Activity Screening Research Articles

Genome-Wide Association Studies Reveal That the Abietane Diterpene Isopimaric Acid Promotes Rice Growth through Inhibition of Defense Pathways.

Plants are an important source for the discovery of novel natural growth regulators. We used activity screening to demonstrate that treatment of Nipponbare seeds with 25 μg/mL isopimaric acid significantly increased the resulting shoot length, root length, and shoot weight of rice seedlings by 11.37 ± 5.05%, 12.96 ± 7.63%, and 27.98 ± 10.88% and that it has a higher activity than Gibberellin A3 (GA3) at the same concentration. A total of 213 inbred lines of different rice lineages were screened, and we found that isopimaric acid had different growth promotional activities on rice seedlings of different varieties. After induction with 25 μg/mL isopimaric acid, 15.02% of the rice varieties tested showed increased growth, while 15.96% of the varieties showed decreased growth; the growth of the remaining 69.02% did not show any significant change from the control. In the rice varieties showing an increase in growth, the shoot length and shoot weight significantly increased, accounting for 21.88% and 31.25%. The root length and weight significantly increased, accounting for 6.25% and 3.13%. Using genome-wide association studies (GWASs), linkage disequilibrium block, and gene haplotype significance analysis, we identified single nucleotide polymorphism (SNP) signals that were significantly associated with the length and weight of shoots on chromosomes 2 and 8, respectively. After that, we obtained 17 candidate genes related to the length of shoots and 4 candidate genes related to the weight of shoots. Finally, from the gene annotation data and gene tissue-specific expression; two genes related to this isopimaric acid regulation phenotype were identified as OsASC1 (LOC_Os02g37080) on chromosome 2 and OsBUD13 (LOC_Os08g08080) on chromosome 8. Subcellular localization analysis indicated that OsASC1 was expressed in the plasma membrane and the nuclear membrane, while OsBUD13 was expressed in the nucleus. Further RT-qPCR analysis showed that the relative expression levels of the resistance gene OsASC1 and the antibody protein gene OsBUD13 decreased significantly following treatment with 25 μg/mL isopimaric acid. These results suggest that isopimaric acid may inhibit defense pathways in order to promote the growth of rice seedlings.

Individualized activity recommendation based on a physical fitness assessment increases short- and long-term regular physical activity in people with multiple sclerosis in a retrospective cohort study.

Despite the evidence of beneficial effects of physical activity (PA), people with multiple sclerosis (pwMS) are less physically active than the general population. To increase PA in pwMS, we developed a structured individually tailored PA promotion program which is conducted within clinical practice in a university-based outpatient clinic since 2016. This study serves as retrospective quality control of this program. In a retrospective cohort study, we assessed the physical fitness of pwMS and the impact of the program on short- and long-term PA changes and behavioral determinants. The program consisted of four appointments each 2-4 weeks apart. Spiroergometric test results of female pwMS were compared to female non-MS controls who underwent a voluntary physical fitness analysis. The short version of the Freiburger questionnaire, self-developed questions and the modified Physical activity screening questionnaire (PASQ) were sent to all participants assessing the PA levels before the program, 3 months after the program (short-term), and at the time of the survey (long-term). Additionally, established questionnaires assessed behavioral determinants before the program and long-term. A total of 166 participants [mean age 38.32 (± 10.61 SD), mean EDSS 2.30 (±1.29 SD)] and mostly females (63.3%, n = 105) were included in the study and started the program. A total of 136 participants completed the program. Out of these 63.9% (n = 87) answered the questionnaires in 12.38 (±11.34 SD) months after finishing the program. At baseline female pwMS (n = 100) showed a lower physical fitness in comparison to non-MS controls (n = 26) (maximal workload (Watts): 138.86 ± 37.85 vs. 191.73 ± 45.25, p < 0.001; peak oxygen consumption (ml min-1 kg-1): 26.40 ± 7.23 vs. 31.56 ± 10.10, p = 0.020). pwMS were more regularly active in short- (62.1%) and long-term (55.2%) compared to baseline (24.2%, p < 0.001). Among the activated participants, we observed improved internal motivation (p = 0.002) and decreased perception of barriers (p = 0.006) compared to baseline. PwMS showed a lower physical fitness in comparison to non-MS controls. An individually tailored PA promotion program might improve behavioral determinants and thereby increase short- and long-term PA levels of pwMS.

