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Objective To investigate the characteristics and objective assessment method of visual field defects caused by optic chiasm and its posterior visual pathway injury. Methods Typical cases of visual field defects caused by injuries to the optic chiasm, optic tracts, optic radiations, and visual cortex were selected. Visual field examinations, visual evoked potential （VEP） and multifocal visual evolved potential （mfVEP） measurements, craniocerebral CT/MRI, and retinal optical coherence tomography （OCT） were performed, respectively, and the aforementioned visual electrophysiological and neuroimaging indicators were analyzed comprehensively. Results The electrophysiological manifestations of visual field defects caused by optic chiasm injuries were bitemporal hemianopsia mfVEP abnormalities. The visual field defects caused by optic tract, optic radiation, and visual cortex injuries were all manifested homonymous hemianopsia mfVEP abnormalities contralateral to the lesion. Mild relative afferent pupil disorder （RAPD） and characteristic optic nerve atrophy were observed in hemianopsia patients with optic tract injuries, but not in patients with optic radiation or visual cortex injuries. Neuroimaging could provide morphological evidence of damages to the optic chiasm and its posterior visual pathway. Conclusion Visual field defects caused by optic chiasm, optic tract, optic radiation, and visual cortex injuries have their respective characteristics. The combined application of mfVEP and static visual field measurements, in combination with neuroimaging, can maximize the assessment of the location and degree of visual pathway damage, providing an effective scheme for the identification of such injuries.

Abstract Chronic pain causes both physical suffering and comorbid mental symptoms such as anhedonia. However, the neural circuits and molecular mechanisms underlying these maladaptive behaviors remain elusive. Here using a mouse model, we report a pathway from vesicular glutamate transporter 3 neurons in the dorsal raphe nucleus to dopamine neurons in the ventral tegmental area (VGluT3DRN →DAVTA) wherein population-level activity in response to innocuous mechanical stimuli and sucrose consumption is inhibited by chronic neuropathic pain. Mechanistically, neuropathic pain dampens VGluT3DRN → DAVTA glutamatergic transmission and DAVTA neural excitability. VGluT3DRN → DAVTA activation alleviates neuropathic pain and comorbid anhedonia-like behavior (CAB) by releasing glutamate, which subsequently promotes DA release in the nucleus accumbens medial shell (NAcMed) and produces analgesic and anti-anhedonia effects via D2 and D1 receptors, respectively. In addition, VGluT3DRN → DAVTA inhibition produces pain-like reflexive hypersensitivity and anhedonia-like behavior in intact mice. These findings reveal a crucial role for VGluT3DRN → DAVTA → D2/D1NAcMed pathway in establishing and modulating chronic pain and CAB.

Two species assigned to Massuria Thorell, 1887 are reviewed. The female of Massuria bandian Tang & Li, 2010 is described for the first time from Jianfengling National Natural Reserve, Hainan Province, China. The species Diaea simplex Xu, Han & Li, 2008 is described as a synonym of Massuria bellula Xu, Han & Li, 2008 based on female and male specimens from Guangdong Province, China. Massuria min sp. nov. described as a new species (female, Fujian Province, China). Detailed illustrations and a distribution map are provided for these three species of Massuria.

Abstract Short-chain fatty acids (SCFAs) are the main metabolites produced by bacterial fermentation of dietary fibre in the gastrointestinal tract. The absorption of SCFAs is mediated by substrate transporters, such as monocarboxylate transporter 1 and sodium-coupled monocarboxylate transporter 1, which promote cellular metabolism. An increasing number of studies have implicated metabolites produced by microorganisms as crucial executors of diet-based microbial influence on the host. SCFAs are important fuels for intestinal epithelial cells (IECs) and represent a major carbon flux from the diet, that is decomposed by the gut microbiota. SCFAs play a vital role in multiple molecular biological processes, such as promoting the secretion of glucagon-like peptide-1 by IECs to inhibit the elevation of blood glucose, increasing the expression of G protein-coupled receptors such as GPR41 and GPR43, and inhibiting histone deacetylases, which participate in the regulation of the proliferation, differentiation, and function of IECs. SCFAs affect intestinal motility, barrier function, and host metabolism. Furthermore, SCFAs play important regulatory roles in local, intermediate, and peripheral metabolisms. Acetate, propionate, and butyrate are the major SCFAs, they are involved in the regulation of immunity, apoptosis, inflammation, and lipid metabolism. Herein, we review the diverse functional roles of this major class of bacterial metabolites and reflect on their ability to affect intestine, metabolic, and other diseases. Video Abstract

Achieving high-performance as-cast OSCs is crucial for industrialization in the future, owing to the advantages of better stability, environmental-friendly, and decreasing production cost. In this regard, we synthesized an A-DA′D-A type acceptor, Y6-eC6-BO, by shortening the straight alkyl side-chains on the thiophene position from C11 to C6 as well as lengthening the branched alkyl side-chains on the pyrrole position of Y6 to achieve a stronger crystallization and better miscibility than Y6. As a result, the corresponding chloroform-processed as-cast PM6: Y6-eC6-BO OSC showed a high PCE of 17.33%, which was one of the highest efficiencies of as-cast OSCs. And the as-cast PM6:Y6-eC6-BO OSCs processed from o-xylene displayed a PCE of 16.38%, as far as we know, this is among the highest efficiencies of non-halogenated-solvent processed as-cast OSCs. These results demonstrated tailoring the alkyl side-chain of NFAs is a feasible and simple approach to achieve high performance as-cast OSCs and provides guideline in molecular design in the future.

