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In India, the National Education Policy 2020 recommends ensuring universal access to high-quality early childhood care and education for children aged 3-6 years by 2030. Using the 75th round of National Statistical Office data (2017-2018), this paper analyses the regional and socioeconomic inequalities in access to pre-primary education. Also, we investigate the specific role of households' economic status and educational attainment in explaining these inequalities. We find considerable regional (rural/urban) and socioeconomic inequalities in access to pre-primary education in India, with girls and children belonging to historically disadvantaged social groups (scheduled castes and scheduled tribes) less likely to attend early childhood education, particularly in rural areas. We find that a substantial portion of the rural-urban gap in access to pre-primary education can be removed by controls for households' economic condition and household head's educational status. In addition, we find gender and socioeconomic inequalities in the household investment in early years education. These findings highlight the need to put policy efforts and commitments to reducing barriers to accessing pre-primary education for children in disadvantaged conditions in India.

Energy harvesting combined with spectrum sharing offers a promising solution to the growing demand for spectrum while keeping energy costs low. New Radio Unlicensed (NR-U) technology enables telecom operators to utilize unlicensed spectrum in addition to the licensed spectrum already in use. Along with this, the energy demands for the Internet of Things (IoT) can be met through energy harvesting. In this regard, the ubiquity and ease of implementation make the RF-powered NR-U network a sustainable solution for cellular IoT. Using a Markov chain, we model the NR-U network with nodes powered by the base station (BS). We derive closed-form expressions for the normalized saturated throughput of nodes and the BS, along with the mean packet delay at the node. Additionally, we compute the transmit outage probability of the node. These quality of service (QoS) parameters are analyzed for different values of congestion window size, TXOP parameter, maximum energy level, and energy threshold of the node. Additionally, the effect of network density on collision, transmission, and energy harvesting probabilities is observed. We validate our model through simulations. [ABSTRACT FROM AUTHOR]

Severe alcohol-associated hepatitis (AH) is a life-threatening form of alcohol-associated liver disease. Liver neutrophil infiltration is a hallmark of AH, yet the effects of alcohol on neutrophil functions remain elusive. Identifying therapeutic targets to reduce neutrophil-mediated liver damage is essential. Bruton's tyrosine kinase (BTK) plays an important role in neutrophil development and function; however, the role of BTK in AH is unknown. Using RNA sequencing of circulating neutrophils, we found an increase in Btk expression (P = 0.05) and phosphorylated BTK (pBTK) in patients with AH compared with healthy controls. In vitro, physiologically relevant doses of alcohol resulted in a rapid, TLR4-mediated induction of pBTK in neutrophils. In a preclinical model of AH, administration of a small-molecule BTK inhibitor (evobrutinib) or myeloid-specific Btk knockout decreased proinflammatory cytokines and attenuated neutrophil-mediated liver damage. We found that pBTK was essential for alcohol-induced bone marrow granulopoiesis and liver neutrophil infiltration. In vivo, BTK inhibition or myeloid-specific Btk knockout reduced granulopoiesis, circulating neutrophils, liver neutrophil infiltration, and liver damage in a mouse model of AH. Mechanistically, using liquid chromatography–tandem mass spectrometry, we identified CD84 as a kinase target of BTK, which is involved in granulopoiesis. In vitro, CD84 promoted alcohol-induced interleukin-1β and tumor necrosis factor–α in primary human neutrophils, which was inhibited by CD84-blocking antibody treatment. Our findings define the role of BTK and CD84 in regulating neutrophil inflammation and granulopoiesis, with potential therapeutic implications in AH. Editor's summary: Alcoholic liver disease is uniquely characterized by the hepatic infiltration of neutrophils. Nagesh et al. now show that Bruton's tyrosine kinase (BTK) is involved in this altered neutrophil homeostasis. Studying mouse models of alcohol-associated hepatitis, they found that BTK directly interacted with CD84 to promote bone marrow granulopoiesis and the inflammatory neutrophil infiltration that drives subsequent liver injury, particularly after alcohol binge. Pharmacological BTK inhibition reduced proinflammatory cytokines and attenuated neutrophil-mediated liver damage in a mouse model of alcohol-associated hepatitis. BTK activation was also found to be increased in patients with alcohol-associated hepatitis, indicating translational relevance of the identified mechanism of alcohol-induced liver injury. —Catherine Charneski [ABSTRACT FROM AUTHOR]

Background and aims: Granulocyte colony-stimulating factor (G-CSF) has been proposed as a therapeutic option for patients with ACLF, however clinical outcomes are controversial. We aimed at dissecting the role of G-CSF in an alcohol-induced murine model of ACLF. Methods: ACLF was triggered by a single alcohol binge (5 g/kg) in a bile duct ligation (BDL) liver fibrosis model. A subgroup of mice received two G-CSF (200 μg/kg) or vehicle injections prior to acute decompensation with alcohol. Liver, blood and brain tissues were assessed. Results: Alcohol binge administered to BDL-fibrotic mice resulted in features of ACLF indicated by a significant increase in liver damage and systemic inflammation compared to BDL alone. G-CSF treatment in ACLF mice induced an increase in liver regeneration and neutrophil infiltration in the liver compared to vehicle-treated ACLF mice. Moreover, liver-infiltrating neutrophils in G-CSF-treated mice exhibited an activated phenotype indicated by increased expression of CXC motif chemokine receptor 2, leukotriene B4 receptor 1, and calprotectin. In the liver, G-CSF triggered increased oxidative stress, type I interferon response, extracellular matrix remodeling and inflammasome activation. Circulating IL-1β was also increased after G-CSF treatment. In the cerebellum, G-CSF increased neutrophil infiltration and S100a8/9 expression, induced microglia proliferation and reactive astrocytes, which was accompanied by oxidative stress, and inflammasome activation compared to vehicle treated ACLF mice. Conclusion: In our novel ACLF model triggered by alcohol binge that mimics ACLF pathophysiology, neutrophil infiltration and S100a8/9 expression in the liver and brain indicate increased tissue damage, accompanied by oxidative stress and inflammasome activation after G-CSF treatment. [ABSTRACT FROM AUTHOR]