Post kala-azar dermal leishmaniasis burden at the village level in selected high visceral leishmaniasis endemic upazilas in Bangladesh

ObjectivesAs post kala-azar Dermal Leishmaniasis (PKDL) threatens the success of the Visceral Leishmaniasis (VL) elimination initiative, we aimed to investigate the PKDL burden, including an active search for PKDL in leprosy-negative skin lesion cases. We also investigated their health-seeking behavior and perceived level of stigma. MethodsThis was a cross-sectional survey among inhabitants in the VL-endemic villages of the five most VL-endemic upazilas. VL experts trained medical officers in Upazila Health Complexes (UHCs) and leprosy facilities in PKDL management. Frontline workers conducted house-to-house surveys, referring PKDL suspects to designated centers. Data analysis involved Epi Info version 7 and IBM SPSS Statistics 25. ResultsAmong 472,435 screened individuals, 4022 had past VL (0.85 %). Among the screened population, 82 were PKDL suspects, and 62 PKDL cases were confirmed. The overall PKDL burden was 1.3 (95 % CI: 1.0-1.7) in the 10,000 population in the endemic villages. Male predominance and macular form of PKDL were observed. Thirty-nine PKDL patients perceived stigma of different levels. Only 27 of 62 (44 %) had received PKDL treatment. Medicine's unavailability and side effects were a major reason behind treatment interruption. Active screening among 137 leprosy-negative PKDL suspects yielded 10 (7.3 %) PKDL cases. ConclusionThe existence of PKDL cases in the VL endemic areas is a concern as those are inter-epidemic reservoirs. As per the WHO roadmap, the PKDL burden must be reduced by 70 % and 100 %, respectively, by 2026 and 2030. NKEP can take the current burden of 1.3 per 10,000 people in VL endemic villages as a baseline. Integrating active case detection for PKDL in leprosy hospitals and screening centers is feasible and worth deploying nationwide.

Screening for antibacterial activity of Cissampelos pareira L. root extract: an in-vitro study

Screening for antibacterial activity of Cissampelos pareira L. root extract: an in-vitro study

Enabling Modular Click Chemistry Library through Sequential Ligations of Carboxylic Acids and Amines.

High-throughput synthesis and screening of chemical libraries play pivotal roles in drug discovery. Click chemistry has emerged as a powerful strategy for constructing highly modular chemical libraries. However, the development of new click reactions and unlocking new clickable building blocks remain exceedingly challenging. Herein, we describe a double-click strategy that enables the sequential ligations of widely available carboxylic acids and amines with fluorosulfuryl isocyanate (FSO2NCO) via a modular amidation/SuFEx (sulfur-fluoride exchange) process. This method provides facile access to chemical libraries of N-fluorosulfonyl amides (RCONHSO2F) and N-acylsulfamides (RCONHSO2NR'R'') in near-quantitative yields under simple and practical conditions. The robustness and efficiency of this double click strategy is showcased by the facile construction of chemical libraries in 96-well microtiter plates from a large number of carboxylic acids and amines. Preliminary biological activity screening reveals that some compounds exhibit high antimicrobial activities against Gram-positive bacterium S. aureus and drug-resistant MRSA (MIC up to 6.25 μg ⋅ mL-1). These results provide compelling evidence for the potential application of modular click chemistry library as an enabling technology in high-throughput medicinal chemistry.

Enabling Modular Click Chemistry Library through Sequential Ligations of Carboxylic Acids and Amines

AbstractHigh‐throughput synthesis and screening of chemical libraries play pivotal roles in drug discovery. Click chemistry has emerged as a powerful strategy for constructing highly modular chemical libraries. However, the development of new click reactions and unlocking new clickable building blocks remain exceedingly challenging. Herein, we describe a double‐click strategy that enables the sequential ligations of widely available carboxylic acids and amines with fluorosulfuryl isocyanate (FSO2NCO) via a modular amidation/SuFEx (sulfur‐fluoride exchange) process. This method provides facile access to chemical libraries of N‐fluorosulfonyl amides (RCONHSO2F) and N‐acylsulfamides (RCONHSO2NR′R′′) in near‐quantitative yields under simple and practical conditions. The robustness and efficiency of this double click strategy is showcased by the facile construction of chemical libraries in 96‐well microtiter plates from a large number of carboxylic acids and amines. Preliminary biological activity screening reveals that some compounds exhibit high antimicrobial activities against Gram‐positive bacterium S. aureus and drug‐resistant MRSA (MIC up to 6.25 μg ⋅ mL−1). These results provide compelling evidence for the potential application of modular click chemistry library as an enabling technology in high‐throughput medicinal chemistry.

