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Abstract Breast cancer metastasis is associated with a poor prognosis and a high rate of mortality. Cathepsin L (CTSL) is a lysosomal cysteine protease that promotes tumor metastasis by degrading the extracellular matrix. Gene set enrichment analysis revealed that CTSL expression was higher in tumorous than in non-tumorous tissues of breast cancer patients and that high-level CTSL expression correlated positively with the epithelial-mesenchymal transition. Therefore, we hypothesized that inhibiting CTSL activity in tumor cells would prevent metastasis. In this study, we characterized the inhibitory activity of SnuCalCpI15, the I29 domain of a CTSL-like cysteine protease from Calotropis procera R. Br., and revealed that the propeptide stereoselectively inhibited CTSL in a reversible slow-binding manner, with an inhibitory constant (K i) value of 1.38 ± 0.71 nM, indicating its potency as an exogenous inhibitor in anti-cancer therapy. SnuCalCpI15 was localized intracellularly in MDA-MB-231 breast cancer cells and suppressed tumor cell migration and invasion. These results demonstrate the potential of SnuCalCpI15 as a novel agent to prevent breast cancer metastasis.

Objective: To assess pregnant women’s knowledge, attitude, and practice regarding nutrition and medication usage, analyse the prescribing pattern, and categorize them based on the Food and Drug Administration (FDA) guidelines. Methods: A cross-sectional study was conducted with 264 pregnant women in the obstetrics and gynaecology department of a tertiary care hospital from October 2022 to August 2023. A knowledge, attitude, and practice (KAP) questionnaire was prepared in English language by the researchers and validated by an expert panel consisting of 12 members. The validated questionnaire was then translated into regional languages, Kannada and Malayalam. The reliability of the questionnaire was assessed with test-retest method with a representative sample population of 30 subjects (10 subjects for each language). The subjects’ knowledge, attitude, and practice were evaluated using the validated KAP questionnaire. The safety of the medication was assessed using the FDA drug safety classification for pregnancy. Results: The mean scores for nutritional and medication usage knowledge, attitude, and practice were 4.14±1.15, 4.50±1.09, and 3.00±1.47, respectively. Among 30 prescribed medications, 3 belong to category A (no risk in human studies), 8 belong to category B (no risk in animal studies), 18 belong to category C (risk cannot be ruled out) and 1 drug is not classified. A significant association was observed between medication knowledge and practice (r=0.159, P=0.010). Conclusions: Most of the study population knows the need to maintain good dietary and medication practices during pregnancy. Counselling pregnant women regarding diet and medication usage is crucial in maternal care.

Abstract Purpose To characterize current lesbian, gay, bisexual, transgender, queer, and intersex (LGBTQI +) health-related undergraduate medical education (UME) curricular content and associated changes since a 2011 study and to determine the frequency and extent of institutional instruction in 17 LGBTQI + health-related topics, strategies for increasing LGBTQI + health-related content, and faculty development opportunities. Method Deans of medical education (or equivalent) at 214 allopathic or osteopathic medical schools in Canada and the United States were invited to complete a 36-question, Web-based questionnaire between June 2021 and September 2022. The main outcome measured was reported hours of LGBTQI + health-related curricular content. Results Of 214 schools, 100 (46.7%) responded, of which 85 (85.0%) fully completed the questionnaire. Compared to 5 median hours dedicated to LGBTQI + health-related in a 2011 study, the 2022 median reported time was 11 h (interquartile range [IQR], 6–16 h, p

Objective: To assess pathways to parenthood, pregnancy outcomes, future pregnancy desire, and fertility counseling experiences among a cross-sectional sample of transgender men and gender diverse individuals assigned female or intersex at birth in the United States Methods: Participants were recruited from The Population Research in Identity and Disparities for Equality (PRIDE) Study and the general public. Eligible participants for this analysis were able to read and understand English, assigned female or intersex at birth, US residents, 18+ years old, and identified as transgender, nonbinary, or gender diverse. We analyzed responses to close-ended survey questions, overall and stratified by gender identity, race/ethnicity, and testosterone use. We also qualitatively assessed open-text responses on fertility counseling. Results: Among the 1694 participants, median age was 27 years (range: 18–72), 12% had ever been pregnant, and 12% were parents. Carrying a pregnancy where the individual was the egg source (36%) was the most common pathway to parenthood. Individuals with an exclusively binary gender identity (ie, transgender man or man) more often reported becoming parents through adoption than individuals with gender diverse identities (19% vs 12%). A third of individuals did not receive fertility counseling prior to initiating testosterone; individuals who exclusively reported nonbinary identities were recommended to investigate fertility preservation options less often (36%) compared to transgender men (50%). Conclusion: Transgender men and gender diverse individuals who were assigned female or intersex at birth build their families through a variety of pathways, including pregnancy, stepparenting, and adoption. Clinicians should avoid making assumptions about reproductive desires in these populations based on gender identities or testosterone use and should provide consistent fertility counseling prior to and after hormone initiation.

Abstract Shigellosis, a leading cause of diarrhoeal mortality and morbidity globally, predominantly affects children under five years of age living in low- and middle-income countries. While whole genome sequence analysis (WGSA) has been effectively used to further our understanding of shigellosis epidemiology, antimicrobial resistance, and transmission, it has been under-utilised in sub-Saharan Africa. In this study, we applied WGSA to large sub-sample of surveillance isolates from South Africa, collected from 2011 to 2015, focussing on Shigella flexneri 2a and Shigella sonnei. We find each serotype is epidemiologically distinct. The four identified S. flexneri 2a clusters having distinct geographical distributions, and antimicrobial resistance (AMR) and virulence profiles, while the four sub-Clades of S. sonnei varied in virulence plasmid retention. Our results support serotype specific lifestyles as a driver for epidemiological differences, show AMR is not required for epidemiological success in S. flexneri, and that the HIV epidemic may have promoted Shigella population expansion.