The current study focuses on analyzing the effects of supplements containing silver nanoparticles (AgNPs) on plant growth and rhizospheric bacterial communities. Specifically, the impact of AgNP supplements was assessed on both plant growth promoting traits and bacterial communities in the soil. To do this, a screening process was conducted to select bacteria capable of synthesizing AgNPs through extracellular biosynthesis. UV‐Visible spectrophotometer, Fourier transform infrared, X‐ray diffraction, scanning electron microscope, and field emission scanning electron microscopy all confirmed, produced AgNPs is in agglomerates form. The resulting AgNPs were introduced into soil along with various supplements and their effects were evaluated after 10 days using next generation sequencing (Illumina—16S rDNA V3–V4 region dependent) to analyze changes in bacterial communities. Seed germination, root‐shoot biomass and chlorophyll content were used to assess the growth of the cotton plant, whereas the bacterial ability to promote growth was evaluated by measuring its culturable diversity including traits like phosphate solubilization and indole acetic acid production. The variance in Bray–Curtis β diversity among six selected combinations including control depends largely on the type of added supplements contributing to 95%–97% of it. Moreover, seed germination improves greatly between 63% and 100% at a concentration range of 1.4 to 2.8 mg/L with different types of supplements. Based on the results obtained through this study, it is evident that using AgNPs along with fructose could be an effective tool for promoting Gossypium hirsutum growth and enhancing plant growth traits like profiling rhizospheric bacteria. The results that have been obtained endorse the idea of boosting the growth of rhizospheric bacteria in a natural way when AgNPs are present. Using these supplements in fields that have been contaminated will lead to a better understanding of how ecological succession occurs among rhizospheric bacteria, and what effect it has on the growth of plants. [ABSTRACT FROM AUTHOR]

Background and Purpose: It has been proposed that genomic mechanisms contribute to adverse effects often experienced by asthmatic subjects who take regular, inhaled β2 -adrenoceptor agonists as a monotherapy. Moreover, data from preclinical models of asthma suggest that these gene expression changes are mediated by β-arrestin-2 rather than PKA. Herein, we tested this hypothesis by comparing the genomic effects of formoterol, a β2 -adrenoceptor agonist, with forskolin in human primary bronchial epithelial cells (HBEC).Experimental Approach: Gene expression changes were determined by RNA-sequencing. Gene silencing and genome editing were employed to explore the roles of β-arrestin-2 and PKA.Key Results: The formoterol-regulated transcriptome in HBEC treated concurrently with TNFα was defined by 1480 unique gene expression changes. TNFα-induced transcripts modulated by formoterol were annotated with enriched gene ontology terms related to inflammation and proliferation, notably "GO:0070374~positive regulation of ERK1 and ERK2 cascade," which is an apparent β-arrestin-2 target. However, expression of the formoterol- and forskolin-regulated transcriptomes were highly rank-order correlated and the effects of formoterol on TNFα-induced inflammatory genes were abolished by an inhibitor of PKA. Furthermore, formoterol-induced gene expression changes in BEAS-2B bronchial epithelial cell clones deficient in β-arrestin-2 were comparable with those expressed by their parental counterparts. Contrariwise, gene expression was partially inhibited in clones lacking the α-catalytic subunit (Cα) of PKA and abolished following the additional knockdown of the β-catalytic subunit (Cβ) paralogue.Conclusions: The effects of formoterol on inflammatory gene expression in airway epithelia are mediated by PKA and involve the cooperation of PKA-Cα and PKA-Cβ. [ABSTRACT FROM AUTHOR]

Alcohol use disorder is associated with systemic inflammation and organ dysfunction especially in the liver and the brain. For more than a decade, studies have highlighted alcohol abuse-mediated impairment of brain function and acceleration of neurodegeneration through inflammatory mechanisms that directly involve innate immune cells. Furthermore, recent studies indicate overlapping genetic risk factors between alcohol use and neurodegenerative disorders, specifically regarding the role of innate immunity in the pathomechanisms of both areas. Considering the pressing need for a better understanding of the relevance of alcohol abuse in dementia progression, here we summarize the molecular mechanisms of neuroinflammation observed in alcohol abuse and Alzheimer's disease, the most common cause of dementia. In addition, we highlight mechanisms that are already established in the field of Alzheimer's disease that may be relevant to explore in alcoholism to better understand alcohol mediated neurodegeneration and dementia, including the relevance of the liverbrain axis. [ABSTRACT FROM AUTHOR]

