played a crucial role in regulating the ecological balance of intestinal microbiota. This research also showed that carboxymethylated pachyman can alleviate 5-FU-induced colon injury, and the mechanism may be related to regulation of the NF-κB, Nrf2/antioxidant responsive element, and MAPK/p38 pathways. Albuca bracteata also have strong antitumor activity. Experimental data show that A. bracteata polysaccharides either alone or in combination with 5-FU can reduce the concentration of cancer cells and the expression of β-catenin and related proteins. Moreover, treatment with A. bracteata polysaccharides can specifically enrich Ruminococcus, Anaerostipes, and Oscillospira, effectively improve the composition of gut microbiota, and improve the levels of fecal SCFAs, such as propionic acid, acetic acid, and butyric acid, to improve the antitumor efficacy of 5-FU and reduce adverse reactions to 5-FU. LPS is a significant product of intestinal gram-negative flora. In blood and cancer tissues from patients with CRC, the level of LPS increased significantly. This suggests that LPS is an important target for the treatment of CRC. Bacillus polymyxa. Because these bacteria can reasonably enter the host gut and then remove LPS and regulate the CRC microenvironment, they may achieve therapeutic effects.Owing to the lack of carbohydrate-activated enzymes in the human body, most polysaccharides cannot be directly digested and absorbed by the human body . HoweverPectin (PC) is a kind of water-soluble food fiber that can protect the intestinal wall, activate useful bacteria in the intestine, adjust gastrointestinal function, remove intestinal waste, and prevent CRC. Polyphenol  is the gShort-chain fatty acids, such as butyric acid and propionic acid, are produced via the fermentation of dietary fiber by the intestinal flora. A high concentration of butyric acid can inhibit the proliferation of CRC cells independently of the Warburg effect and inactivate a large number of carcinogenic signals by inhibiting histone deacetylases. In addition, butyric acid can promote the proliferation of regulatory T cells and strengthen intestinal immunity . It has Clostridium butyricum is a probiotic that produces butyric acid, which is a classical SCFA with strong anticancer activity. So how does butyric acid work? Data from Fusobacterium nucleatum, Bacteroides fragilis, and Prevotella intermedia , irinotecan (XELIR regimen), cyclooxygenase-2 inhibitors, cetuximab, or bevacizumab. According to investigation data, however, the therapeutic efficacy of chemotherapy frequently leads to failure of CRC treatment as a result of drug resistance.Chemotherapeutic approaches for treating CRC have received increased attention in recent years. Many cytotoxic agents are regularly used in combination, for example, 5-FU in combination with There is a growing amount of empirical data suggesting that the use of metformin increases the level of SCFA-producing intestinal microorganisms. Metformin  indirectPrevotella, Akkermansia, and Ruminococcaceae spp. while reducing the abundance of Bacteroides, Parabacteroides, and Dorea spp., which is closely associated with the reduction of the risk of CRC achieved with aspirin  by intestinal microflora produces high levels of SCFAs, such as butyric acid. High levels of SCFAs may reduce the risk of the development of CRC. Butyric acid induces apoptosis in colon cells, inhibits the activity of CRC cells by blocking the expression of genes regulating histone deacetylase , and alsRecent work has demonstrated that micronutrients can influence the development and progression of CRC by modulating the structure of the intestinal microbial community.Akkermansia muciniphila. Vitamin D  and increase the abundance of probiotics   . They caronidase . In addiroidetes ; Table 3At present, the study of microbial communities has been applied in related fields of human disease and has achieved success. However, the role and significance of microbial communities in treatment have not been fully studied, and we still face many unresolved problems. Therefore, it is necessary to conduct further research on current topics to verify existing findings and develop treatment strategies. It is worth noting that current research on microbial regulation of anti-CRC therapy mostly focuses on mice, and how to apply the resulting academic findings in clinical practice remains a challenge. Although the pathological and immune responses of mice implanted with human microbiota are similar to those of humans, there are still differences .In the future, if the most beneficial microbial compositions under various clinical conditions can be identified, it will be possible to use microbial compositions as biomarkers, diagnostic tools, or therapeutic targets and develop microbial therapies that can not only enhance the effects of anticancer therapies but also reduce their systemic toxicity. Therefore, treatment interventions targeting microbial groups will become one of the next areas of focus for precise and personalized treatment of cancer. This may lead to breakthroughs in various areas of medicine and not only support the development and production of immunotherapies or innovative vaccines for cancer treatment but also improve drug delivery in other intestinal diseases and prevent and reduce inflammation. A clinical trial of this strategy has the potential to improve the feasibility of using probiotics as comprehensive drug carriers in non-invasive cancer treatment in humans and as suitable adjuvants in traditional anticancer therapy.MC, LS, and SZ: conceptualization. MC, WL, and NL: writing—original draft preparation. MC, AZ, QW, SZ, and LS: writing—review and editing. AZ and LS: visualization. All authors have read and agreed to the published version of the manuscript.


Renal involvement is a frequent complication of systemic lupus erythematosus (SLE). It occurs in up to two-thirds of patients, often early during the disease course, and is the most important predictor of the morbidity and mortality of SLE patients. Despite tremendous improvements in the approach of the lupus nephritis (LN) therapy, including the recent approval of two new disease-modifying therapies, up to 50% of patients do not obtain a renal response and up to 25% will eventually progress to end-stage renal disease (ESRD) within 10 years of diagnosis. Given the lack of correlation between clinical features and histological lesions, there is an increasing need for a histology-guided approach to the management of patients with LN. Apart from the initial diagnosis of type and severity of renal injury in SLE, the concept of a repeat kidney biopsy (either in a for-cause or a per-protocol scenario) has begun to gain increasing popularity in the nephrology community. Herein, we will provide a comprehensive overview of the most important areas of utility of the kidney biopsy in patients with LN. Systemic lupus erythematosus (SLE) is the prototype of autoimmune disorders caused by a loss of tolerance to endogenous nuclear antigens triggering an aberrant autoimmune response that determines a broad spectrum of organ manifestations with a wide range of severity ,2. RenalRecent years have brought ground-breaking results to the LN treatment landscape that have led to the FDA-approval of two new diseases—modifying therapies (belimumab and voclosporin) as add-on agents to the current standard of care (mycophenolate mofetil or cyclophosphamide-based regimens) ,5. DespiIn line with the overall low-response rates, up to 30% of patients with LN will eventually progress to ESRD . In a meIn fact, one possible limitation of the current LN trials is that they fail to identify the highest risk patients with the most severe underlying histology that may actually benefit from different treatment regimens. It is now increasingly acknowledged that clinical and histologic features of LN can be discordant . The pasAccordingly, the one-size-fits-all approach may not be applicable in a clinical setting when an individualized patient management is needed. As such, the kidney biopsy remains an invaluable tool to guide the management of patients with LN, but there is an unmet need to better refine the indications for the kidney biopsy in patients with SLE, to define the value of initial histology in the management of such patients and to identify the clinical scenarios in which a repeat biopsy is needed.Herein, we will provide a comprehensive overview of the most important areas of utility of the kidney biopsy in patients with LN.During the past decades, attention has focused on patients with LN in terms of a better understanding of the pathogenesis, the characterization of the long-term outcomes, and the refinement of the IS regimens. Nonetheless, we need to acknowledge that virtually all renal compartments can be affected in SLE, with different patterns of injury frequently overlapping, complicating the assessment of prognosis and obligating to an individualization of the patient’s management .To date, there are no clinical features, laboratory tests, or imaging modalities capable of predicting the histology of the kidney in LN . Apart fCrescents are commonly encountered in biopsy specimens of patients with LN, while the incidence, pathogenic mechanism, and clinical outcome of true crescentic necrotizing glomerulonephritis (GN) is less well described . In a stRenal manifestations of SLE can be a consequence of injury to every cell type, including podocytes. Most frequently, podocyte injury occurs subsequent to immune complex deposition in glomerular capillary walls. Nonetheless, there is accumulating evidence of podocyte injury in SLE that morphologically resembles minimal-change disease (MCD) or focal and segmental glomerulosclerosis (FSGS) with diffuse foot process effacement (≥70%), with mesangial dense deposits and the absence of any subepithelial or subendothelial dense deposits . These oIn addition to lupus podocytopathy, a newly recognized pathological entity called podocyte infolding glomerulopathy is consistently reported in association with SLE. It is characterized by the appearance of numerous microspheres or microtubular structures in the glomerular basement membrane (GBM) believed to be invaginations of podocytes occurring as a result of intra-GBM complement activation .Despite the fact that the current ISN/RPS  classification focuses primarily on glomerular pathology, it is recommended that both tubulointerstitial and vascular lesions should be described in the pathology report . MoreoveApart from these tubulointerstitial lesions, the presence of interstitial B-cells organized into tertiary lymphoid structures are being increasingly recognized as a driver of local autoimmunity and inflammation . MoreoveVascular lesions are frequently encountered in patients with SLE and, despite the fact that they have received little attention over the past decades, their presence might be associated with renal outcome, patient survival, and vascular events . In a reKidney biopsy remains the gold-standard in assessing the renal involvement in SLE, evaluating the severity of underlying lesions, and, thus, guiding the management of such patients. Despite the fact