Abstract Background We describe the genotypic characteristics and antimicrobial resistance (AMR) determinants of Salmonella enterica serovar Isangi (Salmonella Isangi) clinical isolates in South Africa from 2020 through 2021. Methods During the years 2020 to 2021, the Centre for Enteric Diseases of the National Institute for Communicable Diseases, a national reference centre in South Africa for human infections resulting from enteric bacterial pathogens, investigated a total of 3549 clinical isolates of Salmonella species. Whole genome sequencing (WGS) was performed using Illumina NextSeq Technology. WGS data was analyzed using Centre for Genomic Epidemiology-based tools and EnteroBase web-based platform. Genotypic relatedness and cluster analysis was investigated based on core-genome multilocus sequence typing. Results Forty-nine isolates were confirmed to be Salmonella Isangi, with most submitted from Gauteng Province (24/49, 49%). The most prevalent sequence type was ST335 (48/49, 98%), and the remaining 1 isolate was ST216. All ST335 isolates were genotypically multidrug-resistant (MDR), with resistance to fluoroquinolones, chloramphenicol, trimethoprim-sulfamethoxazole and tetracycline; the ST216 isolate was resistant only to aminoglycosides. All ST335 isolates carried ESBL genes, the most common being bla CTX-M-15. Five clusters (consisting of isolates related within five allele differences) were detected, all being ST335. Conclusions Most Salmonella Isangi isolates in South Africa are MDR and ESBL-positive. Ongoing monitoring of the epidemiology and AMR profile of this serovar is important for public health and treatment guidelines.

Lesbian, gay, bisexual, transgender, queer, intersex, asexual, aromantic, and other sexual and/or gender minority (LGBTQIA+) communities are underrepresented in health research and subject to documented health disparities. In addition, LGBTQIA+ communities have experienced mistreatment, discrimination, and stigma in health care and health research settings. Effectively engaging LGBTQIA+ communities and individuals in health research is critical to developing representative data sets, improving health care provision and policy, and reducing disparities. However, little is known about what engagement approaches work well with LGBTQIA+ people. This paper describes the development of PRIDEnet (pridenet.org), a national network dedicated to catalyzing LGBTQIA+ community involvement in health research and built upon well-established community-engaged research (CEnR) principles. PRIDEnet’s relationship building and digital communications activities engage thousands of LGBTQIA+-identified people across the country and offer multiple low-threshold ways to participate in specific studies and shape research. These activities comprise a CEnR infrastructure that engages LGBTQIA+ people on behalf of other projects, primarily The PRIDE Study (pridestudy.org) and the National Institutes of Health’s All of Us Research Program (joinallofus.org/lgbtqia). Our impact, results, and lessons learned apply to those engaging communities underserved in biomedical research and include: the importance of building adaptable infrastructure that sustains transformational relationships long-term; implementing high-touch activities to establish trust and broad-reach activities to build large data sets; nurturing a team of diverse professionals with lived experiences that reflect those of the communities to be engaged; and maintaining CEnR mechanisms that exceed advice-giving and result in substantive research contributions from beginning to end.

No abstract available.

Inclusion at academic events is facing increased scrutiny as the communities these events serve raise their expectations for who can practically attend. Active efforts in recent years to bring more diversity to academic events have brought progress and created momentum. However, we must reflect on these efforts and determine which underrepresented groups are being disadvantaged. Inclusion at academic events is important to ensure diversity of discourse and opinion, to help build networks, and to avoid academic siloing. All of these contribute to the development of a robust and resilient academic field. We have developed these Ten Simple Rules both to amplify the voices that have been speaking out and to celebrate the progress of many Equity, Diversity, and Inclusivity practices that continue to drive the organisation of academic events. The Rules aim to raise awareness as well as provide actionable suggestions and tools to support these initiatives further. This aims to support academic organisations such as the Deep Learning Indaba, Neuromatch Academy, the IBRO-Simons Computational Neuroscience Imbizo, Biodiversity Information Standards (TDWG), Arabs in Neuroscience, FAIRPoints, and OLS (formerly Open Life Science). This article is a call to action for organisers to reevaluate the impact and reach of their inclusive practices.

BackgroundPerson-centered care (PCC) encourages patients to actively participate in health care, thus facilitating care that fits the life of the patient. Therefore, health care professionals (HCPs) need to know the patient. As part of a broad policy for improving PCC, a digital questionnaire (“We would like to know you”) consisting of 5 questions has previously been developed to help HCPs to get to know the patient with the help of patient and staff involvement. ObjectiveThe purpose of this study was to provide insight into the content and aims of the questionnaire to understand its potential and usability. MethodsWe conducted a qualitative, retrospective content analysis of patients’ answers using NVivo Pro (QSR International). The questionnaire was used in the outpatient neuro-oncology department of a Dutch academic hospital. ResultsOf 374 invited patients, 78 (20.9%) completed the questionnaire. We selected a sample of 42 (54%) of the 78 patients. Patients used a median of 16 (IQR 7-27) words per question, and most answers were easily interpretable. When asked about important activities, social activities, sports, or maintaining a normal life were most frequently mentioned. Patients wrote about fear of the disease, its possible influence on life, or fear of the future in general. Patients wanted HCPs to know about their care and communication preferences or shared personal information. They formulated expectations about effective treatment, communication, and the care process. ConclusionsThe questionnaire seems usable because patients provide interpretable answers that take little time to read, which HCPs can use to personalize care. Our study shows the potential of the questionnaire to help deliver PCC.