Objective: There are no major head-to-head comparative studies till date to compare the differences in glycemic efficacy, safety, or cardio-renal effects within SGLT2 inhibitors. This survey was conducted to understand the different parameters that clinicians identify while choosing an SGLT2 inhibitor in routine clinical practice. Materials and methods: A cross-sectional questionnaire-based survey of healthcare professionals (HCP) was conducted across India. Data were analyzed and expressed as descriptive statistics. Results: In clinical practice, the majority of HCPs identified a history of cardiovascular disease (CVD) as the most important factor for prescribing SGLT2 inhibitors in patients with T2DM. The majority of HCPs opined that among all the SGLT2 inhibitors, canagliflozin had the strongest effect on HbA1c reduction (56%), reduction in body weight (59%), and renal benefit (66%), whereas empagliflozin was associated with CV benefits (48%). In terms of heart failure, canagliflozin, empagliflozin, and dapagliflozin were similarly preferred. Conclusions: This survey gives us an understanding of the current clinical practice prevalent among Indian physicians as far as the prescription pattern of SGLT2 inhibitors is concerned. [ABSTRACT FROM AUTHOR]

Massive inflammation and liver failure are main contributors to the high mortality in alcohol‐associated hepatitis (AH). In recent clinical trials, granulocyte colony‐stimulating factor (G‐CSF) therapy improved liver function and survival in patients with AH. However, the mechanisms of G‐CSF‐mediated beneficial effects in AH remain elusive. In this study, we evaluated effects of in vivo G‐CSF administration, using a mouse model of AH. G‐CSF treatment significantly reduced liver damage in alcohol‐fed mice even though it increased the numbers of liver‐infiltrating immune cells, including neutrophils and inflammatory monocytes. Moreover, G‐CSF promoted macrophage polarization toward an M2‐like phenotype and increased hepatocyte proliferation, which was indicated by an increased Ki67‐positive signal colocalized with hepatocyte nuclear factor 4 alpha (HNF‐4α) and cyclin D1 expression in hepatocytes. We found that G‐CSF increased G‐CSF receptor expression and resulted in reduced levels of phosphorylated β‐catenin in hepatocytes. In the presence of an additional pathogen‐associated molecule, lipopolysaccharide (LPS), which is significantly increased in the circulation and liver of patients with AH, the G‐CSF‐induced hepatoprotective effects were abolished in alcohol‐fed mice. We still observed increased Ki67‐positive signals in alcohol‐fed mice following G‐CSF treatment; however, Ki67 and HNF‐4α did not colocalize in LPS‐challenged mice. Conclusion: G‐CSF treatment increases immune cell populations, particularly neutrophil counts, and promotes M2‐like macrophage differentiation in the liver. More importantly, G‐CSF treatment reduces alcohol‐induced liver injury and promotes hepatocyte proliferation in alcohol‐fed mice. These data provide new insights into the understanding of mechanisms mediated by G‐CSF and its therapeutic effects in AH. [ABSTRACT FROM AUTHOR]

Background:Oral cancer is one of the most common cancers in India. Prevalence of tobacco use in both urban and rural areas in the form of smoking, chewing Gutakha use is very high. Aim and Objectives: To study the effectiveness of cancer literacy activities in motivating rural men of Satara district. Material and Methods: For creating awareness among rural population of Satara district of Maharashtra, India Cancer Literacy Satara Initiative was started by Health Department of Zilla Parishad, Satara, in collaboration with Krishna Institute of Medical Sciences "Deemed to be University" (KIMSDU) Karad, from 2017 to 2019. Experiences about awareness programme for men about oral cancer are presented in this paper.Out of 11 talukas of Satara District, four talukas were taken up for this project, two talukas in the vicinityof KIMSDU and two far away. A schedule of visits by mobile team of experts from KIMSDU was planned to cover 33 Primary Health Centers (PHCs) from these talukas in collaboration with medical officers of these PHCs. Knowledge, Attitude and Practice (KAP) study, followed by health education and screening of the males aged above 30 years was carried out.During first round of visits of mobile team KAP survey was carried out along with Information, Education and Communication (IEC) and screening activities. From second round onwards only IEC and screening activities were continued. Results: There were 165 males who attended the awareness programme. KAP study revealed that 12% were totally ignorant about causation, risk factors, screening, and prognostic aspects of oral cancers. More than 50% were unaware that females were also at risk, and chewing of tobacco and consumption of gutakha were associated with oral cancer as well as the fact that cancer of the tongue is associated with many complications like the inability to speak and swallow food. Over 64% knew association of smoking and oral cancer. Screening was done after IEC activities in 473 males, 165 of which were subjected to KAP study, 83 were found with non-healing ulcers and leukoplakia and were referred for further management. Limitations of this research study was that some of the men identified for the awareness activity organized by PHCs could not attend it due to problems related to job and loss of daily wages. Conclusion: The Health Care Workers (HCW) males could be trained to screen oral cancer with inspection and clinical examination of the oral cavity for precancerous and cancerous lesions. Motivation of all men for undergoing screening after attending Health Education sessions at PHCs is possible.For those who missed these sessions, the trained HCWs could screen them when they next came to the PHCs or during routine home visits of these HCWs. [ABSTRACT FROM AUTHOR]

