High-intensity interval training vs. yoga in improving binge eating and physical fitness in inactive young females.

Yoga is effective in binge eating disorder (BED) treatment, but it does not seem effective enough to improve low physical fitness. In contrast, high-intensity interval training (HIIT) is effective in improving physical fitness but has never been studied in the context of BED. In the study, 47 young inactive females with mild to moderate BED were recruited and randomly assigned to a HIIT group (HIIT), a Yoga group (YG), or a control group (CG; age, 19.47 ± 0.74, 19.69 ± 0.874, and 19.44 ± 0.63 years; BMI, 21.07 ± 1.66, 21.95 ± 2.67, and 20.68 ± 2.61 kg/m2, respectively). The intervention groups participated in 8-week specific exercises, while the CG maintained their usual daily activity. Before and after the training, participants were evaluated for BED using the binge eating scale (BES) and for physical fitness. The obtained data were compared within groups and between groups, and a correlation analysis between BES and physical fitness parameters was performed. After the training, the YG presented significant improvements in BES (- 20.25%, p = 0.006, ηp2 = 0.408), fat mass (FM, - 3.13%, p = 0.033, ηp2 = 0.269), and maximal oxygen consumption (VO2max, 11.51%, p = 0.000, ηp2 = 0.601), whereas the HIIT showed significant improvements in body weight (BW, - 1.78%, p = 0.006, ηp2 = 0.433), FM (- 3.94%, p = 0.033, ηp2 = 0.285), and BMI (- 1.80%, p = 0.006, ηp2 = 0.428), but not in BES. Comparisons between groups revealed that both HIIT and YG had significantly higher VO2max levels than CG (HIIT 12.82%, p = 0.006, ηp2 = 0.088; YG: 11.90%, p = 0.009, ηp2 = 0.088) with no difference between HIIT and YG. Additionally, YG presented significantly lower BES than both HIIT (15.45%, p = 0.02, ηp2 = 0.03) and CG (11.91%, p = 0.022, ηp2 = 0.03). In conclusion, Yoga is an effective treatment for BED, but HIIT is not, despite its high efficacy in improving physical fitness.

Analysis of resting status reveals distinct elevational variation in metabolisms of lizards.

Animals spend a considerable proportion of their life span at rest. However, resting status has often been overlooked when investigating how species respond to environmental conditions. This may induce a large bias in understanding the local adaptation of species across environmental gradients and their vulnerability to potential environmental change. Here, we conducted an empirical study on montane agamid lizards, combined with mechanistic modeling, to compare elevational variations in body temperature and metabolisms (cumulative digestion and maintenance cost) between resting and active status. Our study on three populations of an agamid lizard along an elevational gradient revealed a trend of decreasing body temperature toward higher elevations, the main contributor of which was resting status of the lizards. Using population-specific reaction norms, we predicted greater elevational variation in hourly and cumulative digestion for resting lizards than for active lizards. Climate-change impacts, estimated as the change in cumulative digestion, also show greater elevational variation when resting status is factored into the analysis. Further, our global analysis of 98 agamid species revealed that in about half of their combined distributional range, the contribution of resting status in determining the elevational variation in cumulative digestion and maintenance cost of lizards was greater than the contribution made by a lizard's active status. Our study highlights the importance of considering resting status when investigating how species respond to environmental conditions, especially for those distributed over tropical and subtropical mountain areas.

Growth pattern of de novo small clusters of colorectal cancer is regulated by Notch signaling at detachment.

Cancer cell clusters have a higher capacity for metastasis than single cells, suggesting cancer cell clusters have biological properties different from those of single cells. The nature of de novo cancer cell clusters that are newly formed from tumor masses is largely unknown. Herein, we generated small cell clusters from colorectal cancer organoids and tracked the growth patterns of the clusters up to four cells. Growth patterns were classified into actively growing and poorly growing spheroids (PG). Notch signaling was robustly activated in small clusters immediately after dissociation, and Notch signaling inhibition markedly increased the proportion of PG spheroids. Only a limited number of PG spheroids grew under growth-permissive conditions in vitro, but xenograft tumors derived from Notch inhibited clusters showed growth rates comparable to those of untreated spheroids. Thus, de novo clusters are composed of cells with interchangeable growth fates, which are regulated in a context-dependent manner by Notch signaling.