BACKGROUND: Although 10% to 20% of cisgender women aged 18 to 40 years have a sexual minority identity (eg, bisexual, lesbian, and queer), there is limited research on the family building and pregnancy experiences of sexual minority cisgender women. Improving our understanding of the family building and pregnancy experiences of cisgender sexual minority women is critical for improving the perinatal health of this population. OBJECTIVE: This study aimed to compare the mode of family building, past pregnancy experiences, and future pregnancy intentions among cisgender sexual minority women by sexual orientation. STUDY DESIGN: This is an observational study which was conducted using cross-sectional data collected in 2019 from a national sample of 1369 cisgender sexual minority women aged 18 to 45 years. RESULTS: Most participants (n=794, 58%) endorsed multiple sexual orientations, most commonly queer (n=641, 47%), lesbian (n=640, 47%), and/or bisexual (n=583, 43%). There were 243 (18%) cisgender sexual minority women who were parents. Pregnancy was used by 74% (181/243) of women to build their families. Among participants who used pregnancy, 60% (108/181) became pregnant through sexual activity with another parent of the child, whereas 27% (64/243) of women used donor sperm. An additional 10% (n=24) became parents through second-parent adoption, 10% (n=25) through adoption, and 14% (n=35) through step-parenting. Bisexual women more often used sexual activity to become parents (61/100, 61%) compared with queer (40/89, 45%) and lesbian women (40/130, 31%). In contrast, lesbian (50/130, 39%) and queer (25/89, 27%) women more often used donor sperm to become parents compared with bisexual women (11/100, 11%). Among the 266 (19%) cisgender sexual minority women who had ever been pregnant, there were 545 pregnancies (mean, 2.05 pregnancies per woman). Among those pregnancies, 59% (n=327) resulted in live birth, 23% (n=126) resulted in miscarriage, 15% (n=83) resulted in abortion, and 2% (n=9) resulted in ectopic pregnancy. A quarter of women had future pregnancy intentions, with no differences by sexual orientation. Overall, few participants (16%) reported that all of their healthcare providers were aware of their sexual orientation. CONCLUSION: Cisgender sexual minority women primarily built their families through pregnancy and a quarter have future pregnancy desires. In addition, there were important differences in family building methods used by sexual orientation. Providers should be aware of the pregnancy and family-building patterns, plans, and needs of cisgender sexual minority women.

Abstract Background Although the Eating Disorder Examination-Questionnaire (EDE-Q) is one of the most widely used self-report assessments of eating disorder symptoms, evidence indicates potential limitations with its original factor structure and associated psychometric properties in a variety of populations, including sexual minority populations. The aims of the current investigation were to explore several previously published EDE-Q factor structures and to examine internal consistency and measurement invariance of the best-fitting EDE-Q model in a large community sample of cisgender gay men and cisgender lesbian women. Methods Data were drawn from 1624 adults (1060 cisgender gay men, 564 cisgender lesbian women) who participated in The PRIDE Study, a large-scale longitudinal cohort study of sexual and gender minorities from the United States. A series of confirmatory factor analyses (CFAs) were conducted to explore the fit of eight proposed EDE-Q models; internal consistency (Cronbach’s alphas, Omega coefficients) and measurement invariance (multi-group CFA) were subsequently evaluated. Results A brief seven-item, three-factor (dietary restraint, shape/weight overvaluation, body dissatisfaction) model of the EDE-Q from Grilo et al. (Obes Surg. 23:657–662, 2013), consistently evidenced the best fit across cisgender gay men and lesbian women. The internal consistencies of the three subscales were adequate in both groups, and measurement invariance across the groups was supported. Conclusions Taken together, these findings support the use of the seven-item, three-factor version of the EDE-Q for assessing eating disorder symptomatology in cisgender gay men and lesbian women. Future studies can confirm the current findings in focused examinations of the seven-item, three-factor EDE-Q in diverse sexual minority samples across race, ethnicity, socioeconomic status, and age ranges.

Abstract Background Gender minority (GM; individuals whose gender is not aligned with that traditionally associated with the sex that was assigned to them at birth) people have widely reported mistreatment in healthcare settings. Mistreatment is enacted by individuals within society who hold stigmatizing beliefs. However, the relationship between healthcare mistreatment and societal stigma (i.e., the degree to which society disapproves of GM people) is unclear and not measured consistently. Methods We analyzed data from 2,031 GM participants in The Population Research in Identity and Disparities for Equality (PRIDE) Study’s 2019 Annual Questionnaire to determine whether societal stigma was associated with participants’ past-year reports of mistreatment (defined as denial of healthcare services and/or lower quality care) in medical or mental healthcare settings. We created a proxy measure of societal stigma by incorporating variables validated in existing literature. Participants reported whether they had experienced mistreatment in medical and mental health settings independently. Results Healthcare denial and/or lower quality care during the past year was reported by 18.8% of our sample for medical settings and 12.5% for mental health settings. We found no associations between the societal stigma variables and past-year reports of healthcare denial and/or lower quality care in medical or mental healthcare settings. Conclusions Although a high proportion of GM people reported past-year healthcare mistreatment in both medical and mental health settings, mistreatment had no relationship with societal stigma. Factors other than societal stigma may be more important predictors of healthcare mistreatment, such as healthcare workers’ knowledge of and attitudes toward GM people. However, other measures of societal stigma, or different types of mistreatment, may show stronger associations. Identifying key factors that contribute to mistreatment can serve as targets for intervention in communities and healthcare settings.

Since February 2022, Malawi has experienced a cholera outbreak of >54,000 cases. We investigated 6 cases in South Africa and found that isolates linked to the outbreak were Vibrio cholerae O1 serotype Ogawa from seventh pandemic El Tor sublineage AFR15, indicating a new introduction of cholera into Africa from south Asia.