that all the major clinical trials in LN used clinical endpoints  to assess the treatment efficacy, there is in fact a weak correlation between clinical features and histological findings in patients with LN . There iThe available clinical guidelines have discordant indications on when to perform a kidney biopsy in patients with SLE. The 2012 American College of Rheumatology Guideline for LN indicates that to perform a kidney biopsy in patients with a decline of renal function, a proteinuria over 1 g/day or over 0.5 g/day with additional abnormalities of urinary sediment . SimilarNonetheless, there is substantial evidence from observational studies that patients without clinical signs of renal involvement have substantial histologic activity . In a stApart from initial diagnosis of renal involvement in SLE, the histologic evaluation of kidney biopsies remains essential to further guide the therapeutic approach. Since the initial publication of the World Health Organization (WHO) classification of LN in 1974, over the past decades there have been several revisions of the original form, including a transition to the ISN/RPS LN classification in 2003 .Despite the fact that several studies have shown that these classifications are able to predict the long-term outcome of LN, there are still a number of criticisms on its ability to guide treatment and forecast LN prognosis ,39,40,412; 95% CI, 0.97–1.00), and non-white race ) [2, 95% CI, 0.85–0.91) and 24-h proteinuria , the percentage of glomeruli with crescents , the presence of adhesions , and the presence of tubulitis  are independent predictors of outcome in patients with LN [In an attempt to overcome the limitations of the ISN/RPS classification, Rijnink et al. analyzed the prognostic significance for renal outcome in LN of 50 histological variables outside the framework of the ISN/RPS classification . ESRD wa–21.91)) . In an aThus, the 2018 revision of the ISN/RPS classification proposed that the designation of activity/chronicity by the terms A, A/C, and C is too broad and should be replaced by a semiquantitative assessment of histological lesions in the form of a modified NIH activity and chronicity index ,48. NoneThe role of repeat kidney biopsy has been increasingly recognized over the past decades as an invaluable tool to assess the histological stratification and adjust immunosuppressive therapy in patients with LN . NonetheSeveral studies over the past decades have evaluated the utility of per-protocol repeat biopsy post-induction therapy . Malvar A collaborative effort from the Lupus Nephritis Trials Network designed a prospective, randomized, multinational study with the aim to investigate whether a per-protocol repeat kidney biopsy after 12 months from initiation of IS therapy in incident cases of active LN results in treatment changes and, subsequently, in improved long-term outcomes  ,53) withA per-protocol repeat kidney biopsy during maintenance therapy is another strategy to evaluate the optimal moment for IS therapy withdrawal .De Rosa et al. evaluated, by a repeat kidney biopsy, 36 patients that stopped the IS therapy after being in complete clinical remission for at least 12 months and having received at least 36 months of IS . About aGiven that the kidney biopsy remains an invasive procedure with potential serious complications, there is a need to identify and validate potential biomarkers reflecting the disease activity in LN ,81. SeveComplement activation plays a major role in the pathogenesis of LN and is the mediator of renal injury subsequent to immune complex deposition . The intOne of the most promising non-invasive tools to assess disease activity in LN is the measurement of urinary soluble CD163 (usCD163) . CD163 iIn summary, kidney biopsy remains an invaluable tool to guide the management of patients with LN. Given the unsatisfactory renal response rates with current immunosuppressive regimens in LN, there is a need to better stratify the risk of progression and incorporate tissue-based information into meaningful clinical trials endpoints.


Progressive loss of physiological integrity and accumulation of degenerative changes leading to functional impairment and increased susceptibility to diseases are the main features of aging. The ovary, the key organ that maintains female reproductive and endocrine function, enters aging earlier and faster than other organs and has attracted extensive attention from society. Ovarian aging is mainly characterized by the progressive decline in the number and quality of oocytes, the regulatory mechanisms of which have yet to be systematically elucidated. This review discusses the hallmarks of aging to further highlight the main characteristics of ovarian aging and attempt to explore its clinical symptoms and underlying mechanisms. Finally, the intervention strategies related to aging are elaborated, especially the potential role of stem cells and cryopreservation of embryos, oocytes, or ovarian tissue in the delay of ovarian aging. Ovarian aging is characterized by the gradual decline in the quantity and quality of oocytes, mainly due to the low number of primordial follicles (PMFs) at birth and high monthly depletion during the reproductive period , 2. OvarAging can be defined as the progressive accumulation of degenerative changes that ultimately leads to an increased probability of functional impairment and mortality. Lopez-Otin C and Blasco MA et al. proposed that the current molecular and cellular hallmarks of aging be grouped into three categories: primary, antagonistic, and integrative hallmarks . While tThe primary hallmarks are considered to be the actual cause of aging and have a clear negative impact on deoxyribonucleic acid (DNA) . They fiSustaining genome integrity requires the integration of multiple mechanisms and signaling pathways, and its stability is crucial for individual growth and human health . Genome The main function of telomeres is to protect the ends of chromosomes to maintain genomic integrity –26. Age Epigenetic alterations in DNA methylation, histone modification, and chromatin remodeling affect aging and longevity . Among vIn addition, the maintenance of proteostasis is the key to ensuring normal organism development, resisting environmental stress, and promoting healthy aging and longevity , 37. As Antagonistic hallmarks, including cell senescence, mitochondrial dysfunction, and deregulated nutrient sensing, respond to the damage caused by primary hallmarks and are considered to be part of the compensatory or antagonistic response to damage. These responses initially mitigate the damage, and if enlarged or aggravated, they ultimately become deleterious and cause further damage.Cell senescence is a generally irreversible and permanent state in the cell cycle caused by different stresses , includiAs the primary site of oxidation of carbohydrates, fats, and amino acids to produce adenosine triphosphate (ATP), the quality and activity of mitochondria are essential for homeostasis maintenance, cell cycle control, and programmed cell death –53. MitoThe ability of cells to respond to nutrient-sensitive signaling pathways is tightly linked with nutrient availability and metabolic homeostasis, affecting the acquisition and maintenance of cell growth, cellular senescence, metabolism, and other physiological processes –62. MultStem cell exhaustion and altered intercellular communication are thought to be integrative hallmarks because they directly affect tissue homeostasis and function. When the cumulative damage caused by the primary and antagonistic hallmarks cannot be compensated for through tissue homeostatic mechanisms, integrative hallmarks arise and inevitably lead to the functional decline associated with aging.Stem cell exhaustion, including the loss of stem cell number or function, is a progressive process and a comprehensive result of multiple aging-related injuries, leading to sustained and irreversible changes in the inherent features of stem cells –69. ThroIn a study of human ovarian histomorphology, the ovaries of fetuses at 9-40 weeks of gestation are mostly almond-shaped and arranged obliquely in the fetal period . In the via apoptosis in the second half of fetal life, leaving only 1-2 million PMFs at birth  axis during the regular menstrual cycle . OvarianOvary reproductive function is the result of numerous interactions, among which follicular reserve plays a fundamental role. It is known that the PMF pool constitutes the ovarian reserve, and both reproductive and endocrine functions are limited by the PMF pool . MultiplOvarian endocrine function is jointly affected by ovarian sympathetic innervation, feedback regulation of the HPO axis, and complex interactions of the hormone axis . FolliclOvarian aging is linked to changes in the HPO axis and a progressive decline in ovarian endocrine function, especially disorders of sex hormone levels. Among many sex hormones, anti-Müllerian hormone (AMH) is still the preferred ovarian reserve indicator in various clinical situations . AMH is The female reproductive system, especially the ovaries, is aging before any other organ system. This phenomenon has obvious clinical significance and may lead to infertility, abortion, birth defects, menstrual cycle disorders, or even amenorrhea and systemic deterioration caused by estrogen deficiency . A cohorThe lifespan of the ovary depends on the delicate balance between the survival and death of oocytes. PMF activation is the basis for ovarian folliculogenesis and maintenance of fertility . HoweverSince the first use of [3H]-thymidine ([3H]-TdR) incubation to distinguish between slow-growing follicles and dormant PMFs, studies related to ovarian folliculogenesis have been conducted for more than 30 years. The regulatory mechanism of folliculogenesis, especially PMF activation, remains difficult to uncover due to the sophisticated process. Otsuka and Shimasaki demonstrated that the mitotic activities of oocyte-derived bone morphogenetic protein-15 and GC-derived kit ligand depend on the oocyte-GC communication system, which may play a pivotal role in ovarian folliculogenesis . AdditioForkhead box L2 (FOXL2), a winged helix/forkhead domain transcription factor, is preferentially expressed in the ovary, eyelids, and pituitary gland . StudiesObviously, abnormal follicular activation and atresia are the intrinsic mechanisms of ovarian aging, which may involve endocrine, paracrine, or autocrine signaling pathways. Follicular atresia is closely related to autophagy or apoptosis . AutophaCell apoptosis, especially the intrinsic mitochondrial pathway, is regulated by B-cell lymphoma-2 (BCL-2) family proteins . MyeloidDelaying childbearing among women has become a universal phenomenon due to sociodemographic, economic, medical, lifestyle and behavioral factors , 146. HuCalorie restriction, the reduction of dietary intake to below energy requirements while maintaining optimal nutrition, is considered one of the most promising nutritional interventions to attenuate aging , 152. Dein vivo are regulated by GH, and IGF-1 also has a negative feedback regulation on GH secretion .The 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.


