Acquisition of psychomotor skills is of utmost importance for competent preclinical restorative dentistry. Recent advancements in haptic feedback technology have been incorporated into preclinical dental education to augment the conventional phantom head-based training.This systematic review aims to assess the effectiveness of haptic feedback device, Simodont, in improving the skill development and learning outcomes of dental students during their preclinical training.Electronic databases Web of Science, Scopus, PubMed were searched for relevant studies since inception up until March, 2023. Only English language studies that assessed the effectiveness of haptic feedback devices in preclinical dental education were included. We excluded studies that did not use Simodont as the haptic feedback device or did not involve preclinical restorative work. Study quality was assessed using the revised Cochrane risk of bias tool and ROBINS-I. The primary goal of the study is to evaluate the efficacy of Simodont as a complementary training modality for dentistry students.Results from 9 high-quality studies were analyzed and synthesized to evaluate the overall impact of haptic feedback devices on various aspects of preclinical training. The studies were conducted on 826 undergraduate dental students enrolled in various years of their training across dental colleges and universities in different parts of the world. A majority of studies showed some concerns regarding risk of bias. Haptic feedback devices added a new layer to Virtual Reality (VR) through the perception of touch and force feedback. It assisted junior dental students improve their psychomotor skills and movement skills. Instantaneous feedback on the students' performance helped enhance their self-assessment and correction, and also eliminated the subjectivity of evaluation. Data derived from virtual simulators helped stratify dental students and predict their clinical performance, providing an opportunity to tailor the learning process to meet individual diversity in students' expertise.Based on the limited evidence available, Simodont was effective in preclinical training of dental students, offering advantages such as unlimited reproducibility, objective evaluation of preparation by computer assessment, and cost reduction. And further studies are warranted to explore the incorporation of patient's oral environment simulation for better skill training. Dentistry requires the development of precise manual dexterity. In contrast to many other health sciences disciplines, dentistry primarily focuses on practical applications, including the manual administration of restorative treatments. The primary focus and central competence of preclinical operative dentistry is the development of psychomotor abilities among dental students. This aspect receives the majority of curriculum time during the preclinical phase .Students are often instructed on phantom heads in conventional preclinical training. Phantom head or mannequin training is a pedagogical strategy used in dental education that use a simulated human head or mannequin to give students with a safe and genuine environment in which to improve their procedural abilities. These training models are designed to mimic the physical characteristics and anatomy of a human head, including the teeth, gums, and jaw, allowing students to practice procedures such as tooth extraction, filling, and crown preparation. It allows students to practice their motor skills, develop their dexterity and hand–eye coordination, and improve their understanding of dental anatomy and oral physiology . HoweverThe integration of haptic feedback technology in dental education aligns with the evolving educational landscape, emphasizing evidence-based approaches and technology-driven pedagogy. Haptic feedback devices have been proposed as a complementary modality for conventional preclinical training methods, such as working with mannequins or extracted teeth . Haptic Haptics dental suites displays the tooth and the instrument in three-dimensions in true size on screen. The tooth is presented digitally as a series of voxels of varying density . Each poSimodont is a dental training simulator that utilizes haptic technology to provide realistic tactile feedback while performing virtual dental procedures . SimodonFew published studies have systematically examined the effectiveness of preclinical haptic dental training of undergraduate students , 21. ExiThis systematic review was conducted in accordance with the guidelines outlined in the Preferred Reporting for Systematic Reviews and Meta-analysis (PRISMA) statement .Are Simodont haptic feedback devices effective in the clinical training of dental students?”.The focused question was “Inclusion criteria consists of undergraduate dental students from all over the world who are in different stages of their training and come from different dental colleges and universities. In our study, the intervention is the use of haptic feedback devices, like the Simodont haptic training system, for preclinical training of dental students. The comparison group is made up of students who do their preclinical training without using haptic feedback devices. The primary outcome in the study is the development and acquisition of Psychomotor skills/clinical skills/dexterity in dental students during preclinical training. And we considered numerous types of studies, like randomised control studies, controlled clinical trials, and cohort studies.The criteria for inclusion are written in the PICOS format, which stands for Population, Intervention, Comparison, Outcome, and Study type. This framework is used to precisely articulate the study selection criteria and research question in systematic reviews and meta-analyses.(P) Population: Dental students.(I) Intervention: Training using Simodont haptic feedback devices.(C) Control: Phantom head or no control.(O) Outcome: Psychomotor skills/clinical skills/dexterity.(S) Study type: Randomised control studies, controlled clinical trials, cohort studies.Case reports, conference proceedings, systematic reviews, opinion articles, letters to the editor, case reports and articles in languages other than English were excluded.A comprehensive search was conducted on electronic databases including Pubmed, Scopus, and Web of Science. The search query for PubMed included a combination of Medical Subject Headings (MeSH) terms and relevant keywords related to haptic interfaces and technology, dental students, and Simodont. The search strategy for Scopus included a combination of relevant terms related to haptic technology, dental training, and Simodont; whereas for Web of Science, the search query combined the keywords "haptic" and "dental students". The search was limited to papers published in the English language, with no constraints imposed on the start date. The search was performed in March 2023. After executing the search queries, a total of 64 articles were retrieved from PubMed, 3 articles from Scopus, and 17 articles from Web of Science. Details of the search strategy are provided in Table The data extraction form used in this systematic review was developed based key attributes and characteristics that were relevant to our research, including study details , study population , intervention details , and outcome measures . Additionally, we included specific criteria for assessing the risk of bias in the included studies. The process of data extraction from the shortlisted studies was conducted by two reviewers (XX and XX) who worked independently. To ensure the correctness of the extracted data, a third author (XX) validated the results. The pertinent attributes of the studies that were included, such as the names of the authors, the year of publication, the country of origin, the methodological details the sample size, the treatment regimen, and the duration, were manually extracted and recorded in a customised template.The quality of the selected studies was by two reviewers (SP and FL) individually. They assessed the risk of bias for randomized studies using the revised Cochrane Risk of Bias tools for randomised trials (RoB-2) and non-randomized controlled studies using the Risk of Bias in Non-randomised Studies of interventions (ROBINS-I) tool , 33. AnyRoB-2 was used to assess the risk of bias in studies by assessing five domains: bias arising from the randomization process, bias due to deviations from intended interventions, bias due to missing outcome data, bias in the measurement of the outcome, and bias in the selection of reported results. Each domain was evaluated through a set of signaling questions to identify potential sources of bias in the study. The responses to the signaling questions were used to assign a judgment of low, high, or some concerns regarding the risk of bias for each domain.In ROBINS-I, signaling questions focusing on seven domains during pre-intervention, at-intervention, and post-intervention, were used to evaluate the studies. The evaluated domains encompass confounding variables, participant selection, intervention classification, deviations from intended interventions, missing data, outcome measurement, and selection of reported results. For each domain, specific criteria are used to evaluate the risk of bias, and the overall risk of bias is rated as low, moderate, serious, or critical.The GRADE evidence grading system, which is described in Sect. 12.2 of the Cochrane Handbook for Systematic Reviews of Interventions, was used to rate the quality of the evidence for each outcome in the Summary of Findings . One of We found 103 results in our first pass through the database searches. After removing 38 duplicates, the remaining papers were screened on the basis of title and abstract for eligibility. Sixteen full-length papers were obtained for assessment. Citation searching of papers led to an additional four papers. Finally, nine articles published between the years 2017 and 2023 were included in the present review . The PRIMost studies have considerable problems owing to unclear and insufficient reporting. Three out of nine studies showed a high risk of bias, while six studies, including three randomised trials, showed some concerns. Poorly reported items across the studies included sample size calculation and report of losses to follow up, raising apprehension about reliability and validity reflected in the higher risk of bias ratings. A summary of the risk of bias assessment is shown in Figs. Low-certainty evidence implies that Simodont training may have a favourable impact on dental students' psychomotor skill acquisition and development, enhancing motor abilities, manual dexterity, and clinical performance when compared to traditional training. The evidence was downgraded by two steps, due to bias and the fact that majority of the studies were non-randomised. The summary of findings is shown in Table The participant demographics and study settings varied, encompassing undergraduate dental students at different stages of their training and institutions located across different regions of the world. The studies were conducted on undergraduate dental students enrolled on the dentistry programme in their first , 28, 29,ndyear to 2 years later when they performed on patients [The study duration varied from practically no pretraining to an exercise period of fifteen minutes to a longitudinal study where students who completed the first year were followed for 2 years and re-evaluated in the third year , 28, 29.patients .. gave the participants free practice time of 10 min to become acquainted with the device, followed by crown preparation [. allowed participants to practice for three months with a standard amount of force feedback (FFB) to enhance their fine motor skills [The duration and intensity of practice varied across studies, with some studies incorporating short practice sessions while others implemented longer and more extensive practice periods. Hattori et alparation . Farag aparation . De Boerr skills . In anotr skills ..did not mention the version of Simodont