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Abstract Background Breast cancer, one of the most common forms of cancer, is associated with the highest cancer-related mortality among women worldwide. In comparison to other types of breast cancer, patients diagnosed with the triple-negative breast cancer (TNBC) subtype have the worst outcome because current therapies do not produce long-lasting responses. Hence, innovative therapies that produce persisting responses are a critical need. We previously discovered that hyperactivating purinergic receptors (P2RXs) by increasing extracellular adenosine triphosphate (eATP) concentrations enhances TNBC cell lines’ response to chemotherapy. Heparan sulfate inhibits multiple extracellular ATPases, so it is a molecule of interest in this regard. In turn, heparanase degrades polysulfated polysaccharide heparan sulfate. Importantly, previous work suggests that breast cancer and other cancers express heparanase at high levels. Hence, as heparan sulfate can inhibit extracellular ATPases to facilitate eATP accumulation, it may intensify responses to chemotherapy. We postulated that heparanase inhibitors would exacerbate chemotherapy-induced decreases in TNBC cell viability by increasing heparan sulfate in the cellular microenvironment and hence, augmenting eATP. Methods We treated TNBC cell lines MDA-MB 231, Hs 578t, and MDA-MB 468 and non-tumorigenic immortal mammary epithelial MCF-10A cells with paclitaxel (cytotoxic chemotherapeutic) with or without the heparanase inhibitor OGT 2115 and/or supplemental heparan sulfate. We evaluated cell viability and the release of eATP. Also, we compared the expression of heparanase protein in cell lines and tissues by immunoblot and immunohistochemistry, respectively. In addition, we examined breast-cancer-initiating cell populations using tumorsphere formation efficiency assays on treated cells. Results We found that combining heparanase inhibitor OGT 2115 with chemotherapy decreased TNBC cell viability and tumorsphere formation through increases in eATP and activation of purinergic receptors as compared to TNBC cells treated with single-agent paclitaxel. Conclusion Our data shows that by preventing heparan sulfate breakdown, heparanase inhibitors make TNBC cells more susceptible to chemotherapy by enhancing eATP concentrations.

Kelley Flesher,1 Amal Mathew,2 Yuliya Borovskiy,3,4 Krzysztof Laudanski5 1Department of Neurology, Division of Neurocritical Care, University of Pennsylvania, Philadelphia, PA, USA; 2School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA, USA; 3Corporate Informational Service, Penn Medicine, Philadelphia, PA, USA; 4Data Analytics Core, Penn Medicine, Philadelphia, PA, USA; 5Department of Anesthesiology and Perioperative Care, Mayo Clinic, Rochester, MN, USACorrespondence: Krzysztof Laudanski, Department of Anesthesiology and Perioperative Care, Division of Critical Care Medicine, Mayo Clinic, 200 1st St, Rochester, MN, 55902, USA, Tel +1 (507) 255-5123, Email laudanski.krzysztof@mayo.eduPurpose: Surgery-related stress may affect the metabolome, leading to abnormal lipid profiles and ineffective glycemic control. Here, we gauge these changes as they may accelerate atherosclerosis, limiting the benefits of interventions aimed at improving coronary artery disease (CAD) progression.Patients and Methods: Electronic medical records were queried to identify patients undergoing coronary artery bypass grafting (CABG), percutaneous coronary intervention (PCI), or aortic valve replacement (AVR). 7573 records denoted lipid profile (cholesterol, LDL, HDL, VLDL, triglycerides) and glucose metabolism impairment (HbA1c). Pre-procedure lipid and glucose laboratory values were compared with periods representing acute periprocedural inflammation (1– 3 months), resolution of acute inflammation (3– 6 months), convalescence (6– 12 months), and medium- (1– 2 years), and long-term periods (2– 5 years).Results: Baseline values differed between groups (AVR: Cholesterol↑↓, LDL↓↑, HDL↓, Triglycerides↑, HbA1c↓; CABG: Cholesterol↓, LDL↓, HDL↓, Triglycerides↓, HbA1c↓; PCI: Cholesterol↑↓, LDL↑↓, HDL↑↓, Triglycerides↓, HbA1c↓). Interestingly, total cholesterol and LDL had opposite trajectories after CABG vs AVR even five years after surgical procedure and the effects were moderate as denoted by d-Cohen statistics. HDL declined acutely after CABG and AVR but not after PCI. Triglycerides were elevated for 2 years after AVR but depressed after CABG and PCI. HbA1c remained depressed for up to 5 years after any studied procedure.Conclusion: Our data suggest surgical procedures result in prolonged lipid profile and glycemic metabolism disturbances, particularly after aortic valve replacement, indicating more aggressive post-surgical treatment of these metabolic abnormalities may be warranted.Keywords: cardiac surgery, inflammation, lipid profile, glycated hemoglobin

The wear characteristics of coated H13 tool steel and as-casted H13 tool steel in dry sliding conditions were investigated through a pin-on-disc tribometer, where the H13 steel is used as a pin and EN31 steel is used as disc material. The study was focused on evaluating the tribological behaviour by examining the friction characteristics, surface morphology and wear performance. Initially, to improve the hardness of the untreated (as-casted) H13 steel, the tempering process where carried out on the samples, which helped elevate the hardness from 38 to 55 HRC. The worn surface of the samples was analysed using atomic force microscopy (AFM). Among the four samples (as-casted, heat-treated, AlCrN coated and TiN coated) the as-casted samples were affected by oxidation and adhesive wear. The material loss measured for as-casted, heat-treated, AlCrN and TiN samples was 30.34, 7.85, 0.78 and 0.14 mg, respectively. The measured coefficient of friction was 0.541 for as-casted, 0.492 for the heat-treated, 0.48 for the AlCrN and 0.147 for the TiN sample. From the study, the major conclusion was that the TiN coating offers major wear protection and lower friction.

Background: Lipoprotein(a) [Lp(a)] is an independent risk factor for atherosclerotic cardiovascular disease. The relationship between Lp(a) and major adverse cardiovascular events (MACE) in the context of high-sensitivity C-reactive protein (hs-CRP) levels remains controversial due to conflicting results from previous studies. Objectives: This systematic review and meta-analysis aimed to clarify the association between Lp(a) and risk of MACE across different hs-CRP levels in both primary and secondary prevention settings. Methods: We performed a systematic review by searching MEDLINE (PubMed), Embase (Ovid), Cochrane CENTRAL (Wiley), and Web of Science (Clarivate) from their inception to February 2024. Eligible studies reported the association of Lp(a) with MACE stratified by hs-CRP level. Data extraction and quality assessment were systematically conducted. Meta-analyses used random-effects models to compute pooled HRs for individuals with low (

Salmonella was isolated from 23/79 (29.1%) pooled gecko stool samples from households in southern Malawi. Whole genome sequencing of 47 individual isolates within this collection revealed 27 Salmonella serovars spanning two subspecies. Our results demonstrate that geckos play an important role in the carriage of Salmonella within households.