Cytotoxic and Anti-HSV-1 Effects of Caulerpin Derivatives.

Marine organisms represent a potential source of secondary metabolites with various therapeutic properties. However, the pharmaceutical industry still needs to explore the algological resource. The species Caulerpa lamouroux Forssk presents confirmed biological activities associated with its major compound caulerpin, such as antinociceptive, spasmolytic, antiviral, antimicrobial, insecticidal, and cytotoxic. Considering that caulerpin is still limited, such as low solubility or chemical instability, it was subjected to a structural modifications test to establish which molecular regions could accept structural modification and to elucidate the cytotoxic bioactive structure in Vero cells (African green monkey kidney cells, Cercopithecus aethiops; ATCC, Manassas, VA, USA) and antiviral to Herpes simplex virus type 1. Substitution reactions in the N-indolic position with mono- and di-substituted alkyl, benzyl, allyl, propargyl, and ethyl acetate groups were performed, in addition to conversion to their acidic derivatives. The obtained analogs were submitted to cytotoxicity and antiviral activity screening against Herpes simplex virus type 1 by the tetrazolium microculture method. From the semi-synthesis, 14 analogs were obtained, and 12 are new. The cytotoxicity assay showed that caulerpin acid and N-ethyl-substituted acid presented cytotoxic concentrations referring to 50% of the maximum effect of 1035.0 µM and 1004.0 µM, respectively, values significantly higher than caulerpin. The antiviral screening of the analogs revealed that the N-substituted acids with methyl and ethyl groups inhibited Herpes simplex virus type 1-induced cytotoxicity by levels similar to the positive control acyclovir.

SCREEN TIME IN PRESCHOOL-AGED CHILDREN

The World Health Organization defines sedentary screen time as the time spent in passive screen-based entertainment (TV, computer, mobile phone), excluding active screen time, specifically time spent playing games requiring physical activity or movement. Researchers agree that preschool-aged children spend longer periods of time in front of screens than recommended for their age, contradicting WHO guidelines on sedentary screen time for children up to 5 years old. The aim of our research was to obtain data on the age at which children are first exposed to screens, determine the duration of screen exposure on a daily basis, the most common type of screen, and the situations in which preschool-aged children use them. The sample consisted of 200 children, aged 48 to 60 months, of both genders. A specially constructed sociodemographic questionnaire was used for the research, which included questions regarding the age at which the child was first exposed to screens, the duration of daily exposure, as well as the most common type of screen and situations in which the child uses them. Informants were the parents of the children included in the study. The research was conducted in preschool institutions in Bosnia and Herzegovina, during February and March 2024. The results of the research show that children are first exposed to screens as early as at the age of 7 to 12 months, and that screen exposure on a daily basis exceeds the recommended time by WHO guidelines for most participants. The most common type of screen to which children are exposed is TV, and the most common situations in which they use them are during meals or while parents perform various household chores. Attention should be directed towards further identifying factors leading to excessive screen usage and providing clear guidelines to parents regarding the timing, content, technology, and joint activities related to screen time for young children in various cultural settings.

The leaf essential oil of Ecuadorian Ophryosporus peruvianus (J.F. Gmel.) R.M. King & H. Rob: chemical composition, enantioselective analysis, and in vitro enzymatic inhibitory activity