Background/purpose: Few studies have focused on the influence of simulated toothbrush abrasion on the surface qualities of novel nanofilled and nanohybrid composites. The aim of the study was to evaluate the surface roughness and gloss values of resin-based composite (RBC) materials with various filler types before and after simulated toothbrush abrasion. Materials and methods: One nanofilled (Filtek Z350 XT [FT3]), two nanohybrids (Harmonize [HM] and Clearfil Majesty [CM]) and one microhybrid (Filtek Z250 [FT2]) were evaluated. Twelve specimens of each material were made and polished with silicon carbide sandpapers. Initial surface roughness and gloss values were measured as negative controls. Then, all specimens were subjected to simulated toothbrush abrasion on a custom-made apparatus. After 2000, 4000 and 8000 cycles, the surface roughness and gloss values of all specimens were tested. One additional specimen from each group was selected for scanning electron microscope (SEM) analysis. Results: For FT3, Ra and GU values did not significantly change until after 8000 cycles during the process of toothbrushing (P > 0.05). For HM, CM and FT2, the Ra and GU values significantly decreased after 4000 and 8000 cycles of toothbrush abrasion (P

Contact metamorphism occurs when magma intrudes into the coal seam, resulting in changes to the microfraction, grade, chemical composition, physico-chemical structure and process properties of the coal. Different types of contact metamorphic products are formed under different tectonic-thermal conditions. In order to reveal the variability of different types of contact metamorphic coals and their controlling factors from the macromolecular structure scale, a comparative study of natural coke series samples from the Tashan mine in Datong, Shanxi Province and coal-based graphite series samples from the Lutang mine in Hunan Province was carried out using industrial analysis, elemental analysis, reflectance determination, X-ray diffraction (XRD) and Raman spectroscopy (Raman) test methods, and combined with geological background analysis. The results show that the small shallow-formed rocks have a short thermal action time, poor thermal confinement conditions, belong to high temperature and low pressure condition, narrow contact metamorphic zone, and develop natural coke - thermal transformation coal sequence; the series is in the carbonation stage, and the coal macromolecular structure is dominated by chemical changes, with aromatization and ring condensation dominating. It shows carbon enrichment, dehydrogenation, deoxygenation, reduction of defects in the active sites such as side chains and functional groups, growth of aromatic structural units leading to an increase in defects within the aromatic level, and the aromatic lamellae are not ordered. The acidic and moderately acidic deep-formed rock bodies such as strains and bases intruded in a regional extrusive tectonic setting are well heated, thermally confined and under high temperature and pressure conditions, and the contact metamorphic width can exceed 1km, developing graphite-semi-graphite-anthracite metamorphic sequences; the chemical composition of the coal-based graphite series is highly mature and less variable, and the macromolecular structure is dominated by physical changes, mainly occurring as collagenesis and rank physicochemical interactions. The non-oriented aromatic lamellae are spliced and stacked and rotated and oriented by forces, with a continuous reduction of defects and a transition to a three-dimensional ordered crystal structure.

Copper-based solid lubrication inlay technology is widely used in industrial production, especially in low-speed and heavy load conditions, and the structure and distribution of the filling pore have a significant influence on the friction performance due to the distribution of contact stress. In this paper, based on the operating conditions of the bottom pivot of the Three Gorges gate, graphite is used as a solid filled lubricant. The effects of filling pore diameter, filling pore depth, and area distribution rate on the friction and wear properties were studied by orthogonal equivalent test on MMW-1A tester with grease. Combining the three-dimensional morphology test and ferrography analysis, the results show that: 1) the influence of three parameters on the test results are: filling pore diameter > area distribution rate > filling pore depth; 2) when the filling pore diameter is 3 mm, the area distribution rate is 12%, and the filling pore depth is 0.5 mm, which is the equivalent the optimal structure of the filling pore size under working conditions. According to this conclusion, the actual filling structure can be obtained based on the similarity theory. As Coulomb friction is material and contact stress related, the calculation of the stress distribution during dynamic operation is difficult and therefore the analysis is carried out experimentally.