Abstract In-vivo corneal confocal microscopy is a powerful imaging technique which provides clinicians and researcher with the capabilities to observe microstructures at the ocular surfaces in significant detail. In this Mini Review, the optics and image analysis methods with the use of corneal confocal microscopy are discussed. While novel insights of neuroanatomy and biology of the eyes, particularly the ocular surface, have been provided by corneal confocal microscopy, some debatable elements observed using this technique remain and these are explored in this Mini Review. Potential improvements in imaging methodology and instrumentation are also suggested.

Objective: To investigate associations between reproductive endocrinology and infertility (REI) providers’ prior training and current knowledge, skills, attitudes, and behaviors regarding fertility preservation and family building for transgender and gender-diverse (T/GD) patients. Design: The survey was distributed to members of the Society for Reproductive Endocrinology and Infertility, the REI-physician-focused professional body within the American Society for Reproductive Medicine, with additional participants recruited through snowball sampling. Results: Participants (n = 206) reported on training in T/GD care; 51% endorsed prior training. Most participants (93%) believed T/GD individuals were as fit for parenthood as cisgender individuals. Prior training was associated with an increased likelihood of offering T/GD health resources and more frequent consultations with specialist colleagues.Common barriers to providing care indicated by respondents included cost, delays in gender-affirming care, and lack of knowledge of the potential impact of hormonal interventions. Common facilitators included education and training, prior experience, and affordability of services. Conclusions: Most REI providers believed T/GD individuals are fit for parenthood and agreed that prior training facilitates care for T/GD patients. The lack of provider knowledge emerged as a barrier to care. Although training helped facilitate some components of care, systemic barriers such as the cost and variability of patient population characteristics/experiences are important considerations when serving T/GD individuals.

Objective Transgender, non-binary and intersex people are less likely to receive appropriate cancer screening for their bodies and have a higher incidence of certain cancers than cisgender people. We aimed to elicit community-generated solutions to improve cancer screening for these populations.Methods and analysis We conducted six online, asynchronous focus groups in English and Spanish with transgender, non-binary, intersex and cisgender participants who were at least 15 years of age from across the USA. Participants shared their experiences with cancer screening and related conversations with healthcare providers and recommendations for making screening practices more inclusive of their bodies and experiences. Focus group data were exported into transcripts and analysed with thematic analysis.Results The 23 participants represented a diversity of races, genders, sexualities, ages and geographical locations. Transgender, non-binary and intersex participants, particularly Black, Indigenous and/or people of colour, reported having to self-advocate to receive necessary care by initiating conversations about screening with their providers, requesting specific screenings and educating providers about the appropriate care for their body. Notably, no white or cisgender participants described having to request relevant screenings or initiate conversations with their providers. Participants recommended that forms ask about body parts and allow for self-identification.Conclusion The ability to properly screen patients can have a direct impact on cancer outcomes. More inclusive intake forms may alleviate the need for transgender, non-binary and intersex patients to self-advocate to receive necessary care. More work should be done to educate providers on cancer risk for transgender, non-binary and intersex individuals.

Improving the digital presentation of fabrics enhances the online shopping experience and, in turn, reduces textile waste. In this study, we examined how the manipulation of simple surface reflectance models can bias the perception of fabric properties simulated online in a web browser. We showed that motion and three-dimensional (3D) folds (i.e., rumple) influence the perception of sheen for different fabric types (cotton knit and satin). Also, we found complex interactions between these parameters in their effects on perceived sheen and perceived color saturation. Moreover, we showed that changing the level of specular roughness significantly influences visual perception of sheen, color and lightness, which in turn, can categorically alter perceptual judgments of material type. In contrast to visual attributes, specular roughness did not influence visually perceived tactile characteristics of digital fabrics (thickness and stretch). The knowledge gained about perceptual biases of digital fabrics from this study will inform future considerations for optimizing the fidelity of textiles depicted in digital commerce.

Context: Adverse drug reactions (ADRs) are “any response to a drug which is noxious and unintended, and which occurs at doses normally used in man for prophylaxis, diagnosis, or disease therapy.” Antipsychotics used for treating mental illnesses are highly vulnerable to ADRs due to the need for lifelong therapy. Early detection and regular monitoring of ADRs can minimize complications and improve patient's quality of life. Aims: The study aims to identify ADRs in patients with psychiatric disorders and determine the cause of ADRs. Settings and Design: A prospective cross-sectional study conducted in the outpatient department of psychiatry at a tertiary care teaching hospital. Materials and Methods: Patients were approached to identify ADRs at the psychiatry outpatient department. Informed consent was obtained from the participants before enrollment. Data collected from patients were documented in the patient data collection forms and suspected ADR reporting forms have been used to record ADRs. Statistical Analysis Used: Chi-square test was used for statistical analysis. Results: Among 190 recruited, 60 ADRs were reported from 39 outpatients. A significant multiple psychotropic drug usage was found in the patients (P ≤ 0.005). Both the genders showed an equal propensity toward ADRs. The antipsychotic drug sodium valproate held responsible for most of the ADRs. Tremor an extrapyramidal side effect was the most common adverse effect identified. Most of the patients required dose alteration to manage their symptoms. Conclusions: Regular observation is necessary for psychiatry patients to ensure safety and compliance with the therapy. Spontaneous reporting and regular monitoring are necessary to avoid ADR occurrence and its severity.

Abstract Main goal of the JUNO experiment is to determine the neutrino mass ordering using a 20 kt liquid-scintillator detector. Its key feature is an excellent energy resolution of at least 3% at 1 MeV, for which its instruments need to meet a certain quality and thus have to be fully characterized. More than 20,000 20-inch PMTs have been received and assessed by JUNO after a detailed testing program which began in 2017 and elapsed for about four years. Based on this mass characterization and a set of specific requirements, a good quality of all accepted PMTs could be ascertained. This paper presents the performed testing procedure with the designed testing systems as well as the statistical characteristics of all 20-inch PMTs intended to be used in the JUNO experiment, covering more than fifteen performance parameters including the photocathode uniformity. This constitutes the largest sample of 20-inch PMTs ever produced and studied in detail to date, i.e. 15,000 of the newly developed 20-inch MCP-PMTs from Northern Night Vision Technology Co. (NNVT) and 5000 of dynode PMTs from Hamamatsu Photonics K. K.(HPK).

