Design, synthesis and biological evaluation of naphthyl amide derivatives as reversible monoacylglycerol lipase (MAGL) inhibitors.

Monoacylglycerol lipase (MAGL) is a key enzyme responsible for the metabolism of the endocannabinoid 2-arachidonoylglycerol (2-AG), and has attracted great interest due to its involvement in various physiological and pathological processes, such as cancer progression. In the past, a number of covalent irreversible inhibitors have been reported for MAGL, however, experimental evidence highlighted some drawbacks associated with the use of these irreversible agents. Therefore, efforts were mainly focused on the development of reversible MAGL inhibitor in recent years. Here, we designed and synthesized a series of naphthyl amide derivatives (12-39) as another type of reversible MAGL inhibitors, exemplified by ± 34, which displayed good MAGL inhibition with a pIC50 of 7.1, and the potency and selectivity against endogenous MAGL were further demonstrated by competitive ABPP. Moreover, the compound showed appreciable antiproliferative activities against several cancer cells, including H460, HT29, CT-26, Huh7 and HCCLM-3. The investigations culminated in the discovery of the naphthyl amide derivative ± 34, and it may represent as a new scaffold for MAGL inhibitor development, particularly for the reversible ones.

Recovery of the Infraorbital Nerve Following Open Reduction and Fixation Surgery of Zygomaticomaxillary Complex Fractures-A Prospective Cohort Study Based on Quantitative Sensory Testing.

This study aimed to assess the sensory function of the infraorbital nerve in patients with fractures of the zygomatic complex who underwent open reduction and internal fixation at different time points using quantitative sensory testing, which was established by the German Neuropathic Pain Research Network, comprising a 7-item mechanical and thermal sensory test. A total of 21 patients (age range 17-46 y, 14 males) with unilateral zygomatic complex fractures were included. Quantitative sensory testing was conducted before the operation and at 1 week, 3 months, and 6 months operatively, with cold detection threshold, warmth detection threshold, cold pain threshold, heat pain threshold, mechanical detection threshold, mechanical pain threshold, pressure pain threshold, and vibration detection threshold being measured in bilateral infraorbital regions. Notable changes in sensitivity were observed in all values except for the mechanical pain threshold. In the majority of patients with zygomaticomaxillary complex fractures, infraorbital hypoesthesia was significantly improved within 3 months postoperatively, and almost complete recovery could be achieved by 6 months postoperatively.

Chip-scale high-performance photonic microwave oscillator.

Optical frequency division based on bulk or fiber optics provides unprecedented spectral purity for microwave oscillators. To extend the applications of this approach, the challenges are to develop miniaturized oscillators without trading off phase noise performance. Here, we report a chip-scale high-performance photonic microwave oscillator based on integrated electro-optical frequency division. Dual distributed-feedback lasers are co-self-injection locked to a single silicon nitride spiral resonator to provide a record-high-stability, fully on-chip optical reference. An integrated electro-optical frequency comb based on a thin-film lithium niobate phase modulator chip is leveraged to perform optical-to-microwave frequency division. The resulting integrated photonic microwave oscillator achieves a record-low phase noise for chip-scale oscillators. The results represent a major advance in high-performance, integrated photonic microwave oscillators for applications including signal processing, radar, timing, and coherent communications.

Distinct basal forebrain-originated neural circuits promote homoeostatic feeding and suppress hedonic feeding in male mice.

Feeding behaviour is influenced by two primary factors: homoeostatic needs driven by hunger and hedonic desires for pleasure even in the absence of hunger. While efficient homoeostatic feeding is vital for survival, excessive hedonic feeding can lead to adverse consequences such as obesity and metabolic dysregulations. However, the neurobiological mechanisms that orchestrate homoeostatic versus hedonic food consumption remain largely unknown. Here we show that GABAergic proenkephalin (Penk) neurons in the diagonal band of Broca (DBB) of male mice respond to food presentation. We further demonstrate that a subset of DBBPenk neurons that project to the paraventricular nucleus of the hypothalamus are preferentially activated upon food presentation during fasting periods and transmit a positive valence to facilitate feeding. On the other hand, a separate subset of DBBPenk neurons that project to the lateral hypothalamus are preferentially activated when detecting a high-fat high-sugar (HFHS) diet and transmit a negative valence to inhibit food consumption. Notably, when given free choice of chow and HFHS diets, mice with the whole DBBPenk population ablated exhibit reduced consumption of chow but increased intake of the HFHS diet, resulting in accelerated development of obesity and metabolic disturbances. Together, we identify a molecularly defined neural population in male mice that is crucial for the maintenance of energy balance by facilitating homoeostatic feeding while suppressing hedonic overeating.