Given the effectiveness and overall safety in several psychiatry conditions, electroconvulsive therapy remains a widely used procedure in current medical practice. Informed consent is still a requirement for the use of ECT both in voluntary and compulsory treatment; however, since severe mental illness can affect decision-making capacity and insight of the need for treatment, this requirement often constitutes an obstacle to its use. In addition, stigma around ECT still contributes to treatment refusal.To summarize the most recent evidence published about ECT and discuss the ethical and legal implications of its use, enlightened by the empirical description of a clinical vignette.Review of literature on the ethical and legal issues involving the ECT use in patients on compulsory treatment, considering the efficacy, risks, the mental health legislation in Portugal, and several international directives.Informed consent is the basic tenet in the contemporary physician-patient relationship. In principle, ECT can only be administered to patients who prior consent to the treatment. In contemporary practice, providing the best medical assistance and respecting the patient’s autonomy are two fundamental principles. However, we often face an ethical dilemma, when severely ill patients, whose insight, the ability for self-determination and decision-making capacity may be impaired, refuse a potential beneficial treatment as ECT.The use of ECT in severe mental illness is still hampered by legal and ethical constraints. A future revision of the law could protect patients from being excluded from a treatment that may change the course of the disease.No significant relationships.


Widely involved in cell signalling, either by direct signal transduction or acting as a second-messenger, calcium regulates a large range of physiological cell functions and processes including regulatory effects on many enzymes and proteins, muscle contraction, neuronal transmission and genesis, cellular motility and growth. Calcium, together with phosphate, also participates in the mineralization of calcified tissues where bones act as calcium storage site, intimately linked with the preservation of calcium balance within the non-bone tissues of the body.3), produced by the proximal tubular cells in the kidney. The regulation of PTH secretion in response to serum calcium variation is monitored by the calcium sensing receptor (CaSR). Although PTH secretion and action has been long known, the activity of the CaSR was characterized recently. Additionally, the role of FGF23, a molecule associated with phosphate metabolism, remains limited in calcium homeostasis  and SLC34A1  have been recognized as the main causes of this clinical entity. The authors have explored the contribution of other genes, normally involved in the renal phosphate transport, in the clinical manifestation of this rare condition, thus providing the knowledge about intriguing complexity of calcium regulation in the kidney.Continuing in the same direction, ORAI1, STIM1) are associated with distinct disease syndromes, channelopathy including amelogenesis imperfecta, immune dysfunction, ectodermal dysplasia, muscle weakness and anhidrosis , focusing on the effects of a worldwide phenomenon caused by excessive amounts of fluoride, and how it can alter the calcium function leading to dental fluorosis.Recent research has focused on understanding the intracellular, transcellular and paracellular pathways of calcium transport. Indeed, several mutations in some of the components of intracellular calcium influx  widely used for post-menopausal osteoporosis through suppression of bone resorption, has demonstrated its efficacy in other rare pathological entities as giant cell tumours, aneurysmatic bone cysts and several other osteolytic diseases , 4, 5. BFAM20A gene which is characterized by ectopic accumulation of calcium phosphate complexes within gingival, pulp and renal tissues (Escorcia et al.in the original article “Pathogenesis of enamel-renal syndrome associated gingival fibromatosis: a proteomic approach”  in particular how proteins of the extra-cellular matrix influence the ectopic calcifications.Finally, little is known about a regulatory system preventing the harmful deposition of ectopic calcium phosphate complexes in soft non-mineralized tissues. The Enamel Renal Syndrome is a rare disorder due loss-of-function mutation in the  tissues . The newVVZ designed and prepared the manuscript, CB designed and reviewed the mansucript. All authors contributed to the article and approved the submitted version.The authors declare 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.


Unfortunately, traditional electrolytes with narrow electrochemical windows fail to compromise the catalysis of high-voltage cathodes and infamous reactivity of the Li metal anode, which serves as a major contributor to detrimental electrochemical performance fading and thus impedes their practical applications. Developing stable electrolytes is vital for the further development of HVLMBs. However, optimization principles, design strategies, and future perspectives for the electrolytes of the HVLMBs have not been summarized in detail. This review first gives a systematical overview of recent progress in the improvement of traditional electrolytes and the design of novel electrolytes for the HVLMBs. Different strategies of conventional electrolyte modification, including high concentration electrolytes and CEI and SEI formation with additives, are covered. Novel electrolytes including fluorinated, ionic-liquid, sulfone, nitrile, and solid-state electrolytes are also outlined. In addition, theoretical studies and advanced characterization methods based on the electrolytes of the HVLMBs are probed to study the internal mechanism for ultrahigh stability at an extreme potential. It also foresees future research directions and perspectives for further development of electrolytes in the HVLMBs.High-voltage lithium metal batteries (HVLMBs) have been arguably regarded as the most prospective solution to ultrahigh-density energy storage devices beyond the reach of current technologies. Electrolyte, the only component inside the HVLMBs in contact with both aggressive cathode and Li anode, is expected to maintain stable electrode/electrolyte interfaces (EEIs) and facilitate reversible Li Through increasing the salt concentration, the ion transfer mechanisms in HCEs and LHCEs are remarkably different as compared with traditional electrolytes. In conventional electrolytes, a big solvation structure is formed through coordination between Li+ and solvent, which seriously decreases Li+ mobility. However, the anion almost does not enter the solvation shell. Therefore, the conventional electrolytes own low Li+ transference numbers (<0.4), leading to abundant anions gathering on the cathode, generating severe concentration polarization and large overpotential dioxathiolane-2,2-dioxide (PDTD), diphenyl disulfide (DPDS), tris borate (TTFEB), and ionanofluid (InF)) and antioxidation solvent  in the mixed electrolyte can individually wet the two electrodes, which facilitates bielectrode affinity. Besides, the complex interface evolution process should be simulated by ab initio molecular dynamics, where electron/ion transport and combination are imitated by the PAW way, all molecular evolution is caught in the NVT ensemble using a Nosé-Hoover thermostat, and the free energy of the system can be obtained by integrating the position-dependent mean constraint forces.Novel Characterization Methods. Accurate characterizations of the electrolyte and interphases are still very difficult nowadays, which is ascribed to their low content, sensitivity to electron radiation and X-ray, and reactivity to water and oxygen. In situ characterization technology can collect signals from electrolyte and interphases during battery operation, which is undoubted of paramount significance for the accurate and deep research of the internal changes of the HVLMBs. The application of cryoelectron microscopy in the HVLMBs is groundbreaking, which minimizes the influence of oxygen and water during the test. Current in situ characterization technologies are mainly based on coin-cell configuration. It is suggested that the progressive characterization should be further integrated with pouch and cylindrical cells.Although valuable progress has been made, several critical issues remain to be resolved for the electrolyte of the practical HVLMBs :Higher