PELP1 is a large scaffolding protein implicated in many cellular activities, including ribosome assembly as part of the Rix1 complex, comprising PELP1, WDR18, TEX10 and other components. Here, authors present the cryo-EM structure of PELP1 in complex with its binding partner WDR18, revealing the architecture of PELP1's numerous signaling motifs.

Abstract Background Stool samples submitted for diagnostic testing represent a proportion of diarrhoeal cases seeking healthcare, and an even smaller proportion of diarrhoeal cases in the community. Despite this, surveillance relies heavily on these laboratory results. This study described diarrhoeal diagnostic practices and aetiological agents of diarrhoea in patients admitted to three South African public hospitals in order to understand biases in surveillance data, and inform guidelines, diagnostic and laboratory practices to improve clinical management. Methods A doctors’ survey was conducted to determine sample submission, diarrhoeal treatment and barriers to submitting samples for testing. Results for all samples submitted for routine diagnostics were obtained from the NHLS Central Data Warehouse. An enhanced surveillance study enrolled patients with acute diarrhoea at the same hospitals over the same period. Differences between routine culture results and molecular testing from the surveillance study were described. Results Stool samples were seldom submitted for diagnostic testing (median of 10% of admitted cases). Current diagnostic guidelines were not useful, hence most doctors (75.1%) relied on their own clinical judgement or judgement of a senior clinician. Although most doctors (90.3%) agreed that diagnostics were helpful for clinical management, they reported patients being unwilling to provide samples and long laboratory turnaround times. Routine diagnostic data represent cases with chronic diarrhoea and dysentery since doctors are most likely to submit specimens for these cases. Pathogen yield (number of pathogens detected for samples tested for specific pathogens) was significantly higher in the surveillance study, which used molecular methods, than through routine diagnostic services (73.3% versus 8.2%, p

Understanding structure-property relationship of dye arrays is of great importance for designing organic photonic and photovoltaic materials. Here, authors present a slip-stacked perylene bisimide array as a model system to investigate singlet fission mechanisms by depending upon interchromophoric interaction.

Abstract Recombinant human bone morphogenetic protein-2 (rhBMP-2), a key regulator of osteogenesis, induces the differentiation of mesenchymal cells into cartilage or bone tissues. Early orthopedic and dental studies often used mammalian cell-derived rhBMP-2, especially Chinese hamster ovary (CHO) cells. However, CHO cell-derived rhBMP-2 (C-rhBMP-2) presents disadvantages such as high cost and low production yield. To overcome these problems, Escherichia coli-derived BMP-2 (E-rhBMP-2) was developed; however, the E-rhBMP-2-induced signaling pathways and gene expression profiles during osteogenesis remain unclear. Here, we investigated the E-rhBMP-2-induced osteogenic differentiation pattern in C2C12 cells and elucidated the difference in biological characteristics between E-rhBMP-2 and C-rhBMP-2 via surface plasmon resonance, western blotting, qRT-PCR, RNA-seq, and alkaline phosphatase assays. The binding affinities of E-rhBMP-2 and C-rhBMP-2 towards BMP receptors were similar, both being confirmed at the nanomolecular level. However, the phosphorylation of Smad1/5/9 at 3 h after treatment with E-rhBMP-2 was significantly lower than that on treatment with C-rhBMP-2. The expression profiles of osteogenic marker genes were similar in both the E-rhBMP-2 and C-rhBMP-2 groups, but the gene expression level in the E-rhBMP-2 group was lower than that in the C-rhBMP-2 group at each time point. Taken together, our results suggest that the osteogenic signaling pathways induced by E-rhBMP-2 and C-rhBMP-2 both follow the general Smad-signaling pathway, but the difference in intracellular phosphorylation intensity results in distinguishable transcription profiles on osteogenic marker genes and biological activities of each rhBMP-2. These findings provide an extensive understanding of the biological properties of E-rhBMP-2 and the signaling pathways during osteogenic differentiation.

ABSTRACT Lipases, which catalyze the hydrolysis of long-chain triglycerides, diglycerides, and monoglycerides into free fatty acids and glycerol, participate in various biological pathways in fungi. In this study, we examined the biological functions and regulatory mechanisms of fungal lipases via two approaches. First, we performed a systemic functional characterization of 86 putative lipase-encoding genes in the plant-pathogenic fungus Fusarium graminearum. The phenotypes were assayed for vegetative growth, asexual and sexual reproduction, stress responses, pathogenicity, mycotoxin production, and lipase activity. Most mutants were normal in the assessed phenotypes, implying overlapping roles for lipases in F. graminearum. In particular, FgLip1 and Fgl1 were revealed as core extracellular lipases in F. graminearum. Second, we examined the lipase activity of previously constructed transcription factor (TF) mutants of F. graminearum and identified three TFs and one histone acetyltransferase that significantly affect lipase activity. The relative transcript levels of FgLIP1 and FGL1 were markedly reduced or enhanced in these TF mutants. Among them, Gzzc258 was identified as a key lipase regulator that is also involved in the induction of lipase activity during sexual reproduction. To our knowledge, this study is the first comprehensive functional analysis of fungal lipases and provides significant insights into the genetic and regulatory mechanisms underlying lipases in fungi. IMPORTANCE Fusarium graminearum is an economically important plant-pathogenic fungus that causes Fusarium head blight (FHB) on wheat and barley. Here, we constructed a gene knockout mutant library of 86 putative lipase-encoding genes and established a comprehensive phenotypic database of the mutants. Among them, we found that FgLip1 and Fgl1 act as core extracellular lipases in this pathogen. Moreover, several putative transcription factors (TFs) that regulate the lipase activities in F. graminearum were identified. The disruption mutants of F. graminearum-lipase regulatory TFs all showed defects in sexual reproduction, which implies a strong relationship between sexual development and lipase activity in this fungus. These findings provide valuable insights into the genetic mechanisms regulating lipase activity as well as its importance to the developmental stages of this plant-pathogenic fungus.