Short-term intermittent hypoxia exposure for dyspnea and fatigue in post-acute sequelae of COVID-19: A randomized controlled study.

BACKGROUND: Post-acute sequelae of COVID-19 (PASC) is incurring a huge health and economic burden worldwide. There is currently no effective treatment or recommended drug for PASC. METHODS: This prospective randomized controlled study was conducted in a hospital in China. The effect of intermittent hypoxia exposure (IHE; 5-min hypoxia alternating with 5-min normal air, repeated five times) on dyspnea and fatigue was investigated in patients meeting the NICE definition of PASC. Patients were computationally randomized to receive normoxia exposure (NE) and routine therapy or IHE and routine therapy. Six-minute walk distance (6MWD) and spirometry were tested before and after the interventions; the Borg Dyspnea Scale (Borg) and the modified Medical Research Council Dyspnea Scale (mMRC) were used to assess dyspnea; and the Fatigue Assessment Scale (FAS) and the Chalder Fatigue Scale-11 (CFQ-11) were used to assess fatigue. The study was registered in the Chinese Clinical Trial Registry (ChiCTR2300070565). FINDINGS: Ninety-five participants (33 males and 62 females) were recruited between March 1, 2023 and December 30, 2023. Forty-seven patients in the IHE group received 10.0 (9.0, 15.0) days of IHE, and 48 patients in NE group received 10.0 (8.0, 12.0) days of NE. 6MWD, forced vital capacity (FVC), FVC %pred, forced expiratory volume in 1 s (FEV1), FEV1 %pred, tidal volume (VT), and dyspnea and fatigue scales markedly improved after IHE (p < 0.05), and improvements were greater than in the NE group (all p < 0.05). Furthermore, participants in IHE group had better subjective improvements in dyspnea and fatigue than those in the NE group (p < 0.05). Compared with <10 days of IHE, ≥10 days of IHE had a greater impact on 6MWD, FVC, FEV1, FEV1 %pred, VT, FAS, and CFQ-11. No severe adverse events were reported. INTERPRETATION: IHE improved spirometry and 6MWD and relieved dyspnea and fatigue in PASC patients. Larger prospective studies are now needed to verify these findings.

Carbon dot-loaded Fe3O4as photonic pigments for multilevel anti-counterfeiting.

Amorphous arrays assembled from colloidal microspheres are a way to obtain angle-independent structural colors. In order to obtain additional properties, colloidal microspheres as constituent units can be modified with other materials. Here, we utilized the silane functionalized carbon quantum dots (SiCDs) by incorporating them into the Stöber reaction to fabricate Fe3O4@SiO2/SiCDs nanospheres with a core-shell structure. ACAs were constructed on commercial printing paper using Fe3O4@SiO2/SiCDs nanoparticles as structural units by simple permeation assembly. Macroscopically, the prepared ACAs exhibits the magnetic properties of Fe3O4, while under sunlight, it displays bright, angle-independent structural colors. Under ultraviolet light, the array shows significant fluorescent luminescence. This enables the presentation of multidimensional information under varying magnetic and lighting conditions. By adjusting the thickness of the outer SiO2/SiCDs composite layer, the optical properties and magnetism can be easily controlled. Moreover, due to the strong light absorption capability and high refractive index of Fe3O4, the digital patterns constructed with Fe3O4@SiO2/SiCDs nanospheres demonstrate excellent multi-level anti-counterfeiting characteristics, even under water erosion. The magnetic properties of Fe3O4@SiO2/SiCDs nanospheres, along with their distinct display characteristics under different optical environments, suggest their wide applicability in the fields of color multifunctional anti-counterfeiting pigments, bioimaging, and sensing displays.

Ubiquitin-specific protease UBP14 stabilizes HY5 by deubiquitination to promote photomorphogenesis in Arabidopsis thaliana.