used [Most studies used various versions of the Simdont such as the Moog Simodont dental trainer  , 27, 29 ont used .Seven out of the nine studies measured the efficacy of Simodont in restorative work either by operating on the standard caries removal protocol or the cutting of some form of geometric shape , 29, 31.Two studies measured the efficacy of Simodont in crown preparation , 30. The.reported lower scores for students performing tooth preparation using the haptic simulator compared to the conventional method [Nine studies were reviewed to evaluate the heterogeneity of results and to determine if Simodont is a valid tool for preclinical undergraduate education. Out of the nine studies, eight reported that Simodont is a valid tool for training dental students –29, 31, l method .Studies found that the effect of force feedback was important in achieving high precision tasks in dentistry. Students practicing with the effect of force feedback outperformed those practicing without it . Manual Haptic feedback devices have emerged as valuable tools in dental education, offering a three-dimensional virtual reality environment that replicates real dental settings. This controlled environment allows students to practice diverse dental procedures, and their effectiveness in preclinical training has been an ongoing subject of research and discussion , 35, 36.Studies reported that Simodont assisted in the acquisition and retention of fundamental psychomotor abilities needed for performing operative dentistry, particularly when combined with instructor feedback . HoweverThe force feedback feature in haptic technology emerged as a critical aspect, enabling students to achieve the high precision levels necessary for manual dexterity tasks in dentistry . Skills Simodont's advantages could extend beyond the technical aspects, as it has the potential to reduce anxiety levels among dental students. The immediate feedback provided by haptic devices promotes self-assessment, allowing students to identify areas for improvement , 38. MorVincent et al. where haptic simulators could monitor and guide the progression of novices during cavity preparation [Multiple studies have reported that instantaneous feedback on student performance improved self-assessment, adaptation and eliminated subjectivity –42. Thisparation ; though paration . VR simuparation . Howeverparation .. suggested that eight hours of computerized dental simulation training delivered early in the preclinical operative dentistry course is required to improve students' performance [It is recommended that students practice for a sufficient amount of time to ensure transferability of the skill in real-life situations. Urbankova et alformance . Data frformance .A major strength of this review is the comprehensive search strategy, which aimed to identify all relevant studies on virtual Objective Structured Clinical Examination (OSCE) in dental education. The use of two independent reviewers in study selection, data extraction, and quality assessment also enhances the reliability of the findings. However, the review also has several limitations that need to be considered. The number of studies included in the review is relatively small, and the sample sizes of the individual studies are generally low, which may affect the generalizability of the findings. Additionally, the study designs and assessment methods used in the included studies were not standardized, which limits the ability to draw definitive conclusions. The studies included in the review also had a moderate to serious risk of bias, which may affect the validity of the findings. Furthermore, the review only focused on Simodont in dental education, limiting the generalizability of the findings to other haptic training devices. Given the limited availability of data, these results warrant cautious interpretation. A majority of studies were conducted in first world countries with no studies conducted in lower and middle-income countries (LMICs) where where infrastructural resources may be relatively scarce. Hence, larger datasets are required to validate and replicate these findings, which could potentially contribute to the assessment, design, and targeting of haptic interventions.Overall, Simodont has the potential to be an effective and accepted adjunctive training method in dental education, but further research is needed to determine its full impact. Overall, our review addresses the need for dental educators to adopt new and innovative methods of teaching preclinical skills to dental students, and provides valuable insights into the potential benefits of haptic feedback devices in this regard. The findings of this review may inform educators and policymakers about the potential benefits of Simodont haptic feedback devices as a teaching tool for preclinical dental training. The incorporation of Simodont can bridge the gap between preclinical simulation and real-world clinical practice, enhancing the preparation of dental students for patient care. Given the potential benefits and positive outcomes observed in the selected studies, further research, and collaboration between dental educators and Simodont developers are essential to maximize the impact of this technology on dental education and, ultimately, improve patient outcomes –57.This systematic review evaluated the effectiveness of Simodont in the preclinical training of dental students. Based on the limited evidence available, there is low-certainty evidence that Simodont is effective in improving the motor skills, manual dexterity, and clinical performance of dental students. The effect of force feedback feature is important to acquire manual skills and if practised for long enough these skills can be transferred to reality. While acknowledging the limitations in reporting and study designs, the majority of the reviewed studies highlight the value of Simodont in preclinical dental education. However, well-planned high-quality studies with larger sample sizes are required for further evaluation of the assessment methods.


Antibodies represent a relatively mature detection means and serve as therapeutic drug carriers in the clinical diagnosis and treatment of cancer—among which monoclonal antibodies (mAbs) currently occupy a dominant position. However, the emergence and development of small-molecule monodomain antibodies are inevitable due to the many limitations of mAbs, such as their large size, complex structure, and sensitivity to extreme temperature, and tumor microenvironments. Thus, since first discovered in Chondroid fish in 1995, IgNAR has become an alternative therapeutic strategy through which to replace monoclonal antibodies, thus entailing that this novel type of immunoglobulin has received wide attention with respect to clinical diagnoses and tumor therapies. The variable new antigen receptor (VNAR) of IgNAR provides an advantage for the development of new antitumor drugs due to its small size, high stability, high affinity, as well as other structural and functional characteristics. In that respect, a better understanding of the unique characteristics and therapeutic potential of IgNAR/VNAR in clinical and anti-tumor treatment is needed. This article reviews the advantages of its unique biochemical conditions and molecular structure for clinical diagnoses and novel anti-tumor drugs. At the same time, the main advantages of the existing conjugated drugs, which are based on single-domain antibodies, are introduced here, thereby providing new ideas and methods for the development of clinical diagnoses and anti-tumor therapies in the future. Cancer and chronic inflammatory diseases are currently the main indications for antibody therapy; this is due, in part, to the systemic accessibility of the target antigens. To date, the clinically approved therapeutic drug market is still dominated by mAbs of the traditional IgG type, and they continue to show great commercial impact and sustainable market growth . The intAntibody fragments with a smaller molecular weight, which have been shown to have a more uniform distribution than mAbs in tissues, can improve diffusivity and vascular permeability . In diagIn 1989, two variable domains of an antibody heavy chain with antigen-binding abilities were screened out from mice by Ward et al. ; they weStructurally, the conventional antibodies (IgG) are mostly heterodimers of 150–160 kDa, with two heavy chains (VHs) and two light chains (VLs) . By contCertain limitations in monoclonal antibody treatments have existed in the clinical diagnosis and treatment stages. First, mammalian IgG, as a drug, is unstable and orally unachievable; at the same time, it is often blocked when penetrating solid tumors  and crosIn addition to its own limitations, a potential predominance of shark-derived VNAR therapeutic efficacy and response over that of mAbs has been observed in emerging viruses or new acute infectious diseases ,26. The Therefore, due to the limitations of traditional antibodies in clinical applications, developing diagnostic reagents and therapeutic drugs based on new types of antibody molecules is necessary.Newly developed biologics should overcome the inherent limitations of traditional antibodies. Furthermore, they have the ability to quickly cross the tissue barrier while retaining the specificity and affinity of antibodies, making them a meaningful supply for current monoclonal antibody therapies. Meanwhile, the activity of antibody drugs in vivo should be further optimized to increase their efficacy and expand their clinical applications. One of the candidate biological inhibitors with potential is based on the discovery of VNAR, which was found in the antigen-binding variable region of IgNAR in chondroid fish . It has The immunoglobulin neoantigen receptor antibody (IgNAR) from sharks is a heavy-chain protein dimer without associated light chains . The speIn a natural VNAR phage library constructed from six naive nurse sharks , the preVNARs have high chemical and thermal stability. Influenced by the critical evolutionary environment, IgNARs are resistant to chemical denaturants that can be more stable than classical antibodies. This option is attractive for drug delivery, diagnostics, and imaging. It is stable in the blood of sharks that contain 350 mmol/L urea and 1000 mOsm/kg osmotic salt ions. It can also maintain great stability at high temperatures in liquid, lyophilized, and immobilized forms for a long time. Katherine et al. exposed recombinant VNARs to mouse gastric scraping (pH = 5) and intestinal samples (proteinase-rich environment) and showed no evident signs of degradation after 1 h of incubation, thus demonstrating the stability of VNARs in extreme pH environments and their ability to resist proteinase hydrolytic cleavage ,36. In aVNARs are distinct from typical Ig VH and VL domains as well as camelid VHH domains. They share higher structural homology with immunoglobulin VL and T-cell receptor V domains than with immunoglobulin VH . The totIn 2013, on the basis of screening specific VNARs , KovalenGinglymostoma cirratum) [Orectolobus ornatus) [Heterodontus francisci) [Early studies on sdAbs mainly focused on camelids because raising camelids is easier than raising sharks ,47. Contornatus) , and horancisci) , etc., wChiloscyllium plagiosum (white-spotted bamboo shark) is an attractive alternative ideal model to study and obtain antigen-specific VNARs through immunization as it has stable VNAR production, easy breeding conditions, as well as better maneuverability and repeatability of antigen immunization. However, the generation of VNARs is hindered by the high cost and cumbersome care process of large shark breeding. They are difficult to maintain in captivity because of their endangered state, large body size, slow maturity, aggressive temper, and fast movement. In addition, certain cartilaginous fish fail to produce antigen-specific IgNARs, such as the small spotted catshark . CompareBamboo shark is a small, demersal species that seldom bites, has a strong body shape, and matures quickly . It can The