Background: Promotion of maternal health should be an integrated approach comprising adequate planning of pregnancy coupled with the awareness of the available maternal and child health services and its utilization. Objectives: The aim of this study is to determine birth preparedness and complication readiness (BPACR) among antenatal and postnatal women and to assess the factors related to it. Materials and Methods: This hospital-based cross-sectional study was conducted on 400 antenatal and postnatal women attending a tertiary care hospital of Karad. Antenatal women in their third trimester and postnatal women up to Postnatal day-7 were included. Institutional ethical clearance was obtained before the commencement of the study. All the women were interviewed after their informed consent using the appropriately validated and modified BPACR tool developed with respect to the Indian setup. Chi-square and multivariate logistic regression analysis were carried out to determine the various associated factors with BPACR. Results: The study population comprised 55.5% antenatal mothers and 44.5% postnatal mothers. The BPACR index was found to be 59.56, and the maximum had a good BPACR 208 (52%). There was poor knowledge regarding blood transfusion, danger signs, and available community resources. A higher level of education had a statistically significant association with BPACR (46.2%) in women educated above high school). Women belonging to the upper class had two times, and postnatal women had 2.02 times increased chances for a good BPACR. Conclusion: An inclusion of components related to BPACR during pregnancy will improve timely and adequate access to healthcare, better management of complications, and thereby improve both maternal and fetal outcomes. [ABSTRACT FROM AUTHOR]

In the present study, α,α‐dibromoacetophenones are used as efficient precursors for the facile synthesis of several new hydrazonothiazoles, ethyl 3‐((4‐arylthiazol‐2‐yl)hydrazono)butanoates, which undergo Vilsmeier‐Haack cyclization to obtain thiazolylpyrazole esters, ethyl 3‐methyl‐1‐(4‐arylthiazol‐2‐yl)‐1H‐pyrazole‐4‐carbxylates, basic hydrolysis of which gives the corresponding acids, 3‐methyl‐1‐(4‐arylthiazol‐2‐yl)‐1H‐pyrazole‐4‐carbxylic acids. All these compounds are tested for antibacterial activity against Gram‐positive bacteria Staphylococcus aureus and Bacillus subtilis; Gram‐negative bacteria Escherichia coli and Pseudomonas aeruginosa and antifungal activity against Saccharomyces cerevisiae and Candida albicans. [ABSTRACT FROM AUTHOR]

Most studies pertaining to the returns to education literature focus on estimating benefits of education that accrue to the individual who spends more years in school. However, from a public policy perspective it is crucial to understand the gains of education to the society at large. This study is an attempt to estimate these social returns to education, that is, the impact of an increase in average education on individual health outcomes. In particular, we try to assess if (above and beyond individual educational attainment), average years of schooling at a district level has an impact on individual health. We obtain individual level data from two rounds of the India Human Development Survey (IHDS) and calculate district level average education using data from the National Sample Survey Organisation (NSSO) surveys for the same years. We use a logit model to estimate the probability of suffering from short-term morbidity and find that there is a strong negative association between short-term morbidity and average education. We also study the impact of average education on health seeking outcomes such as consumption of cigarettes and tobacco. We find that after accounting for individual education and income, the average education at the district level has a strong positive influence on better health seeking behaviour. The results from our study lend support to the notion that in addition to policies aimed at improving healthcare, an increase in average education can potentially lead to improvement in health outcomes. [ABSTRACT FROM AUTHOR]

Objective: To determine the feasibility of detecting and differentiating middle ear effusions (MEEs) using an optical coherence tomography (OCT) otoscope.Study Design: Cross-sectional study.Setting: US tertiary care children's hospital.Subjects and Methods: Seventy pediatric patients undergoing tympanostomy tube placement were preoperatively imaged using an OCT otoscope. A blinded reader quiz was conducted using 24 readers from 4 groups of tiered medical expertise. The primary outcome assessed was reader ability to detect presence/absence of MEE. A secondary outcome assessed was reader ability to differentiate serous vs nonserous MEE.Results: OCT image data sets were analyzed from 45 of 70 total subjects. Blinded reader analysis of an OCT data subset for detection of MEE resulted in 90.6% accuracy, 90.9% sensitivity, 90.2% specificity, and intra/interreader agreement of 92.9% and 87.1%, respectively. Differentiating MEE type, reader identification of nonserous MEE had 70.8% accuracy, 53.6% sensitivity, 80.1% specificity, and intra/interreader agreement of 82.9% and 75.1%, respectively. Multivariate analysis revealed that age was the strongest predictor of OCT quality. The mean age of subjects with quality OCT was 5.01 years (n = 45), compared to 2.54 years (n = 25) in the remaining subjects imaged (P = .0028). The ability to capture quality images improved over time, from 50% to 69.4% over the study period.Conclusion: OCT otoscopy shows promise for facilitating accurate MEE detection. The imageability with the prototype device was affected by age, with older children being easier to image, similar to current ear diagnostic technologies. [ABSTRACT FROM AUTHOR]