Abstract Terrestrial groundwater travels through subterranean estuaries before reaching the sea. Groundwater‐derived nutrients drive coastal water quality, primary production, and eutrophication. We determined how dissolved inorganic nitrogen (DIN), dissolved inorganic phosphorus (DIP), and dissolved organic nitrogen (DON) are transformed within subterranean estuaries and estimated submarine groundwater discharge (SGD) nutrient loads compiling > 10,000 groundwater samples from 216 sites worldwide. Nutrients exhibited complex, nonconservative behavior in subterranean estuaries. Fresh groundwater DIN and DIP are usually produced, and DON is consumed during transport. Median total SGD (saline and fresh) fluxes globally were 5.4, 2.6, and 0.18 Tmol yr−1 for DIN, DON, and DIP, respectively. Despite large natural variability, total SGD fluxes likely exceed global riverine nutrient export. Fresh SGD is a small source of new nutrients, but saline SGD is an important source of mostly recycled nutrients. Nutrients exported via SGD via subterranean estuaries are critical to coastal biogeochemistry and a significant nutrient source to the oceans.

Drones have emerged as a powerful tool in animal detection, significantly advancing wildlife monitoring, conservation, and management by capturing high-resolution, real-time imagery over areas often inaccessible or challenging for human observers to reach. However, manual analysis of drone imagery for animal detection is labour-intensive and time-consuming. The application of deep learning methods, particularly convolutional neural networks, in automating animal detection from drone imagery has the potential to revolutionise wildlife monitoring, conservation, and management protocols.This review provides a comprehensive overview of the increasing use and prospects of deep learning in animal detection using drone imagery. It explores successful applications of deep learning for animal detection, localisation, recognition, and their combinations. The paper also discusses the challenges, limitations, and future research directions of this field. A key message from this review is the need for representative training data covering the various scenarios in which target animals may appear, image annotation difficulties, and the comparability of DL model results across studies. Many studies have focused on single species, locations, or images with a high density of common target species. Assessments of models are potentially biased from using a single test set; many studies lack metrics to evaluate model efficiency, feasibility, and generalizability, and there are uncertainties regarding the optimal number of training images and required ground sample distance (GSD) for different animal detection tasks in drone imagery.The potential applications of deep learning in wildlife monitoring, conservation, and ecological research using drone imagery are substantial. By enhancing the accuracy and efficiency of animal detection in imagery, this technology could contribute to the understanding and protecting animal populations. To expand the applicability of deep learning to diverse species, environments, and spatial scales, researchers should create standardised benchmark datasets and prioritise open collaboration and data sharing, which would aid in addressing the current challenges.

IntroductionFriction drilling is an innovative method in hole-making for sheet metal applications, thin sheets of conventional structural alloy materials like copper, titanium, steel etc., even though there are other methods, such as thermal distortion for the welding of nuts, riveting of nuts, and threading. For the last hundred years, researchers have focused on studying the development of this technique to maintain strength, hole roughness, hole geometry, hardness etc. It is interested in finding solutions for wear, tool life, and plastic deformation.MethodFriction drilling is also called a green hole-making process because this process uses the friction between the rotating tool and the workpiece. In this research, instead of regular HSS and Tungsten Carbide tools, the H13 tool steel is used, because the H13 steel tool has unique chemical compositions like chromium and molybdenum, which give high toughness, hot hardness, and wear resistance. Diamond-like-carbon (DLC) coating has been used in this research to enhance tool life and AZ31B magnesium alloy is used as the work material. Initially, in this research, the wear stability of the DLC-coated H13 tool was investigated, and later, the tool surface roughness and hole quality were verified.Results and DiscussionThe material loss observed for the DLC-coated H13 steel tool in the pin-on-disk test was 0.05 g. This investigation used two different diameter tools, namely 3 and 7 mm. Research has concluded that the 7 mm tool is better for friction drilling by seeing the roughness and hole quality. However, the conditions were that the spindle should rotate at 4,000 rpm and the feed rate of the tool to be at 200 mm/rev.

Background: Obtaining intravenous access in hypotensive patients is challenging and may critically delay resuscitation. The Graduated Vascular Access for Hypotensive Patient (GAHP) protocol leverages intraosseous fluid boluses to specifically dilate proximal veins. This study aims to evaluate the efficacy of GAHP in maximizing venous targets through early distal intraosseous access and a small fluid bolus. Methods: This was a prospective randomized cadaveric pilot study to evaluate extremity venous engorgement during intraosseous infusion. Cadavers (n = 23) had an intraosseous needle inserted into four sites: distal radius, proximal humerus, distal femur, and distal tibia. Intraosseous saline was rapidly infused, venous optimization was measured using real-time ultrasound. Primary outcome was maximum vessel circumference increase with intraosseous infusion. Secondary outcomes were: time to maximum circumference, and infusion volume required. Statistical analyses included Levene’s test for equality of variances, Wilcoxon signed-rank test, and generalized estimating equation. Results: There was a significant mean increase of 1.03 cm (95% CI 0.86, 1.20), representing a difference of 102%. We found no significant difference in time to optimize vessel circumference across sites, but volume required significantly differed. Conclusion: GAHP quickly and effectively increased the circumference of anatomically adjacent veins. Anatomical sites did not differ on time to reach maximum enlargement of vessels following intraosseous infusion but did differ in terms of volume required to maximize vessel circumference. Further research is needed using live, hypotensive patients.

Colorectal cancer (CRC) remains one of the most prevalent and lethal cancers worldwide, prompting ongoing research into innovative therapeutic strategies. This review aims to systematically evaluate the role of gelatinases, specifically MMP-2 and MMP-9, as therapeutic targets in CRC, providing a critical analysis of their potential to improve patient outcomes. Gelatinases, specifically MMP-2 and MMP-9, play critical roles in the processes of tumor growth, invasion, and metastasis. Their expression and activity are significantly elevated in CRC, correlating with poor prognosis and lower survival rates. This review provides a comprehensive overview of the pathophysiological roles of gelatinases in CRC, highlighting their contribution to tumor microenvironment modulation, angiogenesis, and the metastatic cascade. We also critically evaluate recent advancements in the development of gelatinase inhibitors, including small molecule inhibitors, natural compounds, and novel therapeutic approaches like gene silencing techniques. Challenges such as nonspecificity, adverse side effects, and resistance mechanisms are discussed. We explore the potential of gelatinase inhibition in combination therapies, particularly with conventional chemotherapy and emerging targeted treatments, to enhance therapeutic efficacy and overcome resistance. The novelty of this review lies in its integration of recent findings on diverse inhibition strategies with insights into their clinical relevance, offering a roadmap for future research. By addressing the limitations of current approaches and proposing novel strategies, this review underscores the potential of gelatinase inhibitors in CRC prevention and therapy, inspiring further exploration in this promising area of oncological treatment.