The first public 0.9–4.4 μ m NIRCam images of the North Ecliptic Pole Time Domain Field uncovered galaxies displaying point-source features in their cores as seen in the longer-wavelength filters. We visually identified a sample of 66 galaxies (∼1 galaxy arcmin ^–2 ) with pointlike cores and have modeled their two-dimensional light profiles with GalFit , identifying 16 galactic nuclei with measurable point-source components. GalFit suggests that the visual sample is a mix of both compact stellar bulge and point-source galaxy cores. This core classification is complemented by spectral energy distribution modeling to infer the sample’s active galactic nucleus (AGN) and host-galaxy parameters. For galaxies with measurable point-source components, the median fractional AGN contribution to their 0.1–30.0 μ m flux is 0.44, and 14/16 are color-classified AGN. We conclude that near-infrared point-source galaxy cores are signatures of AGN. In addition, we define an automated sample-selection criterion to identify these point-source features. This criterion can be used in other extant and future NIRCam images to streamline the search for galaxies with unresolved IR-luminous AGN. The James Webb Space Telescope’s superb angular resolution and sensitivity at infrared wavelengths are resurrecting the morphological identification of AGN.

We set the stage for reassessing how star formation, emission-line nebulae, and active galactic nuclei (AGNs) in brightest cluster galaxies (BCGs) depend on the thermodynamics of the intracluster medium (ICM). Our work is based on the 25 clusters observed in the CLASH program for which the aforementioned attributes in their BCGs can be well scrutinized, as has the thermodynamics of their ICM. Nine of these BCGs display complex UV morphologies tracing recent star formation, whereas the remaining 16 are characterized by a relatively compact central UV enhancement. Here, we show definitively that three of the latter BCGs also display star formation, whereas the diffuse UV of the remaining 13 is entirely consistent with old low-mass stars. The overall results support the previously established dependence of star formation and nebulae in BCGs on an “excess core entropy,” K _0 , for the ICM: all 11 clusters with K _0 ≤ 24 keV cm ^2 (but only one of 14 clusters with K _0 ≥ 42 keV cm ^2 ) host star-forming BCGs that almost if not always possess nebulae. Instead of an entropy floor, we show that K _0 reflects the degree to which the radial entropy profile decreases inward within ∼100 kpc rather than (except perhaps at large K _0 ) actually flattening: clusters with lower ICM entropies and hence shorter cooling times at their cores preferentially host BCGs displaying star formation, nebulae, and more radio-luminous AGNs. Nearly all BCGs possess detectable AGNs, however, indicating multiple pathways for fuelling their AGNs.

Formation of active HIV-1 reverse transcriptase (RT) proceeds via a structural maturation process that involves subdomain rearrangements and formation of an asymmetric p66/p66′ homodimer. These studies were undertaken to evaluate whether the information about this maturation process can be used to identify small molecule ligands that retard or interfere with the steps involved. We utilized the isolated polymerase domain, p51, rather than p66, since the initial subdomain rearrangements are largely limited to this domain. Target sites at subdomain interfaces were identified and computational analysis used to obtain an initial set of ligands for screening. Chromatographic evaluations of the p51 homodimer/monomer ratio support the feasibility of this approach. Ligands that bind near the interfaces and a ligand that binds directly to a region of the fingers subdomain involved in subunit interface formation were identified, and the interactions were further characterized by NMR spectroscopy and X-ray crystallography. Although these ligands were found to reduce dimer formation, further efforts will be required to obtain ligands with higher binding affinity. In contrast with previous ligand identification studies performed on the RT heterodimer, subunit interface surfaces are solvent-accessible in the p51 and p66 monomers, making these constructs preferable for identification of ligands that directly interfere with dimerization.

Plain English Summary Gender-expansive describes gender identities that do not fit within the binary gender identity system, such as man or woman. We asked gender-expansive participants in The PRIDE Study to fill out a widely used survey about muscle dysmorphia (when someone is worried about not being muscular enough). We found that this issue about muscularity has three parts for gender-expansive people: (1) a desire to be bigger and more muscular, (2) dissatisfaction with the way their body looks, and (3) problems with normal life functions. We find that this survey is appropriate for use in gender-expansive people. These results can help providers and researchers understand the muscle-related problems that gender-expansive people face.