Screening is possible for cancer of cervix and breast which are the first two commonest cancers in women. Trained nurses know how to carry out vaginal examination hence there is a possibility of training them VIA, VILI and taking of PAP smears. Theoretically CBE can be taught to them so that any woman coming to the PHC for any reason can be screened for these two cancer sites. A study was therefore planned to find out feasibility of skill transfer of screening of cancer cervix and cancer breast. Thirty nine nurses were from KIMS and 8 from randomly selected 4 PHCs. After orientation in first session 12 hands on training sessions were taken. Two nurses were trained at a time. The technique and the lesions were demonstrated with the A. V. aids. After first three hands on training sessions, the trainee nurses were instructed to undertake screening on their own between two hands on training sessions. All suspected cases were called again on weekly training days for confirmation of findings of nursing staff. A theory and practical examination were undertaken at the end of the training. Thirty eight out of 39 nurses attended all the training sessions and could master the skill of screening the women for cancer cervix by VIA, VILI and could take PAP smear by the spatula as well as CBE. Nurses scored more than 50% marks with min. 57% and max. 78%. Difficulties encountered in the training like obtaining acetic acid and Lugol's iodine at PHCs needs to be addressed. It is possible to do skill transfer for VIA, VILI and taking of PAP smears as well as CBE to nurses by 12 hands on training sessions. If nurses are trained in this way they can start opportunistic screening of the women visiting PHCs regularly in the PHCs in rural area and hospitals in urban area. [ABSTRACT FROM AUTHOR]

Introduction: Screening of cervix and breast cancer is not considered a routine activity at PHCs. Aim and Objectives: To study a three-stepped approach of creating awareness, train ANMs while screening and possibly continue educational and screening activity after withdrawing the mobile team. Material and Method: A mobile team at KIMS deemed to be University, Karad, Maharashtra was formed of specialists from concerned faculties. Four PHCs were randomly selected from the Satara district. Three selected ASHA workers motivated fifty women >30 years to attend camp at PHC on a prefixed date. Pre-training and post-training assessments of knowledge among women and health care workers, training of two ANMs and Medical Officer per PHC in cervical and breast cancer screenings by VIA, VILI, and CBE respectively while screening was done by the mobile team during intensive weekly activity of three months at each PHC. After withdrawal of the team, PHCs were visited to see continuity of educational and screening activities. Results: Of 1440 women motivated by 12 ASHA workers from 4 PHCs, 1037 attended awareness programme and 430 got screened. Of the 37 VIA positive and 17 lump in breast cases identified, one cervical and two breast cancers confirmed cases were managed. Nonsurgical treatment was given there. Out of four PHCs, the activity of education and screening was continued satisfactorily at two, sporadically at one and absent at one PHC. Conclusion: There was significant improvement in knowledge scores of community and health-care workers after the awareness programme. The ANMs could be trained in screening cervical and breast cancer. Education and screening activities continued after one year of withdrawal of the mobile team in 50% of PHCs. An entire district should be studied to find possible solutions of screening cervical and breast cancer as routine activities at PHCs after this pilot project. [ABSTRACT FROM AUTHOR]

Despite growing public-sector investment in education in developing economies, there are few studies that have examined the efficacy of these investments. In this paper, we estimate social returns to education in Indonesia, using individual-level data on wages from five waves of the Indonesia Family Life Surveys (1993–2014) and subdistrict-level data on average education levels from the National Socioeconomic Survey (SUSENAS), a large-scale national-level socioeconomic survey. Our identification strategy rests on the within-sibling variation in average education levels, which is generated because our analysis includes a large sample of siblings who live in different subdistricts. Using sibling fixed effects, we find that a 1-year increase in average education results in a 6%–8% increase in wages. Our results are robust to several robustness checks, including the addition of several controls for labor demand conditions and adjustments for potential measurement error in individual-level education. [ABSTRACT FROM AUTHOR]

Aim: To assess the antimicrobial efficacy of five solvent extracts of two Piper species commonly used in diet and traditional medicine, P. cubeba and P. longum, against selected bacterial and oral fungal pathogens i.e. Streptococcus mutans, Staphylococcus aureus, Candida albicans and Saccharomyces cerevisiae. Methods: The antimicrobial activity of five extracts of cubeb berries and Indian long pepper fruits was determined by the agar well diffusion method. The minimum inhibitory concentration (MIC) for the acetonic, methanolic and ethanolic extracts was determined by the modified agar well diffusion method. Results: Of the 5 fruit extracts evaluated, acetone, ethanol and methanol extracts of both the Piper spp. were found to have variable antimicrobial activities against all the four oral pathogens. The acetonic fruit extract of P. cubeba was the most effective against both the yeasts with the highest zone of inhibition (15.31 mm) against C. albicans followed by the methanolic (12.31 mm) and ethanolic (11.94 mm) extracts. C. albicans was found to be most sensitive pathogen, which survived up to 6.25 mg/mL in the acetonic extract (MIC = 12.5 mg/mL) followed by the methanolic and ethanolic extracts (MIC = 25 mg/mL). The acetonic, methanolic and ethanolic extracts of P. longum fruits showed almost equal inhibition zones of both yeasts, ranging between 10.64 and 14 mm. C. albicans survived up to 12.5 mg/mL (MIC= 25 mg/mL) while S. cerevisiae survived up to 25 mg/mL (MIC = 50 mg/mL). Conclusions: The crude extracts obtained from the fruits of the two Piper spp. may be used to treat oral fungal species, especially C. albicans, as they produced larger inhibition zones than antifungal drugs often used to treat these pathogens. [ABSTRACT FROM AUTHOR]