ABSTRACT An Ecuadorian specimen of Ophryosporus peruvianus produced an essential oil with a yield of 0.4% of the weight of the fresh plant material. A total of thirty-two compounds were detected and quantified. The chemical composition showed the predominance of monoterpene hydrocarbons, with sabinene (22.5%), β-pinene (15.1%), limonene (8.3%), β-phellandrene (29.7%), δ-elemene (2.1%), and epi-α-cadinol (2.7%) being the main components, expressed as mean values on two stationary phases of different polarity. This composition was very different from that reported in the literature for the essential oil of a Peruvian specimen, which was dominated by sesquiterpene hydrocarbons. These results indicate the existence of different chemotypes of O. peruvianus. Moreover, an enantioselective analysis of the major chiral constituents was performed, which revealed (R)-(-)-β-phellandrene, (R)-(-)-β-phellandrene and (1R,9R,E)-(-)-β-caryophylleneas enantiomerically pure compounds. On the other hand, β-thujene, β-pinene, β-pinene, sabinene, limonene, and terpinen-4-ol were scalemic mixtures. Finally, a preliminary screening of enzymatic inhibitory activity was performedin vitro, showing modest but interesting inhibition of both butyrylcholinesterase and lipase.

Active vs Passive Screening for Colorectal Cancer: Insights From the National Colonoscopy Study.

Active vs Passive Screening for Colorectal Cancer: Insights From the National Colonoscopy Study.

Discovery and Optimization of Aryl Piperidinone Ureas as Selective Formyl Peptide Receptor 2 Agonists.

We report the discovery and optimization of aryl piperidinone urea formyl peptide receptor 2 (FPR2) agonists from a weakly active high-throughput screening (HTS) hit to potent and selective agonists with favorable efficacy in acute in vivo models. A basis for the selectivity for FPR2 over FPR1 is proposed based on docking molecules into recently reported FPR2 and FPR1 cryoEM structures. Compounds from the new scaffold reported in this study exhibited superior potency and selectivity and favorable ADME profiles. Furthermore, select compounds were evaluated in an acute rat lipopolysaccharide (LPS) inflammation model and demonstrated robust dose-dependent induction of IL10, a marker for inflammation resolution, providing a valuable proof of concept for this class of FPR2 agonists.

Non-chemical stresses do not strongly induce male offspring in Daphnia magna ascertained using the short-term juvenile hormone activity screening assay.

Juvenile hormone (JH), together with ecdysone, regulates molting, metamorphosis, growth, and reproduction in arthropods. The effects of its analogs used as insecticides on nontarget species are of concern. Since JH and JH analogs (JHAs) induce male offspring in daphnids, which generally reproduce by parthenogenesis, short-term JH activity screening assay (JHASA) using the male offspring ratio as an endpoint has been developed as a detection method for JHA. However, the production of male offspring is also induced by environmental stresses such as temperature, short-day length, overcrowding, and food limitation. Thus, it is vital to prevent non-chemical stresses from inducing male offspring during the test to detect chemicals with potential JH activity accurately. Therefore, we investigated the effects of temperature (low and high), hardness, high density with low feeding, and day length on male production utilizing JHASA. Male offspring were not strongly induced by any stresses in JHASA, although the male ratios of 4-12% were observed in the preculture under high density (≥70 daphnid/L) and constant darkness. The Clone A strain was relatively more sensitive to high density and day length compared with the strain from National Institute for Environmental Studies (NIES). The selection of strains that rarely produce males under non-chemical stresses and finding the culturing conditions for each strain appropriate for not-inducing male offspring are recommended to control and prevent male offspring induction during JHASA.

LIM-domain-only 4 (LMO4) enhances CD8+ T-cell stemness and tumor rejection by boosting IL-21-STAT3 signaling

High frequencies of stem-like memory T cells in infusion products correlate with superior patient outcomes across multiple T cell therapy trials. Herein, we analyzed a published CRISPR activation screening to identify transcriptional regulators that could be harnessed to augment stem-like behavior in CD8+ T cells. Using IFN-γ production as a proxy for CD8+ T cell terminal differentiation, LMO4 emerged among the top hits inhibiting the development of effectors cells. Consistently, we found that Lmo4 was downregulated upon CD8+ T cell activation but maintained under culture conditions facilitating the formation of stem-like T cells. By employing a synthetic biology approach to ectopically express LMO4 in antitumor CD8+ T cells, we enabled selective expansion and enhanced persistence of transduced cells, while limiting their terminal differentiation and senescence. LMO4 overexpression promoted transcriptional programs regulating stemness, increasing the numbers of stem-like CD8+ memory T cells and enhancing their polyfunctionality and recall capacity. When tested in syngeneic and xenograft tumor models, LMO4 overexpression boosted CD8+ T cell antitumor immunity, resulting in enhanced tumor regression. Rather than directly modulating gene transcription, LMO4 bound to JAK1 and potentiated STAT3 signaling in response to IL-21, inducing the expression of target genes (Tcf7, Socs3, Junb, and Zfp36) crucial for memory responses. CRISPR/Cas9-deletion of Stat3 nullified the enhanced memory signature conferred by LMO4, thereby abrogating the therapeutic benefit of LMO4 overexpression. These results establish LMO4 overexpression as an effective strategy to boost CD8+ T cell stemness, providing a new synthetic biology tool to bolster the efficacy of T cell-based immunotherapies.