Abstract Background Lean methodology helps maximize value by reducing waste, first by defining what value and waste are in a system. In ophthalmology clinics, value is determined by the number of patients flowing through the clinic for a given time. We aimed to increase value using a lean-methodology guided policy change, then assessed its impact on clinic flow using an automated radiofrequency identification (RFID) based real-time locating system (RTLS). Methods A total of 6813 clinical visits occurred at a single academic institution’s outpatient glaucoma clinic between January 5, 2018 to July 3, 2018. Over that period, 1589 patients comprising 1972 (29%) of visits were enrolled, with 1031 clinical visits occurring before and 941 visits after a policy change. The original policy was to refract all patients that improved with pinhole testing. The policy change was not to refract patients with a visual acuity ≥20/30 unless a specific request was made by the patient. Pre-post analysis of an automated time-motion study was conducted for the data collected 3 months before and 3 months after the policy change occurred on March 30, 2018. Changes to process and wait times were summarized using descriptive statistics and fitted to linear mixed regression models adjusting for appointment type, clinic volume, and daily clinic trends. Results One thousand nine hundred twenty-three visits with 1588 patients were included in the analysis. Mean [SD] age was 65.9 [14.7] years and 892 [56.2%] were women. After the policy change, technician process time decreased by 2.9 min (p

IntroductionOutcomes of catheter ablation for non-paroxysmal atrial fibrillation (AF) remain suboptimal. Non-invasive stratification of patients based on the presence of atrial cardiomyopathy (ACM) could allow to identify the best responders to pulmonary vein isolation (PVI).MethodsObservational multicentre retrospective study in patients undergoing cryoballoon-PVI for non-paroxysmal AF. The duration of amplified P-wave (APW) was measured from a digitally recorded 12-lead electrocardiogram during the procedure. If patients were in AF, direct-current cardioversion was performed to allow APW measurement in sinus rhythm. An APW cut-off of 150 ms was used to identify patients with significant ACM. We assessed freedom from arrhythmia recurrence at long-term follow-up in patients with APW ≥ 150 ms vs. APW

Abstract The present study aims to compare the rate of depressive symptoms and inflammation levels between sexual minorities and heterosexuals. Data were obtained from the National Health and Nutrition Examination Survey from 2005 to 2010. Depressive-related symptoms were measured using the Patient Health Questionnaire-9 scoring system. C-reactive protein was analyzed with the Behring Nephelometer. Of 8538 participants, 95.8% self-reported as heterosexual and 4.2% as sexual minority. Depressive symptoms were reported in 7.1% of heterosexuals compared to 15.8% in sexual minorities (P = 0.001). In heterosexuals, C-reactive protein was higher in those with depressive symptoms compared to those without (P

Abstract This article presents the potential of a combined analysis of the JUNO and KM3NeT/ORCA experiments to determine the neutrino mass ordering. This combination is particularly interesting as it significantly boosts the potential of either detector, beyond simply adding their neutrino mass ordering sensitivities, by removing a degeneracy in the determination of ∆ m 31 2 $$ {m}_{31}^2 $$ between the two experiments when assuming the wrong ordering. The study is based on the latest projected performances for JUNO, and on simulation tools using a full Monte Carlo approach to the KM3NeT/ORCA response with a careful assessment of its energy systematics. From this analysis, a 5σ determination of the neutrino mass ordering is expected after 6 years of joint data taking for any value of the oscillation parameters. This sensitivity would be achieved after only 2 years of joint data taking assuming the current global best-fit values for those parameters for normal ordering.

A novel lipase (triacylglycerol acylhydrolase, EC 3.1.1.3) was discovered from Korean chestnut (Castanea crenata). The lipase was isolated and purified by ammonium sulfate precipitation and a fast protein liquid chromatography system equipped with HiTrap DEAE-Sepharose Fast Flow, HiTrap Q-Sepharose Fast Flow, and HiPrep Sephacryl S-100 Hi-Resolution columns. The purified C. crenata lipase showed a 15.8% yield, purification fold number of 465.8, and specific activity against triolein of 88.5 mU/mg. The enzyme exhibited hydrolytic activity toward tributyrin, trilaurin, and triolein, and was maximally active at pH 8.0 and 35 °C, with triolein used as the substrate. The activation energy (Ea) and deactivation energy (Ed) of triolein hydrolysis were 38.41 and 83.35 kJ/mol, respectively. In the enzyme kinetic study, Vmax, Km, and kcat were 110.58 mU/mg, 0.11 mM, and 0.221 min−1, respectively. The relatively low Km value indicated that the lipase has high affinity for its substrate. Moreover, Mg2+ and Ca2+ increased the lipase activity to 115.4% and 108.3%, respectively. The results of peptide fingerprinting revealed that the C. crenata lipase with a molecular weight of 33.3 kDa was structurally similar to the mannose-binding lectin of the jacalin-related lectin domain superfamily, implying that it has potential as a therapeutic agent for use in the biomedical industry.

Diabetic foot ulcers (DFUs) are among the most severe and debilitating complications of diabetes, causing considerable suffering and economic consequences for the patients. The review aims to elaborate on the importance, types, and effects of educational intervention among DFU patients. This review was conducted by electronic search of PubMed, MEDLINE, Scopus, Cochrane Collaboration Database, and Google Scholar with keywords like ‘diabetic foot ulcer,’ ‘educational intervention,’ ‘treatment outcomes,’ etc. The review includes randomization controlled study, cross-sectional, systematic reviews, meta-analysis, cohort studies, etc. The articles were published in English and unpublished and other languages were excluded. This review identified that most of the educational interventions implemented were group education sessions and leaflets that improved the self-foot care practices, foot care knowledge, health status, and medication adherence of the DFU patients. Among the treatment modalities, the dressing was found to be used in most of the patients. Biofilms affect wound healing and delay the healing process. Implementing educational interventions by a multidisciplinary team of physicians, nurses, clinical pharmacists, and podiatrists enhances diabetic foot care practices and knowledge, preventing the DFUs. This review concluded that educational interventions were beneficial to DFU patients in improving their self-care practices and foot care knowledge.