Colorectal cancer (CRC) is a common malignant tumor with a high frequency of recurrence and metastasis, which are the major causes of death in patients. The prerequisite for the invasion and metastasis is the strong mobility of CRC cells to transport far away from the original site to the distant organs and tissues, where they settle down and proliferate. It was reported that the epithelial-mesenchymal transition (EMT) is involved in the occurrence and development of various tumors in the entire process of tumor invasion and metastasis. Therefore, as a vital factor for the biological characteristics of tumor cells, EMT markers may serve as prognostic predictors and potential therapeutic targets in CRC. This article mainly reviews the current status of CRC with metastasis, the studies of EMT, the possible relationship of EMT with CRC, as well as the potential targeted therapy. According to the annual report of the World Health Organization (WHO), CRC is the third highest incidence of malignant cancer worldwide, following lung cancer and breast cancer . AlthougCurrently, CRC treatment may include surgery and non-surgical therapy. Surgery mainly includes new surgical treatment (complete mesocolic excision), abdominal surgery, and palliative surgical treatment . Non-surThe 5-year survival rate of patients with early diagnosed CRC is greater than 90%. However, as a result of no obvious symptoms in the early stage and the lack of sufficient effective diagnosis methods, CRC was commonly diagnosed in the advanced stage. In recent years, with the progress of surgery and treatment, the therapeutic efficacy of CRC patients has greatly improved. Unfortunately, the 5-year survival rate of patients with advanced CRC is still very low, this being less than 12% .As described, tumor invasion and metastasis are determined by the transition of the intrinsic properties of tumor cells, especially closely related to the microenvironment . The tumCRC with distant metastasis, one of the main causes of death, was found in about 20% of patients at their first diagnosis . Even woEMT is a highly conserved and fundamental process that controls morphological changes during development. EMT is a process in which cells lose polarity and break intercellular junctions , thus, the integrity of the basement membrane is destroyed, and cells transform from immobile epithelial cells to mobile mesenchymal cells. The intercellular adhesion ability of interstitial cells is decreased, and the mobility ability is enhanced, which can promote the invasion and metastasis of tumor cells . EMT is E-cadherin and the increase of vimentin can be considered as symbols of the occurrence of EMT. E-cadherins are transmembrane glycoproteins whose extracellular regions can mediate adhesion to neighboring cells [The decrease of ng cells . As a cyng cells .The EMT process involves a synergy of different signal transduction pathways and is also co-regulated by various cytokines and growth factors . In mostDuring tumor development, the EMT process of cell is indispensable, and is also considered to be the primary element of the development and metastasis in CRC . TransfoE-cadherin and many critical genes related to epithelial cell adhesion and differentiation, such as the E-cadherin-related gene CDH1. The NF-κB and PI3K/AKT signaling pathways, which play an important role in the regulation of EMT and tumorigenesis, also serve as important regulators of ZEB1 transcription.It was also found that EMT directly or indirectly downregulated the expression of E-cadherin to regulate the development of CRC, mainly through three core transcription factors: (1) the transcription factors of the Snail zinc finger protein family (Snail1 and Slug); (2) the E-box binding zinc finger protein homology protein family (ZEB1 and ZEB2) ; and (3)E-cadherin downregulation and N-cadherin up-regulation are important steps in most EMT processes. E-cadherin, an essential cell-to-cell adhesion protein, forms epithelial cell sheets and maintains cell quiescence [N-cadherin is generally observed in migrating neurons and mesenchymal cells to enhance motility and spread.After EMT occurred, malignant tumor cells acquire the ability of invasion and metastasis, which can pass through the lymph tract, blood vessel, or body cavity to grow at other sites  where neiescence . In contIn addition to being mobile and aggressive, cells undergoing EMT also gained resistance to drugs. The overexpression of non-coding regions of EMT is sufficient in cells with ineffective protein coding of Snail or ZEB1 to increase treatment resistance . TGF sigE-cadherin and catenin to explore the phenotype transition process and its potential regulatory force during metastasis formation. In their study, MET was first detected in metastasis, and in most cases the same differentiation as the primary tumor occurred. Thus, they proposed a well-differentiated tumor progression model including the epithelial and mesenchymal phenotype transition. EMT as an invasion frontier can induces tumor cell dedifferentiation, subsequent re-differentiation, restoration of epithelial characteristics, and basic survival ability process, suggesting that EMT is a transient process [Brabletz et al.  used E-c process . Under t process . In thisNotably, the conclusion of EMT cannot be fully applied to the invasion and metastasis of CRC. The important marker of EMT, vimentin, is not equally expressed in different cell lines of the same tumor . In detaCRC is a highly heterogeneous disease with a variety of molecular subtypes and genetic variation. Only a small number of patients with CRC metastasis are suitable for surgical treatment for reasons such as too large organ metastasis, too close to large blood vessels, and multiple metastases. For patients with CRC at an advanced stage, novel drugs need to be developed by the study of the metastasis process so that patients can obtain individualized treatment to further improve the survival rate and quality of survival. Targeted therapy is a current research hotspot with the advantages of better efficacy and less adverse effects.The focus on molecular biomarkers has switched from simple prognostic predictors to potential therapeutic targets. More than half of CRC cases exhibited mutations in the KRAS and BRAF genes . Then, dThe significantly different expression of RNA in CRC tumors and normal tissues suggests that RNA may be used as a molecular marker for the non-invasive diagnosis and prognosis of CRC. On the other hand, RNA interference and miRNA silencing provide new directions for the treatment . Some miStudies have shown that miRNA is closely related to the occurrence, invasion, and metastasis of CRC, which regulate the expression of genes as tumor suppressors or inducers. For example, miRNA-375 acts as a tumor suppressor to inhibit the invasion and migration of CRC by inhibiting EMT . In the Although lncRNA is less characterized than small non-coding microRNA , lncRNA N-cadherin and vimentin expression, to inhibit its migration, which sparked new ideas for cancer treatment.The traditional view of gene regulation in biology focuses on the gene-encoded proteins in order of DNA-mRNA-proteins . Most ofMany pathways are involved in the development of CRC , among wDickkopf-1 (DKK1) is an inhibitor of the Wnt signaling pathway that can inhibit CRC progression by inhibiting EMT . Canel eThe invasion and metastasis-related factors are crucial points in CRC treatment and drug development. In the study of the mechanism of basement membrane turnover in malignant CRC progression, Spaderna et al.  proposedThe downregulation of EMT inducers and the subsequent MET are necessary for metastasis and colonization at a large scale . The indIn order to solve a large number of problems derived from the EMT during the invasion and metastasis of CRC, researchers have developed many relevant drugs to regulate the expression of invasion and metastasis-related factors and then inhibit the EMT process, which is also one of the clinical strategies to reduce tumor invasion and metastasis, as well as chemoresistance. Widely used bevacizumab can bind specifically to vascular endothelial growth factor (VEGFR) to inhibit tumor metastasis by reducing microvascular growth. As a current systemic therapy, regorafenib  is an orIn the development of most CRC, the inevitable processes are the invasion and metastasis of tumor cells and EMT. These two processes are complementary with multiple signaling pathways and factors. The EMT-related factors and drugs for targeted therapy of CRC were summarized as


A key area of focus in the field of epigenetics pertains the comprehension of the functional relevance of the epigenetic mechanisms occurring during embryogenesis to shape normal developmental trajectories and adult phenotypes .Danio rerio, commonly known as zebrafish, is an excellent vertebrate model for research purposes in the field of epigenetics .Several evidence showed that key components of the epigenetic machinery specifically control substrates other than chromatin. In this connection, Recently, comparative studies among different organs in different vertebrate species showed that alteration of gene expression profiles is strictly associated with alteration of the epigenetic landscape. Following this line of thought, Komada and Nishimura reviewed published studies associating microglial neuroinflammation with dysregulation of the epigenetic landscape, including changes in DNA methylation and miRNA transcription, using a comparative approach between zebrafish and mammal models.Panara et al. examined how the combination of the latest technologies in epigenetics, such as ATAC-seq, CAGE-seq, ChIP-seq, CUT&RUN and CUT&Tag, are being used in zebrafish to determine chromatin states and cis-regulatory elements that shape the zebrafish vascular network.Finally, in their review article, In conclusion, the collection of high-quality articles included in this Research Topic encompasses different relevant areas of investigation, demonstrating the impact that the zebrafish model has on our understanding of the interplay among epigenetic regulation dynamics and diverse biological processes. From these papers, it is evident that the field is highly active and producing exceptional work that warrants further research.We would like to thank all authors, co-authors, and reviewers who accepted our invitation to contribute to this Research Topic, and we hope that the data and information we conveyed will be beneficial to the scientific community.