Abstract Objectives Special needs dentistry (SND) is a vast and fragmented field of study. This comprehensive bibliometric analysis aimed to evaluate the scope of SND, including the existing knowledge base, distribution structure, quantitative relationships, and research trends. Material and Methods A systematic search was conducted on March 10, 2022, using the Web of Science Core Collection database, covering the period from 1985 to 2021, focusing on studies reporting on special needs populations in a dentally relevant context. Records were title‐screened and analyzed for key bibliometric indicators. Results Among 48,374 articles, 13,869 underwent bibliometric analysis. Peak SND research occurred during 1985–1997. United States led in productivity, trailed by Brazil and Japan. University of Sao Paulo excelled in Brazil, University of Washington and University of North Carolina in the United States. The Journal of Dental Research was the most productive source of research and also had the highest number of citations, followed by Community Dentistry and Oral Epidemiology. Keyword analysis revealed that “elderly”, “caries”, and “epidemiology” were the most commonly used author keywords. Conclusions This study represents the first bibliometric analysis of SND literature. It emphasizes the need for increased collaboration between institutions and authors. Furthermore, it suggests focusing on research input from non‐dental disciplines and populations with rarer intellectual or developmental conditions.

Abstract Background Hepatocellular carcinoma (HCC) remains a leading life-threatening health challenge worldwide, with pressing needs for novel therapeutic strategies. Sphingosine kinase 1 (SphK1), a well-established pro-cancer enzyme, is aberrantly overexpressed in a multitude of malignancies, including HCC. Our previous research has shown that genetic ablation of Sphk1 mitigates HCC progression in mice. Therefore, the development of PF-543, a highly selective SphK1 inhibitor, opens a new avenue for HCC treatment. However, the anti-cancer efficacy of PF-543 has not yet been investigated in primary cancer models in vivo, thereby limiting its further translation. Methods Building upon the identification of the active form of SphK1 as a viable therapeutic target in human HCC specimens, we assessed the capacity of PF-543 in suppressing tumor progression using a diethylnitrosamine-induced mouse model of primary HCC. We further delineated its underlying mechanisms in both HCC and endothelial cells. Key findings were validated in Sphk1 knockout mice and lentiviral-mediated SphK1 knockdown cells. Results SphK1 activity was found to be elevated in human HCC tissues. Administration of PF-543 effectively abrogated hepatic SphK1 activity and significantly suppressed HCC progression in diethylnitrosamine-treated mice. The primary mechanism of action was through the inhibition of tumor neovascularization, as PF-543 disrupted endothelial cell angiogenesis even in a pro-angiogenic milieu. Mechanistically, PF-543 induced proteasomal degradation of the critical glycolytic enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3, thus restricting the energy supply essential for tumor angiogenesis. These effects of PF-543 could be reversed upon S1P supplementation in an S1P receptor-dependent manner. Conclusions This study provides the first in vivo evidence supporting the potential of PF-543 as an effective anti-HCC agent. It also uncovers previously undescribed links between the pro-cancer, pro-angiogenic and pro-glycolytic roles of the SphK1/S1P/S1P receptor axis. Importantly, unlike conventional anti-HCC drugs that target individual pro-angiogenic drivers, PF-543 impairs the PFKFB3-dictated glycolytic energy engine that fuels tumor angiogenesis, representing a novel and potentially safer therapeutic strategy for HCC.

Abstract Background Commercial anti-CD19 chimeric antigen receptor T-cell therapies (CART19) are efficacious against advanced B-cell non-Hodgkin lymphoma (NHL); however, most patients ultimately relapse. Several mechanisms contribute to this failure, including CD19-negative escape and CAR T dysfunction. All four commercial CART19 products utilize the FMC63 single-chain variable fragment (scFv) specific to a CD19 membrane-distal epitope and characterized by slow association (on) and dissociation (off) rates. We hypothesized that a novel anti-CD19 scFv that engages an alternative CD19 membrane-proximal epitope independent of FMC63 and that is characterized by faster on- and off-rates could mitigate CART19 failure and improve clinical efficacy. Methods We developed an autologous CART19 product with 4-1BB co-stimulation using a novel humanized chicken antibody (h1218). This antibody is specific to a membrane-proximal CD19 epitope and harbors faster on/off rates compared to FMC63. We tested h1218-CART19 in vitro and in vivo using FMC63-CART19-resistant models. We conducted a first-in-human multi-center phase I clinical trial to test AT101 (clinical-grade h1218-CART19) in patients with relapsed or refractory (r/r) NHL. Results Preclinically, h1218- but not FMC63-CART19 were able to effectively eradicate lymphomas expressing CD19 point mutations (L174V and R163L) or co-expressing FMC63-CAR19 as found in patients relapsing after FMC63-CART19. Furthermore, h1218-CART19 exhibited enhanced killing of B-cell malignancies in vitro and in vivo compared with FMC63-CART19. Mechanistically, we found that h1218-CART19 had reduced activation-induced cell death (AICD) and enhanced expansion compared to FMC63-CART19 owing to faster on- and off-rates. Based on these preclinical results, we performed a phase I dose-escalation trial, testing three dose levels (DL) of AT101 (the GMP version of h1218) using a 3 + 3 design. In 12 treated patients (7 DLBCL, 3 FL, 1 MCL, and 1 MZL), AT101 showed a promising safety profile with 8.3% grade 3 CRS (n = 1) and 8.3% grade 4 ICANS (n = 1). In the whole cohort, the overall response rate was 91.7%, with a complete response rate of 75.0%, which improved to 100% in DL-2 and -3. AT101 expansion correlates with CR and B-cell aplasia. Conclusions We developed a novel, safe, and potent CART19 product that recognizes a membrane-proximal domain of CD19 with fast on- and off-rates and showed significant efficacy and promising safety in patients with relapsed B-cell NHL. Trial registration NCT05338931; Date: 2022–04-01.

Mutations in the PINK1 and PRKN genes are the most frequent genetic cause of early-onset Parkinson disease. The pathogenic p.R275W substitution in PRKN is the most frequent substitution observed in patients, and thus far has been characterized mostly through overexpression models that suggest a possible gain of toxic misfunction. However, its effects under endogenous conditions are largely unknown. We used patient fibroblasts, isogenic neurons, and post-mortem human brain samples from carriers with and without PRKN p.R275W to assess functional impact. Immunoblot analysis and immunofluorescence were used to study mitophagy activation, and mitophagy execution was analyzed by flow cytometry of the reporter mitoKeima. The functional analysis was accompanied by structural investigation of PRKN p.R275W. We observed lower PRKN protein in fibroblasts with compound heterozygous p.R275W mutations. Isogenic neurons showed an allele-dose dependent decrease in PRKN protein. Lower PRKN protein levels were accompanied by diminished phosphorylated ubiquitin and decreased MFN2 modification. Mitochondrial degradation was also allele-dose dependently impaired. Consistently, PRKN protein levels were drastically reduced in human brain samples from p.R275W carriers. Finally, structural simulations showed significant changes in the closed form of PRKN p.R275W. Our data suggest that under endogenous conditions the p.R275W mutation results in a loss-of-function by destabilizing PRKN.