Background: Semen from the chimpanzee species becomes a colloidal solid after ejaculation. The formation of this copulatory plug is believed to prevent additional spermatozoa of subsequent mating events from accessing the ova. However, this naturally preserved strategy hampers the processes for sperm preparation. In this study, we investigated whether collagenase can be used to degelify the semen plug and accelerate the semen liquefaction process in zoo captive chimpanzee species (Pan troglodytes). Results: We showed that incubation of chimpanzee ejaculates with 0.1% type I collagenase efficiently and significantly (p < 0.05) releases 2.7-fold more spermatozoa from the coagulated ejaculates, and this degelification process did not alter sperm morphology or viability; nor did it stimulate spontaneous capacitation or an acrosome reaction as assessed by tyrosine phosphorylation and peanut agglutinin stains; moreover, based on computer assisted sperm analysis assay, motility-related parameters remained similar to those of untreated spermatozoa. When collagenase effects were evaluated on cryopreserved sperm samples, we observed post collagenase treatment in which 2.5% glycerol, as a cryoprotectant, preserved sperm acrosome integrity better than 7.8%; however, 7.8% glycerol, as a cryoprotectant, maintained sperm motility better than that of 2.5% glycerol. Conclusions: Our results demonstrated for the first time that type I collagenase can be used to obtain a significantly higher number of spermatozoa from colloid chimpanzee semen ejaculate without affecting the physiological properties of spermatozoa, and these results are critical for the subsequent gamete development. Our results would benefit sperm preparation processes and cryopreservation efficiency per ejaculate, as more unaffected spermatozoa can be released from the semen plug within a shorter period of time. These results would also benefit the genetic diversity of the chimpanzee species, using sperm cells from less dominant individuals, and for achieving better pregnancy success in primates with significantly higher amounts of sperm for artificial insemination. [ABSTRACT FROM AUTHOR]

Objective: Alcohol use in metabolic dysfunction-associated steatohepatitis (MASH) is associated with an increased risk of fibrosis and liver-related death. Here, we aimed to identify a mechanism through which repeated alcohol binges exacerbate liver injury in a high fat-cholesterol-sugar diet (MASH diet)-induced model of MASH., Design: C57BL/6 mice received either chow or the MASH diet for 3 months with or without weekly alcohol binges. Neutrophil infiltration, neutrophil extracellular traps (NETs) and fibrosis were evaluated., Results: We found that alcohol binges in MASH increase liver injury and fibrosis. Liver transcriptomic profiling revealed differential expression of genes involved in extracellular matrix reorganisation, neutrophil activation and inflammation compared with alcohol or the MASH diet alone. Alcohol binges specifically increased NET formation in MASH livers in mice, and NETs were also increased in human livers with MASH plus alcohol use. We discovered that cell-free NETs are sensed via Nod-like receptor protein 3 (NLRP3). Furthermore, we show that cell-free NETs in vitro induce a profibrotic phenotype in hepatic stellate cells (HSCs) and proinflammatory monocytes. In vivo, neutrophil depletion using anti-Ly6G antibody or NET disruption with deoxyribonuclease treatment abrogated monocyte and HSC activation and ameliorated liver damage and fibrosis. In vivo, inhibition of NLRP3 using MCC950 or NLRP3 deficiency attenuated NET formation, liver injury and fibrosis in MASH plus alcohol diet-fed mice (graphical abstract)., Conclusion: Alcohol binges promote liver fibrosis via NET-induced activation of HSCs and monocytes in MASH. Our study highlights the potential of inhibition of NETs and/or NLRP3, as novel therapeutic strategies to combat the profibrotic effects of alcohol in MASH., Competing Interests: Competing interests: GS reports being a paid consult for Durect Corporation, Cyta Therapeutics, Generon, Terra Firma, Quest Diagnostics, Pandion Therapeutics, Surrozen, Merck, Novartis, Pfizer, Lab Corp, Intercept and Takeda. She has stock options in Glympse Bio, Satellite Bio and Ventyx., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