Transcription factor ELONGATED HYPOCOTYL5 (HY5) is the central hub for seedling photomorphogenesis. E3 ubiquitin (Ub) ligase CONSTITUTIVE PHOTOMORPHOGENIC 1 (COP1) inhibits HY5 protein accumulation through ubiquitination. However, the process of HY5 deubiquitination, which antagonizes E3 ligase-mediated ubiquitination to maintain HY5 homeostasis has never been studied. Here, we identified that Arabidopsis thaliana deubiquitinating enzyme, Ub-SPECIFIC PROTEASE 14 (UBP14) physically interacts with HY5 and enhances its protein stability by deubiquitination. The da3-1 mutant lacking UBP14 function exhibited a long hypocotyl phenotype, and UBP14 deficiency led to the failure of rapid accumulation of HY5 during dark to light. In addition, UBP14 preferred to stabilize nonphosphorylated form of HY5 which is more readily bound to downstream target genes. HY5 promoted the expression and protein accumulation of UBP14 for positive feedback to facilitate photomorphogenesis. Our findings thus established a mechanism by which UBP14 stabilizes HY5 protein by deubiquitination to promote photomorphogenesis in A. thaliana.

Uncovering the Size-Dependent Thermal Solid Transformation of Akaganéite.

Investigating the structural evolution and phase transformation of iron oxides is crucial for gaining a deeper understanding of geological changes on diverse planets and preparing oxide materials suitable for industrial applications. In this study, in-situ heating techniques are employed in conjunction with transmission electron microscopy (TEM) observations and ex-situ characterization to thoroughly analyze the thermal solid-phase transformation of akaganéite 1D nanostructures with varying diameters. These findings offer compelling evidence for a size-dependent morphology evolution in akaganéite 1D nanostructures, which can be attributed to the transformation from akaganéite to maghemite (γ-Fe2O3) and subsequent crystal growth. Specifically, it is observed that akaganéite nanorods with a diameter of ∼50 nm transformed into hollow polycrystalline maghemite nanorods, which demonstrated remarkable stability without arresting crystal growth under continuous heating. In contrast, smaller akaganéite nanoneedles or nanowires with a diameter ranging from 20 to 8 nm displayed a propensity for forming single-crystal nanoneedles or nanowires through phase transformation and densification. By manipulating the size of the precursors, a straightforward method is developed for the synthesis of single-crystal and polycrystalline maghemite nanowires through solid-phase transformation. These significant findings provide new insights into the size-dependent structural evolution and phase transformation of iron oxides at the nanoscale.

[Interpretation of the 2023 "Guidelines for parenteral nutrition in preterm infants: the American Society for Parenteral and Enteral Nutrition"]. / ã€Šç¾Žå›½è‚ å¤–è‚ å† è¥å »å­¦ä¼šæ—©äº§å„¿è‚ å¤–è¥å »æŒ‡å—ï¼ˆ2023）》解读.

The "Guidelines for parenteral nutrition in preterm infants: the American Society for parenteral and enteral nutrition" were developed by the American Society for Parenteral and Enteral Nutrition and published in the Journal of Parenteral and Enteral Nutrition in September 2023. The guidelines provide recommendations on 12 key clinical questions regarding parenteral nutrition (PN) for preterm infants. In comparison to similar guidelines, this set offers more detailed perspectives on PN for preterm infants. It presents evidence-based recommendations for the commencement time, nutrient dosage, and composition of PN, considering primary outcomes such as growth and development, as well as secondary outcomes like sepsis, retinopathy of prematurity, parenteral nutrition-related liver disease, and jaundice. This article aims to interpret the guidelines to provide a reference for colleagues in the field.

Analysis of clinical characteristics of terbinafine-induced subacute cutaneous lupus erythematosus.