Land use & land cover dynamics and its relationship with nitrate pollution in groundwater around inactive mine areas using geospatial techniques, SW part of Cuddapah basin, Southern India.

Geospatial maps can show how the ineffective operations of inactive mines affect water and aquifer quality. As such, the purpose of this study is to assess the impact of mining and irrigation on the aquifer ecosystem through the evaluation of LULC and slope maps through the application of Landsat 8 OLI/TIRS and DEM data. A total of 50 groundwater samples were prepared from villages in the close proximity to inactive mines during pre and post monsoon periods in 2021. The results of the analysis revealed alarming statistics, that 14% of groundwater samples exceeded the WHO nitrate limit in pre & post monsoon season, indicating a high-risk in the study area. According to guidelines (USEPA, 2014), 34% in pre-monsoon and 26% post-monsoon of samples exceeded the THI levels for adults and children respectively, indicating non-carcinogenic health risks. In addition, 80% of the samples in both seasons exhibited high NPI values, indicating nitrate contamination associated with blue baby syndrome. From the Geospatial analysis the findings from the LULC classification indicate that there has been a significant increase in cropland area from 2016 to 2021 due to changes in forest land, fallow land, and water resources. These problems have been exacerbated by the expansion of cultivated land, which has increased from 71.1 square kilometers in 2016 to 118 square kilometers in 2021, accounting for 13.1% of the total area. This expansion, coupled with elevated water body resource availability, has compounded the nitrate pollution including in intensely irrigated regions. The slope map analysis revealed that the inactive mines occur at low slope, high rainfall areas and these are compounded by runoff from other sources such as domestic and agricultural wastes. For these matters, sealing and remediating these inactive mines is essential so as to prevent further nitrate leakage.

Paediatric excipient risk assessment (PERA) tool and application for selecting appropriate excipients for paediatric dosage forms - Part 2.

It is necessary to use a scientifically sound process for excipient risk evaluation, selection, and management in order to develop paediatric medicinal products that are both safe and effective. The "Paediatric Excipient Risk Assessment (PERA)" framework, which proposes a comprehensive approach by considering all relevant factors related to patient, dosage form, and excipient attributes, was developed and published as part 1 of this paper series, to enable the rational selection of excipients for paediatric medicinal products. This article is Part 2 of the series and presents the PERA tool that allows easy adoption of the PERA framework. Using a straightforward heat map scoring approach (Red, Yellow, and Green category) for risk evaluation, the PERA tool can be used to compare and choose excipients. The PERA tool will help users identify potential gaps in excipients information that will help with risk-based mitigation planning. Several case studies covering frequently used and novel excipients for oral, as well as the choice of excipient for parenteral products for neonatal administration, serve to illustrate the PERA tool's usefulness.

Factors Associated With Physical Activity and Sedentary Behavior in People With Parkinson Disease: A Systematic Review and Meta-Analysis.

OBJECTIVE: The goal of this review was to investigate factors associated with physical activity and sedentary behavior in people with Parkinson disease (PD). The magnitude of these associations were investigated in line with the International Classification of Functioning, Disability and Health components. METHODS: A systematic literature review was conducted until February 2023, searching 4 databases (PubMed, EMBASE, Web of Science, and Scopus) for original articles investigating associations with physical activity or sedentary behavior in people with PD. Two independent researchers performed data extraction, and the risk of bias in the included studies was assessed using the Quality in Prognosis Studies tool. Meta-analyses were conducted to determine the magnitude of the associations, and significant regression models from the included studies were described. RESULTS: Forty-two studies were included. Twenty-one factors associated with overall physical activity were identified. Higher levels of physical activity had small association with cognition and body mass index, and fair association with 17 factors related to self-efficacy, physical function, mobility, quality of life, age, PD symptoms, and more. Better manual dexterity and functional gait had moderate to good association with higher levels of physical activity. The regression model with the higher magnitude was composed mostly of contextual factors, except for the body max index. The magnitude of factors associated with physical activity intensity or sedentary behavior could not be identified. CONCLUSION: Functional gait and manual dexterity were the strongest factors related to physical activity in people with PD. Further investigation is needed to understand the factors associated with physical activity intensity and sedentary behavior. IMPACT: This study emphasizes the significance of considering contextual factors alongside body function and structure, activity and participation, and the health condition to enhance physical activity improvement during the rehabilitation process. By adopting such holistic approach, rehabilitation professionals can optimize the overall health and wellbeing of individuals with Parkinson disease.