Abstract Itch is a complex aversive sensory and emotional experience. As a most upsetting symptom in many dermatological and systemic diseases, it lacks efficient treatments. The lateral habenula nucleus (LHb) encodes negative emotions in the epithalamus and has been implicated in pain and analgesia. Nevertheless, the role of the lateral habenula nucleus in the pruritic sensation and emotion remains elusive. Here we defined the crucial role of glutamatergic neurons within the lateral habenula nucleus (GluLHb) in itch modulation in mice. We established histamine-dependent and histamine-independent models of acute pruritus, as well as the acetone-ether-water (AEW) model of chronic pruritus. We first assessed the effects of pruritogen injection on neural activation in both medial and lateral divisions of LHb in vitro. We then demonstrated that the population activity of GluLHb neurons was increased during the acute itch and chronic itch-induced scratching behaviors in vivo. In addition, electrophysiological data showed that the excitability of GluLHb neurons was enhanced by chronic itch. Chemogenetic suppression of GluLHb neurons disrupted both acute and chronic itch-evoked scratching behaviors. Furthermore, itch-induced conditioned place aversion (CPA) was abolished by GluLHb neuronal inhibition. Finally, we dissected the LHb upstream brain regions. Together, these findings reveal the involvement of LHb in processing both the sensational and emotional components of pruritus and may shed new insights into itch therapy.

Abstract Designing the microstructure of Fe-Ni permalloy produced by additive manufacturing (AM) opens new avenues to tailor its magnetic properties. Yet, AM-produced parts suffer from spatially inhomogeneous thermal-mechanical and magnetic responses, which are less investigated in terms of process modeling and simulations. We present a powder-resolved multiphysics-multiscale simulation scheme for describing magnetic hysteresis in AM-produced material, explicitly considering the coupled thermal-structural evolution with associated thermo-elasto-plastic behaviors and chemical order-disorder transitions. The residual stress is identified as the key thread in connecting the physical processes and phenomena across scales. By employing this scheme, we investigate the dependence of the fusion zone size, the residual stress and plastic strain, and the magnetic hysteresis of AM-produced Fe21.5Ni78.5 on beam power and scan speed. Simulation results also suggest a phenomenological relation between magnetic coercivity and average residual stress, which can guide the magnetic hysteresis design of soft magnetic materials by choosing appropriate processing parameters.

Abstract Introduction Ischemic diseases caused by diabetes continue to pose a major health challenge and effective treatments are in high demand. Mesenchymal stem cells (MSCs) derived exosomes have aroused broad attention as a cell-free treatment for ischemic diseases. However, the efficacy of exosomes from adipose-derived mesenchymal stem cells (ADSC-Exos) in treating diabetic lower limb ischemic injury remains unclear. Methods Exosomes were isolated from ADSCs culture supernatants by differential ultracentrifugation and their effect on C2C12 cells and HUVECs was assessed by EdU, Transwell, and in vitro tube formation assays separately. The recovery of limb function after ADSC-Exos treatment was evaluated by Laser-Doppler perfusion imaging, limb function score, and histological analysis. Subsequently, miRNA sequencing and rescue experiments were performed to figure out the responsible miRNA for the protective role of ADSC-Exos on diabetic hindlimb ischemic injury. Finally, the direct target of miRNA in C2C12 cells was confirmed by bioinformatic analysis and dual-luciferase report gene assay. Results ADSC-Exos have the potential to promote proliferation and migration of C2C12 cells and to promote HUVECs angiogenesis. In vivo experiments have shown that ADSC-Exos can protect ischemic skeletal muscle, promote the repair of muscle injury, and accelerate vascular regeneration. Combined with bioinformatics analysis, miR-125b-5p may be a key molecule in this process. Transfer of miR-125b-5p into C2C12 cells was able to promote cell proliferation and migration by suppressing ACER2 overexpression. Conclusion The findings revealed that miR-125b-5p derived from ADSC-Exos may play a critical role in ischemic muscle reparation by targeting ACER2. In conclusion, our study may provide new insights into the potential of ADSC-Exos as a treatment option for diabetic lower limb ischemia.

Objective: Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disease associated with a high incidence of complications in the mid and late stages of gestation. This study investigates differences in the composition of intestinal flora among pregnant women diagnosed with ICP, employing Illumina MiSeq high-throughput sequencing technology. Methods: This case-control study obtained patient data from the hospital information system (HIS) and the laboratory information system (LIS). Fecal samples were collected from 25 pregnant women who did not undergo intestinal preparation before delivery between December 2020 and March 2021. Whole-genome analysis was performed. PCR was used to amplify the 16S rRNA V3–V4 variable region, which was then sequenced. Alpha and beta diversity were computed, and the maternal intestinal flora's abundance and composition characteristics were analyzed. Differences in intestinal flora between the two sample groups were examined. Results: Bacteroides and Proteobacteria exhibited positive correlations with TBIL and IBIL. Betaproteobacteria, Gammaproteobacteria, and Erysipeiotrichi showed positive correlations with TBIL, IBIL, and DBIL, while Lactobacillus, Delftia, and Odoribacter demonstrated positive correlations with ALT. Conclusion: The ICP group displayed significantly higher levels of total bile acid and ALT compared to the control group. The intestinal flora composition comprised four primary phyla: Firmicutes, Actinobacteria, Bacteroidetes, and Proteobacteria. ICP patients exhibited a lower relative abundance of intestinal flora across different levels of community composition when compared to the control group. Specific correlations between certain intestinal flora and clinical liver parameters were identified.