Abstract Invasive non-typhoidal Salmonella (iNTS) disease manifesting as bloodstream infection with high mortality is responsible for a huge public health burden in sub-Saharan Africa. Salmonella enterica serovar Typhimurium (S. Typhimurium) is the main cause of iNTS disease in Africa. By analysing whole genome sequence data from 1303 S. Typhimurium isolates originating from 19 African countries and isolated between 1979 and 2017, here we show a thorough scaled appraisal of the population structure of iNTS disease caused by S. Typhimurium across many of Africa’s most impacted countries. At least six invasive S. Typhimurium clades have already emerged, with ST313 lineage 2 or ST313-L2 driving the current pandemic. ST313-L2 likely emerged in the Democratic Republic of Congo around 1980 and further spread in the mid 1990s. We observed plasmid-borne as well as chromosomally encoded fluoroquinolone resistance underlying emergences of extensive-drug and pan-drug resistance. Our work provides an overview of the evolution of invasive S. Typhimurium disease, and can be exploited to target control measures.

Abstract Introduction The immunomodulatory impact of corticosteroids and concurrent chemotherapy is poorly understood within triple-negative breast cancer (TNBC). On a biochemical level, steroids have been linked to the signaling of chemotherapy-resistant pathways. However, on a clinical level, steroids play an essential role in chemotherapy tolerance through the prevention of chemotherapy-induced nausea and vomiting (CINV) and hypersensitivity reactions. Given these conflicting roles, we wanted to evaluate this interplay more rigorously in the context of early-stage TNBC. Methods We performed a retrospective analysis of patients with operable TNBC who received neoadjuvant chemotherapy (NAC) between January 2012 and November 2018, with the primary goal of examining the dose-dependent relationship between pathological complete response (pCR) rates and corticosteroid use. Secondary endpoints included the impact of steroid dosing on overall survival (OS) and recurrence-free survival (RFS), along with a breakdown in pCR rates based on steroid doses provided during each chemotherapy phase. Further adjusted analyses were performed based on patient age, diabetic status, and anatomical stage. Finally, we explored the relationship between tumor-infiltrating lymphocytes (TILs) seen on tissue samples at baseline and dexamethasone doses in terms of pCR rates. Results In total, of the 174 patients screened within this study period, 116 met full eligibility criteria. Of these eligible patients, all were female, with a median age of 51.5 years (27.0 to 74.0) and a mean body mass index (BMI) of 29.7 [standard deviation (SD) 7.04]. The majority were nondiabetic (80.2%). For cancer stage, 69.8% (n = 81) had stage 2 breast cancer. We found no statistically significant association between pCR rates and dexamethasone use, both in terms of the total dose (p = 0.55) and mean dose per NAC cycle (p = 0.74). Similarly, no difference was noted when adjusting for diabetic status, metformin use, or age at diagnosis, regardless of the total steroid dose provided (p = 0.72) or mean dose per cycle (p = 0.49). No meaningful changes to pCR rate were seen with higher mean or higher total steroid doses during the paclitaxel (T) phase (adjusted p = 0.16 and p = 0.76, respectively) or doxorubicin and cyclophosphamide (AC) phase (adjusted p = 0.83 and p = 0.77, respectively). Furthermore, we found no clinically significant association between dexamethasone dose and either RFS (p = 0.45) or OS (p = 0.89). Of the 56 patients who had available pre-treatment biopsy tissue samples, 27 achieved pCR, with higher TILs at baseline being associated with higher pCR rates, regardless of the mean dexamethasone dose used. Conclusion Our findings demonstrate that dexamethasone has no clinically significant impact on pCR, RFS, or OS when given concurrently with NAC in patients with curative TNBC, regardless of diabetic status.

Prioritisation of sub-watersheds (SWs) is becoming increasingly important in the conservation of natural resources, particularly in watershed planning. In this study, sub-watershed for the Neyyar basin was prioritised using three methods: morphometric analysis, principal component analysis (PCA) and hypsometric analysis. Morphometric analysis and hypsometric analysis were carried out using remote sensing (RS) and geographic information system (GIS) techniques, while PCA was performed for dimensionality reduction of morphometric parameters. The watershed was divided into 11 sub-watersheds (SW1–SW11), and each sub-watershed was given priority. To rank and prioritise SWs, 15 morphometric parameters were selected from the quantitative measures of morphometric analysis, including linear, relief, and areal. PCA was used to rank and prioritise SWs based on three highly correlated morphometric parameters. The hypsometric integral (HI) values were determined using the elevation relief ratio approach, and HI values were utilised to prioritise SWs. For both methods, such as morphometric analysis and PCA, a higher priority has been given to SW1. Using hypsometric analysis, higher priorities have been assigned to SW1, SW7, SW8, SW9, SW10 and SW11. The most common SWs that belong to the same priority of SWs and have a high correlation between them among the three methods are SW1, SW2, and SW5.The results of this analysis indicate that SW1 is a common high priority area with a significant risk of soil erosion, runoff and peak discharge. Therefore, decision-makers may utilise the high-priority sub-watershed to guide planning and development, measure conservation efforts and manage the land to prevent.

Hepatocellular carcinoma (HCC) is the fourth-leading cause of cancer-related death worldwide. Due to the high mortality rate in HCC patients, discovering and developing novel systemic treatment options for HCC is a vital unmet medical need. Among the numerous molecular alterations in HCCs, microRNAs (miRNAs) have been increasingly recognised to play critical roles in hepatocarcinogenesis. We and others have recently revealed that members of the microRNA-181 (miR-181) family were up-regulated in some, though not all, human cirrhotic and HCC tissues—this up-regulation induced epithelial–mesenchymal transition (EMT) in hepatocytes and tumour cells, promoting HCC progression. MiR-181s play crucial roles in governing the fate and function of various cells, such as endothelial cells, immune cells, and tumour cells. Previous reviews have extensively covered these aspects in detail. This review aims to give some insights into miR-181s, their targets and roles in modulating signal transduction pathways, factors regulating miR-181 expression and function, and their roles in HCC.

Introduction No whole-school interventions which seek to reduce physical, sexual and emotional violence from peers, intimate partners and teachers have been trialled with adolescents. Here, we report a protocol for a pilot trial of the Good School Toolkit-Secondary Schools intervention, to be tested in Ugandan secondary schools. Our main objectives are to (1) refine the intervention, (2) to understand feasibility of delivery of the intervention and (3) to explore design parameters for a subsequent phase III trial.Methods and analysis We will conduct a pilot cluster randomised controlled trial, with two arms and parallel assignment. Eight schools will be randomly selected from a stratified list of all eligible schools in Kampala and Wakiso Districts. We will conduct a baseline survey and endline survey 18 months after the baseline, with 960 adolescents and 200 teachers. Qualitative data and mixed methods process data collection will be conducted throughout the intervention. Proportion of staff and students reporting acceptability, understanding and implementing with fidelity will be tabulated at endline for intervention schools. Proportions of schools consenting to participation, randomisation and proportions of schools and individual participants completing the baseline and endline surveys will be described in a Consolidated Standards of Reporting Trials diagram.Ethics and dissemination The ethical requirements of our project are complex. Full approvals have been received from the Mildmay Ethics Committee (0407-2019), the Uganda National Council for Science and Technology (SS 6020) and the London School of Hygiene & Tropical Medicine (16212). Results of this study will be published in peer-reviewed academic journals, and shared with public bodies, policy makers, study participants and the general public in Uganda.Trial registration number PACTR202009826515511.