production of sdAbs is important for the detection and identification of potential candidate proteins for further drug studies ,39. In r10, from which antibodies with high affinity and those with a specific recognition of tumor treatment-related antigens and viruses could be obtained. Currently, the most popular and broadest approach through which to isolate target antigens for shark VNAR is through phage display . Using tDuan et al.  transforIntact mAbs dominate clinically approved therapeutic drugs. However, due to the inherent characteristics that limit the development of these antibodies, antibody fragments that are smaller and easier to permeate tissues have been developed for in vivo imaging and clinical treatments . In termWhen combined with traditional antibodies, VNARs have high affinity and clearly high tissue penetration. Based on its unique structure, the potential of VNAR technology as a powerful “engine” for novel drug discovery is evident. The small size and unique topology of shark VNARs provide an opportunity through which to penetrate tissues and bind to novel and hidden targets that are difficult to access through the larger spherical binding domains that are currently available. VNARs demonstrate a surprising ability for specific and high-affinity binding to diverse antigens by using just two variable domains per molecule. VNARs have evident advantages in developing highly specific and effective drugs against specific targets given their ability and versatility ; they alRapid distribution and elimination are desirable features of disease-specific biologics ; as suchDue to the large number of recombinant VNAR proteins that can be expressed in prokaryotes and the low cost of preparation, although there are still many challenges for the development of VNAR-based drugs, such as the need for humanization of the sequence and the short half-life of the vector, the price is much lower than that of traditional antibody drugs, and this serves as the basis for their widespread use. Increasing numbers of next-generation antibodies and novel scaffolds have been introduced into the research of biotechnology and biopharmaceutical companies to overcome the limitations of traditional antibodies, as well as provide additional opportunities for new disease-targeting and alternative drug delivery methods. The advantages of VNARs, such as their stable quality, low production cost, easy storage, and long half-life, are beneficial to the efficacy of their clinical applications. Ongoing preclinical developments, such as immunoassay , medicalChiloscyllium plagiosum [VNARs may be an effective neutralizing agent against mutated virus strains based on their ability to bind highly variable influenza viruses (which cause great immunogenicity). In 2021, Gauhar et al.  reportedlagiosum  due to tlagiosum . The intlagiosum . These rCurrently, three companies in the world are engaged in the research and development of shark antibody drugs: Ossianix, Elasmogen, and AdAlta. Only Ad-214 from AdAlta has been used in clinical practice thus far . Ad-214 When antibodies are used as enzyme inhibitors, they can inhibit enzyme activity by changing the conformation of the active site(s) or directly binding to the active site(s) of the enzyme . BurgessA well-defined high tissue penetration was verified in VNAR treatment. Drug delivery across the BBB remains an important barrier for the development of biopharmaceuticals with therapeutic effects on the central nervous system. On the basis of the small size of VNARs and their extended CDR3 loop, Pawel et al.  screenedGiven the special structure of the corneas, Kocaleva et al.  administThe success of these applications showed that VNARs are druggable after perfect design and adjustment and that they satisfy the requirements of drug discovery and development, thus ensuring that VNARs could become a valuable platform for various medical treatments.Antibody drugs are mostly used in the treatment of cancers, autoimmune diseases, as well as infectious diseases, cardiovascular diseases, and organ transplant rejection. Antibody drugs are widely used in clinical treatment as targeted drugs; in addition, they account for a large proportion of the new FDA-approved drugs. Cancers and chronic inflammatory diseases are currently the main indications for antibody therapy, and this is in part due to the systemic accessibility of the target antigens . As an eThe main limitation to the wide clinical use of ADCs is their non-uniform distribution in solid tumors. Another major factor affecting the efficacy of ADCs is the heterogeneity of their intratumoral distribution . In addiTorchia et al.  chemicalMeanwhile, a proof-of-concept study based on the generation of VNAR antibody–drug conjugates has been reported. The high specificity of VNAR antibodies provides a therapeutic window for the eradication of lymphoma B cells, and future experiments may result in VNAR-Fc antibody formats with a higher binding valence. Treatment with VNARs has many advantages over monoclonal antibodies . VNARs hAs potential chemotherapeutic agents, sdAds may passively target and penetrate tumor tissue with their excellent permeability, all the while their clearance by the lymphatic system is reduced. Adam et al.  proposedIn 2017, Ubah et al.  immunizeFavorable therapeutic effects have been achieved in hematological malignancies since the introduction of chimeric antigen receptor (CAR) T cell therapy in this field. However, solid tumors remain a challenge due to the lack of appropriate antigen targets and immunosuppressive tumor microenvironments.VNARs can overcome the disadvantages of traditional IgG drugs and effectively penetrate solid tumors with the help of their small size and high antigen-binding affinity. The PD-L1 immune pathway is crucial for tumor cells to escape from immune surveillance in the human body. Broos  stated, Dan Li et al.  construcThe progress of research into sdAbs as valuable drug conjugates is summarized in this review. The structural characteristics and potential applications in clinical tests, as well as the anti-tumor drugs, were highlighted to reveal the value of sdAbs as biomedical reagents. Biological agents predominate the market for therapeutic drugs, and innovation drives the development of the next generation of medical products. The development of therapeutic antibodies has focused on smaller, more stable, and more flexible products to improve the efficacy of the drugs and expand their clinical use. The structure of shark sdAbs brings about specific functions for these molecules, including a small size, excellent thermal stability, penetration into tumor epitopes, and a low production cost. These advantages will hopefully lead to the development of highly specific, stable, and effective drugs in the future . These cShark-derived sdAbs and their conjugates can still be improved in terms of their stability, expression level, protease resistance, and the aggregation caused by synthetic linkers. Small-size proteins are usually associated with short serum half-lives. Generally, any molecules smaller than the threshold for glomerular filtration (approximately 60 kDa) will be rapidly eliminated from the body. Fusion to the Fc domain can solve this problem. However, if a small size is advantageous, then the addition of several extra domains  would counteract the advantage of a small size. Although a large number of preclinical studies on shark-derived sdAbs have been conducted, their progress into clinical use has been slow. Considering the great evolutionary distance between cartilaginous fishes and humans, potential immunogenicity should be considered prior to clinical application. However, the feasibility of humanizing VNAR domains to prevent xenoreactivity has been demonstrated in previous studies . AlthougThis study also indicated that bamboo shark, as a model organism for the preparation of high-affinity VNARs, may contribute to paving the path for VNAR application as a clinical drug candidate. However, in the process of IgNAR preparation, identifying methods to dynamically monitor IgNARs in sharks for observation and recording is still necessary.The main direction of antibody development at present is to reduce the size and complexity of antibodies while maintaining their affinity and selectivity for their targets. This approach includes natural antibodies (such as single-domain antibodies), antibody-like domains, and scaffolds. sdAbs should still be modified and clinically verified for their aspects, such as with respect to their immunogenicity and functionalization, even though these antibodies can efficiently expand potential drug targets due to their unique structural characteristics . Envafol


The fear conditioning task in rodents serves as a valuable tool for studying learning and memory, as well as enhancing our understanding of post-traumatic stress disorder (PTSD) and other stress-related disorders. By utilizing controlled experimental paradigms, traumatic experiences can be mimicked in rodents, allowing investigation of underlying neurobiological mechanisms. During the fear conditioning task, animals learn to associate a neutral stimulus, such as a tone or a context, with an aversive, unconditioned stimulus, most often a mild foot shock. Then, the previously neutral stimulus becomes conditioned stimulus, and when the animals are re-exposed to it, they show fear response. The fear response is most commonly measured as the percentage of time spent freezing, which is defined as the time the animal spends motionless, except for cardiac and respiratory movement.While several brain regions are involved in processing and storing of these associative episodic-like memories, the spatial attributes rely primarily on the hippocampus, while emotional valence depends mostly on the amygdala Maren, . UnderstHartner and Schrader's article explores the effects of stress hormones, norepinephrine (NE), and glucocorticoids on inhibitory signaling in the Layer 2 of medial entorhinal cortex (MEC_LII) circuitry. The authors show the ability of NE to increase the frequency and amplitude of inhibitory inputs to the MEC, an effect that is cell-specific, mediated by the activation α1 adrenergic receptors, and modulated by co-administration of corticosteroids. This study sheds light on how stress influences underlying mechanisms of fear memory formation by demonstrating the ability of stress hormones to alter inhibitory synaptic inputs within the MEC-LII.Hippocampal formation and entorhinal cortex show a high degree of interconnectivity and functional interaction between the hippocampus and MEC is crucial for spatial memory processing  of the amygdala. As the amygdala plays a crucial role in fear conditioning  or conditioning context on its own, without the previously predictive unconditioned stimulus, such as mild foot shock. This leads to the formation of a new, inhibitory memory  and the ventral tegmental area (VTA) are key regions involved in emotional processing and assignment of valence (Namburi et al., The aim of this Research Topic is to offer New Insights into Synaptic Plasticity in Fear Conditioning. While previous studies on fear conditioning have mostly focused on examining the triad of brain regions crucial for fear conditioning -hippocampus, amygdala, and medial prefrontal cortex-, the articles in this Research Topic broaden the scope by investigating circuits and molecular mechanisms of other brain regions that play important role in fear conditioning and emotion processing. Additionally, this Research Topic is putting a spotlight on the inhibitory transmission, and the inhibition/excitation balance. The inhibitory transmission has been historically understudied. Albeit interneurons are fewer in number in areas crucial for fear conditioning they are not passive gain regulators but exert their robust inhibition via intricate network of connections on the excitatory projection neurons, thus shaping the network activity (Lucas and Clem, ACr: Writing—original draft. ACi: Writing—review and editing. AY: Writing—original draft.