Poverty alleviation is a common cause for all human beings. The purpose of this study is to evaluate the efficiency of financial poverty alleviation in 18 cities in Henan, China, and to explore the factors affecting the efficiency of financial poverty alleviation, so as to contribute new knowledge to the cause of poverty alleviation. Based on the relevant data of 18 cities in Henan, using output-oriented DEA model and Tobit regression model with bootstrap method, this study evaluates the efficiency of financial poverty alleviation in various cities in Henan, and explores the determinants of the efficiency of financial poverty alleviation. The results show that the overall poverty alleviation efficiency of Henan is high, and the financial poverty alleviation efficiencies of different cities show distinct heterogeneities. The efficiencies of financial poverty alleviation in Zhengzhou and Luoyang are 1, and there are different spaces for improvement in the efficiency of financial poverty alleviation in other cities. Financial subsidies are the most important positive factors affecting the efficiency of financial poverty alleviation. For every 1% increase in the value of financial subsidies, the poverty alleviation efficiency will increase by 0.213%. The urban-rural dualistic economic structure is negatively correlated with the efficiency of financial poverty alleviation. Every 1% increase in the value of the urban-rural dualistic economic structure will reduce the poverty alleviation efficiency by 0.11%. Industrial structure is positively related to the efficiency of financial poverty alleviation. For every 1% increase in the value of the industrial structure, the poverty alleviation efficiency will increase by 0.072%. The formulation of financial poverty alleviation policies in various regions should be combined with their own characteristics, and promote the efficiency of financial poverty alleviation by strengthening the advantages and making up for the deficiencies. Eradicating poverty is the biggest global challenge facing the world today , 2. In tChina’s poverty alleviation and development is an important part of the global poverty reduction cause, and has received long-term support from the UNDP and other international agencies. The Chinese government has incorporated poverty alleviation and development into the strategic layout of "four comprehensives" and vigorously implemented targeted poverty alleviation. On November 23, 2020, Guizhou announced that the last nine deep poverty-stricken counties would be withdrawn from the poverty-stricken county series, which not only marked the overall poverty eradication of 66 poverty-stricken counties in Guizhou, but also marked the removal of all 832 poverty-stricken counties designated by the Chinese government and the completion of the national poverty eradication goal. In June 2018, an exhibition on China’s achievements in poverty alleviation was held at the UN headquarters under the theme of "Pursuing a Better Life". It is the first time that China has held an exhibition on poverty eradication on the multilateral stage. Ms. Amina Mohammed, the Deputy Secretary General of the UN, believed that over the past few decades, China had made great achievements in poverty reduction and contributed greatly to all mankind. About 800 million people have been lifted out of poverty according to the international poverty line standards . China’sThere are many ways of poverty alleviation, including industrial poverty alleviation , educatiBecause of the heterogeneities of endowments and development levels, there are differences in the efficiency of financial poverty alleviation among regions. Ignoring these differences may have a negative impact on the sustainable development of poverty alleviation and the healthy development of finance. To fill this gap, based on the basic assumption of variable return to scale, this study uses DEA-BCC model to calculate the efficiency of financial poverty alleviation of cities in Henan, and explores the root causes of the differences of the efficiency of financial poverty alleviation, which has important theoretical and practical significances for optimizing the allocation of resources, consolidating the achievements of poverty alleviation, and orderly linking rural revitalization.In recent years, scholars around the world, including China, have conducted extensive research on financial poverty alleviation. Representative achievements mainly include the role, path and mode of financial development in poverty alleviation, and the difficulties, dilemmas and performance of financial poverty alleviation and other areas.Firstly, financial development helps alleviate poverty , and theSecondly, the efficiency of financial poverty alleviation is a hot research topic in academia. The fundamental problem of management is efficiency . ImproviThirdly, the performance of financial poverty alleviation in China varies depending on the poverty alleviation method, subjects and regions, and the sustainability of financial poverty alleviation faces challenges. A study by Tu  using DEReviewing of the above research findings reveals that various new advances have been made on financial poverty alleviation in the past two or three decades , 53, butHenan is a provincial administrative region of China with Zhengzhou as the capital, and is located in the heart part of China. Henan is bounded by 31°23’-36°22’ north latitude and 110° 21’-116°39’ east longitude. It lies in the mid-lower reach of the Yellow River, with an area of 160 thousand square kilometers, and a population of nearly 98.83 million by the end of 2021. Henan is a traditional agricultural province and populous province, but also a growing economy and industry province. Henan is an important comprehensive transportation hub and the center of the flow of people and logistics in China.The terrain is high in the west and low in the east, which consists of plains and basins, mountains, hills and water surfaces. Most regions are located in the warm temperate zone, and the south is trans-subtropical, which belongs to the continental monsoon climate of transition from north subtropical zone to warm temperate zone. Located at the junction of the open coastal areas and the backward western areas, it is the middle zone of China’s economic development from east to west. Henan has 18 prefecture-level cities. The regional GDP of Henan is 5,888.741 billion yuan, and the three industrial structures are 10:41:49.The location of Henan determines that the social development is closely related to many provinces in China, and it also bears the major national strategic arrangements such as The Belt and Road Initiative. However, compared with the eastern coastal areas, the factors of production of Henan have no obvious advantages, and the complicated historical factors have deepened the poverty level of Henan relative to the whole country. At the same time, Henan is a big province of economy, population and agriculture. Henan’s transportation network extends in all directions. Railways, highways and aviation constitute a convenient three-dimensional transportation system, which is an artery of China’s economic and social development. In addition, Henan is facing the situation of slow economic development, weak industrial foundation and fragile ecological environment. Studying the poverty alleviation efficiency in Henan can reflect the poverty alleviation effect with China characteristics. The location of Henan in China and the distribution of 18 cities in Henan are shown in Output-oriented DEA-BCC model. Data Envelopment Analysis (DEA) is a nonparametric programming method for evaluating the effectiveness of decision-making units using multi-input and multi-output, which was first proposed by famous operations researchers A Charnesand Cooper  in 1978.n DMUs to be evaluated, and each DMU has m input-variables and s output-variables, whose input- and output matrices are xj = T and yj = T, and corresponding weight matrix are v = T and u = T respectively, the evaluation equation of each decision-making unit can be obtained as Formula , per capita farm-related loans of rural population (Lp), number of employees (Lb), Balance of pro-poor micro-credit (Bp), and Per capita disposable income of rural residents (Dr)).The above DEA financial poverty alleviation performance evaluation model is affected by various factors, which are difficult to quantify. Comprehensively considering the feasibility of index selection, as well as the availability of data, this study, drawing on existing literature and from the perspective of financial poverty alleviation hardware and software input, selects four indicators namely the number of bank outlets per 10Panel Tobit model. In the process of influencing factor analysis, because the efficiency value calculated by DEA method is selected as the explained variable, the value is 0 and 1. If the least square method is selected for regression, the parameter estimation will be biased and inconsistent. Therefore, in order to better analyze the factors affecting efficiency, this paper selects Tobit model for regression analysis. Tobit model, also known as censored regression model, refers to a class of models in which dependent variables are approximately continuously distributed on positive values, but contain a part of the observed values with positive probabilities of 0. The form of the equation is as shown in Formula .To enhance the certainty of the model regression results, this study uses the bootstrap method, proposed by Efron , to resaEfit = 1) in year t of the ith region is 1, it will be compressed into a point. At this time, the probability distribution of Efit will become a mixed distribution, consisting of a discrete distribution (the case of Efit = 1) and a continuous distribution (the case of Efit<1). Therefore, this study adopts the panel Tobit model with bootstrap method, which takes into account not only the distribution of the dependent variable as a mixed distribution, but also the deterministic issue of the prediction model.In addition, Tobin panel Tobit regression model  is selecEfit). Efficiency refers to the evaluation method of using resources most effectively to meet the given wishes and needs under the given conditions of input and technology. DEA is a linear programming model, expressed as a ratio of outputs to inputs. By comparing the efficiency of a specific decision-making unit with the performance of a group of decision-making units that provide similar services, the efficiency of the specific decision-making unit is maximized. In this process, the units that obtain 100% efficiency are referred to as relatively efficient units, while the other units with efficiency scores below 100% are referred to as inefficient units. In this study, we use the Output-oriented DEA method to construct an efficiency accounting model with four inputs and one output. The specific indicators are shown in Dependent variable. (1) Efficiency of financial poverty alleviation (Independent variables. (1)Dualistic economic structure(Deit). China has a unique urban-rural dualistic economic structure, which has a profound impact on the migration and allocation of financial capital between urban and rural areas. As China’s reform enters a deeper and more difficult period, the lack of regulation in the financial market has led to a lack of financial incentives to help the poor among Chinese regions, which is increasingly reflected through the dualistic economic structure. The urban-rural income ratio, i.e. urban per capita disposable income / rural per capita net income, is used to examine the impact of the dualistic economic structure on financial poverty alleviation.Isit). Henan is located in the plain area with developed agriculture, abundant grain crops. The arable land area of Henan is 6.871 million hectares, ranking second in China. It is China’s major province of grain production and labor export. At the same time, Henan is the birthplace of Chinese civilization, with abundant natural and cultural tourism resources. Therefore, an important way to help the poor through finance in Henan is to adjust the industrial structure according to the unique natural and cultural resources, develop characteristic ecological agriculture and tourism, and transform the green mountains and rivers and precious folk culture into the driving force to eliminate poverty. Hence, industry structure, namely the proportion of gross output value of primary industry and tertiary industry to GDP, is selected to measure the impact of industrial structure on the efficiency of financial poverty alleviation.