Comparison of Excipients in Approved Parenteral Products and Their Maximum Daily Exposure Values.

The following article analyses the excipients used in the parenteral formulations registered by the U.S. Food and Drug Administration (FDA) in the years 2011 and 2021. It adds real-word data for parenteral excipients in approved products from the New Zealand Medicines and Medical Devices Safety Authority (Medsafe) and the Irish Health Products Regulatory Authority (HPRA) in 2021. Maximum daily exposures (MDEs) for all parenteral excipients that had their amount listed either in the Medsafe or HPRA database are presented. Altogether, there were 355 excipients found in the parenteral dosage forms across all markets (US, New Zealand, and Ireland). Only 90 excipients (25.3%) were found in all three markets. In contrast, there were 187 (52.7%) excipients found in only one market. The MDE values of parenteral excipients from New Zealand and Ireland are frequently higher than the values found in the FDA inactive ingredients database (IID), adding important new information when the toxicity of these excipients is considered. There is a heterogenicity between the markets in use of parenteral excipients, with the US market leading in the number of total excipients as well as excipients present only in the US market. Nevertheless, there are several excipients not found in the US market that are registered in other markets. The comprehensive listing of parenteral excipients used worldwide presented in this article enables formulation scientists to quickly reference all potential parenteral excipients that are already proven safe and acceptable when designing a new parenteral formulation. Further, a list of new values for the MDE, often higher than those listed in the IID, provides important information for formulation scientists and toxicologists about the potential toxicity of these excipients.

Fusion of FokI and catalytically inactive prokaryotic Argonautes enables site-specific programmable DNA cleavage.

Site-specific nucleases are crucial for genome engineering applications in medicine and agriculture. The ideal site-specific nucleases are easily reprogrammable, highly specific in target site recognition, and robust in nuclease activities. Prokaryotic Argonaute (pAgo) proteins have received much attention as biotechnological tools due to their ability to recognize specific target sequences without a protospacer adjacent motif, but their lack of intrinsic dsDNA unwinding activity limits their utility in key applications such as gene editing. Recently, we developed a pAgo-based system for site-specific DNA cleavage at physiological temperatures independently of the DNA form, using peptide nucleic acids (PNAs) to facilitate unwinding dsDNA targets. Here, we fused catalytically dead pAgos with the nuclease domain of the restriction endonuclease FokI and named this modified platform PNA-assisted FokI-(d)pAgo (PNFP) editors. In the PNFP system, catalytically inactive pAgo recognizes and binds to a specific target DNA sequence based on a programmable guide DNA sequence; upon binding to the target site, the FokI domains dimerize and introduce precise dsDNA breaks. We explored key parameters of the PNFP system including the requirements of PNA and guide DNAs, the specificity of PNA and guide DNA on target cleavage, the optimal concentration of different components, reaction time for invasion and cleavage, and ideal temperature and reaction buffer, to ensure efficient DNA editing in vitro. The results demonstrated robust site-specific target cleavage by PNFP system at optimal conditions in vitro. We envision that the PNFP system will provide higher editing efficiency and specificity with fewer off-target effects in vivo.

Recent Progress in Organic Electrochemical Transistor-Structured Biosensors.

The continued advancement of organic electronic technology will establish organic electrochemical transistors as pivotal instruments in the field of biological detection. Here, we present a comprehensive review of the state-of-the-art technology and advancements in the use of organic electrochemical transistors as biosensors. This review provides an in-depth analysis of the diverse modification materials, methods, and mechanisms utilized in organic electrochemical transistor-structured biosensors (OETBs) for the selective detection of a wide range of target analyte encompassing electroactive species, electro-inactive species, and cancer cells. Recent advances in OETBs for use in sensing systems and wearable and implantable applications are also briefly introduced. Finally, challenges and opportunities in the field are discussed.

The role of control groups in non-pharmacological randomised controlled trials of treatment-resistant schizophrenia: A systematic review and meta-analysis.