Guzmania species, Wallisia cyanea, Tillandsia streptopylla (Tillandsieae) and Catopsis morreniana (Catopsideae). It is absent in Vriesea guttata (Vrieseeae), Racinaea crispa and various Tillandsia species (Tillandsieae). Secretion is produced by peltate trichomes on the adaxial surface of young bracts and comprises hydrophilic and lipophilic substances. Bract anatomy revealed an internal mucilage-secreting tissue with wide distribution within the subtribe Vrieseinae. Our results point to a broad occurrence of secretion associated with bracteal scales in inflorescences of Tillandsioideae. Secretory function is strongly related to trichomes of the adaxial surface, whereas the indumentum of the abaxial side is lacking or likely associated with water absorption; the latter case is especially related to small, xeric plants. Exudates might engage in colleter-like roles, protecting against desiccation, high-radiation and herbivores. Directions for future research are presented.Bromeliaceae display many water-use strategies, from leaf impounding tanks to Crassulacean acid metabolism (CAM) photosynthesis and absorbing trichomes. Recent studies show that trichomes in inflorescences of bromeliads can exude viscous secretions, protecting against various stresses, including excessive water loss. In light of this, and considering the knowledge gap regarding inflorescence trichomes in bromeliads, we aimed to investigate the presence, source and chemical nature of inflorescence secretions in species of the Tillandsioideae (Bromeliaceae) and to describe the anatomy of their floral bracts focusing on trichome structure and position. We conducted a prospection of secretory activity and anatomy in floral bracts in 52 species of Tillandsioideae and 1 early divergent Bromeliaceae species. We used histochemical tests to investigate the presence and nature of secretion combined with standard light microscopy methods. Secretion appears in all studied species of tribe Vrieseeae, in  Peltate trichomes are a typical feature of bromeliads. These scale-like appendages account for the establishment of some of the most extreme epiphytic life forms among vascular plants. The investigation of their secretory function in the floral bracts of several bromeliad species revealed that their newly discovered ability to synthesize and release mucilage, oils or resins is an overlooked phenomenon that might be widespread. While further studies are needed, the structure and position of the trichomes, the chemical nature of their secretion and other anatomical features of the bracts produce new insights into the ecology, evolution and systematics of bromeliads. Water is the major limiting resource for growth in land plants . It is rTillandsia species and water-impounding taxa. Trichomes of the reproductive organs, in turn, are much less understood.Among these adaptative features, the typical peltate trichomes of bromeliads, also called scales, are considered a key trait due to their capacity for efficient water absorption . Our main goals were to investigate the presence and source of secretion in inflorescences, including the general nature of the exudate, and to describe the anatomy of floral bracts in the studied species, focusing on trichome structure and position. We specifically tested the following hypotheses: (a) secretion by inflorescence bracts is widespread within Tillandsioideae, potentially comprising a synapomorphy of the subfamily; (b) secretion, when present, is produced by peltate trichomes; (c) the secretions are mainly mucilaginous in nature, the presence of lipophilic secretions in Vriesea species . We sampled 52 species of Tillandsioideae (12 genera) and one early-divergent bromeliad species, B. reducta , as W. cyanea Barfuss & W. Till  and Jardim Botânico de Belo Horizonte . Additionally,  W. Till .Samples were collected from inflorescences at an early stage of flowering and divided into two categories, following Inflorescences at an early stage of flowering were screened for the presence of secretion both in the field and in the laboratory with a stereomicroscope . We searched for the presence of secretion outside the overall inflorescence and in the interior  of floral bracts, recording the aspect , and overall abundancy . Additionally, secretion drops were deposited onto glass slides and left to dry; we observed whether this secretion changed viscosity over time and if residual material, such as solid films and gums, was left on the slide. The dried product was also stained with Ruthenium Red  were carefully scrapped  were obtained, fixed under a slight vacuum in Karnovsky solution  often exhibiting a larger, dome-shaped uppermost cell (i.e. dome cell), and a distal flattened shield . The shipendages .Vriesea species, as well as S. goniorachis, showed trichomes with relatively well-organized, symmetrical shields in which wing cells were juxtaposed and roughly the same size, ending in a round tip that rendered a circular outline to the trichomes . In Alcantarea spp., trichomes were numerous, often juxtaposed in groups of two or more . Secretions tested positive for mucilage in all cases . The presence of dense cells and conspicuous nuclei, as observed in young trichomes of the adaxial bract surface, indicates their secretory function , 2000. TTillandsia and V. poenulata, the absence of young developing trichomes is explained by a particularly early and rapid development.The remarkable distinctions observed between trichomes of young and mature bracts  indicate that the secretory activity is limited to young trichomes in bracts not fully expanded , and W. cyanea (Tillandsieae) . V. aff. bituminosa and V. stricta presented scales more closely related to type B trichomes , possibly representing a transformation in this character  . We beliharacter .Jagrantia, Josemania, Lutheria, Zizkaea) and the unresolved phylogeny of the Cipuropsis-Mezobromelia Complex  or present type C features . This differential distribution of trichomes suggests that distinctive selective pressures have acted on the adaxial and abaxial surfaces of floral bracts in Tillandsioideae species. At least in tribe Vrieseeae, and in part of the Tillandsieae , these pressures seem to have favoured a glandular indumentum in the adaxial surface of floral bracts, perhaps associated with a more mesic, tank-forming habit. Within the remaining Tillandsieae, our sampling does not allow any meaningful insight regarding possible trends or patterns. The presence of secretion in T. streptophylla and its absence in the other sampled tillandsias is unclear. It is likely that the lack of glandular trichomes in the underside of most atmospheric species is related to a reduction in the size of the inflorescence  allied to additional means of water acquisition and conservation ; see Tillandsia streptophylla possess considerably larger and branched inflorescences in which the flowering period extends to a much broader time span. Nonetheless, future efforts with a broader sampling of Tillandsia are needed to clarify these observations further.Regarding the position of the trichomes, our results show that trichomes of the adaxial surface are strongly related to secretory function. In contrast, the indumentum in the underside of bracts is either scarce  cannot be interpreted functionally in the same manner as the secretion in the remaining species. An inconspicuous coverage of secretion is likely not effective in the protective roles discussed above. Instead, the mucilage secretion observed in C. morreniana and T. streptophylla might be exclusively related to the putative absorptive capacity of the trichomes in these species, providing a highly hygroscopic surface associated with the scales.The distinct secretory activity observed in V. fenestralis, V. stricta; see Regarding the aspect and abundance of the secretion in the studied species, exudates with sticky, greasy and oily aspects are usually related to the presence of considerable amounts of lipophilic compounds, such as lipids or even terpenes  included in this complex share the same feature. Nonetheless, the evolution of this trait needs further scrutiny since it also appears in non-related species such as C. morreniana, W. cyanea and T. streptophylla.Floral bracts of Tillandsioideae species seem to share several features with the overall structure of bromeliads leaves, mostly notably xeric traits such as sclerotic epidermis and the presence of hypodermis, which is often differentiated in a water-storage tissue . Conversely, mesic species often present such characteristics .Our results suggest that the presence of a sclerotic hypodermis might be more associated with a structural function  than a xeric trait . Particularly, the presence of non-secretory trichomes in the outgroup species B. reducta and the evidence of secretion by bract trichomes in the early diverging genus Catopsis, corroborates this view. Nevertheless, the prospection of secretion in inflorescences of this subfamily is a challenging enterprise, and a broader sampling, including additional species of Brochinnia, Racinea and Tillandsia, as well as members of the monotypic tribe Glomeropitcairnieae, is necessary to corroborate this proposition further. In V. guttata, the absence of secretion suggests an autapomorphic trait by reversal, at least within Vriesea. In R. crispa, besides the possible effects of size reduction previously discussed, the presence of stomata on the adaxial surface of bracts might indicate that distinctive selective pressures acted on the bracts in this species, perhaps also accounting for the lack of secretion.As previously stated, secretion in species of all major groups of Tillandsioideae suggests that the occurrence of secretory scales in inflorescences of this subfamily is not uncommon. In fact, we believe that this feature might comprise an ancestral trait of tillandsioid bromeliads, which then suffered reversals in A. blanchetiana . Moreover, G. chrysostachys share type B trichomes with M. pleiosticha and V. aff. rubra (Cipuropsis-Mezobromelia Complex) and the presence of an adaxial sclerotic layer with V. aff rubra.Our results seem to corroborate the finding of W. cyanea from Tillandsia as proposed by Tillandsia species by the presence of abundant secretion in the inflorescences and trichomes with type A features predominantly in the adaxial surface of the bracts.We also found evidence that further corroborates the separation of Our results show that while the vegetative axis of bromeliads is relatively well-known, our knowledge of the anatomy, ecophysiology and evolution of the reproductive axis needs further scrutiny. Some points for future research in this area include:broader analysis of the secretory capacity of scales in bromeliad inflorescences. This includes broader sampling within Tillandsioideae, but also in the remaining subfamilies. The presence of secretory scales in A. blanchetiana ((a) chetiana  might bedetailed accounts of the anatomy and development of the ‘mucilaginous tissue’. A better understanding of this unusual secretory tissue is strongly encouraged. Efforts in this direction should focus on both bracts and sepals. Further studies on the development, structure and position of internal mucilage-secreting tissues in bromeliad reproductive organs are strongly encouraged, as they could provide insights into the taxonomy, evolution and ecology of the group.(b) experimental evidence on the modes of water acquisition by the reproductive axis. While an extensive amount of research has been done on strategies to obtain and use water by the vegetative shoot of bromeliads, virtually nothing is known about the modes of acquisition of water and nutrients in the reproductive axis of bromeliads that lack functional roots or depend heavily on stored water.(c) relationship between mucilaginous secretions and water balance. Due to the hygroscopic characteristics of mucilage, the secretion produced by the trichomes, the ‘mucilaginous tissue’ and other internal mucilage-secreting structures could be associated with mechanisms of water acquisition and allocation in the inflorescences of some bromeliads.(d) relationships between lipophilic secretions, protection against desiccation, high-radiance, herbivory and indirect nutrient supply. The ability of lipophilic secretions to avoid excessive transpiration, provide insulation and protect against herbivores needs further evaluation. Likewise, the involvement of these secretions in an indirect input of nutrients  Vriesea , the secretion is resinous  exudates. At least in some members of Bract anatomy revealed the presence of a distinct ‘mucilaginous tissue’ in the midrib portion. This feature is largely unknown in bromeliads, and we present evidence of a widespread occurrence within subtribe Vrieseinae, comprising a putative synapomorphy.