It has been proposed that inhaled E-prostanoid 4 (EP 4 )-receptor agonists could represent a new class of bronchodilators for the treatment of asthma that are as effective as β 2 -adrenoceptor agonists. However, the genomic impact of such drugs is unknown despite being potentially deleterious to respiratory health. Herein, we used mRNA-seq to compare the transcriptomic responses produced by 2-[3-[(1R,2S,3R)-3-hydroxy-2-[(E,3S)-3-hydroxy-5-[2-(methoxymethyl)phenyl]pent-1-enyl]-5-oxo-cyclopentyl]sulphanylpropylsulphanyl] acetic acid (ONO-AE1-329; an EP 4 -receptor agonist) and vilanterol (a β 2 -adrenoceptor agonist) in BEAS-2B human airway epithelial cells. We also determined if an increase in cAMP mediated by different G protein-coupled receptors (GPCRs) promoted distinct transcriptional signatures by expanding this inquiry to include the adenosine A 2B - and I-prostanoid receptor agonists, 2-[[6-amino-3,5-dicyano-4-[4-(cyclopropylmethoxy)phenyl]-2-pyridinyl]thio]-acetamide (Bay60-6583) and taprostene, respectively. Maximally-effective concentrations of ONO-AE1-329 and vilanterol significantly regulated ( q ≤ 0.05; ≥1.5-/≤0.67-fold) 232 and 320 genes, respectively of which 217 were shared. Spearman analysis showed these gene expression changes to be highly rank order correlated, indicating that the functional overlap between the two interventions should be considerable. Unexpectedly, the genomic effects of ONO-AE1-329, vilanterol, Bay 60-6583, and taprostene were also highly rank order correlated. This finding suggests that cAMP generated by any GPCR would initiate the same transcriptional program. Nevertheless, relative to vilanterol, ONO-AE1-329 typically behaved as a partial agonist that varied across transcripts. These data indicate that each ONO-AE1-329-regulated gene differs in sensitivity to cAMP and is defined by a unique receptor occupancy-response relationship. Moreover, if this relatively modest genomic response in BEAS-2B cells is retained in vivo, then inhaled EP 4 -receptor agonists could represent an alternative, and possibly safer, class of bronchodilators. SIGNIFICANCE STATEMENT: The genomic consequences of β 2 -adrenoceptor agonists in asthma are often overlooked despite being potentially harmful to lung health. We determined that ONO-AE1-329, an EP 4 -receptor agonist and effective bronchodilator, produced gene expression changes in BEAS-2B cells that were typically modest relative to the β 2 -adrenoceptor agonist vilanterol. Furthermore, ONO-AE1-329 behaved as a partial agonist that varied across transcripts. If this genomic activity is reproduced in vivo, then EP 4 -receptor agonists could represent an alternative, and possibly safer, class of bronchodilators., (Copyright © 2024 by The American Society for Pharmacology and Experimental Therapeutics.)

Objective: Our objectives were to determine the no-show and nonattendance rate for an outpatient academic otolaryngology practice, to identify patient and systemic factors associated with nonattendance, and to evaluate the impact that the COVID-19 pandemic had on the rate of nonattendance., Methods: This is a retrospective review of the Epic practice management and billing reports from all scheduled outpatient visits at a multi-physician, academic, general, and sub-specialty otolaryngology practice from January 2019 to December 2021., Results: Over three years, 121,347 clinic visits were scheduled in the otolaryngology practice. The overall nonattendance rate was 18.3%. A statistically significant increase in nonattendance was noted during the COVID-19 pandemic (16.8% vs. 19.8%, p < 0.001). The rate of nonattendance in patients of younger age (under 18 years) (p <0.001), female gender (p=0.03), afternoon appointments (p=0.04), and extended time between the day of scheduling and the day of appointment (p <0.001) increased. Head and neck clinics were found to have the lowest nonattendance rates, while pediatric otolaryngology clinics had the highest (12.6% vs. 21.3%). On multivariate regression, younger age (p < 0.001), female gender (p=0.01), afternoon appointments (p< 0.001), and online self-scheduling (p< 0.001) were significantly associated with nonattendance., Conclusions: Both patient and appointment-related factors were found to impact rates of nonattendance in this academic otolaryngology practice. In this study, young age, female gender, afternoon appointments, and online self-scheduling were associated with increased nonattendance. In addition, the COVID-19 pandemic significantly impacted no-show rates across all otolaryngologic subspecialties., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Yuhan et al.)

Atoms confined in optical tweezer arrays constitute a platform for the implementation of quantum computers and simulators. State-dependent operations are realized by exploiting electrostatic dipolar interactions that emerge, when two atoms are simultaneously excited to high-lying electronic states, so-called Rydberg states. These interactions also lead to state-dependent mechanical forces, which couple the electronic dynamics of the atoms to their vibrational motion. We explore these vibronic couplings within an artificial molecular system in which Rydberg states are excited under so-called facilitation conditions. This system, which is not necessarily self-bound, undergoes a structural transition between an equilateral triangle and an equal-weighted superposition of distorted triangular states (Jahn-Teller regime) exhibiting spin-phonon entanglement on a micrometer distance. This highlights the potential of Rydberg tweezer arrays for the study of molecular phenomena at exaggerated length scales.

Ambient temperature varies constantly. However, the period of circadian pacemakers is remarkably stable over a wide-range of ecologically- and physiologically-relevant temperatures, even though the kinetics of most biochemical reactions accelerates as temperature rises. This thermal buffering phenomenon, called temperature compensation, is a critical feature of circadian rhythms, but how it is achieved remains elusive. Here, we uncovered the important role played by the Drosophila PERIOD (PER) phosphodegron in temperature compensation. This phosphorylation hotspot is crucial for PER proteasomal degradation and is the functional homolog of mammalian PER2 S478 phosphodegron, which also impacts temperature compensation. Using CRISPR-Cas9, we introduced a series of mutations that altered three Serines of the PER phosphodegron. While all three Serine to Alanine substitutions lengthened period at all temperatures tested, temperature compensation was differentially affected. S44A and S45A substitutions caused undercompensation, while S47A resulted in overcompensation. These results thus reveal unexpected functional heterogeneity of phosphodegron residues in thermal compensation. Furthermore, mutations impairing phosphorylation of the per s phosphocluster showed undercompensation, consistent with its inhibitory role on S47 phosphorylation. We observed that S47A substitution caused increased accumulation of hyper-phosphorylated PER at warmer temperatures. This finding was corroborated by cell culture assays in which S47A slowed down phosphorylation-dependent PER degradation at high temperatures, causing PER degradation to be excessively temperature-compensated. Thus, our results point to a novel role of the PER phosphodegron in temperature compensation through temperature-dependent modulation of the abundance of hyper-phosphorylated PER. Our work reveals interesting mechanistic convergences and differences between mammalian and Drosophila temperature compensation of the circadian clock., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Joshi, Cai, Xia, Chiu and Emery.)