Control groups used in randomised controlled trials investigating psychological interventions for depression and anxiety disorders have effects of their own. This has never been investigated for schizophrenia, in particular treatment-resistant schizophrenia. This systematic review and meta-analysis aimed to examine how control groups in randomised controlled trials on psychological interventions for treatment-resistant schizophrenia behave in their effects on general symptomatology. In a search of various databases until July 2023, 31 eligible studies with 3125 participants were found whose control groups were assigned to four categories: active, inactive, treatment as usual and waitlist. The analyses showed that psychological interventions had a greater effect on symptom reduction to all control groups combined. When separating the control groups, only compared to TAU and waitlist controls the psychological interventions were superior. The difference was larger when less active control groups (e.g. waitlist - or treatment as usual control groups) were used. All control groups were associated with an improvement in symptoms from pre- to post-measurement point, with the greatest improvement observed in the inactive control group. The results are preliminary, but they suggest that the choice of the control group has a considerable impact on study effects as it has been shown in other psychiatric diagnoses.

Expression of a kinase inactive SLK is embryonic lethal and impairs cell migration in fibroblasts.

Kinases are known to have kinase activity independent functions. To gain further insights into potential kinase-independent functions of SLK/STK2, we have developed a kinase-dead allele, SLKK63R using in vivo CRISPR/Cas technology. Our studies show that blastocysts homozygote for SLKK63R do not develop into viable mice. However, heterozygotes are viable and fertile with no overt phenotypes. Analyses of mouse embryonic fibroblasts show that expression of SLKK63R results in a 50% decrease in kinase activity in heterozygotes. In contrast to previous studies, our data show that SLK does not form homodimers and that the kinase defective allele does not act in a dominant negative fashion. Expression of SLKK63R leads to altered Rac1 and RhoA activity, increased stress fiber formation and delayed focal adhesion turnover. Our data support a previously observed role for SLK in cell migration and suggest that at least 50% kinase activity is sufficient for embryonic development.

Inhibition of Mir-21-5p Affects the Expression of LNCRNA X-Inactive Specific Transcript and Induces Apoptosis in MCF-7 Breast Cancer Cells.

Background: We aimed to investigate miR-21-5p inhibition effect on lncRNA-XIST expression and apoptosis status of MCF-7 cells. Methods: The MCF-7 cells were cultured and transfected by the anti-miR-21-5p oligonucleotide and expression of miR-21-5p, lncRNA-XIST, apoptosis-associated genes (bax and p53) and one miR-21-5p-unrelated lncRNA (BC200) was assessed by RT-qPCR. Furthermore, cell viability checked by MTT assay and apoptosis and cell cycle in transfected cells were detected by flow cytometry. Also, bioinformatics analysis on the transcriptome data confirmed that the lncRNA XIST might have a critical role in breast cancer (BC) cell apoptosis through ceRNAs mechanism and possible regulatory interactions with miR-21-5p. Results: Expression of miR-21-5p and lncRNA-XIST was significantly down- and up-regulated respectively (P<0.05). However, there was no significant change in lncRNA-BC200 expression. Also, the expression of bax and p53 upraised significantly (P<0.05). In transfected cells, MTT and flow cytometry assays reported a highly significant decrease and increase in viability and apoptosis respectively. Conclusion: Inhibition of miR-21-5p resulted in significant upregulation of lncRNA-XIST and apoptosis-associated genes bax and p53, which led to the induction of apoptosis in MCF-7 cells. Therefore, more investigations may provide a valuable target for studies on molecular therapies for BC.

Reactivation Risk of Latent Tuberculosis or Inactive Hepatitis B Virus Infection and Effectiveness of Ustekinumab in Chinese Plaque Psoriasis Patients: A 28-Week Retrospective, Observational Study.