Q was set for the predicted and true values of pesticide residue concentrations, then combined with the K-means++ algorithm to assess the quality of wheat during storage. The results of the study demonstrate that the Autoformer model achieved the optimal prediction results and the smallest error values. The mean absolute error (MAE) and the other four error values are 0.11017, 0.01358, 0.04681, 0.11654, and 0.13005. The findings offer technical assistance and a scientific foundation for enhancing the quality of stored wheat.Proper grain storage plays a critical role in maintaining food quality. Among a variety of grains, wheat has emerged as one of the most important grain reserves globally due to its short growing period, high yield, and storage resistance. To improve the quality assessment of wheat during storage, this study collected and analyzed monitoring data from more than 20 regions in China, including information on storage environmental parameters and changes in wheat pesticide residue concentrations. Based on these factors, an Autoformer-based model was developed to predict the changes in wheat pesticide residue concentrations during storage. A comprehensive wheat quality assessment index  With an annual global yield of over 700 million tonnes, wheat is the primary grain crop grown in temperate regions , and onePesticides such as dimethoate  and chloFaced with such a status quo, there is an increasing demand from the public for higher quality and quantity of cereal grains , resulti2 concentration and the number of harmful insects in grain storage to predict the grain quality conditions in Indian grain silos. Duan et al. [Recently, time-series analysis  has beenn et al.  and Yangn et al.  used then et al.  used an After a comprehensive review of the existing literature, this study presents a novel proposal that the concentration of pesticide residues in wheat storage is influenced by temperature and humidity during storage, which further affects the quality of wheat, so we assess the quality of wheat at different time points by evaluating the concentration of pesticide residues in wheat during storage. In order to complete this work, we first constructed an Autoformer-based model to predict pesticide residue changes in wheat during storage. Then a K-means++-based model was constructed for the quality assessment grading of wheat during storage. Between the two models mentioned above, the Autoformer model has advantages over other prediction models because the degradation of pesticide residues in wheat is a long process and the Autoformer model is also more suitable for dealing with long time-series data. In comparison, K-means++ has better classification results and algorithmic stability. By conducting comparative experiments, we found that the model in this study outperforms other similar models. The results have an important reference value for helping the technical managers of grain storage to adjust the settings of optimal storage conditions for wheat grain storage according to time points, promote the reduction rate of pesticide residues in wheat, and reduce the quality loss of stored wheat.This study sourced its wheat storage monitoring data from five primary wheat-producing regions in China , covering several provinces and more than twenty regions. Wheat was stored in 10 shallow round silos. We collected samples every day during the storage period, which were obtained by dividing the cuttings into three layers and subdividing each layer into a total of 13 sampling points. After mixing the samples from the entire bin, we obtained the final samples for analysis, which included a total of 2655 data points for the quality of wheat samples. In addition, the specific environmental parameters affecting the concentration of pesticide residues in wheat during storage in this study were storage temperature and humidity, and the experimental data involved storage humidities of 54%, 65%, and 75% and storage temperatures of 10 °C, 25 °C, and 35 °C. The Maximum Residue Limits of Pesticides in Food of the National Food Safety Standard  specifieThe experimental platform in this research utilized the PyTorch  deep leaIn this paper, we construct a prediction model based on Autoformer  to prediThe series decomposition block uses the traditional decomposition operation to flatten the period term and emphasize the trend term based on the sliding average idea for the pesticide residue data in wheat. The model alternately performs prediction result optimization and series decomposition, i.e., gradually separating trend and period terms from hidden variables to achieve progressive decomposition.In the above equations, Encoder: the input of Encoder will be the known raw time-series data. After this, the output result consists of two components, trend term and seasonal term, followed by gradual elimination of the trend term to obtain the period term In the above equation, “Decoder: the Decoder input contains two parts, the trend part after sequence decomposition and other remaining parts. The Decoder part uses a two-way processing mode, a multi-stacked auto-correlation mechanism block for the seasonal part and a cumulative mechanism structure for the trend part accumulation, respectively. The upper branch processes the seasonal part, and the lower branch processes the trend-cyclical part. The upper branch first uses auto-correlation to extract the temporal dependencies inherent in the future predicted states, then uses encoder–decoder auto-correlation to extract information from the historical series with higher-order temporal dependencies from the encoder output, and finally passes through the Feed Forward layer. The lower branch gradually extracts the trend information from the predicted hidden variables, and the outputs of each sub-layer of the upper branch are summed together using the weighted addition method. The specific equation is shown as follows.Autoformer’s core auto-correlation mechanism, which is key to discovering period-based dependencies by calculating sequence auto-correlation coefficients, consists of period-based dependencies and time-delay aggregation. The dependence of the period in the auto-correlation mechanism is found from the efficient computation of the auto-correlation coefficients, as shown in In the above equation, Next, time-delay aggregation of auto-correlation first aligns the subsequences with the same phase based on the estimated cycle length using the Q was constructed in this study, which integrates the present and predicted pesticide residue concentrations of wheat; the equation of the evaluation index Q is shown in (15).In order to better assess the quality of stored wheat during storage, a comprehensive evaluation index In the formula, During the study, since the wheat quality data were small-sample data with little noise, the clustering method K-means++  was used(1)Randomly select a point from S as the initial clustering center (2)For each data point x in S, calculate the minimum distance between each point and the currently existing clustering center, denoted by (3)Select the next cluster center (4)Iterate step (2) and step (3) up to k clustering centers.(5)Execute the standard K-means algorithm to allocate data points to the closest cluster centers and modify the locations of the cluster centers until convergence.Given dataset S with N data points, let k be the desired number of clusters. The algorithm outputs a set of k centroids {The evaluation of wheat quality relies on analyzing the changes in pesticide residue levels as wheat is exposed to different environmental conditions during storage. Hence, the ability to accurately predict changes in pesticide residues will affect the accuracy of wheat quality assessment.Five assessment criteria, including MAE, mean squared error (MSE), mean absolute percentage error (MAPE), root-mean-square error (RMSE), and symmetric mean absolute percentage error (SMAPE), were employed in this study to gauge the fluctuations in pesticide residue levels in wheat over the course of storage. These measures were computed using the following formulae:In the above formulae, For the clustering results acquired through the K-means++ algorithm, we used the silhouette coefficient (SC)  and the The silhouette coefficient is calculated as follows:In Equation (21), N represents the quantity of training samples, The Davies–Bouldin Index is calculated as follows:In Equation (22), According to the characteristics of pesticide residue degradation in the process of grain storage, this study used a 90-day period to collect experimental data on six dimensions of information: time, temperature, humidity, and concentrations of dimethoate, chlorpyrifos, and chlorpyrifos-methyl. The concentrations of these pesticides were used as predictors, while moisture content and temperature were treated as control variables. As shown in the figures, we can initially see that all three types of pesticide residue in wheat gradually degraded with time. The higher the temperature, the faster the concentration of pesticide residues decreased under the same storage humidity; also, the higher the humidity, the faster the concentration of pesticide residues decreased under the same storage temperature. However, comprehensively comparing the three types of pesticide residue, the degradation rates of dimethoate and chlorpyrifos-methyl were the fastest and the most affected by temperature; humidity had a facilitating effect on the degradation rate of two pesticides, but the effect was not significant enough. In addition, the degradation rate of chlorpyrifos was less affected by both temperature and humidity. From the results of the dataset, it can be seen that the optimum storage humidity for pesticide residue degradation is 75%, and the optimum temperature is 35 °C.To demonstrate the effectiveness of the prediction model in the research, the Autoformer model was compared with several existing widely used neural network prediction models. For the same wheat pesticide residue quality assessment dataset, RNN, LSTM, and Transformer were used in this study to conduct comparison experiments with Autoformer. Five model evaluation metrics, MAE, MSE, MAPE, RMSE, and SMAPE, were also employed to estimate the prediction capabilities. In The Autoformer model achieved MAE, MSE, MAPE, RMSE, and SMAPE values of 0.11017, 0.01358, 0.04681, 0.11654, and 0.13005, respectively, and as can be seen from the previous section, the larger the value of the evaluation index of the prediction model, the larger the error of the prediction. It is also evident from the results in Q values of individual samples of wheat were used as the clustering feature input to the model. While applying the K-means++ and conventional K-means algorithms for wheat quality assessment of three pesticide residues in wheat storage grains, in order for the experiments to be more useful, two clustering evaluation indexes SC and DBI were used in this paper to evaluate their clustering results reasonably, while conducting experiments. The findings are presented in According to the results of the prediction of pesticide residue