Diarrhoea is a recognised complication of HIV-infection, yet there are limited local aetiological data in this high-risk group. These data are important for informing public health interventions and updating diagnostic and treatment guidelines. This study aimed to determine the pathogenic causes of diarrhoeal admissions in people living with HIV (PLHIV) compared to hospital controls between July 2018 and November 2021. Admitted diarrhoeal cases (n = 243) and non-diarrhoeal hospital controls (n = 101) ≥5 years of age were enrolled at Kalafong, Mapulaneng and Matikwana hospitals. Stool specimens/rectal swabs were collected and pathogen screening was performed on multiple platforms. Differences in pathogen detections between cases and controls, stratified by HIV status, were investigated. The majority (n = 164, 67.5%) of enrolled diarrhoeal cases with known HIV status were HIV-infected. Pathogens could be detected in 66.3% (n = 228) of specimens, with significantly higher detection in cases compared to controls (72.8% versus 50.5%, p

IntroductionSexual and gender minority (SGM) communities, including lesbian, gay, bisexual, transgender, queer, intersex, asexual, and Two-Spirit people, have historically been researched from a deficits-based approach that fails to highlight the ways communities survive and thrive in the face of adversity. This study endeavored to create a model of resources that promote SGM resilience using a sample that amplified traditionally underrepresented perspectives, including individuals from racial and/or ethnic minority groups, trans and/or gender diverse individuals, individuals on the asexual spectrum, and older adults.MethodsParticipant responses to three open-ended questions from The PRIDE Study's (an online national longitudinal cohort study of SGM people) 2018 Annual Questionnaire were analyzed using constructivist grounded theory. These questions examined what brings people joy and what they appreciate most about their SGM identity. Participants (n = 315) were randomly selected from a larger sample of people who had responded to demographic questions and at least one open-ended question (N = 4,030) in a manner to ensure diverse representation across race/ethnicity, gender identity, sexual orientation, age, and region of residence.ResultsThe proposed model includes social resources (Connecting with Others, Cultivating Family, Helping Others, Participating in Culture and Spirituality), affective generative resources (Engaging in Enriching Pursuits, Accessing Economic Resources), and introspective resources (Exploring One's Authentic Self, Persevering through Hardship) that are theorized to contribute to SGM resilience across the life course.ConclusionsSGM communities may tap into various resources to promote resilience. As public health practitioners, we can help to foster this resilience by resourcing and supporting initiatives that foster social connection, create spaces for community members to engage with various types of enrichment, facilitate access to economic resources, and provide support and inclusion for all SGM community members.

We describe the molecular epidemiology of cholera in South Africa during 2018–2020. Vibrio cholerae O1 sequence type (ST) 75 recently emerged and became more prevalent than the V. cholerae O1 biotype El Tor pandemic clone. ST75 isolates were found across large spatial and temporal distances, suggesting local ST75 spread.

Abstract The OSIRIS detector is a subsystem of the liquid scintillator filling chain of the JUNO reactor neutrino experiment. Its purpose is to validate the radiopurity of the scintillator to assure that all components of the JUNO scintillator system work to specifications and only neutrino-grade scintillator is filled into the JUNO Central Detector. The aspired sensitivity level of $$10^{-16}\hbox { g/g}$$ 10 - 16 g/g of $$^{238}\hbox {U}$$ 238 U and $$^{232}\hbox {Th}$$ 232 Th requires a large ( $$\sim 20\,\hbox {m}^3$$ ∼ 20 m 3 ) detection volume and ultralow background levels. The present paper reports on the design and major components of the OSIRIS detector, the detector simulation as well as the measuring strategies foreseen and the sensitivity levels to U/Th that can be reached in this setup.

ABSTRACT Salmonella enterica serovar Enteritidis is one of the most commonly reported serovars of nontyphoidal Salmonella causing human disease and is responsible for both gastroenteritis and invasive nontyphoidal Salmonella (iNTS) disease worldwide. Whole-genome sequence (WGS) comparison of Salmonella Enteritidis isolates from across the world has identified three distinct clades, global epidemic, Central/East African, and West African, all of which have been implicated in epidemics: the global epidemic clade was linked to poultry-associated gastroenteritis, while the two African clades were related to iNTS disease. However, the distribution and epidemiology of these clades across Africa are poorly understood because identification of these clades currently requires whole-genome sequencing capacity. Here, we report a sensitive, time- and cost-effective real-time PCR assay capable of differentiating between the Salmonella Enteritidis clades to facilitate surveillance and to inform public health responses. The assay described here is limited to previously confirmed S. Enteritidis isolates. IMPORTANCE Challenges in the diagnosis and treatment of invasive Salmonella Enteritidis bloodstream infections in sub-Saharan Africa are responsible for a case fatality rate of approximately 15%. It is important to identify distinct clades of S. Enteritidis in diagnostic laboratories in the African setting to determine the different health outcomes associated with particular outbreaks. Here, we describe the development of a high-quality molecular classification assay for clade typing of S. Enteritidis that is ideal for use in public health laboratories in resource-limited settings.

Introduction: Dispensing errors challenge the patient safety and may induce unwanted and noxious events. The objective of this study was to estimate the incidence and types of dispensing errors in the pharmacy of a tertiary care charitable hospital. Materials and methods: This was a prospective observational study conducted for a period of 15 months in the patient counseling area of a 1000 bed hospital. A suitable data collection tool was developed and was approved by the research advisory committee. The required data were obtained randomly from 1852 patients visiting the hospital's pharmacy. The collected data were analyzed for incidence and types of dispensing errors using SPSS (version 20.0). Results: A total of 5353 drugs were dispensed on 1852 prescriptions. The average number of drugs per prescription was found to be three (2.89). The maximum number of drugs prescribed in a prescription was twelve and the minimum was one. Pantoprazole was the most frequently prescribed drug (n = 633, 34.18%). A total of 26 dispensing errors were identified in 21 prescriptions, accounting for a rate of 1.40%. Out of the total errors identified, wrong dose was found to be the most common type of dispensing error accounting for (n = 8, 30.76%), followed by incorrect labeling and wrong quantity (n = 4, 15.38% each). Conclusion: The incidence of dispensing errors was 1.4% and most of the errors were related to the dose/strength of the dispensed drugs.