Introduction: This study observed the effectiveness of ustekinumab and reactivation risk of concurrent latent tuberculosis infection (LTBI) and inactive hepatitis B virus (HBV) infection in Chinese mainland psoriasis patients on ustekinumab treatment. Methods: This retrospective, multicenter, observational study was conducted in three centers in China. Adult patients with moderate to severe plaque psoriasis were treated with ustekinumab for 28 weeks. The effectiveness endpoint included 75% and 90% improvement in Psoriasis Area Severity Index (PASI75/90) response rate, percentage of PASI improvement, change of absolute PASI score and body surface area involvement (BSA) score, absolute PASI ≤1/3 and Physicians' Global Assessment (PGA)=0/1, as well as Dermatology life quality index (DLQI)=0/1 response rate at week 4, 16 and 28. Screening of tuberculosis and hepatitis were performed at baseline and week 28. Results: A total of 82 patients were enrolled between March 2021 and May 2023 and the number of patients combined with LTBI and inactive HBV infection was 20 and 21 respectively. The PASI75 and PASI90 response rate at week 28 was 95.1% and 81.7% respectively. The mean PASI score decreased from 14.93 ± 12.07 at baseline to 0.78 ± 1.86 at week 28, and the mean BSA score decreased from 21% ± 18% at baseline to 1% ± 2% at week 28 (both P<0.001 compared with baseline). DLQI 0/1 response rate at week 28 was 73.2%. No reactivation of LTBI and inactive HBV infection and also no new-onset tuberculosis and hepatitis B occurred in patients without LTBI and inactive HBV infection at baseline. Conclusion: Ustekinumab demonstrated great effectiveness in Chinese plaque psoriasis patients and good safety in psoriasis concurrent with LTBI and inactive HBV infection under the real-world setting.

The impact of previous SARS-CoV-2 infection on post-vaccine adverse events in individuals vaccinated with TURKOVAC or CoronaVac -inactivated COVID-19 vaccines.

This study- a secondary analysis of data from a randomized, observer-blinded, non-inferiority study among volunteers between 18-55 y old in Türkiye- evaluated the impact of previous SARS-CoV-2 infection before the first dose of inactive TURKOVAC on post-vaccine local and systemic adverse events (AEs) comparing with CoronaVac. Of 1266 participants analyzed, 27.7% had a previous COVID-19 history. Local and systemic AEs were observed in 37.3% and 39% of the participants. The frequency of AEs was slightly higher in the first 30 minutes and 24 hours among participants with a COVID-19 history; none were severe. 1203 participants had a second dose vaccination, and 27.3% had a history of COVID-19. The frequencies of local and systemic AEs after the second dose were similar between those with and without a COVID-19 history. The TURKOVAC and CoronaVac showed similar frequencies of local and systemic AEs in the first 30 minutes after vaccination.

Role of iRhom2 in Olfaction: Implications for Odorant Receptor Regulation and Activity-Dependent Adaptation.

The cell surface metalloprotease ADAM17 (a disintegrin and metalloprotease 17) and its binding partners iRhom2 and iRhom1 (inactive Rhomboid-like proteins 1 and 2) modulate cell-cell interactions by mediating the release of membrane proteins such as TNFα (Tumor necrosis factor α) and EGFR (Epidermal growth factor receptor) ligands from the cell surface. Most cell types express both iRhoms, though myeloid cells exclusively express iRhom2, and iRhom1 is the main iRhom in the mouse brain. Here, we report that iRhom2 is uniquely expressed in olfactory sensory neurons (OSNs), highly specialized cells expressing one olfactory receptor (OR) from a repertoire of more than a thousand OR genes in mice. iRhom2-/- mice had no evident morphological defects in the olfactory epithelium (OE), yet RNAseq analysis revealed differential expression of a small subset of ORs. Notably, while the majority of ORs remain unaffected in iRhom2-/- OE, OSNs expressing ORs that are enriched in iRhom2-/- OE showed fewer gene expression changes upon odor environmental changes than the majority of OSNs. Moreover, we discovered an inverse correlation between the expression of iRhom2 compared to OSN activity genes and that odor exposure negatively regulates iRhom2 expression. Given that ORs are specialized G-protein coupled receptors (GPCRs) and many GPCRs activate iRhom2/ADAM17, we investigated if ORs could activate iRhom2/ADAM17. Activation of an olfactory receptor that is ectopically expressed in keratinocytes (OR2AT4) by its agonist Sandalore leads to ERK1/2 phosphorylation, likely via an iRhom2/ADAM17-dependent pathway. Taken together, these findings point to a mechanism by which odor stimulation of OSNs activates iRhom2/ADAM17 catalytic activity, resulting in downstream transcriptional changes to the OR repertoire and activity genes, and driving a negative feedback loop to downregulate iRhom2 expression.

Contribution of an alternative 16S rRNA helix to biogenesis of the 30S subunit of the ribosome.