INTRODUCTION: Terbinafine may cause subacute cutaneous lupus erythematosus (SCLE), and we aimed to analyze its clinical characteristics. METHODS: We collected literature on terbinafine-induced SCLE from 1997 to 2023 for retrospective analysis. Thirty-seven patients (33 females and 4 males) were included. RESULTS: The patients have a median age of 49.5 years (range 18-79) and onset time of 5 weeks (range 1-12). SCLE is mainly manifested as annular erythematous (83.3%), scaly erythematous (44.4%), and maculopapular erythematous (13.9%). Mainly, histopathological manifestations are lymphocytic infiltrate (55.6%), hyperkeratosis (38.9%) and keratinocyte necrosis (38.9%). Positive immunological parameters mainly include antinuclear antibody (100.0%), anti-Ro/SSA antibody (94.1%), and anti-La/SSB antibody (72.2%). Past medical history usually includes photosensitivity (33.3%), inflammatory disease (33.33%), and lupus erythematosus (12.1%). Symptoms are completely resolved within a median time of 35 days (range 7-84) after discontinuation of terbinafine and treatment with topical corticosteroids, systemic corticosteroids, hydroxychloroquine, and immunosuppressant. No recurrence was observed within 12 months (range 1.5-48) of follow-up. CONCLUSION: These results suggest that terbinafine-induced SCLE should be comprehensively diagnosed based on clinical symptoms, histopathological manifestations, immunological parameters, and past medical history. Terbinafine should be immediately discontinued when SCLE occurs, while systemic and topical corticosteroids combined with hydroxychloroquine may be an effective treatment.

Exploring the impact of women-specific reproductive factors on phenotypic aging and the role of life's essential 8.

BACKGROUND: Aging is an inevitable biological process. Accelerated aging renders adults more susceptible to chronic diseases and increases their mortality rates. Previous studies have reported the relationship between lifestyle factors and phenotypic aging. However, the relationship between intrinsic factors, such as reproductive factors, and phenotypic aging remains unclear. METHODS: This study utilized data from the National Health and Nutrition Examination Survey (NHANES), spanning from 1999 to 2010 and 2015-2018, with 14,736 adult women. Random forest imputation was used to handle missing covariate values in the final cohort. Weighted linear regression was utilized to analyze the relationship between women-specific reproductive factors and PhenoAgeAccel. Considering the potential impact of menopausal status on the results, additional analyses were conducted on premenopausal and postmenopausal participants. Additionally, the Life's Essential 8 (LE8) was used to investigate the impact of healthy lifestyle and other factors on the relationship between women-specific reproductive factors and PhenoAgeAccel. Stratified analyses were conducted based on significant interaction p-values. RESULTS: In the fully adjusted models, delayed menarche and gynecological surgery were associated with increased PhenoAgeAccel, whereas pregnancy history were associated with a decrease. Additionally, early or late ages of menopause, first live birth, and last live birth can all negatively impact PhenoAgeAccel. The relationship between women-specific reproductive factors and PhenoAgeAccel differs between premenopausal and postmenopausal women. High LE8 scores positively impacted the relationship between certain reproductive factors (age at menarche, age at menopause, age at first live birth, and age at last live birth) and phenotypic age acceleration. Stratified analysis showed significant interactions for the following variables: BMI with age at menarche, pregnancy history, and age at menopause; ethnicity with age at menopause, age at first live birth, and parity; smoking status with use of contraceptive pills and gynecologic surgery; hypertension with use of contraceptive pills, pregnancy history, and age at menopause. CONCLUSION: Delayed menarche, gynecological surgery, and early or late ages of menopause, first live birth, and last live birth are associated with accelerated phenotypic aging. High LE8 score may alleviate the adverse effects of reproductive factors on phenotypic aging.

Thyroid dysfunction in the wake of Omicron: understanding its role in COVID-19 severity and mortality.

Purpose: SARS-CoV-2 can invade the thyroid gland. This study was to delineate the risk of thyroid dysfunction amidst the prevalence of the Omicron variant, and to investigate the correlation between thyroid function and Coronavirus disease 2019 (COVID-19) outcomes. The study also aimed to ascertain whether thyroid dysfunction persisted during COVID-19 recovery phase. Methods: This was a retrospective cohort study. COVID-19 patients from the Renmin Hospital of Wuhan University, China during the epidemic of Omicron variants were included, and their thyroid function were analyzed in groups. Results: A history of thyroid disease was not associated with COVID-19 outcomes. COVID-19 can lead to a bimodal distribution of thyroid dysfunction. The severity of COVID-19 was inversely proportional to the levels of thyroid- stimulating hormone (TSH), free triiodothyronine (FT3) and free thyroxine (FT4), leading to a higher prevalence of thyroid dysfunction. Severe COVID-19 was a risk factor for euthyroid sick syndrome (ESS) (OR=22.5, 95% CI, 12.1 - 45.6). Neutrophil to lymphocyte ratio mediated the association between severe COVID-19 and ESS (mediation effect ratio = 41.3%, p < 0.001). ESS and decreased indicators of thyroid function were associated with COVID-19 mortality, while high levels of FT3 and FT4 exhibited a protective effect against death. This effect was more significant in women (p < 0.05). During the recovery period, hyperthyroidism was quite uncommon, while a small percentage of individuals (7.7%) continued to exhibit hypothyroidism. Conclusion: COVID-19 severity was linked to thyroid dysfunction. Severe COVID-19 increased the risk of ESS, which was associated with COVID-19 mortality. Post-recovery, hyperthyroidism was rare, but some individuals continued to have hypothyroidism.