Effects of outdoor activity time, screen time, and family socioeconomic status on physical health of preschool children.

Experienced 3 years of pandemic-induced home life, in the post-epidemic period, preschoolers in China are falling short of the World Health Organization's standards for screen time and outdoor activities. This notably impacts their physical well-being. The study aims to probe the associations between screen time, outdoor activities, and the physical health of preschoolers, offering insights to shape interventions targeting myopia and obesity prevention in children. A cross-sectional study was conducted in Guangdong Province, involving a representative sample of 23,992 preschoolers and their caregivers recruited through proportional stratified cluster sampling. Data collection utilized the Chinese Early Human Capability Index (CHeHCI, eHCi), a questionnaire on children's media use in daily family life, and Body Mass Index (BMI). Linear regression and binary logistic regression models were employed to analyze the impact of screen time and outdoor activity duration on the physical health of preschoolers. In the high family socioeconomic status (SES) group, children had significantly less screen time compared to those in the medium and low SES groups. Outdoor activity time varied significantly based on SES, with higher SES linked to extended outdoor engagement. Additionally, children's eHCi health dimension score exhibited significant SES-related differences, showcasing higher scores for children in higher SES groups. In terms of gender differences, boys dedicated significantly more time to outdoor activities than girls, yet boys had a notably higher overweight rate. Furthermore, girls demonstrated better health outcomes based on eHCi health scores. A significant association emerged between overweight and screen time in children with high SES, indicating that prolonged screen time was linked to a higher likelihood of overweight based on BMI. Additionally, a substantial negative correlation was observed between children's eHCi health dimension score and screen time. Furthermore, children's outdoor activity time exhibited a significant positive correlation with eHCi health dimension score. Regression analysis revealed that screen time could significantly negatively predict children's physical health score, while outdoor activity time could significantly positively predict children's eHCi physical health score. The current study highlights that family SES, age, and gender play pivotal roles in influencing preschoolers' screen time and outdoor activity duration, with family SES being particularly influential. Higher family SES correlates with reduced screen time, increased outdoor activity, and elevated health levels among children. Importantly, children's screen time negatively predicts their health status, while outdoor time positively predicts their health status.

TFEB activator tanshinone IIA and derivatives derived from Salvia miltiorrhiza Bge. Attenuate hepatic steatosis and insulin resistance

Ethnopharmacological relevanceSalvia miltiorrhiza Bge. (SMB) is an herbal medicine extensively used for improving metabolic disorders, including Nonalcoholic fatty liver disease (NAFLD). However, the potential material basis and working mechanism still remained to be elucidated. Aim of the studyTo find potential ingredients for therapy of NAFLD by high content screening and further verify the efficacy on restoring hepatic steatosis and insulin resistance, and clarify the potential working mechanism. Materials and methodsThe mouse transcription factor EB (Tfeb) in preadipocytes was knocked out by CRISPR-Cas9 gene editing. High content screening of TFEB nuclear translocation was performed to identify TFEB activators. The effect of candidate compounds on reducing lipid accumulation was evaluated using Caenorhabditis elegans (C. elegans). Then the role of Salvia miltiorrhiza extract (SMB) containing Tanshinone IIA and the derivatives were further investigated on high-fat diet (HFD) fed mice. RNA-seq was performed to explore potential molecular mechanism of SMB. Finally, the gut microbiota diversity was evaluated using 16S rRNA sequencing to investigate the protective role of SMB on regulating gut microbiota homeostasis. ResultsKnockout of Tfeb led to excessive lipid accumulation in adipocytes while expression of TFEB homolog HLH-30 in C. elegans (MAH240) attenuated lipid deposition. Screening of TFEB activators identified multiple candidates from Salvia miltiorrhiza, all of them markedly induced lysosome biogenesis in HepG2 cells. One of the candidate compounds Tanshinone IIA significantly decreased lipid droplet deposition in HFD fed C. elegans. Administration of SMB on C57BL/6J mice via gastric irrigation at the dose of 15 g/kg/d markedly alleviated hepatic steatosis, restored serum lipid profile, and glucose tolerance. RNA-seq showed that gene expression profile was altered and the genes related to lipid metabolism were restored. The disordered microbiome was remodeled by SMB, Firmicutes and Actinobacteriotawere notably reduced, Bacteroidota and Verrucomicrobiota were significantly increased. ConclusionTaken together, the observations presented here help address the question concerning what were the main active ingredients in SMB for alleviating NAFLD, and established that targeting TFEB was key molecular basis for the efficacy of SMB.