Background: Mesalazine, a preparation of 5-aminosalicylic acid, is a medication widely used in clinical practice as a first-line therapy in the treatment of mild and moderate inflammatory bowel disease. However, the long-term safety of mesalazine in large sample population was unknown. The current study was to assess mesalazine -related adverse events of real-world through data mining of the US Food and Drug Administration Adverse Event Reporting System (FAERS).Methods: Disproportionality analyses, including the reporting odds ratio (ROR), the proportional reporting ratio the Bayesian confidence propagation neural network and the multi-item gamma Poisson shrinker (MGPS) algorithms were employed to quantify the signals of mesalazine -associated AEs.Results: Out of 14,149,980 reports collected from the FDA Adverse Event Reporting System database, 24,284 reports of mesalazine -associated AEs were identified. A total of 170 significant disproportionality preferred terms conforming to the four algorithms simultaneously were retained. The most common AEs included colitis ulcerative, diarrhoea, condition aggravated, crohn’s disease, fatigue, abdominal pain, nausea, haematochezia, which were corresponding to those reported in the specification and clinical trials. Unexpected significant AEs as dizziness, drug ineffective, drug hypersensitivity, infection, off label use, weight decreased, decreased appetite, arthralgia, rash might also occur. The median onset time of mesalazine -related AEs was 1,127 days (interquartile range [IQR] 1,127–1,674 days), and most of the cases occurred 2 years later (n = 610, 70.93%) and within the first 1 month (n = 89, 10.35%) after mesalazine initiation.Conclusion: Results of our study were consistent with clinical observations. We also found potential new and unexpected AEs signals for mesalazine, suggesting prospective clinical studies were needed to confirm these results and illustrate their relationship. Our results could provide valuable evidence for further safety studies of mesalazine.

IntroductionThe Omicron variant has rapidly spread throughout the world compared to the Delta variant and poses a great threat to global healthcare systems due to its immune evasion and rapid spread. Sex has been identified as a factor significantly associated with COVID-19 mortality, but it remains unclear which clinical indicators could be identified as risk factors in each sex group and which sex-specific risk factors might shape the worse clinical outcome, especially for Omicrons. This study aimed to confirm the relationship between sex and the progression of the Omicron variant and to explore its sex-biased risk factors.MethodsWe conducted a retrospective study including 1,132 hospitalized patients with the COVID-19 Omicron variant from 5 December 2022 to 25 January 2023 at Shanghai General Hospital, and the medical history data and clinical index data of the inpatients for possible sex differences were compared and analyzed. Then, a sex-specific Lasso regression was performed to select the variables significantly associated with critical illness, including intensive care unit admission, invasive mechanical ventilation, or death. A logistic regression was used to construct a sex-specific predictive model distinctively for the critical illness outcome using selected covariates.ResultsAmong the collected 115 clinical indicators, up to 72 showed significant sex differences, including the difference in merit and the proportion of people with abnormalities. More importantly, males had greater critical illness (28.4% vs. 19.9%) and a significantly higher intensive care unit occupancy (20.96% vs. 14.49%) and mortality (13.2% vs. 4.9%), and males over 80 showed worse outcomes than females. Predictive models (AUC: 0.861 for males and 0.898 for females) showed 12 risk factors for males and 10 for females. Through a comprehensive sex-stratified analysis of a large cohort of hospitalized Omicron-infected patients, we identified the specific risk factors for critical illness by developing prediction models.DiscussionSex disparities and the identified risk factors should be considered, especially in the personalized prevention and treatment of the COVID-19 Omicron variant.

The development of 1,8-naphthalimide derivatives as cell probes, DNA targeting agents, and anti-tumor drugs is one of the research hotspots in the field of medicine. Naphthalimide compounds are a kind of DNA embedder, which can change the topological structure of DNA by embedding in the middle of DNA base pairs, and then affect the recognition and action of topoisomerase on DNA. Aminofide and mitonafide are the first 2 drugs to undergo clinical trials. They have good DNA insertion ability, can embed DNA double-stranded structure, and induce topoisomerase II to cut part of pBR322DNA, but not yet entered the market due to their toxicity. In this paper, the design and structure-activity relationship of mononaphthalimide and bisaphthalimide compounds were studied, and the relationship between the structure of naphthalimide and anti-tumor activity was analyzed and discussed. It was found that a variety of structural modifications were significant in improving anti-tumor activity and reducing toxicity.