Mitigation of Parasitic and Drift Capacitance-Induced Nonlinear Current Responses for Stable and Sensitive Perovskite X-ray Detectors.

The development of perovskite direct X-ray detectors shows potential for advancing medical imaging and industrial inspection precision. To ensure the optimal energy conversion efficiency of X-rays for reducing radiation doses, it is necessary for perovskites with thicknesses reaching hundreds of micrometers or even several millimeters to be utilized. However, the nonlinear current response becomes uncertain with such high thicknesses. For instance, the prevailing theory regarding the rapid trapping and release of charges by shallow-level defects falls short in explaining the nonlinear current response observed in high-quality single-crystal samples. Moreover, a significant nonlinear current response can degrade the detection performance. Here, we elucidate peculiar parasitic and drift capacitance-induced nonlinear current responses in perovskites, which arise from bulk structural deficiencies and interface junction width variation in addition to shallow-level defects. Both theoretical analysis and experimental findings demonstrate the effective suppression of nonlinear current responses by establishing bulk heterojunctions and refining interface junctions. Consequently, we have successfully developed highly linear current-responsive detectors based on polycrystalline MAPbI3 thick films. Notably, these detectors achieve a record sensitivity of 2.3 × 104 µC·Gyair-1·cm-2 under 100 kVp X-ray irradiation with a low bias of 0.1 V/µm, enabling enduring and high-resolution X-ray imaging for high-density objects. Successful fabrication and testing of a 64 × 64-pixel flat-panel prototype detector affirm the widespread applicability of these strategies in rectifying nonlinear current responses in perovskite-based X-ray detectors.

RiskFormer: Exploring the temporal associations between multi-type aberrant driving events and crash occurrence.

With the development of driving behavior monitoring technologies, commercial transportation enterprises have leveraged aberrant driving event detection results for evaluating crash risk and triggering proactive interventions. The state-of-the-art applications were established based upon instant associations between events and crash occurrence, which assumed crash risk surged with aberrant events. Consequently, the generated crash risk monitoring results merely contain discrete abrupt changes, failing to depict the time-varying trend of crash risk and posing challenges for interventions. Given the multiple types of aberrant events and their various temporal combinations, the key to depict crash risk time-varying trend is the analysis of multi-type events' temporal coupling influence. Existing studies employed event frequency to model combined influence, lacking the capability to differentiate the temporal sequential characteristics of events. Hence, there is an urgent need to further explore multi-type events' temporal coupling influence on crash risk. In this study, the temporal associations between multi-type aberrant driving events and crash occurrence are explored. Specifically, a contrastive learning method, fusing prior domain knowledge and empirical data, was proposed to analyze the single event temporal influence on crash risk. After that, a novel Crash Risk Evaluation Transformer (RiskFormer) was developed. In the RiskFormer, a unified encoding method for different events, as well as a self-attention mechanism, were established to learn multi-type events' temporal coupling influence. Empirical data from online ride-hailing services were employed, and the modeling results unveiled three distinct time-varying patterns of crash risk, including decay, increasing, and increasing-decay pattern. Additionally, RiskFormer exhibited remarkable crash risk evaluation performance, demonstrating a 12.8% improvement in the Area Under Curve (AUC) score compared to the conventional instant-association-based model. Furthermore, the practical utility of RiskFormer was illustrated through a crash risk monitoring sample case. Finally, applications of the proposed methods and their further investigations have been discussed.

A Triple Crosslinked Binder with Hierarchical Stress Dissipation and High Ionic Conductivity for Advanced Silicon Anodes in Lithium-ion Batteries.