Chronic use of β 2 -adrenoceptor agonists as a monotherapy in asthma is associated with a loss of disease control and an increased risk of mortality. Herein, we tested the hypothesis that β 2 -adrenoceptor agonists, including formoterol, promote biased, β -arrestin (Arr) 2-dependent activation of the mitogen-activated protein kinases, ERK1/2, in human airway epithelial cells and, thereby, effect changes in gene expression that could contribute to their adverse clinical outcomes. Three airway epithelial cell models were used: the BEAS-2B cell line, human primary bronchial epithelial cells (HBEC) grown in submersion culture, and HBEC that were highly differentiated at an air-liquid interface. Unexpectedly, treatment of all epithelial cell models with formoterol decreased basal ERK1/2 phosphorylation. This was mediated by cAMP-dependent protein kinase and involved the inactivation of C-rapidly-activated fibrosarcoma, which attenuated downstream ERK1/2 activity, and the induction of dual-specificity phosphatase 1. Formoterol also inhibited the basal expression of early growth response-1, an ERK1/2-regulated gene that controls cell growth and repair in the airways. Neither carvedilol, a β 2 -adrenoceptor agonist biased toward β Arr2, nor formoterol promoted ERK1/2 phosphorylation in BEAS-2B cells, although β 2 -adrenoceptor desensitization was compromised in ARRB2 -deficient cells. Collectively, these results contest the hypothesis that formoterol activates ERK1/2 in airway epithelia by nucleating a β Arr2 signaling complex; instead, they indicate that β 2 -adrenoceptor agonists inhibit constitutive ERK1/2 activity in a cAMP-dependent manner. These findings are the antithesis of results obtained using acutely challenged native and engineered HEK293 cells, which have been used extensively to study mechanisms of ERK1/2 activation, and highlight the cell type dependence of β 2 -adrenoceptor-mediated signaling. SIGNIFICANCE STATEMENT: It has been proposed that the adverse effects of β 2 -adrenoceptor agonist monotherapy in asthma are mediated by genomic mechanisms that occur principally in airway epithelial cells and are the result of β -arrestin 2-dependent activation of ERK1/2. This study shows that β 2 -adrenoceptor agonists, paradoxically, reduced ERK1/2 phosphorylation in airway epithelia by disrupting upstream rat sarcoma-C-rapidly accelerated fibrosarcoma complex formation and inducing dual-specificity phosphatase 1. Moreover, these effects were cAMP-dependent protein kinase-dependent, suggesting that β 2 -adrenoceptor agonists were not biased toward β -arrestin 2 and acted via canonical, cAMP-dependent signaling., (Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics.)

There is a clear, unmet clinical need to identify new drugs to treat individuals with asthma, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF) in whom current medications are either inactive or suboptimal. In preclinical models, EP 4 -receptor agonists display efficacy, but their mechanism of action is unclear. In this study, using human bronchial epithelial cells as a therapeutically relevant drug target, we hypothesized that changes in gene expression may play an important role. Several prostanoid receptor mRNAs were detected in BEAS-2B cells, human primary bronchial epithelial cells (HBECs) grown in submersion culture and HBECs grown at an air-liquid interface with PTGER4 predominating. By using the activation of a cAMP response element reporter in BEAS-2B cells as a surrogate of gene expression, Schild analysis determined that PTGER4 mRNAs encoded functional EP 4 -receptors. Moreover, inhibitors of phosphodiesterase 4 (roflumilast N -oxide [RNO]) and cAMP-dependent protein kinase augmented and attenuated, respectively, reporter activation induced by 2-[3-[(1 R ,2 S ,3 R )-3-hydroxy-2-[(E,3 S )-3-hydroxy-5-[2-(methoxymethyl)phenyl]pent-1-enyl]-5-oxo-cyclopentyl]sulphanylpropylsulphanyl] acetic acid (ONO-AE1-329), a selective EP 4 -receptor agonist. ONO-AE1-329 also enhanced dexamethasone-induced activation of a glucocorticoid response element reporter in BEAS-2B cells, which was similarly potentiated by RNO. In each airway epithelial cell variant, numerous genes that may impart therapeutic benefit in asthma, COPD, and/or IPF were differentially expressed by ONO-AE1-329, and those changes were often augmented by RNO and/or dexamethasone. We submit that an EP 4 -receptor agonist, either alone or as a combination therapy, may be beneficial in individuals with chronic lung diseases in whom current treatment options are inadequate. SIGNIFICANCE STATEMENT: Using human bronchial epithelial cells as a therapeutically relevant drug target, we report that EP 4 -receptor activation promoted gene expression changes that could provide therapeutic benefit in individuals with asthma, COPD, and IPF in whom current treatment options are ineffective or suboptimal., (Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics.)