Background: South Africa has one of the highest incidences of rape globally. Understanding the epidemiological pattern of rape is needed to inform the design of effective intervention programmes for rape prevention and management of alleged rape cases. Aims: To investigate important epidemiological patterns associated with rape in Kimberly, Northern Cape Province, South Africa. Setting: The Robert Mangaliso Sobukwe Hospital (RMSH) forensic unit. Methods: A descriptive, retrospective cross-sectional clinical audit of rape cases. Results: The majority (93.3%) of the alleged rape victims were women, with a mean age (SD) of 21.6 years (11.3); the male population made up 6.7% of the cases, with a mean age (SD) of 10.5 years (6.9). The highest incidence of alleged rape in the male population was seen in the age group ≤ 16 years (81.8%) and for women 17–30 years (50.3%). Most of the incidents occurred at the perpetrators’ homes (42.7%); on the days Fridays (14.6%), Saturdays (29.9%) and Sundays (23.2%); at night up to midnight 20:00–23:59 (32.9%) (p = 0.01) and involved threats of violence (55.5%). The majority (56.0%) of the perpetrators were known to the victims. Conclusion: Important information about the victims and circumstances in which rape occurs as reported herein can be used to inform the design of effective intervention programmes for sexual crime prevention and management in Kimberly, South Africa. Contribution: This study helped to advance knowledge and understanding of the epidemiological pattern associated with rape in Kimberley, Northern Cape Province of South Africa.

The performance of on-orbit GaAs-based solar cells is susceptible to the displacement damage effect. The proton-induced primary displacement damage in GaAs on a geosynchronous equatorial orbit (GEO) was simulated and analyzed by combining the Monte Carlo (MC) and molecular dynamics (MD) methods. The MC simulation provided the distribution of primary knock-on atoms (PKAs) in GaAs induced by GEO-related protons to the MD simulation. In MD simulations, the effects of radiation fluence and ambient temperature on the displacement damage were considered. The simulation results showed that GEO-related protons generated a significant number of PKAs within an energy range of below 10 keV in GaAs. The high-fluence radiation emulated by the binary PKA could generate more point defects and cluster defects in GaAs than the low-fluence radiation emulated by single PKAs. As compared to room temperature (300 K), both a low (100 K) and high (500 K) ambient temperature could deteriorate the displacement damage. In addition, a high ambient temperature of 500 K could induce widespread thermal spikes in GaAs as compared to 100 and 300 K. This work can provide useful insight into the proton-induced displacement damage in GaAs and the radiation hardening of GaAs-based photoelectric devices in space.

Objective: ASCL1, a pioneer transcription factor, is essential for neural cell differentiation and function. Previous studies have shown that Ascl1 expression is increased in pancreatic β-cells lacking functional KATP channels or after feeding of a high fat diet (HFD) suggesting that it may contribute to the metabolic stress response of β-cells. Methods: We generated β-cell-specific Ascl1 knockout mice (Ascl1βKO) and assessed their glucose homeostasis, islet morphology and gene expression after feeding either a normal diet or HFD for 12 weeks, or in combination with a genetic disruption of Abcc8, an essential KATP channel component. Results: Ascl1 expression is increased in response to both a HFD and membrane depolarization and requires CREB-dependent Ca2+ signaling. No differences in glucose homeostasis or islet morphology were observed in Ascl1βKO mice fed a normal diet or in the absence of KATP channels. However, male Ascl1βKO mice fed a HFD exhibited decreased blood glucose levels, improved glucose tolerance, and increased β-cell proliferation. Bulk RNA-seq analysis of islets from Ascl1βKO mice from three studied conditions showed alterations in genes associated with the secretory function. HFD-fed Ascl1βKO mice showed the most extensive changes with increased expression of genes necessary for glucose sensing, insulin secretion and β-cell proliferation, and a decrease in genes associated with β-cell dysfunction, inflammation and dedifferentiation. HFD-fed Ascl1βKO mice also displayed increased expression of parasympathetic neural markers and cholinergic receptors that was accompanied by increased insulin secretion in response to acetylcholine and an increase in islet innervation. Conclusions: Ascl1 expression is induced by stimuli that cause Ca2+-signaling to the nucleus and contributes in a multifactorial manner to the loss of β-cell function by promoting the expression of genes associated with cellular dedifferentiation, attenuating β-cells proliferation, suppressing acetylcholine sensitivity, and repressing parasympathetic innervation of islets. Thus, the removal of Ascl1 from β-cells improves their function in response to metabolic stress.

Inflammatory breast cancer (IBC) poses an ongoing challenge as rates of disease recurrence and mortality remain high compared to stage-matched controls. However, frontline therapy has evolved through the years, including the widespread use of neoadjuvant chemotherapy (NAC) given the prognostic importance of pathologic complete response (pCR). Due to these sweeping changes, we need new data to assess current recurrence and survival outcomes for locally advanced IBC in the context of matched non-inflammatory controls. We conducted a retrospective analysis of institutional IBC data from 2010 to 2016 with the primary objective of comparing overall survival (OS), relapse-free survival (RFS), and distant relapse-free survival (DRFS). We matched IBC patients to non-inflammatory controls based on age, receptor status, tumor grade, clinical stage, and receipt of prior NAC. Secondary objectives included assessing pCR rates and identifying prognostic factors. Among NAC recipients, we observed similar pCR rates (47.6 % vs. 49.4 %, p = 0.88) between IBC (n = 84) and matched non-IBC (n = 81) cohorts. However, we noted a significant worsening of OS (p = 0.0001), RFS (p = 0.0001), and DRFS (p = 0.001) in the IBC group. Specifically, 5-year OS in the IBC cohort was 58.9 % vs. 86.7 % for matched controls (p = 0.0003). Older age was a weak negative predictor for OS (HR 1.03, p = 0.001) and RFS (HR 1.02, p = 0.01). For DRFS, older age was also a weak negative predictor (HR 1.02, p = 0.02), whereas the use of NAC was a positive predictor (HR 0.47, p = 0.02). Despite no clear difference in pCR, survival outcomes remain poor for IBC compared to matched non-inflammatory controls.