Bone fracture: Identifying a protein that hinders repair during infection A protein that is overexpressed during bone fracture infection blocks a key signaling pathway and prevents bone repair. Infection following bone fracture remains a leading cause of delayed or unsuccessful healing. Stem cells from bone marrow are the main source of osteoblasts, bone-forming cells necessary for healthy bone regeneration and repair. Infection causes disruption to stem cell function and hinders bone healing, but the exact mechanisms involved remain unclear. In experiments on human tissue samples and a mouse model, Jun Fei and Xiang Xu at the Army Medical University in Chongqing, China, and co-workers examined the role of the fibulin2 protein in infected bone fractures. Fibulin2 is overexpressed in infected tissues, and the protein suppresses stem cell differentiation into osteoblasts by deactivating a key signaling pathway. Blocking fibulin2 in mice models restored bone formation.

BackgroundEmerging evidence reveals that SARS-CoV-2 possesses the capability to disrupt the gastrointestinal (GI) homeostasis, resulting in the long-term symptoms such as loss of appetite, diarrhea, gastroesophageal reflux, and nausea. In the current review, we summarized recent reports regarding the long-term effects of COVID-19 (long COVID) on the gastrointestine.ObjectiveTo provide a narrative review of abundant clinical evidence regarding the development and management of long-term GI symptoms in COVID-19 patients.ResultsLong-term persistent digestive symptoms are exhibited in a majority of long-COVID patients. SARS-CoV-2 infection of intestinal epithelial cells, cytokine storm, gut dysbiosis, therapeutic drugs, psychological factors and exacerbation of primary underlying diseases lead to long-term GI symptoms in COVID-19 patients. Interventions like probiotics, prebiotics, fecal microbiota transplantation, and antibiotics are proved to be beneficial in preserving intestinal microecological homeostasis and alleviating GI symptoms.ConclusionTimely diagnosis and treatment of GI symptoms in long-COVID patients hold great significance as they may contribute to the mitigation of severe conditions and ultimately lead to the improvement of outcomes of the patients.

ABSTRACTIntestinal dysbiosis frequently occurs in abdominal radiotherapy and contributes to irradiation (IR)-induced intestinal damage and inflammation. Akkermansia muciniphila (A. muciniphila) is a recently characterized probiotic, which is critical for maintaining the dynamics of the intestinal mucus layer and preserving intestinal microbiota homeostasis. However, the role of A. muciniphila in the alleviation of radiation enteritis remains unknown. In this study, we reported that the abundance of A. muciniphila was markedly reduced in the intestines of mice exposed to abdominal IR and in the feces of patients who received abdominal radiotherapy. Abundance of A. muciniphila in feces of radiotherapy patients was negatively correlated with the duration of diarrhea in patients. Administration of A. muciniphila substantially mitigated IR-induced intestinal damage and prevented mouse death. Analyzing the metabolic products of A. muciniphila revealed that propionic acid, a short-chain fatty acid secreted by the microbe, mediated the radioprotective effect. We further demonstrated that propionic acid bound to G-protein coupled receptor 43 (GRP43) on the surface of intestinal epithelia and increased histone acetylation and hence enhanced the expression of tight junction proteins occludin and ZO-1 and elevated the level of mucins, leading to enhanced integrity of intestinal epithelial barrier and reduced radiation-induced intestinal damage. Metformin, a first-line agent for the treatment of type II diabetes, promoted intestinal epithelial barrier integrity and reduced radiation intestinal damage through increasing the abundance of A. muciniphila. Together, our results demonstrated that A. muciniphila plays a critical role in the reduction of abdominal IR-induced intestinal damage. Application of probiotics or their regulators, such as metformin, could be an effective treatment for the protection of radiation exposure-damaged intestine.

IntroductionApplication of organic fertilizers affects soil properties and microbial communities, which in turn alters soil N transformation processes. Unfortunately, it is not clear how the difference in the character of the organic fertilizer DOM affects the soil nitrogen retention capacity and its microbial processes.MethodsAccording to the principle of equal nutrients, the treatments of chemical fertilizer alone (treatment CF), chemical fertilizer with organic fertilizer DOM hydrophilic components (treatment H), and chemical fertilizer with organic fertilizer DOM hydrophobic components (treatment P) were set up, where the characteristics of soil nitrogen transformation and changes in microbial community structure were studied with soil culture conditions for 24 days.ResultsIt was discovered that the addition of organic fertilizer DOM components (H and P) slowed nitrification rate and increased protease activity resulting in a higher NH4+-N content compared to the CF treatment. The DOM addition (H and P) increased the microbial biomass nitrogen (MBN) levels in the soil and increased the soil nitrogen pool capacity.ConclusionsMoreover, the carbon use efficiency of the hydrophilic components is higher than that of the hydrophobic components, resulting in its further increase in nitrogen reservoir capacity and higher nitrogen retention capacity. Network analysis showed that the addition of organic fertilizer DOM hydrophilic components increased network complexity and synergy between microorganisms. In combination with random forest analysis, it was shown that Sphingomonas and Massilia were key species influencing soil nitrogen retention capacity and nitrogen availability characteristics.