changes based on Autoformer, for further work on wheat quality assessment, the daily evaluation index As shown in Comparing the evaluation indexes of the two clustering models together, we can easily see that for the wheat quality assessment dataset, despite the use of different clustering algorithms, both have the best results in terms of classification results when there are three clusters, i.e., classifying wheat quality into three levels. After comparing the evaluation metrics for both the SC and DBI with three clusters, according to the line graphs, we concluded that the K-means++ clustering model performed better than K-means for wheat quality assessment during storage. Therefore, K-means++ was used as the clustering model for wheat quality assessment during storage in this study, and in this way the wheat quality variation dataset was divided into three categories according to the K-means++ algorithm model. The wheat quality data of different categories corresponded to the corresponding quality levels, and the two-dimensional clustering centers of the three pesticide residue concentrations in wheat and the results of the number of samples in each class are shown in As shown in Dimethoate, chlorpyrifos, and chlorpyrifos-methyl were used as the three most common pesticide residues in cereals to measure the quality assessment of wheat. The results suggested that all three pesticide residues degraded gradually over time, and the rate of degradation became faster with increasing storage temperature and humidity. Of these, temperature is the main element affecting the degradation of pesticide residues in wheat. Moreover, the concentration of chlorpyrifos in the results degraded slowly and was less dependent on the environmental conditions of storage. This may be due to a number of reasons, one being the properties of chlorpyrifos itself, such as chemical structure or volatility, the other is the influence of the type of grain, as the rate of degradation of the same pesticide residue in various grains may be different. Pesticide residues in the natural environment degrade faster due to factors such as sunlight, wind, and precipitation. However, in the process of grain storage, storage conditions are mostly airtight and protected from light. The chemical properties of pesticide residues during storage are more stable and not easily degraded, posing a threat to the quality of wheat. Furthermore, unlike other grains, wheat is generally stored for a longer period of time after harvest. In order to ensure quality during storage, for pesticides with slow degradation rates during storage and low national limit standards, such as chlorpyrifos, according to the degradation rate of such pesticides, to strictly limit its detection limit before storage. In addition, for chlorpyrifos-methyl, the grain protectant with a faster degradation rate and higher national limit standards, it is necessary to master its application cycle in the storage process.During storage, there are a variety of elements that affect the quality of wheat, and it is scientific to assess wheat quality by changes in pesticide residue concentrations in wheat. Along with the high-speed growth of computer technology, deep-learning-related technology, which can automatically learn and improve the feature extraction of quality, has created new ideas for wheat quality detection and assessment. By monitoring and predicting the quality changes of wheat during storage, and assessing the quality condition of wheat in grain storage in a timely manner, grain storage monitors can be inspired to timely adjust the storage environment conditions to control the degradation of pesticide residues, enhancing the quality condition of wheat.Playing an essential role in cereal crops, wheat is an indispensable food in people’s daily life, especially for food security in a country with a large population such as China, so its quality is very important. The use of pesticides in large quantities has increased the yield of wheat, but the safety of grain quality from pesticide residues has also attracted attention. These pesticide residues may affect the quality of wheat, and in serious cases may even be potentially harmful to human health.Q was constructed using existing and predicted pesticide residue concentrations to make a reasonable grading assessment of the quality of wheat. The results showed that the degradation speed of pesticide residues during storage is influenced by environmental parameters such as temperature and humidity, and considering the three pesticide residues together, the most suitable environmental parameters for their residue dissipation were a storage humidity of 75% and a temperature of 35 °C. Therefore, suitable storage conditions will promote the degradation of pesticide residues in wheat.The quality of wheat is mainly affected by the harvest time and storage conditions. In this study, starting from the storage environment, we used the temperature, storage humidity, and the concentration of pesticide residues in wheat during storage, which are elements that can easily contribute to the quality of wheat, and then innovatively combined the degradation changes of pesticide residues occurring during wheat storage. We used an Autoformer-based deep neural networks model to accurately predict the levels of different pesticide residues in wheat under different environmental influences in grain storage, and an evaluation index However, it should be noted that our study only investigated the effects of two major environmental factors on the degradation of pesticide residues during storage. Other factors such as the pH value of the storage environment and the moisture content of the wheat itself could also impact the degradation of pesticide residues in wheat storage and warrant further investigation. Additionally, beyond pesticide residues, other quality indicators such as cultivar, fungal and bacterial content, sensory features, degree of oxidation, etc., could also be considered in future quality assessments of stored wheat.


The optimal treatment of a ruptured anterior cruciate ligament (ACL) restores the patient’s native anatomy and biomechanics as close to normal as possible. The purpose of this technical note is to describe an ACL reconstruction technique in which a double-bundle concept is used, wherein one bundle contains repaired ACL tissue and the second bundle contains a hamstring autograft, and each bundle is tensioned independently. Even in chronic cases, this technique allows for incorporation of the native ACL because, more often than not, there is sufficient tissue of good quality available for repair of one bundle. By augmenting the ACL repair with an autograft sized to the fit the individual anatomy, the patient’s ACL tibial footprint can be closely restored to normal, and the potential benefits of tissue preservation are combined with the biomechanical strengths of an autograft double-bundle ACL reconstruction. Step-by-step technique description of the double-bundle anterior cruciate ligament reconstruction with primary repair and hamstring autograft augmentation (left knee). Informed consent was obtained from the subject and parent. However, single-bundle ACL reconstruction fails to normalize knee biomechanics and does not prevent osteoarthritis.In this technique description , the posPreoperative MR imaging is used to measure the ACL tibial footprint . FollowiSwitching between AM and AL portals, the ACL tear characteristics are evaluated using a probe , Fig 1A.The semitendinosus tendon is harvested in the standard fashion. On the basis of the preoperative MR imaging and intraoperative measurements, the graft is either doubled, tripled, or quadrupled, and, if necessary, supplemented with a gracilis tendon, so that the combined final graft diameter plus the remnant tibial footprint diameter approximate that of the native ACL tibial footprint. The graft is secured with TightRope RT devices (Arthrex).Looking from the AM portal, the femoral drill guide is entered through the AL portal and positioned at the anatomic location of the femoral AM attachment , A and BLooking from the AL portal, a guide pin is advanced from the anteromedial aspect of the tibia using the hamstring harvesting incision through the center of the anatomic AM bundle attachment of the native ACL , A and BAfter cycling of the knee, the graft is tensioned using the TightRope RT with extension button for tibial fixation, with the knee in extension plus a combined posterior and external rotation vector , A and BA standardized ACL reconstruction protocol under the guidance of a physical therapist is prescribed. Weight bearing is as allowed as tolerated unless meniscal repair was performed. A brace is not routinely used.The concept of ACL repair with autograft augmentation is not new. Open repair of an acute ACL injury with semitendinosus tendon augmentation, often supplemented with a lateral extra-articular reinforcement, provided good to excellent results in active patients.,Preservation of ACL remnant during ACL reconstruction was found to enhance graft revascularization and integration, with greater initial graft coverage with ACL remnant tissue, resulting in greater postoperative stability. Primary ACL repair results in the greatest degree of remnant preservation, and with advances in fixation and tensioning devices, its use has seen a resurgence. However, even when the repair was restricted to adolescents with acute, proximal avulsions of the ACL, failure rate of ACL repair with suture augmentation was significantly increased relative to ACL reconstruction.The current surgical technique incorporates the novel ACL repair methods in a double-bundle procedure, wherein one bundle contains repaired ACL tissue, and the second bundle contains a hamstring autograft, and each bundle is tensioned independently. The advantage of this technique is that the possible benefits of ACL remnant preservation are combined with the biomechanical advantages of two individually tensioned bundles for the control of rotational laxity. The technique is less challenging than a four-tunnel, two-graft double-bundle reconstruction. However, the technique is undeniably more demanding than a standard single-bundle ACL reconstruction, with decreased visibility due to obstruction of the preserved ACL tissue, risk of femoral tunnel convergence, and intricate suture management. Nevertheless, these technical challenges can be minimized as detailed in The current surgical concept can be individualized to the patient’s ACL anatomy and surgeon’s preference. The described steps could be followed to incorporate a quadriceps or bone-patellar tendon-bone autograft instead of a hamstring autograft, or semitendinosus tendon with its tibial insertion left attached, into the double-bundle ACL.In conclusion, by augmenting the ACL repair with an autograft sized to the fit the individual anatomy, the patient’s ACL tibial footprint can be closely restored to normal and the potential benefits of tissue preservation are combined with the biomechanical strengths of an autograft double-bundle ACL reconstruction.