Abstract Background Cerebral arteriovenous malformations (cAVM) are a significant cause of intracranial hemorrhagic stroke and brain damage. The arteriovenous junctions in AVM nidus are known to have hemodynamic disturbances such as altered shear stress, which could lead to endothelial dysfunction. The molecular mechanisms coupling shear stress and endothelial dysfunction in cAVMs are poorly understood. We speculated that disturbed blood flow in artery–vein junctions activates Notch receptors and promotes endothelial mesenchymal plasticity during cAVM formation. Methods We investigated the expression profile of endothelial mesenchymal transition (EndMT) and cell adhesion markers, as well as activated Notch receptors, in 18 human cAVM samples and 15 control brain tissues, by quantitative real-time PCR (qRT-PCR) and immunohistochemical evaluation. Employing a combination of a microfluidic system, qRT-PCR, immunofluorescence, as well as invasion and inhibitor assays, the effects of various shear stress conditions on Notch-induced EndMT and invasive potential of human cerebral microvascular endothelial cells (hCMEC/d3) were analyzed. Results We found evidence for EndMT and enhanced expression of activated Notch intracellular domain (NICD3 and NICD4) in human AVM nidus samples. The expression of transmembrane adhesion receptor integrin α9/β1 is significantly reduced in cAVM nidal vessels. Cell–cell adhesion proteins such as VE-cadherin and N-cadherin were differentially expressed in AVM nidus compared with control brain tissues. Using well-characterized hCMECs, we show that altered fluid shear stress steers Notch3 nuclear translocation and promotes SNAI1/2 expression and nuclear localization. Oscillatory flow downregulates integrin α9/β1 and VE-cadherin expression, while N-cadherin expression and endothelial cell invasiveness are augmented. Gamma-secretase inhibitor RO4929097, and to a lesser level DAPT, prevent the mesenchymal transition and invasiveness of cerebral microvascular endothelial cells exposed to oscillatory fluid flow. Conclusions Our study provides, for the first time, evidence for the role of oscillatory shear stress in mediating the EndMT process and dysregulated expression of cell adhesion molecules, especially multifunctional integrin α9/β1 in human cAVM nidus. Concomitantly, our findings indicate the potential use of small-molecular inhibitors such as RO4929097 in the less-invasive therapeutic management of cAVMs. Graphical Abstract

Abstract Antisense oligonucleotide (ASO) therapy for neurological disease has been successful in clinical settings and its potential has generated hope for Alzheimer’s disease (AD). We previously described that ablating SNCA encoding for α-synuclein (αSyn) in a mouse model of AD was beneficial. Here, we sought to demonstrate whether transient reduction of αSyn expression using ASO SNCA could be therapeutic in a mouse model of AD. The efficacy of the ASO SNCA was measured via immunocytochemistry, RT-qPCR and western blotting. To assess spatial learning and memory, ASO SNCA or PBS-injected APP and non-transgenic (NTG) mice, and separate groups of SNCA-null mice, were tested on the Barnes circular maze. Hippocampal slice electrophysiology and transcriptomic profiling were used to explore synaptic function and differential gene expression between groups. Reduction of SNCA transcripts alleviated cognitive deficits in male transgenic animals, but surprisingly, not in females. To determine the functional cause of this differential effect, we assessed memory function in SNCA-null mice. Learning and memory were intact in male mice but impaired in female animals, revealing that the role of αSyn on cognitive function is sex-specific. Transcriptional analyses identified a differentially expressed gene network centered around EGR1, a central modulator of learning and memory, in the hippocampi of SNCA-null mice. Thus, these novel results demonstrate that the function of αSyn on memory differs between male and female brains.

The study of protein-protein interactions (PPIs) and the engineering of protein-based inhibitors often employ two distinct strategies. One approach leverages the power of combinatorial libraries, displaying large ensembles of mutant proteins, for example, on the yeast cell surface, to select binders. Another approach harnesses computational modeling, sifting through an astronomically large number of protein sequences and attempting to predict the impact of mutations on PPI binding energy. Individually, each approach has inherent limitations, but when combined, they generate superior outcomes across diverse protein engineering endeavors. This synergistic integration of approaches aids in identifying novel binders and inhibitors, fine-tuning specificity and affinity for known binding partners, and detailed mapping of binding epitopes. It can also provide insight into the specificity profiles of varied PPIs. Here, we outline strategies for directing the evolution of tissue inhibitors of metalloproteinases (TIMPs), which act as natural inhibitors of matrix metalloproteinases (MMPs). We highlight examples wherein design of combinatorial TIMP libraries using structural and computational insights and screening these libraries of variants using yeast surface display (YSD), has successfully optimized for MMP binding and selectivity, and conferred insight into the PPIs involved.

IntroductionLiver cancers exhibit abnormal (leaky) vasculature, hypoxia and an immunosuppressive microenvironment. Normalization of tumor vasculature is an emerging approach to treat many cancers. Blockmir CD5-2 is a novel oligonucleotide-based inhibitor of the miR-27a interaction with VE-Cadherin, the endothelial-specific cadherin. The combination of a vasoactive medication with inhibition of immune checkpoints such as programmed cell death protein 1 (PD1) has been shown to be effective in treating liver cancer in humans. We aimed to study the effect of CD5-2 combined with checkpoint inhibition (using an antibody against PD1) on liver tumor growth, vasculature and immune infiltrate in the diethylnitrosamine (DEN)-induced liver tumor mouse model.MethodsWe first analyzed human miR-27a and VE-Cadherin expression data from The Cancer Genome Atlas for hepatocellular carcinoma. CD5-2 and/or anti-PD1 antibody were given to the DEN-treated mice from age 7-months until harvest at age 9-months. Tumor and non-tumor liver tissues were analyzed using histology, immunohistochemistry, immunofluorescence and scanning electron microscopy.ResultsHuman data showed high miR-27a and low VE-Cadherin were both significantly associated with poorer prognosis. Mice treated with CD5-2 plus anti-PD1 antibody had significantly smaller liver tumors (50% reduction) compared to mice treated with either agent alone, controls, or untreated mice. There was no difference in tumor number. Histologically, tumors in CD5-2-treated mice had less leaky vessels with higher VE-Cadherin expression and less tumor hypoxia compared to non-CD5-2-treated mice. Only tumors in the combination CD5-2 plus anti-PD1 antibody group exhibited a more favorable immune infiltrate (significantly higher CD3+ and CD8+ T cells and lower Ly6G+ neutrophils) compared to tumors from other groups.DiscussionCD5-2 normalized tumor vasculature and reduced hypoxia in DEN-induced liver tumors. CD5-2 plus anti-PD1 antibody reduced liver tumor size possibly by altering the immune infiltrate to a more immunosupportive one.

Background: Quality of life comprises multifaceted dimensions encompassing physical, emotional, social, and psychological aspects. Assessing quality of life is essential not only for mothers but also for their children, family members, and the community. Understanding the impact of different modes of delivery on women’s well-being is crucial for healthcare providers to offer appropriate support and interventions. Objective: To assess and compare the quality of life after normal vaginal delivery and caesarean section among mothers at a government tertiary care hospital, Bengaluru. Methodology: A cross-sectional study was conducted among mothers at a tertiary care hospital in Bengaluru. A pilot study was conducted and sample size was calculated as 200, with 100 participants in each group. Samples were selected using a simple random sampling method, and data were collected using a pre-tested, semi-structured questionnaire. The Short Form Health Survey (SF-36) was used to assess the quality of life. The collected data was entered into MS Excel and analyzed using SPSS 21.0 Results: Out of 200 participants, the mean age of the study population was 24.32 ± 5.58 years. Comparison between the vaginal and cesarean groups revealed that the vaginal birth group had higher mean scores in the physical health domain. Factors such as physical functioning, emotional well-being, socioeconomic status, and comorbidities were found to be significantly associated with modes of delivery. Conclusion: Different modes of delivery have their own unique challenges and benefits, this study illuminated distinct differences in quality of life. Normal vaginal delivery was associated with a quicker physical recuperation compared to caesarean section, while caesarean sections demanded a longer recovery period and potential physical limitations.