Biological effects of magnetic fields have been extensively studied in plants, microorganisms and animals, and applications of magnetic fields in regulation of plant growth and phytoprotection is a promising field in sustainable agriculture. However, the effect of magnetic fields especially ultra-high static magnetic field (UHSMF) on genomic stability is largely unclear. Here, we investigated the mutagenicity of 24.5, 30.5 and 33.0 T UHSMFs with the gradient of 150, 95 and 0 T/m, respectively, via whole genome sequencing. Our results showed that 1 h exposure of Arabidopsis dried seeds to UHSMFs has no significant effect on the average rate of DNA mutations including single nucleotide variations and InDels (insertions and deletions) in comparison with the control, but 33.0 T and 24.5 T treatments lead to a significant change in the rate of nucleotide transitions and InDels longer than 3 bp, respectively, suggesting that both strength and gradient of UHSMF impact molecular spectrum of DNA mutations. We also found that the decreased transition rate in UHSMF groups is correlated with the upstream flanking sequences of G and C mutation sites. Furthermore, the germination rate of seeds exposed to 24.5 T SMF with -150 T/m gradient showed a significant decrease at 24 hours after sowing. Overall, our data lay a basis for precisely assessing the potential risk of UHSMF on DNA stability, and for elucidating molecular mechanism underlying gradient SMF-regulated biological processes in the future.

Hepatocellular carcinoma (HCC) is a highly prevalent malignancy and the third highest contributor to cancer-associated deaths globally. Research has increasingly demonstrated a strong correlation between long noncoding RNAs (lncRNAs) and the incidence and progression of HCC. Nonetheless, the exact mechanism whereby the function of lncRNAs in HCC has not been elucidated. This study explored the pathological role of LINC00294 in HCC, as well as the modulatory mechanism involved. Based on the “The Cancer Genome Atlas (TCGA)” database and validation in HCC cell lines and tissues, the expression of LINC00294 was discovered to be upregulated in HCC tissues and correlated with tumor grade and the prognosis of patients with HCC. Functionally, LINC00294 stimulated the proliferation of HCC cells as well as the Warburg effect (aerobic glycolysis) to enhance progression of tumor in vivo. Mechanistically, METTL3/YTHDC1-mediated N6-methyladenosine (m6A) modification underwent a significant enrichment within LINC00294 and was shown to enhance its RNA stability. Moreover, LINC00294 promoted the interaction between YTHDC1 and HK2 and GLUT1 mRNA. Overall, our study illustrates the m6A modification-mediated epigenetic mechanism of LINC00294 expression and regulatory role in HK2and GLUT1 mRNA expression and indicate LINC00294 as a potential biomarker panel for prognostic prediction and treatment in HCC.

Non-healing wound, with limited treatment options, remains a prevalent complication of diabetes mellitus. The underlying causes wherein include oxidative stress injury, bacterial infection, cellular dysfunction, and persistent inflammation. Acellular Dermal Matrix (ADM), a wound dressing composed of natural extracellular matrix and abundant bioactive factors, has been successfully developed to treat various wounds, including burns and diabetic ulcers. Protocatechualdehyde (PA) & trivalent iron ion (Fe3+) complex (Fe3+@PA) exhibits potential antioxidant and antibacterial properties. In this study, we developed a dual hydrogel network by combining Fe3+@PA complex-modified ADM with light-cured gelatin (GelMA), supplemented with exosomes derived from human umbilical vein endothelial cells (HUVEC-Exos), to create an ADM composite hydrogel system (ADM-Fe3+@PA-Exos/GelMA) with antioxidant, antibacterial, and cell-promoting functions for diabetic wound treatment. Through in vitro experiments, we investigated the biosafety, antioxidant and antibacterial properties of ADM composite hydrogel. Furthermore, we examined the protective effects of ADM composite hydrogel on diabetic wound. The above experiments collectively demonstrate that our ADM-Fe3+@PA-Exos/GelMA hydrogel promotes diabetic wound healing by eliminating bacterial infection, reduced the reactive oxygen species (ROS) levels, protecting cells against oxidative stress damage, promotingcollagen deposition and angiogenesis, which provides a promising strategy to optimize ADM for diabetic wound treatment.