Silicon (Si) is a promising anode material for high-energy-density lithium-ion batteries, but the significant volume change of Si particles during alloying/dealloying with lithium (Li) undermines the mechanical integrity of Si anode, causing electrode fracture, delamination and rapid capacity decay. Herein, a robust triple crosslinked network (TCN) binder with high ionic conductivity and hierarchical stress dissipation is reported for Si anodes, which is prepared by in situ chemical crosslinking polyacrylic acid (PAA) and melamine (MA). The triple interactions of hydrogen bonds, electrostatic interactions, and covalent amide bonds enhance the adhesion of binder to Si and synergistically promote stress dissipation within Si anodes, thus strengthening the dynamic structural stability of Si anodes during cycling. Moreover, the rapid coupling/decoupling of Li+ with the TCN binder enables an impressive Li+ transference number of 0.63 and high ionic conductivity of 1.2 × 10-4 S cm-1. Consequently, the Si-TCN anode delivers specific capacity of 2268 mAh g-1 with a high mass loading of 2 mg cm-2, high-rate performance of 1673 mAh g-1 at 5 A g-1, and stable cycling for 250 cycles at 1 A g-1, thus showing great prospects for high-energy-density Si-based batteries.

Analysis of clinical characteristics of mismatch repair status in colorectal cancer: a multicenter retrospective study.

BACKGROUND: Microsatellite instability (MSI) caused by DNA mismatch repair (MMR) deficiency is of great significance in the occurrence, diagnosis and treatment of colorectal cancer (CRC). AIM: This study aimed to analyze the relationship between mismatch repair status and clinical characteristics of CRC. METHODS: The histopathological results and clinical characteristics of 2029 patients who suffered from CRC and underwent surgery at two centers from 2018 to 2020 were determined. After screening the importance of clinical characteristics through machine learning algorithms, the patients were divided into deficient mismatch repair (dMMR) and proficient mismatch repair (pMMR) groups based on the immunohistochemistry results and the clinical feature data between the two groups were observed by statistical methods. RESULTS: The dMMR and pMMR groups had significant differences in histologic type, TNM stage, maximum tumor diameter, lymph node metastasis, differentiation grade, gross appearance, and vascular invasion. There were significant differences between the MLH1 groups in age, histologic type, TNM stage, lymph node metastasis, tumor location, and depth of invasion. The MSH2 groups were significantly different in age. The MSH6 groups had significant differences in age, histologic type, and TNM stage. There were significant differences between the PMS2 groups in lymph node metastasis and tumor location. CRC was dominated by MLH1 and PMS2 combined expression loss (41.77%). There was a positive correlation between MLH1 and MSH2 and between MSH6 and PMS2 as well. CONCLUSIONS: The proportion of mucinous adenocarcinoma, protruding type, and poor differentiation is relatively high in dMMR CRCs, but lymph node metastasis is rare. It is worth noting that the expression of MMR protein has different prognostic significance in different stages of CRC disease.

Hydrogen Sulfide Promotes Platelet Autophagy via PDGFR-α/PI3K/Akt Signaling in Cirrhotic Thrombocytopenia.

Background and Aims: The role of platelet autophagy in cirrhotic thrombocytopenia (CTP) remains unclear. This study aimed to investigate the impact of platelet autophagy in CTP and elucidate the regulatory mechanism of hydrogen sulfide (H2S) on platelet autophagy. Methods: Platelets from 56 cirrhotic patients and 56 healthy individuals were isolated for in vitro analyses. Autophagy markers (ATG7, BECN1, LC3, and SQSTM1) were quantified using enzyme-linked immunosorbent assay, while autophagosomes were visualized through electron microscopy. Western blotting was used to assess the autophagy-related proteins and the PDGFR/PI3K/Akt/mTOR pathway following treatment with NaHS (an H2S donor), hydroxocobalamin (an H2S scavenger), or AG 1295 (a selective PDGFR-α inhibitor). A carbon tetrachloride-induced cirrhotic BALB/c mouse model was established. Cirrhotic mice with thrombocytopenia were randomly treated with normal saline, NaHS, or hydroxocobalamin for 15 days. Changes in platelet count and aggregation rate were observed every three days. Results: Cirrhotic patients with thrombocytopenia exhibited significantly decreased platelet autophagy markers and endogenous H2S levels, alongside increased platelet aggregation, compared to healthy controls. In vitro, NaHS treatment of platelets from severe CTP patients elevated LC3-II levels, reduced SQSTM1 levels, and decreased platelet aggregation in a dose-dependent manner. H2S treatment inhibited PDGFR, PI3K, Akt, and mTOR phosphorylation. In vivo, NaHS significantly increased LC3-II and decreased SQSTM1 expressions in platelets of cirrhotic mice, reducing platelet aggregation without affecting the platelet count. Conclusions: Diminished platelet autophagy potentially contributes to thrombocytopenia in cirrhotic patients. H2S modulates platelet autophagy and functions possibly via the PDGFR-α/PI3K/Akt/mTOR signaling pathway.