Ontogenetic changes in habitat and diet are widespread among marine species. Most species of sea turtles are characterized by extreme ontogenetic changes in habitat use and diet, with large changes occurring in early developmental stages (e.g., neonates to juveniles). Changes can continue even after recruitment to shallow coastal habitats. In places where substantial transitions in habitat occur across short distances, it is possible that the distances of developmental movements from one habitat to another could be short. We investigated ontogenetic changes in home range size, home range location and diet of Chelonia mydas in a tropical coastal lagoon in north-western Australia by combining acoustic telemetry with stable isotope analysis. There was a substantial (but nonlinear) increase in home-range size (kernel utilization distribution: KUD) with length, and an increase in the average distance of the center of home ranges from shore with length: larger turtles tended to occupy larger areas further from the shore. These patterns were accompanied by complex nonlinear changes in δ13C, δ15N and δ34S of red blood cells and nails; changes were rapid from 36 cm (the length of the smallest individual captured) to 50 cm, before reversing more gradually with increasing size. δ15N and δ34S (but not δ13C) of red blood cells and nails increased monotonically with KUD and distance from shore. Seagrass was likely an important food for all sizes, macroalgae was potentially important for small (< 60 cm CCL) individuals, and the proportion of scyphozoan jellyfish in diet increased monotonically with size. The combination of acoustic telemetry and stable isotope analysis revealed ontogenetic shifts in use of space and diet across short distances in a tropical coastal lagoon.

The wear behaviour of AISI 316LN austenitic stainless steel has been studied by varying the duration of nitriding. AISI 316LN steel was nitrided using salt bath nitriding which consist of a mixture of 70:30 ratio of alkaline cynates and carbonates. Nitriding was carried out for two time durations namely 60 min and 100 min. Pin-on-Disc wear test were carried out for both the untreated and treated sample at room temperature. The wear parameters were changed to understand the wear mechanism of AISI 316LN steel along with the nitrided sample by varying the sliding distance for 250 m, 500 m and 1000 m. Due to the presence of different wear mechanism the rate of wear varies as a function of sliding distance. For untreated sample the wear mechanism was dominant with adhesion, abrasion and plastic deformation. An optical micrograph, X-ray diffraction analysis, wear morphology, hardness measurement and surface roughness were carried out. Due to the presence of compound layer as a result of nitriding AISI 316LN austenitic stainless steel, the mechanism of wear was restricted to abrasive wear. Untreated specimens have more significant wear loss when compared to treated specimen as work hardening and an increase in hardness of wear track resulted in material pull out. Stability of the compound layer is achieved as a result of longer duration of nitriding. Abrasive wear is resisted to a greater extend due the availability of compound layer. AISI 316LN steel which was nitrided for 100 min exhibited a more stable compound layer when compared to the same nitrided for 60 min.

Karima Khimani,1,&ast; Victoria Koshevarova,2,&ast; Alfred A Mathew,2 Akshaya K Gupta,1 Mary Schmitz-Brown,1 Praveena K Gupta1 1Department of Ophthalmology and Visual Sciences, University of Texas Medical Branch, Galveston, TX, USA; 2School of Medicine, University of Texas Medical Branch, Galveston, TX, USA&ast;These authors contributed equally to this workCorrespondence: Praveena K Gupta, Department of Ophthalmology and Visual Sciences, University of Texas Medical Branch at Galveston, 301 University Blvd, Galveston, TX, 77555-1108, USA, Tel +409 747 5823, Fax +1 409 747 5824, Email prgupta@utmb.eduPurpose: Long-term video game play and its effects on the skills used in surgical simulators have been previously studied, but little information is available about short-term video game warm-ups and subsequent ophthalmic surgical simulation performance. In this study, we hypothesize that a video game warm-up will improve performance on the Eyesi Ophthalmic Surgical Simulator.Methods: Twenty medical students with no prior surgical simulation experience were recruited for the study. Information regarding prior video game experience was gathered, and half of the participants were then randomly assigned to play a video game session prior to Eyesi performance. All subjects completed three sets of Eyesi modules, and the scores and time to completion were recorded. Bivariate analysis including Fisher’s Exact test and Wilcoxon rank-sum test were used for statistical analysis.Results: The warm-up group scored higher in Navigation, Bimanual, and Forceps modules (33.6, 39.7, 7.2, respectively) compared to non-warm-up group (27.3, 27.3, 3.6, respectively). In addition, average times (sec) were lower (310.5, 117.4, 229.2, respectively) compared to non-warm-up group (321.9, 163.3, 235.8, respectively). It was also observed that significantly more participants in the warm-up group had reported a history of spending > 15 hours per week playing video games compared to the non-warm-up group (80% vs 20%, p=0.0402).Conclusion: In our pilot study, there appears to be a positive trend between video game warm-up and Eyesi simulation performance; however, no statistically significant difference was observed due to lower power. This trend can be explained by a greater collective video game experience within the warm-up group, mechanical factors (increased flexibility and grip strength after playing video games) and feeling more relaxed after the video game warm-up. Larger follow-up studies are needed to further investigate the relationship between short-term video game use on ophthalmic surgical simulation performance.Keywords: Eyesi, education, surgery, simulation, video game

Free-electron lasers are capable of high repetition rates and it is assumed that protein crystals often do not survive the first X-ray pulse. Here the authors address these issues with a demonstration of multi-hit serial crystallography in which multiple FEL pulses interact with the sample without destroying it.

Characterising associations between the methylome, proteome and phenome may provide insight into biological pathways governing brain health. Here, blood protein markers of brain health are integrated with omics data to reveal DNA methylation differences that associate with these protein markers.