ABSTRACTNovel ultralight meta-sandwich structures inspired by Kirigami (MSS) are proposed in this study. The topological designs of uniform (MSS-U) and non-uniform (MSS-N) sizes are studied based on the inconsistent distribution of the biomaterials. First, MSS-U and MSS-N are manufactured using laser powder bed fusion (LPBF) technology, and energy absorption prediction formulas are successfully derived by extracting the experimental deformation features. It is found that MSS-N exhibits a higher energy absorption level than MSS-U. Compared to the conventional corrugated sandwich structures (CSS), the MSS achieves better crashworthiness indicators and more folding numbers. Moreover, the parameter effect of the MSS is analysed, and the minimum/maximum thickness and folding angle significantly influence the crashworthiness responses. The mechanical properties of MSS-N can be regulated by changing the folding angle while maintaining the same thickness. The MSS proposed in this study can achieve a higher energy absorption efficiency at the same density compared to other existing mechanical structures. Interestingly, the feasibility of applying MSS to automobiles and plant protection drones is verified by changing the materials and macro-configurations. The design concept presented in this study provides a promising method for obtaining sandwich structures with excellent cushioning properties for engineering protective equipment.

Objective To investigate whether GRK4 regulates the phosphorylation and function of renal CCKBR. Methods GRK4 A142V transgenic mice were used as an animal model of enhanced GRK4 activity, and siRNA was used to silence the GRK4 gene to investigate the regulatory effect of GRK4 on CCKBR phosphorylation and function. Finally, the co-localization and co-connection of GRK4 and CCKBR in RPT cells were observed by laser confocal microscopy and immunoprecipitation to explore the mechanism of GRK4 regulating CCKBR. Results Gastrin infusion significantly increased urinary flow and sodium excretion rates in GRK4 WT mice (P

Abstract Background Dental treatment associated with unadaptable occlusal alteration can cause chronic primary myofascial orofacial pain. The serotonin (5-HT) pathway from the rostral ventromedial medulla (RVM) exerts descending modulation on nociceptive transmission in the spinal trigeminal nucleus (Sp5) and facilitates chronic pain. The aim of this study was to investigate whether descending 5-HT modulation from the RVM to the Sp5 is involved in the maintenance of primary myofascial orofacial hyperalgesia after persistent experimental occlusal interference (PEOI) or after delayed removal of experimental occlusal interference (REOI). Methods Expressions of 5-HT3A and 5-HT3B receptor subtypes in the Sp5 were assessed by immunofluorescence staining and Western blotting. The release and metabolism of 5-HT in the Sp5 were measured by high-performance liquid chromatography. Changes in the pain behavior of these rats were examined after specific pharmacologic antagonism of the 5-HT3 receptor, chemogenetic manipulation of the RVM 5-HT neurons, or selective down-regulation of 5-HT synthesis in the RVM. Results Upregulation of the 5-HT3B receptor subtype in the Sp5 was found in REOI and PEOI rats. The concentration of 5-HT in Sp5 increased significantly only in REOI rats. Intrathecal administration of Y-25130 (a selective 5-HT3 receptor antagonist) dose-dependently reversed the hyperalgesia in REOI rats but only transiently reversed the hyperalgesia in PEOI rats. Chemogenetic inhibition of the RVM 5-HT neurons reversed the hyperalgesia in REOI rats; selective down-regulation of 5-HT in advance also prevented the development of hyperalgesia in REOI rats; the above two manipulations did not affect the hyperalgesia in PEOI rats. However, chemogenetic activation of the RVM 5-HT neurons exacerbated the hyperalgesia both in REOI and PEOI rats. Conclusions These results provide several lines of evidence that the descending pathway from 5-HT neurons in the RVM to 5-HT3 receptors in the Sp5, plays an important role in facilitating the maintained orofacial hyperalgesia after delayed EOI removal, but has a limited role in that after persistent EOI. Graphical Abstract

Abstract Chronic wounds seriously affect the quality of life of the elderly, obese people, and diabetic patients. The excessive inflammatory response is a key driver of delayed chronic wound healing. Although lavender essential oil (EO [lav]) has been proven to have anti‐inflammatory and accelerate wound curative effects, the specific molecular mechanism involved is still ambiguous. The results showed that the wounds treated with lipopolysaccharide (LPS) not only had delayed healing, but also the expression levels of pro‐inflammatory cytokines, such as tumor necrosis factor‐α (TNF‐α), interleukin‐6 (IL‐6), interleukin‐1β (IL‐1β), and the inflammatory mediator protein, high‐mobility group box 1 protein (HMGB‐1), in the wound tissues were significantly increased. However, treatment of LPS‐induced chronic wounds with EO (lav) accelerated wound healing and decreased IL‐1β and HMGB‐1 expression levels. It was further found that LPS induced macrophage pyroptosis to produce IL‐1β. After treatment with EO (lav), the expression level of macrophage pyroptosis marker Gasdermin D (GSDMD) and pyroptosis‐related cytotoxic effects were significantly reduced. Immunofluorescence results also directly indicate that EO (lav) can protect macrophages from LPS‐induced pyroptosis. Moreover, EO (lav) can down‐regulate expression levels of IL‐1β, GSDMD, and nucleotide‐binding oligomerization domain‐like receptor protein 3 (NLRP3) in the caspase‐11‐related pyroptotic signaling pathway. This study demonstrates that EO (lav) can reduce proinflammatory factor production and ameliorate inflammatory response by inhibiting macrophage pyroptosis, which accelerates LPS‐induced chronic wound healing.