Loss of transient receptor potential channel 5 causes obesity and postpartum depression.

Hypothalamic neural circuits regulate instinctive behaviors such as food seeking, the fight/flight response, socialization, and maternal care. Here, we identified microdeletions on chromosome Xq23 disrupting the brain-expressed transient receptor potential (TRP) channel 5 (TRPC5). This family of channels detects sensory stimuli and converts them into electrical signals interpretable by the brain. Male TRPC5 deletion carriers exhibited food seeking, obesity, anxiety, and autism, which were recapitulated in knockin male mice harboring a human loss-of-function TRPC5 mutation. Women carrying TRPC5 deletions had severe postpartum depression. As mothers, female knockin mice exhibited anhedonia and depression-like behavior with impaired care of offspring. Deletion of Trpc5 from oxytocin neurons in the hypothalamic paraventricular nucleus caused obesity in both sexes and postpartum depressive behavior in females, while Trpc5 overexpression in oxytocin neurons in knock-in mice reversed these phenotypes. We demonstrate that TRPC5 plays a pivotal role in mediating innate human behaviors fundamental to survival, including food seeking and maternal care.

A pilot randomized controlled trial of major ozone autohemotherapy for patients with post-acute sequelae of COVID-19.

This prospective, randomized, controlled clinical trial assessed the therapeutic effects of major ozone autohemotherapy (O3-MAH) in patients with post-acute sequelae of COVID-19 (PASC). Seventy-three eligible participants were randomly assigned to an O3-MAH plus conventional therapy group (n = 35) or a conventional therapy alone group (n = 38). Symptom score, pulmonary function, 6-minute walk distance (6MWD), and hematological, biochemical, and immunological parameters were evaluated before and after the interventions. Both groups demonstrated improvements in various parameters post-intervention, but efficacy was greater in the O3-MAH group than the conventional treatment group; with intervention effectiveness defined as a ≥ 50 % reduction in symptom score, 25 of 35 patients (71 %) responded to O3-MAH, while 17/38 patients (45 %) responded to conventional treatment alone (P = 0.0325). Significant improvements in symptom scores (P = 0.0478), tidal volume (P = 0.0374), predicted 6MWD (P = 0.0032), and coagulation and inflammatory indicators were noted in the O3-MAH group compared with the conventional treatment group. O3-MAH was more likely to be effective in patients with elevated CRP levels. Furthermore, O3-MAH markedly improved cellular immunity, and this improvement became more pronounced with extended treatment duration. In summary, combining O3-MAH with conventional treatment was more effective than conventional therapy alone in improving symptoms, pulmonary function, inflammation, coagulation, and cellular immunity in patients with PASC. Further research is now warranted to validate these findings and individualize the regimen.

Ganoderic Acid A Mitigates Inflammatory Bowel Disease through Modulation of AhR Activity by Microbial Tryptophan Metabolism.

Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is a complex gastrointestinal condition influenced by genetic, microbial, and environmental factors, among which the gut microbiota plays a crucial role and has emerged as a potential therapeutic target. Ganoderic acid A (GAA), which is a lanostane triterpenoid compound derived from edible mushroom Ganoderma lucidum, has demonstrated the ability to modulate gut dysbiosis. Thus, we investigated the impact of GAA on IBD using a dextran sodium sulfate (DSS)-induced colitis mouse model. GAA effectively prevented colitis, preserved epithelial and mucus layer integrity, and modulated the gut microbiota. In addition, GAA promoted tryptophan metabolism, especially 3-IAld generation, activated the aryl hydrocarbon receptor (AhR), and induced IL-22 production. Fecal microbiota transplantation validated the mediating role of the gut microbiota in the IBD protection conferred by GAA. Our study suggests that GAA holds potential as a nutritional intervention for ameliorating IBD by influencing the gut microbiota, thereby regulating tryptophan metabolism, enhancing AhR activity, and ultimately improving gut barrier function.