Introduction: Despite the improvement of early diagnosis methods for multiple pathological entities belonging to the digestive tract, bowel obstruction determined by multiple etiologies represents an important percentage of surgical emergencies. General data: Although sometimes obstructive episodes are possible in the early stages of colorectal cancer, the most commonly installed intestinal obstruction has the significance of an advanced evolutionary stage of neoplastic disease. Development of Obstructive Mechanism: The spontaneous evolution of colorectal cancer is always burdened by complications. The most common complication is low bowel obstruction, found in approximately 20% of the cases of colorectal cancer, and it can occur either relatively abruptly, or is preceded by initially discrete premonitory symptoms, non-specific (until advanced evolutionary stages) and generally neglected or incorrectly interpreted. Success in the complex treatment of a low neoplastic obstruction is conditioned by a complete diagnosis, adequate pre-operative preparation, a surgical act adapted to the case , and dynamic postoperative care. The moment of surgery should be chosen with great care and is the result of the experience of the anesthetic-surgical team. The operative act must be adapted to the case and has as its main objective the resolution of intestinal obstruction and only in a secondary way the resolution of the generating disease. Conclusions: The therapeutic measures adopted  must have a dynamic character in accordance with the particular situation of the patient. Except for certain or probably benign etiologies, the possibility of colorectal neoplasia should always be considered, in low obstructions, regardless of the patient’s age. Despite the improvement of early diagnosis methods for multiple pathological entities belonging to the digestive tract, bowel obstruction determined by multiple etiologies represents an important percentage of surgical emergencies, accounting for approximately 20–30% of the cases diagnosed with acute abdomen . EffortsThis research focuses on the determinism, the physiological mechanisms, and the treatment particularities of obstructive colorectal cancer, an entity representing 60–80% of low bowel obstructions ,4. Intestinal obstruction is commonly found in surgical services, as a stand-alone entity , or as an epiphenomenon of other medical or surgical conditions . Although the clinic is generally sufficient for positive and topographic diagnosis, the etiological and pathogenic details cannot be clearly outlined, losing their specificity due to an intricate clinic with a spectacular dynamic of the suggestive elements for certain generating causes. With the exception of obstructions with ischemic mechanism from the beginning , those of the simple obstructive type present a clinical, dynamic mosaic, which frequently fails the attempts of systematization, creating taxonomic controversies, but justifies hydro-electrolytic, acid-base and nutritional rebalancing measures and finally the surgical procedure .The contribution of paraclinical and laboratory investigations is extremely useful, but even in these conditions a lot of cases remain etiologically obscure ,6. CliniA serious clinical entity by itself, intestinal obstruction can also be complicated  which produces an exponential worsening generating mortality rates comparable to severe digestive bleeding, severe pancreatitis, or major sepsis .Distal bowel obstructions  have a simple obstruction (except volvulus) as their established mechanism. Symptoms are more indefinite, and the worsening of the general condition occurs more slowly. These so-called “advantages” are nullified by factors, such as age, etiology , and multiple complications (most commonly septic). The decompressing factor that the small intestine can have in distal obstructions can be canceled by a pressure-competent ileocecal valve, transforming the colon into a closed, under-pressure loop (double obturated) . MassiveIschemic-type rheologic changes have multiple pathogenies. The cumulative effect of colic parietal vessel elongation , the ischemia produced by direct tissue pressure , extensive hemorrhagic intraparietal changes , or hypovolemic parietal hypoxia contribute to the premature alteration of the mucous-epithelial barrier, and then to colic perforation . Massive fluid-electrolyte intersectoral redistributions, with the formation of the IIIrd surgical space, associated with hydro-electrolyte losses through vomiting, contribute to the establishment of the dysvolemic status , which in association with the installed toxic-septic status, represent a powerful pathogenic association .The first pathogen that occurs is the impairment of lumen freedom, with upstream storage of gas and stercoral content. Secondarily, enteral motility disorders are installed as a result of cholic distension and episodic appearance of hyperperistaltism for evacuation purposes (“fighting colic’’). The tertiary element that occurs is the modification of intestinal wall viability with the addition of infectious factor (tumor abscess) or juxtatumoral or diastatic colic perforations. Low digestive malignancy, along with progressive lumen obstruction, can precipitate the obstructive episode through other mechanisms: invagination of pediculate tumors, extrinsic parietal invasions, obstructive carcinomatosis, the association of ischemic colic sufferings, etc. From this perspective, mechanical intestinal occlusion presents an initiator of pathogenic mechanisms (the obstacle in the colic lumen) and a systemic resonator  that worsens itself by dysvolemia and sepsis .Although sometimes obstructive episodes are possible in the early stages of colorectal cancer, the most commonly installed intestinal obstruction has the significance of an advanced evolutionary stage of neoplastic disease. Malignant colorectal obstructions generally evolve with an afebrile state. “Warm” obstructions suggest the appearance of septic, ischemic or co-existence of multiple metastases with hyperpyrexia, accentuated in the context of intersectoral dehydration .A therapeutic attitude in confirmed or intuited non-ischemic cases begins with measures aimed at hydro-electrolyte, acid-base, metabolic rebalancing, and measures to release the intestinal territory proximal to the stenosis through sustained digestive aspiration  and retrograde rectocolic lavage. The rhythm and duration of these measures remain an equation with multiple unknowns and traps, but aim at reconfiguring the general state, correcting the installed imbalances , impregnating with antibiotic and possibly anticoagulant, cardiac tonic, etc. .Depending on the specific situation, these measures can be adopted regulated or ultra-quickly. In the case of a favorable response, this period can be extended, hoping for complete release, which would allow a safer and more comfortable surgical act, in elective conditions. Failure to respond requires emergency surgery. The surgical attitude cannot be standardized considering the multitude of factors involved, but it ranges from large-scale surgical interventions aimed at solving the generating injury (tumor) as well as the complication (obstruction), to minimal surgical gestures that can contribute to the resolution of the obstruction (cecostomy) ,16.Although there is no unity of opinion regarding surgical strategies depending on topography, for the right colon, the right hemicolectomy followed by ileo-transverse anastomosis maintains a leading position, while for tumors located under the splenic flexure of the colon, the interventions in two or three times with different types of stomas upstream are valid, practiced for reasons of safety or necessity.Quality pre-operative preparation, a well-conducted and adapted surgical act and meticulous postoperative care can bring good results with the resolution of the underlying disease (neoplasm) and its complication (obstruction). However, this morbid association represents a severe pathological circumstance, in front of which optimism must remain moderate and circumspect ,18.Although there are embryological, anatomical, histological, and functional differences between colic and rectal locations respectively, we note the existence of some common elements between the neoplasms of these segments.The middle portion of the primitive intestine (mesenteron) generates the upper structures of the digestive tract , but also cecum, appendix vermiform, ascending colon, and right half of the transverse colon. The metenteron (embryonic posterior intestine) will develop the distal half of the transverse colon, descendant, sigmoid, rectum and upper portion of the anal canal. Studies on the different embryological origins of malignant colorectal segments suggest possible connections between embryology and carcinogenesis, this area of research being of high interest and requiring further studies . The involvement of genetic factors with autosomal dominant transmission was confirmed with the identification of hereditary nonpolyposis neoplasm (Lynch Syndrome I and II) and adenomatous familial polyposis ,21.In addition, it is important to mention the adenoma-carcinoma sequence, which is defined by a set of recurrent driver mutations in a series of genes  that accumulate in the process of adenoma formation and progression to sporadic colorectal cancer .The entire colon and rectum above the pectinated line is lined with one layered columnar epithelium. Below this level, up to the Hilton’s white line, the rectal epithelium is a non-keratinized, pluristratified pavement. In the area of interference between the two territories, histologists describe a state of “cellular unrest”, which predisposes to phenomena of metaplasia and even malignant degeneration. Gland structures with different morphology and function can contribute to oncogenesis .The geographical distribution of colorectal cancer is uneven between different countries or continents. The migration of some population groups to regions with high incidence increases the frequency of this pathology, suggesting the influence of some environmental factors .The distribution of colorectal cancer between the two genders is relatively equal, with the prevalence on the right colon in women and on the left colon in men. The maximum incidence is recorded at 60–70 years of age, although it is more and more common at a young age . In the Inflammatory bowel diseases  and diffuse colic polyposis, register a significant percentage of malignant degeneration in the absence of treatment or in conditions of insufficient or incorrectly conducted treatment ,30. The The low intake of vegetables and cellulose fibers and the excess of animal