Abstract Background A growing body of research suggests that the use of computerized decision support systems can better guide disease treatment and reduce the use of social and medical resources. Artificial intelligence (AI) technology is increasingly being used in medical decision-making systems to obtain optimal dosing combinations and improve the survival rate of sepsis patients. To meet the real-world requirements of medical applications and make the training model more robust, we replaced the core algorithm applied in an AI-based medical decision support system developed by research teams at the Massachusetts Institute of Technology (MIT) and IMPERIAL College London (ICL) with the deep deterministic policy gradient (DDPG) algorithm. The main objective of this study was to develop an AI-based medical decision-making system that makes decisions closer to those of professional human clinicians and effectively reduces the mortality rate of sepsis patients. Methods We used the same public intensive care unit (ICU) dataset applied by the research teams at MIT and ICL, i.e., the Multiparameter Intelligent Monitoring in Intensive Care III (MIMIC-III) dataset, which contains information on the hospitalizations of 38,600 adult sepsis patients over the age of 15. We applied the DDPG algorithm as a strategy-based reinforcement learning approach to construct an AI-based medical decision-making system and analyzed the model results within a two-dimensional space to obtain the optimal dosing combination decision for sepsis patients. Results The results show that when the clinician administered the exact same dose as that recommended by the AI model, the mortality of the patients reached the lowest rate at 11.59%. At the same time, according to the database, the baseline mortality rate of the patients was calculated as 15.7%. This indicates that the patient mortality rate when difference between the doses administered by clinicians and those determined by the AI model was zero was approximately 4.2% lower than the baseline patient mortality rate found in the dataset. The results also illustrate that when a clinician administered a different dose than that recommended by the AI model, the patient mortality rate increased, and the greater the difference in dose, the higher the patient mortality rate. Furthermore, compared with the medical decision-making system based on the Deep-Q Learning Network (DQN) algorithm developed by the research teams at MIT and ICL, the optimal dosing combination recommended by our model is closer to that given by professional clinicians. Specifically, the number of patient samples administered by clinicians with the exact same dose recommended by our AI model increased by 142.3% compared with the model based on the DQN algorithm, with a reduction in the patient mortality rate of 2.58%. Conclusions The treatment plan generated by our medical decision-making system based on the DDPG algorithm is closer to that of a professional human clinician with a lower mortality rate in hospitalized sepsis patients, which can better help human clinicians deal with complex conditional changes in sepsis patients in an ICU. Our proposed AI-based medical decision-making system has the potential to provide the best reference dosing combinations for additional drugs.

Abstract Background DNA double-strand breaks (DSBs) are among the most deleterious DNA lesions, and they can cause cancer if improperly repaired. Recent chromosome conformation capture techniques, such as Hi-C, have enabled the identification of relationships between the 3D chromatin structure and DSBs, but little is known about how to explain these relationships, especially from global contact maps, or their contributions to DSB formation. Results Here, we propose a framework that integrates graph neural network (GNN) to unravel the relationship between 3D chromatin structure and DSBs using an advanced interpretable technique GNNExplainer. We identify a new chromatin structural unit named the DNA fragility–associated chromatin interaction network (FaCIN). FaCIN is a bottleneck-like structure, and it helps to reveal a universal form of how the fragility of a piece of DNA might be affected by the whole genome through chromatin interactions. Moreover, we demonstrate that neck interactions in FaCIN can serve as chromatin structural determinants of DSB formation. Conclusions Our study provides a more systematic and refined view enabling a better understanding of the mechanisms of DSB formation under the context of the 3D genome.

The dynamic recrystallization (DRX) behavior and microstructure evolution of medium-Mn (0.15C–10Mn) steel were investigated through isothermal hot compression tests. The flow stress–strain curves and microstructure analysis, in wide ranges of temperatures (900–1150 °C) and strain rates (10−3 - 1 s−1), were employed to establish constitutive equations and a grain size evolution model. Since the material constants were calculated based on polynomial function of strains, strain compensation was introduced into constitutive analysis. Comparison and verification showed that the constitutive equation had a high predictive ability. The correlation coefficient and average absolute relative error were 0.99 and 4.46%, respectively, which confirm the accuracy and guidance of the model. Metallographic observation was used to implement the grain size evolution analysis of the medium-Mn steel. Microstructure evolution was characterized with a gradual increase in average recrystallized grain size and an obvious expansion in the range of grain size distribution with both deformation temperature and strain rate, which were attributed to the competition between nucleation and grain boundary migration. Besides, a grain size evolution model was established to analyze the microstructure evolution.