(2) Industry structure (Fsit). Poverty alleviation is a systematic project, and financial poverty alleviation requires the cooperation of all parties, especially the investment of government in the construction of financial ecology, including rural infrastructure construction, rural financial publicity and education bases, and government financial subsidies for poverty alleviation credit. Agriculture-related financial subsidies are conducive to improving rural infrastructure construction, laying the foundation for the development and growth of local characteristic advantageous industries, providing an effective carrier for financial poverty alleviation, and also alleviating the rejection of financial institutions for poverty alleviation in remote rural poor areas. In addition, sufficient financial subsidies can ensure that financial capital can participate in poverty alleviation without worries and stimulate financial institutions to invest financial capital in poor rural areas. Therefore, the financial subsidies, namely per capita amount of agriculture-related financial subsidies, is chosen to examine the impact of financial subsidies on the efficiency of financial poverty alleviation.(3) Agriculture-related financial subsidies (Control variables. (4) Overall level of financial development (Olit). The overall level of financial development is the basis for financial poverty alleviation in a region. The overall level of financial development, i.e., regional institutional loan balance / regional GDP, is chosen to examine the impact of the overall level of financial development in different regions on the efficiency of financial poverty alleviation.Psit). The payment services for farmers refers to the basic payment and settlement services such as small withdrawal, balance inquiry, cash remittance, transfer and remittance as well as agent payment provided by bank card acquirers to debit card holders by deploying bank card acceptance terminals at designated cooperative merchant service points in rural villages and townships.(5) Per capita payment services points for farmers . The difference in the degree of financial support for farmers directly affects the availability and cost of financial services in poor rural areas, which in turn has a bearing on whether poor farmers can obtain sufficient funds to carry out production to get out of poverty and become rich. The extent of financial benefits to farmers, i.e., the ratio of balance of financial institutions’ agricultural-related loans to GDP of primary industry, is chosen to examine the impact of different degrees of financial support on the efficiency level of financial poverty alleviation performance in different regions.(6) The extent of financial benefits to farmers  was constructed:conit is the three control variables considered in this study . α0 is the constant term. α1, α2, α3, and βn are the coefficients on each variable. εit is the error term. Where Henan is China’s largest agricultural province, as well as a province with a large agricultural population and a huge rural poor population. The poverty-stricken areas and poor population in Henan have weak self-development ability and high rate of return to poverty. Most of the poor people are concentrated in the traditional plain agricultural areas, the Yellow River floodplains, the mountainous areas of western Henan and the old revolutionary areas. These areas are far away from urban centers and main traffic lines, with poor geographical location and natural resource conditions, coupled with the poor education level of the poor, making them over-reliant on agriculture, especially planting.In addition, due to the low degree of commercialization and marketization of agricultural products in these regions, the regionalization trend of poverty is obvious. To carry out targeted poverty alleviation work, the Chinese government has designated 832 national-level poverty-stricken counties on a county-by-county basis based on indicators such as the average annual net income of local residents. As of October 2019, there are 485 national-level poverty-stricken counties in China, 14 of which are in Henan. Among them, Nanyang City accounted for 4 poor counties, 3 in Zhumadian City, 2 in Luoyang City and Puyang City each, and 1 in Pingdingshan City, Sanmenxia City and Xinyang City each.The data in this study come from China Social Statistical Yearbook, Henan Statistical Yearbook, Statistical Bulletin of National Economic and Social Development of Henan, China Financial Statistical Yearbook, Statistical Bulletin of National Economic and Social Development of each city in Henan, website of China Banking Regulatory Commission, Zhengzhou Central Branch of People’s Bank of China, etc. DEA analysis was conducted using Deap2.1 software, and the data were standardized before analysis. Tobit analysis was performed using State software. Descriptive statistics of the data are shown in According to the method and selected indicators provided in Section 3.1, the financial poverty alleviation efficiency of 18 regions in Henan from 2009–2018 was accounted for using DEAP2.1 software, and the results are shown in From the results shown in In addition, from the perspective of the time sequence evolution of financial poverty alleviation efficiency in 18 regions from 2009 to 2018, the financial poverty alleviation efficiency of each region in Henan has a relatively similar trend of change. The efficiency in Zhengzhou and Luoyang is relatively stable, maintaining an efficiency value level of 1 during the sample period, so the two cities can be called stable efficiency cities. The efficiency values of Jiyuan and Hebi cities fluctuated, so the two cities can be called fluctuating efficiency cities. Other cities in the sample period have steadily increased their efficiency values, which can be called stable and improving efficiency cities.In summary, the financial poverty alleviation efficiency in the 18 sample cities from 2009 to 2018 showed a trend of diminishing returns to scale except for Zhengzhou and Luoyang. In terms of input redundancy, the outlets of the financial institution were relatively over-invested but did not obtain the desired effect, indicating that the financial poverty alleviation work in the sample period focused more on the quantitative expansion of rural financial institutions and less on the internal management, technological innovation, rational allocation of financial resources and improvement of financial service quality. Future financial poverty alleviation policies should regulate this situation.This section introduces the results of Tobie regression according to the selected indicators and constructed models in Section 3.2.Pseudo regressions may be caused by sequence instability. To avoid spurious regressions, this study performed unit root tests for selected variables using two methods, namely Harris-Tzavalis  (HT-TestThe results of the unit root tests for each variable are presented in Deit), Industry structure (Isit), and Agriculture-related financial subsidies (Fsit). Model (D) contains three core variables at the same time. Model (E) considers three control variables, i.e., Overall level of financial development (Olit), Per capita Payment service points for farmers (Bait), The extent of financial benefits to farmers (Ebit), based on model (D). The following conclusions can be drawn from the regression results.With annual data for 18 cities from 2009–2018, a panel-Tobit model with bootstrap regression was employed, and the results are given in (1) Dualistic economic structure is one of the determinants of the efficiency of financial poverty alleviation. Urban-rural dualistic economy structure refers to the widely existing asymmetry of urban-rural production and organization in developing countries, and also a socio-economic form in which the backward traditional agricultural sector and modern economy coexist with obvious disparity. The urban-rural dualistic economic structure was gradually formed with the emergence of cities. The process of urban emergence is the process of urban-rural separation and antagonism. The separation of urban and rural areas and the formation of urban-rural dualistic economic structure on this basis is mainly formed by the difference in productivity development between urban and rural areas, and becomes increasingly prominent as this difference expands. Development economics believes that the process of economic development is a process of continuous transformation of economic and social structures.The regression results show that the urban-rural dualistic economy structure is negatively related to financial poverty alleviation performance. More specifically, for every 1% increase in the value of the urban-rural dualistic economy structure, the efficiency of poverty alleviation decreases by 0.11%. The dualistic economic structure leads to a dualistic financial structure, and China is a typical developing country with a dualistic economic structure and a dualistic financial structure. The developed economy and abundant investment and employment opportunities in cities attract a large influx of capital and talent, which also includes a large outflow of highly educated talent from rural areas. This has resulted in a lack of resources for development in rural areas, which is a serious impediment to economic growth and poverty alleviation in rural areas.(2) Industrial structure is a determinant of the efficiency of financial poverty alleviation. As shown in model (E) of More specifically, for every 1% increase in the value of the industrial structure, the efficiency of poverty alleviation will rise by 0.072%, thus enhancing the effectiveness of financial poverty alleviation. For farmers, agriculture is the basis for effectively improving their economic income, and the organic combination of agriculture and tertiary industry is the effective way to improve their poverty status. When carrying out industrial poverty alleviation, financial institutions in each region should combine special agricultural products and green agricultural products with special tertiary industries . Providing employment opportunities for poor farmers through special agriculture and expanding the marketing and sales of agricultural products through special service industry to truly realize the growth of farmers’ income and help poor farmers achieve poverty alleviation.It is worth noting that increasing the proportion of primary industry or reducing the proportion of tertiary industry alone will not necessarily improve the efficiency of the financial sector in poverty alleviation. Simply increasing the share of the primary sector without reliable consumption channels may lead to overcapacity in the primary sector, which will definitely lower the price of agricultural products and may result in the phenomenon of low grain prices hurting farmers. The general consumption of agricultural products is protected by the state price, so it is difficult to create a driving force in poverty alleviation effect. Only specialty agriculture can stimulate consumption desire through the tertiary industry, increase farmers’ income, and realize the improvement of poverty alleviation efficiency.