fats, carbohydrates, and alcohol predisposes to the development of colorectal neoplasia .The excessive presence of secondary bile acids (deoxycholic and lithocholic) in the digestive tract promotes carcinogenesis. The effect seems mediated by the excessive fixation of dietary calcium, which causes punctual peeling of the cholic mucosa, favoring the appearance of metaplastic changes. Large bile discharges into the digestive tract post-cholecystectomy raised the suspicion that this surgery predisposes to colorectal cancer ,36.Obesity, sedentary lifestyle, smoking, diabetes, abdominal radiotherapy, racial factor, etc., are other factors that can leave their mark on colorectal carcinogenesis ,39,40,41Vitamins A, C, E, beta carotene, aspirin, and non-steroidal anti-inflammatory drugs seem to have a protective role, noting a higher incidence of colorectal neoplasm in those with vitamin deficiencies ,43.The spontaneous evolution of colorectal cancer is always burdened by complications. Their variety is very large. Among the local complications, the most common are: loco-regional invasion with possible inter-visceral or external fistulas, tumor infection with adjacent sclerolipomatous reaction or abscesses, peritonitis by evacuation of tumor abscesses or intestinal perforations, intestinal obstructions, lower digestive bleeding, etc. General complications are represented by anemia, paraneoplastic venous thrombosis, multiple metastases, hepatic abscesses with systemic sepsis, etc. ,45.The most common complication is low bowel obstruction, found in approximately 20% of the cases of colorectal cancer and can occur either relatively abruptly, or is preceded by initially discrete premonitory symptoms, non-specific (until advanced evolutionary stages), and generally neglected or incorrectly interpreted ,46.The common obstructive mechanism is simple obstruction and is specific to situations with preceding manifestations . For forms with sudden onset may occur intussusceptions , volvuluses of supratumoral mobile segments and the association of peritoneal carcinomatosis or enteral ischemic phenomena. Colic volvulus is favored by the increased weight of endoluminal content and hypermobility, with fixed points of the extremities as close as possible. In intestinal volvuluses, necrosis is not directly correlated with the number of rotations of the loop, but with the degree of “constriction of the affected mesenteries” ,47.Low bowel obstruction due to neoplastic cause  presents anatomical and functional characteristics important in stage, pathogenic, topographic, and etiological diagnosis, orienting therapeutic consequences.The simple obstructive mechanism is installed later in colic segments with large caliber. Subsequently, the ileocecal valve follows the segment with the largest diameter (the cecum and the ascending colon), which explains the lower frequency of right colon occlusions if the Bauhin valve is not interested. The diameter of the colic lumen decreases discreetly to the distal segments . Peritumoral sclerolipomatosis and anemia are more common in the right colon, contributing to the shaping of the characteristics specific to this level of tumor location ,49.2O, compared to the one in the small intestine where it is approximately 200–300 cm H2O) [The thickness of the colic wall has less importance regarding the frequency of colorectal neoplasms on certain topographies but has profound relevance in relation to retrograde diastatic perforations (Laplace’s law) . The lar cm H2O) ,51,52,53Although it enjoys two important arterial sources (upper mesenteric artery for the right colon and lower mesenteric artery for the left colon) and marginal arches Drummond and Riolan-Haller and inconstant central intermesenteric anastomosis Huard, the colon does not benefit through long and short vasa recta arteries of a generous arterial flow comparable to the upper segments of the tract digestive system . Mesenteric arteries are the preferred territories for the phenomenon of atheromatosis contributing to the progressive decrease of blood flow in irrigated territories. Elongation of vasa recta in the distended colic wall favors ischemia and parietal microthromboses, precipitating colic perforation. The closing of the venous network  is an additional factor in the irreversibility of parietal lesions ,55.The colorectal area stretches between the ileocecal valve and the anal sphincter. The latter is of limited importance in low intestinal obstruction, being most commonly located under the obstacle. The ileocecal valve is deeply involved in the pressure play and dynamics of the cholic stasis content in low intestinal obstruction. A “permissive” valve can favor the reflux of stercoral content towards the ileal and then jejunal territory, tempering for the moment the axial and lateral pressures from the obstructed colon. Its increased pressure competence can close the possibility of retrograde reflux, with the exponential increase of intracolic pressures.The functional sphincters of the colon  are limited areas with better represented circular musculature and may have a limited role in colon dynamics in the early stages of the obstruction evolution. It can be concluded that Laplace’s physical law may be influenced by cholic morphofunctional characteristics ,57.The mobility of colic segments can influence the dynamics of the obstructive process. If the fixed segments are the site of tumor development, they will suffer a simple process of obstruction, while for mobile segments other obstructive mechanisms may overlap  .Obstruction of the colic lumen is more common in ulcer-vegetative , exophytColic innervation is vegetative, receptor and effector. The Meissner submucous plexus and axons of neurons in the posterior root node of the spinal nerves T11-L1 are responsible for visceral sensitivity. The secretive and motor activities are modulated by the Auerbach myenteric plexus, unequally represented for the right colon (related to the upper mesenteric plexus) and the left colon (dependent on the lower mesenteric plexus). The poor representation of the myenteric plexus is associated with a diminished peristaltic accompanied by a background distension of the left colon (megadolichocolon), decompensated early in the obstacles of colorectal junction or below this level. Colic hyperdistension makes the action of pharmacological active factors  ineffective on tonus and peristalsis ,61.Other functional factors involved in the pathogenic mechanisms of low intestinal obstruction depend on the individual characteristics of each patient, or derive from anatomical considerations: cholic resorptive function, dramatically extracted dysmicrobisms ,63, nutrSuccess in the complex treatment of a low neoplastic obstruction is conditioned by a complete diagnosis, adequate pre-operative preparation, a surgical act adapted to the case  and dynamic postoperative care. Diagnostic errors consist both in overestimating the case , but especially in the negative . Etiological clarification is only possible sometimes, but this aspect is not a major drawback given the indication of surgical exploration, which will clarify this aspect as well.Preoperative management of patients diagnosed with bowel obstruction involves, even from the emergency room, the placement of a peripheric venous catheter and starting the infusion of crystalloid solutions such as saline or Ringer solution. Acid-base and electrolyte rebalancing is a priority, often requiring repeated assessments of serum ions and pH. Considering the potential for dehydration and the rapid evolution of the disease, a urinary catheter is necessary for monitoring diuresis. In patients with severe cardiac, renal, or pulmonary failure, monitoring of fluid and electrolyte rebalancing using central Swan-Ganz catheters may be helpful. Preoperative hematological imbalances such as severe anemic syndromes can be adjusted by blood transfusions and severe thrombocytopenia by administering platelet masses. In the case of coagulopathy  or in case of changes in coagulation parameters due to treatments for various cardiologic disorders, prompt administration of plasma or vitamin K is necessary. Antibiotherapy, thromboembolic prophylaxis, and treatment of associated diseases are equally important ,68,69,70The moment of surgery should be chosen with great care and is the result of the experience of the anesthetic-surgical team. The operative act must be adapted to the case and has as its main objective the resolution of intestinal obstruction and only in a secondary way the resolution of the generating disease. The resection of the involved colorectal segment is performed , respecting oncological principles. Afterward, anastomosis is taken into account when the proximal segment shows no structural changes. Otherwise, to avoid a digestive fistula, it is recommended to close the distal segment and perform an ostomy at the level of the proximal one .Often, the surgical procedure does not involve the removal of the obstructive process, but only the restoration of the digestive transit. This involves cases in which is intended to shorten the duration of the surgical intervention due to the patient’s comorbidities and the general condition at the time or procedures performed for palliative purposes, for advanced neoplasia. In the case of external digestive derivations without removal of the obstructive process, it is recommended to perform a continuous ostomy, in order to avoid a “closed loop” .“The patient with intestinal obstruction is in the situation of a rescued from drowning. This is not the case for a swimming lesson”—Wangensteen.The postoperative stage can crown the effort made to save the patient or compromise the previous efforts and should be managed by a multidisciplinary team. Analgesic, antibiotic, prokinetic, and anticoagulation therapy in the case of prolonged immobilization should be taken into account. Diuresis and intestinal transit will be monitored, and oral nutrition will be gradually resumed. Local complications  or general complications, such as cardiorespiratory, renal, or hepatic failures, should be closely monitored and treated promptly .○The main cause of low bowel obstruction is colorectal cancer.○Preceded by early or sudden signs, low neoplastic obstruction generally has the meaning of a neoplasm in an advanced evolutionary stage.○The therapeutic measures adopted  must have a dynamic character in accordance with the particular situation of the patient.○Except for certain or probably benign etiologies, the possibility of colorectal neoplasia should always be considered, in low obstructions, regardless of the patient’s age.○A “truce” in the fight against the obstruction can be deceptive.