Primary Aldosteronism and Risk of Cardiovascular Outcomes: Genome-Wide Association and Mendelian Randomization Study.

Observational studies have reported associations between primary aldosteronism (PA) and cardiovascular outcomes, including coronary artery diseases (CAD), congestive heart failure (CHF), and stroke. However, establishing causality remains a challenge due to the lack of randomized controlled trial data on this topic. We thus aimed to investigate the causal relationship between PA and the risk of developing CAD, CHF, and stroke. Cross-ancestry meta-analysis of genome-wide association studies combining East Asian and European ancestry (1560 PA cases and 742 139 controls) was conducted to identify single-nucleotide variants that are associated with PA. Then, using the identified genetic variants as instrumental variables, we conducted the 2-sample Mendelian randomization analysis to investigate the causal relationship between PA and incident CAD, CHF, and stroke among both East Asian and European ancestry. Summary association results were extracted from large genome-wide association studies consortia. Our cross-ancestry meta-analysis of East Asian and European populations identified 7 genetic loci significantly associated with the risk of PA, for which the genes nearest to the lead variants were CASZ1, WNT2B, HOTTIP, LSP1, TBX3, RXFP2, and NDP. Among the East Asian population, the pooled odds ratio estimates using these 7 genetic instruments of PA were 1.07 (95% CI, 1.03-1.11) for CAD, 1.10 (95% CI, 1.01-1.20) for CHF, and 1.13 (95% CI, 1.09-1.18) for stroke. The results were consistent among the European population. Our 2-sample Mendelian randomization study revealed that PA had increased risks of CAD, CHF, and stroke. These findings highlight that early and active screening of PA is critical to prevent future cardiovascular events.

New Approach for Plasma Nitrocarburizing of Stainless Steels by a Modified Reactor Configuration Using a Plasma‐Activated Solid Carbon Precursor

Stainless steel surfaces can be modified using plasma‐assisted thermochemical treatments to improve properties like hardness, wear, and pitting corrosion resistance. To specifically adjust the desired properties, a precise control of the produced treatment‐relevant gas species with regard to their type and concentration is essential. This requires the adjustment of the parameters for the generation of the gas species, being independent from heating parameters, as well as their real‐time measurement. Therefore, this study presents the use of a plasma‐activated solid carbon precursor in a cold‐wall reactor using active screen technology and in a modified hot‐wall reactor during plasma nitrocarburizing of austenitic stainless steel. In addition, the modified hot‐wall reactor combined with a compact laser‐based absorption spectroscopy sensor for real‐time monitoring and concentration evaluation of in‐site generated gas species. It is shown that implementing a plasma‐activated solid carbon precursor in a modified hot‐wall reactor enables adjustable generation of C‐containing gas species, particularly HCN, with high production yield by an independent power management. Therefore, HCN is produced independent from heating while the limitations arising during active screen technology using a carbon screen are avoided. The presented technological development thus opens up new possibilities for better control of the plasma nitrocarburizing treatments of steels.