(3) Financial subsidies are the most important affecting factor of financial poverty alleviation efficiency. Model (E) shows that financial subsidies are positively associated with financial poverty alleviation at the 1% level of significance. More specifically, for every 1% increase in the value of financial subsidies, the efficiency of poverty alleviation increases by 0.213%. For poor areas, they do not have the advantage of economic development, coupled with the concentration of poor people, weak industrial strength, and poor infrastructure construction, it is necessary to give full play to the macro-control functions of the government to achieve poverty alleviation. The government’s financial subsidies can play a blood-making function, which helps to explore the advantages of regional resources, adjust the industrial structure and improve the level of infrastructure construction, thus revitalizing the market of poor regions.In addition, financial support for poverty alleviation has a siphon effect, which attracts a large amount of private capital to the poverty alleviation field in addition to the poverty alleviation effect of the financial subsidies themselves. Poverty eradication is a national strategy in China, and the Chinese government has always regarded poverty reduction as an important goal of national development. Since the 1980s, the Chinese government has been carrying out rural poverty alleviation in an organized, planned and large-scale manner, and has formulated and implemented many poverty reduction plans, making poverty alleviation the consensus and action of the whole China. The shortage of funds is an important factor limiting the survival and development of the poor, for which the Chinese government has invested in multiple types and large amounts of subsidies. For example, from 2016 to 2020, the Chinese government has added 20 billion yuan of special central financial funds for poverty alleviation each year for five consecutive years, reaching 146.1 billion yuan in 2020, playing the role of the main channel for precise poverty alleviation funds.Olit), Per capita beneficial agriculture points (Bait), and The extent of financial benefits to farmers (Ebit) affect the efficiency of financial poverty alleviation at 5%, 5%, and 10% significance levels, respectively, and the regression results are as expected. A higher overall level of financial development (Olit) does not only represent a more prosperous economy, but also contains more resources such as talents and equipment to invest in economic development. The impact of per capita beneficial agriculture points (Bait) on the efficiency of financial poverty alleviation is complex, but currently Henan is still at the stage where increasing per capita beneficial agriculture points (Bait) can improve the efficiency of financial poverty alleviation. However, the number of beneficial agriculture points should not be blindly increased, otherwise it may produce negative effects. It is necessary to vigorously increase the extent of financial benefits to farmers(Ebit), which will not only improve the efficiency of financial poverty alleviation, but also enable the majority of poor farmers to obtain well-being.(4) The regression results of the control variables show that three control variables, namely, Overall level of financial development (The robustness test examines of the interpretation ability of evaluation methods and indicators, that is, whether the evaluation methods and indicators still maintain a consistent and stable explanation of the evaluation results when some parameters are changed . The comThis study adopts the DEA method to evaluate the efficiency of financial poverty alleviation in different regions based on the data of 2009–2018 of Henan, a major agricultural province of China. In addition, using the Panel-Tobit model with bootstrap regression, this study explores the influence mechanism of financial poverty alleviation efficiency from the perspectives of dualistic economic structure, industrial structure and financial subsidy, identifing the key determinants of financial poverty alleviation efficiency in different regions. The empirical results are indicative of the following conclusions:First, during the sample period, the efficiency of financial poverty alleviation in Henan has an obvious upward trend, which is the result of the rapid development of China’s social financial industry and the government’s high emphasis on poverty alleviation. In recent years, the Chinese government has continuously highlighted the importance of poverty alleviation, invested a large amount of resources, innovated institutional mechanisms, and implemented the inclusive financial system, gradually formed a scalable and sustainable financial poverty alleviation model with Chinese characteristics.Secondly, there were significant heterogeneities in the efficiency of financial poverty alleviation in different regions. The efficiency values of financial poverty alleviation in Zhengzhou and Luoyang reached 1, indicating that the financial poverty alleviation in the two regions were efficient and achieved Pareto optimality; The financial poverty alleviation projects in the remaining 16 regions still had different degrees of room for progress in financial poverty alleviation; The financial poverty alleviation project in Jiyuan has made remarkable progress; Xuchang, Sanmenxia, Jiaozuo, Xinxiang, Hebi, Puyang and Anyang have made steady progress in the efficiency of financial poverty alleviation; The efficiency of financial poverty alleviation in Zhoukou, Xinyang and Zhumadian was low and needed to be improved. The efficiency of financial poverty alleviation in Zhengzhou and Luoyang was relatively stable, which could be called stable efficiency cities. The efficiency values of Jiyuan and Hebi fluctuated, which could be called fluctuating efficiency cities. The efficiency of financial poverty alleviation in other cities has increased steadily, which can be called efficiency stable cities. It is worth noting that the financial poverty alleviation efficiency of the sample cities in the sample period, except Zhengzhou and Luoyang, showed a decreasing trend of return to scale; Improving the allocation of input resources and thus the efficiency of financial poverty alleviation has become an important way to improve the efficiency of financial poverty alleviation in the future.Thirdly, in terms of the factors affecting the efficiency of financial poverty alleviation, the dualistic economy structure, industrial structure and financial subsidies were all important factors influencing the efficiency of financial poverty alleviation. Among them, the influence of financial subsidies was the most significant, followed by the dualistic economy structure and finally the industrial structure. In addition, financial subsidies can leverage more resources to flow to rural poor areas, which plays a decisive role in financial poverty alleviation in Henan. It is worth noting that the dualistic economic structure between urban and rural areas has a negative impact on the efficiency of financial poverty alleviation, which is universal for developing countries. The improvement of industrial structure and financial subsidies can effectively alleviate the main economic contradictions in poor areas, which is conducive to enhancing the export of products from poor areas and raising the income level of poor people.Based on the findings of this study, the following policy recommendations are proposed to enhance the efficiency of financial poverty alleviation in Henan:Firstly, in view of the significant heterogeneity of financial poverty alleviation efficiency in different regions, a precise mechanism for financial poverty alleviation should be established, e.g. implement differentiated subsidies for different regions and increase financial subsidies for areas with low financial poverty alleviation efficiency. For some deep and contiguous poverty-stricken areas with large poverty population, high incidence of poverty, and great difficulty in getting rid of poverty, it is neither realistic nor effective to adjust the industrial structure and arrange more financial outlets in a short period of time. In these cases, more financial subsidies can be used to improve their financial poverty alleviation efficiency. On the basis of financial subsidies from the central government, cities should also increase their investment in deep poverty areas themselvse to prevent crowding-out effect. Meanwhile, it is necessary to coordinate and integrate the use of agricultural financial subsidies, and closely link the use of funds to poverty alleviation. Implement the requirements of budget performance management, make full use of the dynamic monitoring platform of financial poverty alleviation funds, keep track of the usage of special financial poverty alleviation funds timely, earnestly strengthen the supervision of funds, ensure the quality of poverty alleviation, and establish a long-term mechanism for stable poverty alleviation.Secondly, judging from the basic situation of Henan’s financial poverty alleviation efficiency and its influencing factors, the first is to continue to promote the reform of the dualistic financial system, break down the barriers of the dualistic economy, and attract more talents and enterprises to the countryside. According to the poverty causes and the difference in credit demand of the rural poor, constantly innovate financial poverty alleviation products and service models, and customize financial poverty alleviation measures. The second is to improve the rural industrial structure. As Henan is located in the regional center of the Central Plains, the birthplace of Chinese civilization and rich in historical and cultural resources, it can support the development of local characteristic industries and advantageous industries according to the differences of resource endowment, historical folk culture and industrial development in poverty-stricken areas.It is worth noting that although various financial institutions have made a lot of exploration, negative factors such as the lack of effective collateral for rural credit objects and incomplete credit information still exist. Therefore, the local government should rely on financial support to efficiently optimize and strengthen rural industries; Accelerate the development of new agricultural system and improve the rural financial service system; Hasten the innovation of rural financial products and advance the pertinence of financial services; Give full play to the advantages of financial institutions, form a joint force of rural financial work, and promote the development of rural finance.Thirdly, in addition to the above measures, more measures to improve the efficiency of financial poverty alleviation should be explored according to the influence of the control variables considered in this study. For example, take full advantage of China’s advantages in information infrastructure construction and financial technology, especially under the influence of the epidemic, deeply integrate financial poverty alleviation and Internet Finance, and establish a big data management platform for targeted poverty alleviation, so that limited credit resources and preferential poverty alleviation policies can be reasonably matched with truly poor farmers, optimize the allocation and improve the efficiency of financial poverty alleviation.