30S subunits become inactive upon exposure to low Mg2+ concentration, because of a reversible conformational change that entails nucleotides (nt) in the neck helix (h28) and 3' tail of 16S rRNA. This active-to-inactive transition involves partial unwinding of h28 and repairing of nt 921-923 with nt 1532-1534, which requires flipping of the 3' tail by ∼180°. Growing evidence suggests that immature 30S particles adopt the inactive conformation in the cell, and transition to the active state occurs at a late stage of maturation. Here, we target nucleotides that form the alternative helix (hALT) of the inactive state. Using an orthogonal ribosome system, we find that disruption of hALT decreases translation activity in the cell modestly, by approximately twofold, without compromising ribosome fidelity. Ribosomes carrying substitutions at positions 1532-1533 support the growth of Escherichia coli strain Δ7 prrn (which carries a single rRNA operon), albeit at rates 10%-20% slower than wild-type ribosomes. These mutant Δ7 prrn strains accumulate free 30S particles and precursor 17S rRNA, indicative of biogenesis defects. Analysis of purified control and mutant subunits suggests that hALT stabilizes the inactive state by 1.2 kcal/mol with little-to-no impact on the active state or the transition state of conversion.

The Use of Tenofovir Disoproxil Fumarate in the Management of eAg-Negative Chronic Hepatitis B Infection.

Background/Objectives: Currently, there are insufficient data to recommend the treatment of patients with hepatitis B e antigen (HBeAg)-negative chronic infection who have normal ALT and low HBV DNA, since the prognosis is generally regarded as favorable. The aim of this pilot study was to determine whether the use of tenofovir disoproxil fumarate (TDF) 300 mg/day for 3 years was able to achieve functional cure (HBsAg loss) and HBsAg seroconversion in HBeAb-positive individuals. Methods: Fifty patients not on antiviral therapy (40% men, mean age 48.9 ± 10.9 years, 84% Asians) with minimal fibrosis were enrolled. Results: TDF reduced HBV DNA significantly to undetectable levels after 6 months. Overall, 48.3% of inactive carriers (baseline HBV DNA < 2000 IU/mL) remained HBV DNA negative 6 months after treatment withdrawal, which was significantly higher than the 5.6% in those who were not inactive carriers (baseline HBV DNA ≥ 2000 IU/mL) (p = 0.003). The HBsAg levels did not drop throughout the study period with no difference between inactive carriers versus those who were not. Five inactive carriers achieved functional cure, but none of these were amongst those who were not inactive carriers. No renal dysfunction or ALT flare on treatment withdrawal was observed. Conclusions: TDF could potentially be used to induce functional cure in patients who are inactive carriers with normal ALT, low HBV DNA and without advanced fibrosis.

Exploring Pyroptosis-related Signature Genes and Potential Drugs in Ulcerative Colitis by Transcriptome Data and Animal Experimental Validation.

Ulcerative colitis (UC) is an idiopathic, relapsing inflammatory disorder of the colonic mucosa. Pyroptosis contributes significantly to UC. However, the molecular mechanisms of UC remain unexplained. Herein, using transcriptome data and animal experimental validation, we sought to explore pyroptosis-related molecular mechanisms, signature genes, and potential drugs in UC. Gene profiles (GSE48959, GSE59071, GSE53306, and GSE94648) were selected from the Gene Expression Omnibus (GEO) database, which contained samples derived from patients with active and inactive UC, as well as health controls. Gene Set Enrichment Analysis (GSEA), Weighted Gene Co-expression Network Analysis (WGCNA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed on microarrays to unravel the association between UC and pyroptosis. Then, differential expressed genes (DEGs) and pyroptosis-related DEGs were obtained by differential expression analyses and the public database. Subsequently, pyroptosis-related DEGs and their association with the immune infiltration landscape were analyzed using the CIBERSORT method. Besides, potential signature genes were selected by machine learning (ML) algorithms, and then validated by testing datasets which included samples of colonic mucosal tissue and peripheral blood. More importantly, the potential drug was screened based on this. And these signature genes and the drug effect were finally observed in the animal experiment. GSEA and KEGG enrichment analyses on key module genes derived from WGCNA revealed a close association between UC and pyroptosis. Then, a total of 20 pyroptosis-related DEGs of UC and 27 pyroptosis-related DEGs of active UC were screened. Next, 6 candidate genes (ZBP1, AIM2, IL1ß, CASP1, TLR4, CASP11) in UC and 2 candidate genes (TLR4, CASP11) in active UC were respectively identified using the binary logistic regression (BLR), least absolute shrinkage and selection operator (LASSO), random forest (RF) analysis and artificial neural network (ANN), and these genes also showed high diagnostic specificity for UC in testing sets. Specially, TLR4 was elevated in UC and further elevated in active UC. The results of the drug screen revealed that six compounds (quercetin, cyclosporine, resveratrol, cisplatin, paclitaxel, rosiglitazone) could target TLR4, among which the effect of quercetin on intestinal pathology, pyroptosis and the expression of TLR4 in UC and active UC was further determined by the murine model. These findings demonstrated that pyroptosis may promote UC, and especially contributes to the activation of UC. Pyroptosis-related DEGs offer new ideas for the diagnosis of UC. Besides, quercetin was verified as an effective treatment for pyroptosis and intestinal inflammation. This study might enhance our comprehension on the pathogenic mechanism and diagnosis of UC and offer a treatment option for UC.