UM OLHAR MULTIFOCAL SOBRE O CÂNCER DE COLO DE ÚTERO

This narrative review addresses cervical cancer prevention and screening strategies, including vaccination against the human papillomavirus (HPV) and periodic Pap smears and DNA testing for HPV. Vaccination against HPV has been shown to be effective in preventing infections with viral types related to cervical cancer. Furthermore, regular Pap smears and HPV testing in women have been shown to be crucial in the early detection of precancer and cervical cancer. It is recommended to vaccinate young people before starting sexual activity and regular screening in women after a certain age or beginning of sexual activity. The combined use of these strategies is essential to reduce the incidence and mortality from cervical cancer. It is essential to promote awareness and access to these health interventions to achieve better prevention and control of cervical cancer.

Discovery of novel N2-indazole derivatives as phosphodiesterase 4 inhibitors for the treatment of inflammatory bowel disease

Inflammatory bowel disease (IBD) is a chronic and progressive condition with a significant global burden. Currently, available treatments primarily provide symptomatic relief and retard disease progression, yet they do not offer a cure and are frequently associated with adverse effects. Therefore, the discovery of new targets and therapeutic drugs for IBD is crucial. Phosphodiesterase 4 (PDE4) inhibitors have emerged as promising candidates in the search for effective IBD treatments, although dose-dependent side effects hamper their clinical utility. In this study, building upon heterocyclic biaryl derivatives (TPA16), we designed and synthesized a series of N2-substituted indazole-based PDE4D inhibitors, emphasizing improving safety profiles. An enzyme activity screening discovered an optimized compound, LZ-14 (Z21115), which exhibited high PDE4D7 (IC50 = 10.5 nM) inhibitory activity and good selectivity. More interestingly, LZ-14 has demonstrated promising effects in treating IBD in mouse models by improving the inflammatory response and colon injury. Furthermore, LZ-14 displayed low emetogenic potential in ketamine/xylazine anesthesia mice alternative models.

Seasonal Dynamics of Culturable Yeasts in Ornithogenically Influenced Soils in a Temperate Forest and Evaluation of Extracellular Enzyme Secretion in Tausonia pullulans at Different Temperatures.

The culturable yeast communities in temperate forest soils under the ornithogenic influence were studied in a seasonal dynamic. To investigate the intense ornithogenic influence, conventional and "live" feeders were used, which were attached to trees in the forest and constantly replenished throughout the year. It was found that the yeast abundance in the soil under strong ornithogenic influence reached the highest values in winter compared to the other seasons and amounted to 4.8 lg (cfu/g). This was almost an order of magnitude higher than the minimum value of yeast abundance in ornithogenic soils determined for summer. A total of 44 yeast species, 21 ascomycetes and 23 basidiomycetes, were detected in ornithogenic soil samples during the year. These included soil-related species (Barnettozyma californica, Cyberlindnera misumaiensis, Cutaneotrichosporon moniliiforme, Goffeauzyma gastrica, Holtermanniella festucosa, Leucosporidium creatinivorum, L. yakuticum, Naganishia adeliensis, N. albidosimilis, N. globosa, Tausonia pullulans, and Vanrija albida), eurybionts (yeast-like fungus Aureobasidium pullulans, Debaryomyces hansenii, and Rhodotorula mucilaginosa), inhabitants of plant substrates and litter (Cystofilobasidium capitatum, Cys. infirmominiatum, Cys. macerans, Filobasidium magnum, Hanseniaspora uvarum, Metschnikowia pulcherrima, and Rh. babjevae) as well as a group of pathogenic and opportunistic yeast species (Arxiozyma bovina, Candida albicans, C. parapsilosis, C. tropicalis, Clavispora lusitaniae, and Nakaseomyces glabratus). Under an ornithogenic influence, the diversity of soil yeasts was higher compared to the control, confirming the uneven distribution of yeasts in temperate forest soils and their dependence on natural hosts and vectors. Interestingly, the absolute dominant species in ornithogenic soils in winter (when the topsoil temperature was below zero) was the basidiomycetous psychrotolerant yeast T. pullulans. It is regularly observed in various soils in different geographical regions. Screening of the hydrolytic activity of 50 strains of this species at different temperatures (2, 4, 10, 15 and 20 °C) showed that the activity of esterases, lipases and proteases was significantly higher at the cultivation temperature. Ornithogenic soils could be a source for the relatively easy isolation of a large number of strains of the psychrotolerant yeast T. pullulans to test, study and optimize their potential for the production of cold-adapted enzymes for industry.