Schizophrenia (SZ) is a severe psychiatric disorder which is contributed by both genetic and environmental factors. However, at present, its specific pathogenesis is still not very clear, and there is a lack of objective and reliable biomarkers. Accumulating evidence indicates that long non-coding RNAs (lncRNAs) are involved in the pathophysiology of several psychiatric disorders, including SZ, and hold promise as potential biomarkers and therapeutic targets for psychiatric disorders. In this review, we summarize and discuss the role of lncRNAs in the pathogenesis of SZ and their potential value as biomarkers and therapeutic targets. Schizophrenia (SZ) is a severe psychiatric disorder characterized by the incoordination of mental activities, which involves disorders of sensory perception, thinking, emotion, behavior, and so on . The disLong non-coding RNAs (lncRNAs), a class of RNA transcripts greater than 200 nucleotides in length without protein coding capacity, were once considered as transcriptional noise . Most lnRecent studies have reported that lncRNAs have remarkable spatiotemporal expression profiles and exhibit highly specific expression patterns in the brain , which hRecently, several studies have identified differentially expressed lncRNAs in the peripheral circulating blood and postmortem brain tissues of patients with SZ, and some of them performed bioinformatics analysis of these differentially expressed lncRNAs. Ren et al. found differentially expressed lncRNAs associated with mitochondrial function in peripheral blood of 19 drug-naive early-onset SZ (EOS) patients and 18 healthy control subjects . In addiIn addition to the results of bioinformatics analysis, related basic experimental results further indicated that lncRNAs play an important role in the pathogenesis of SZ, including the involvement of immune function, alternative splicing and expression of genes, etc. . As the Immune dysregulation plays an important role in the pathogenesis of SZ . A meta-Ni et al. found upregulated lncRNA-AC006129.1 expression in the peripheral blood of monozygotic twins discordant for SZ . AC00612Aberrant alternative splicing has been reported in SZ in several genes related to neurodevelopment and neurological function , includiin vivo. MIR137 is located in the same chromosomal region as EU358092, suggesting that EU358092 may regulate MIR137 expression  regions associated with the risk of SZ. Subsequent knockdown and overexpression of DGCR5 in human neural progenitor cells derived from human induced pluripotent stem cells, DGCR5 was found to regulate the expression of several SCZ-related genes . In addivia upregulation of DRDs  within lncRNAs-coding genes involved in the pathogenesis of SZ are associated with the risk of SZ. Rao et al. conducted a two-stage (discovery sample and replication sample) association analysis of eight tag SNPs covering the entire lncRNA MIAT locus in Han Chinese SZ case-control cohorts and found a significant association of rs1894720 of MIAT with paranoid SZ in a Chinese Han population, whereas rs4274 had a weak association . In addiQi et al. found in a Chinese Han population that rs7990916 of linc01080 was significantly associated with the age of onset of SZ patients, and patients with the T allele had an earlier age of onset than CC genotype carriers. In terms of cognitive function, patients with the T allele had lower cognitive scores than CC genotype carriers. It is suggested that rs7990916 of linc01080 may affect the age of onset and cognitive function of patients with SZ . Zhao etIn recent years, to explore whether lncRNAs have potential as biomarkers for SZ, several studies have focused on exploring the expression of lncRNAs in the peripheral circulating blood of patients with SZ . Chen etOthers have explored the diagnostic and prognostic value of nine and four lncRNAs in the plasma and peripheral blood of patients with SZ, respectively. It was found that some of these lncRNAs could serve as biomarkers for the diagnosis and prognosis of SZ , 38. In LncRNAs with key roles in the pathogenesis of SZ may hold promise as potential therapeutic targets. In addition, lncRNAs are lower than proteins in eliciting an immune response in the body, and low expression levels, lack of translation and rapid turnover may contribute to faster therapeutic effects at lower doses . HoweverSiRNAs are double stranded RNA (dsRNA) molecules consisting of 20–25 base pairs that can complement target lncRNAs and then recruit the arginine-containing RNA-induced silencing complex (RISC) to promote lncRNAs degradation. In the study of lncRNAs, siRNAs have been applied in multiple preclinical models to explore the therapeutic implications of targeting lncRNAs in various diseases –58. HoweASOs are a single-stranded DNA oligos, and ASOs are able to interfere with the level of target sequences in many ways, among which one of the most important interference pathways of ASOs is binding to target RNAs, forming a DNA-RNA complex and then recruiting RNase H to degrade RNAs . In receThe CRISPR/Cas9 system is a heritable adaptive immune defense system in prokaryotes. It contains two important components, a single-stranded guide RNA (sgRNA) and the Cas9 endonuclease. The sgRNA complementary to the target sequence guides the Cas9 endonuclease to cleave the specifically targeted DNA . Two DNAFrom the current study, we review and summarize the findings of some lncRNAs that have been implicated in SZ. These lncRNAs may not only play important roles in the pathogenesis of SZ, but also serve as potential biomarkers and therapeutic targets for this disease in the future.Currently, some dysregulated lncRNAs in SZ patients have been identified to play key roles in its pathogenesis. However, the biological functions and mechanisms of lncRNAs in SZ are still preliminary and need to be further explored. This will facilitate further understanding of the pathogenesis of SZ as well as the development of new diagnostic and therapeutic strategies. In addition, genetic mutations in lncRNAs themselves are also involved in the pathogenesis of SZ and increase the risk of SZ, but the specific mechanism needs to be further explored. It is worth noting that aberrant methylation and mutation of lncRNAs genes may be responsible for dysregulated expression of lncRNAs in SZ patients , 81, 82.The current study demonstrated that lncRNAs in peripheral circulating blood could serve as biomarkers for clinical diagnosis and prognosis of SZ. In addition, In addition, recent studies have also found that lncRNAs capture features of SZ tissue more accurately than mRNAs, and machine learning of RNA-seq data from dorsolateral prefrontal cortex (DLPFC) found an average prediction accuracy of 67% for SZ patients based on coding genes and 96% for SZ patients based on lncRNAs . But theSo far, although most studies on therapeutic lncRNAs targeting are still in the preclinical stage , and no In conclusion, lncRNAs are involved in the pathogenesis of SZ and provide a new approach for disease diagnosis and treatment, which is of great clinical research value. However, the current study is still in the preliminary stage, and it deserves further investigation in the future.GW was responsible for reviewing the literature and writing the manuscript. XD, ZL, YD, JL, and XL participated in providing ideas for the article. SL and YX participated in revising the manuscript. All authors contributed to the article and approved the submitted version.