Comparison of macular and optic disc vessel density in thyroid orbitopathy: a comparative octa study.

PURPOSE: To determine the microvascular and structural changes in the peripapillary and macular areas observed in patients with active thyroid orbitopathy(TO) before and after steroid treatment and compare with inactive TO and the control group by optical coherence tomography angiography (OCTA). MATERIAL AND METHOD: This cross-sectional study included 34 eyes of 17 active TO patients, 108 eyes of 54 inactive TO patients, and 60 eyes of 30 healthy controls. Central macular thickness (CMT), ganglion cell layer-inner plexiform layer (GCL-IPL) thickness, central choroidal thickness (CCT), retinal nerve fiber layer (RNFL) thickness, choroidal thickness in the peripapillary region, superficial capillary plexus (SCP), deep capillary plexus (DCP) and choriocapillaris vessel densities were determined by OCTA in before and after 12-week steroid treatment of active TO cases, inactive TO and control groups. RESULTS: Between the three groups in macula OCTA, a statistically significant difference was observed in the inferior and nasal quadrants in SCP (all p = 0.01) and only in the temporal quadrant choriocapillaris (p = 0.005). In peripapillary OCTA, a statistically significant difference was found only in the central choriocapillaris (p = 0.03). In the comparison of the active group before and after treatment, there was a statistically significant decrease in CMT and CCT; a statistically significant increase was observed in GCL-IPL (all p < 0.01). There was a statistically significant decrease in SCP and DCP only in the central (all p < 0.01). There was a statistically significant increase was found in the lower quadrant macular SCP vessel density and mean macular DCP in post-treatment measurements (p = 0.01 and p = 0.03, respectively). Peripapillary SCP and DCP vessel density was increased after treatment (p < 0.01). CONCLUSION: Active TO group had lower vessel density than inactive group and after treatment, vessel density was increased. Non-invasive quantitative analysis of retinal and optic disc perfusion using OCTA could be useful in early treatment before complications occur and monitoring patients with TO.

Classification of Congenital Leptin Deficiency.

PURPOSE: Biallelic pathogenic leptin gene variants cause severe early-onset obesity usually associated with low or undetectable circulating leptin levels. Recently, variants have been described resulting in secreted mutant forms of the hormone leptin with either biologically inactive or antagonistic properties. METHODS: We conducted a systematic literature research supplemented by unpublished data from patients at our center as well as new in vitro analyses to provide a systematic classification of congenital leptin deficiency based on the molecular and functional characteristics of the underlying leptin variants and investigated the correlation of disease subtype with severity of the clinical phenotype. RESULTS: A total of 28 distinct homozygous leptin variants were identified in 148 patients. The identified variants can be divided into 3 different subtypes of congenital leptin deficiency: classical hormone deficiency (21 variants in 128 patients), biologically inactive hormone (3 variants in 12 patients), and antagonistic hormone (3 variants in 7 patients). Only 1 variant (n = 1 patient) remained unclassified. Patients with biological inactive leptin have a higher percentage of 95th body mass index percentile compared to patients with classical hormone deficiency. While patients with both classical hormone deficiency and biological inactive hormone can be treated with the same starting dose of metreleptin, patients with antagonistic hormone need a variant-tailored treatment approach to overcome the antagonistic properties of the variant leptin. MAIN CONCLUSION: Categorization of leptin variants based on molecular and functional characteristics helps to determine the most adequate approach to treatment of patients with congenital leptin deficiency.