Background Cerebral venous thrombosis is a devastating condition with, despite optimal medical management, a significant proportion deteriorating due to involvement of the deep venous system, worsening intracranial pressures, and hemorrhage. In this study, we report the characteristics, immediate and long‐term outcomes of mechanical thrombectomy (MT) using a Forgarty balloon catheter among patients with cerebral venous thrombosis. Methods A prospective study conducted at the Christian Medical College, Vellore over 5 years (February 2017–February 2022), wherein patients with cerebral venous thrombosis who had clinical deterioration despite best medical management and requiring MT were included. MT was performed through retrograde venous access through internal jugular veins using a Fogarty balloon. The primary outcome was composite end point of mortality and proportion of patients with favorable clinical response at last follow‐up, defined as a disability score in modified Rankin scale 0–2. Results Among 546 patients treated in our center during the study period, 57(10%), patients required MT. The median age of the study population was 33 years (interquartile range: 17–70 years) with equal gender predilection. Hemorrhagic venous infarction was seen in 28/57 (50%) patients. The mean duration between starting medical treatment and to MT was 43 hours (interquartile range: 5–260 hours) with the most common indication being clinical deterioration (70%). Five patients (9%) required decompressive hemicraniectomy. The mortality at discharge was 5% (n=3), and at last follow‐up visit was 7% (n=4). Younger patients without hemorrhagic venous infarction and non‐involvement of the frontoparietal lobes seem to benefit the most. Favorable functional outcome at discharge (modified Rankin scale 0–2) was seen in 65% which further improved to 77% at 1‐year follow‐up. Conclusion Balloon‐assisted MT is safe and effective in a subset of patients with severe cerebral venous thrombosis, with clinical deterioration despite optimal medical management.

Digital services such as repositories and science gateways have become key resources for the neuroscience community, but users often have a hard time orienting themselves in the service landscape to find the best fit for their particular needs. INCF has developed a set of recommendations and associated criteria for choosing or setting up and running a repository or scientific gateway, intended for the neuroscience community, with a FAIR neuroscience perspective.

Abstract Depression is assessed in various ways in research, with large population studies often relying on minimal phenotyping. Genetic results suggest clinical diagnoses and self-report measures of depression show some core similarities, but also important differences. It is not yet clear how neuroimaging associations depend on levels of phenotyping. We studied 39,300 UK Biobank imaging participants (20,701 female; aged 44.6 to 82.3 years, M = 64.1, SD = 7.5) with structural neuroimaging and lifetime depression data. Past depression phenotypes included a single-item self-report measure, an intermediate measure of ‘probable’ lifetime depression, derived from multiple questionnaire items relevant to a history of depression, and a retrospective clinical diagnosis according to DSM-IV criteria. We tested (i) associations between brain structural measures and each depression phenotype, and (ii) effects of phenotype on these associations. Depression-brain structure associations were small (β

Abstract Background Understanding of the most economical and sustainable models of providing geriatric care to Africa’s rising ageing population is critical. In Uganda, the number of old adults (60 years and above) continues to rise against absence of policies and guidelines, and models for providing care to this critical population. Our study explored public primary health care provider views on how best community-based geriatric support (CBGS) could be instituted as an adaptable model for delivering geriatric care in Uganda’s resource-limited primary public health care settings. Methods We interviewed 20 key informants from four districts of Bukomansimbi, Kalungu, Rakai, and Lwengo in Southern Central Uganda. Respondents were leads (in-charges) of public primary health units that had spent at least 6 months at the fore said facilities. All interviews were audio-recorded, transcribed verbatim, and analysed based on Hsieh and Shannon’s approach to conventional manifest content analysis. Results During analysis, four themes emerged: 1) Structures to leverage for CBGS, 2) How to promote CBGS, 3) Who should be involved in CBGS, and 4) What activities need to be leveraged to advance CBGS? The majority of the respondents viewed using the existing village health team and local leadership structures as key to the successful institutionalization of CBGS; leveraging community education and sensitization using radio, television, and engaging health workers, family relatives, and neighbors. Health outreach activities were mentioned as one of the avenues that could be leveraged to provide CBGS. Conclusion Provider notions pointed to CBGS as a viable model for instituting geriatric care in Uganda’s public primary healthcare system. However, this requires policymakers to leverage existing village health team and local governance structures, conduct community education and sensitization about CBGS, and bring onboard health workers, family relatives, and neighbors.

In marine turtles, the sex of hatchlings is determined by their egg incubation temperature. Global warming may increase the extinction risk by skewing hatchling sex ratios. Assessment of this risk at the population level requires the identification of sex in hatchlings and juveniles. However, available methods are typically lethal, highly invasive, or difficult to conduct at a large scale. Changes in DNA methylation, an epigenetic modification, have been characterized as part of sex differentiation pathways in some species with environmentally determined sex, but so far not in marine turtles. Neither have epigenetic biomarkers for sex been developed into rapid assays suited to research on wildlife. In this study, we aimed to develop a rapid, minimally invasive, and inexpensive method to identify the sex of marine turtles. We used reduced representation bisulfite sequencing DNA methylation data from adult green sea turtle (Chelonia mydas) skin biopsies to identify 16 genomic regions exhibiting differential methylation between males and females (adjusted p-value < 0.01). We designed methylation sensitive qPCR assays for these regions and tested their capacity to identify the sex of turtles ranging in age between 3-34 years. The qPCR assay identified the correct sex in turtles > 17 years. However, the sex of younger turtles could not be accurately identified. This suggests the sex differences distinguishable by the assay were adult specific, reflecting the training data on which the sex-specific regions were identified, and likely linked to late-stage ontogenetic changes associated with sexual maturity. Epigenetic biomarkers are a promising tool for wildlife research because they can be minimally invasive and high throughput. Future research into sex-specific differentially methylated regions in hatchlings and juveniles should be based on genome-wide DNA methylation data from a wider age range, which includes hatchlings.

There is a growing consensus that a significant proportion of recurrent urinary tract infections are linked to the persistence of uropathogens within the urinary tract and their re-emergence upon the conclusion of antibiotic treatment. Studies in mice and human have revealed that uropathogenic Escherichia coli (UPEC) can persist in bladder epithelial cells (BECs) even after the apparent resolution of the infection. Here, we found that, following the entry of UPEC into RAB27b+ fusiform vesicles in BECs, some bacteria escaped into the cytoplasmic compartment via a mechanism involving hemolysin A (HlyA). However, these UPEC were immediately recaptured within LC3A/B+ autophagosomes that matured into LAMP1+ autolysosomes. Thereafter, HlyA+ UPEC-containing lysosomes failed to acidify, which is an essential step for bacterial elimination. This lack of acidification was related to the inability of bacteria-harboring compartments to recruit V-ATPase proton pumps, which was attributed to the defragmentation of cytosolic microtubules by HlyA. The persistence of UPEC within LAMP1+ compartments in BECs appears to be directly linked to HlyA. Thus, through intravesicular instillation of microtubule stabilizer, this host defense response can be co-opted to reduce intracellular bacterial burden following UTIs in the bladder potentially preventing recurrence.

This work focused on the development of a surrogate model for the prediction of biogas production by anaerobic digestion of slaughterhouse wastewater (SWW) and pretreated pineapple peel waste (PPPW). The process was carried out under mesophilic conditions involving five batch reactors containing different compositions of SWW and PPPW. Physicochemical characterization of SWW indicated that the substrate has a biodegradability ratio (biochemical oxygen demand, BOD5 / chemical oxygen demand, COD) of 62.66%, while FTIR analysis of PPPW depicted the rupturing and flattening of functional groups associated with the presence of lignin following hydrogen peroxide (H2O2) pretreatment. The maximum daily biogas production of 79 ml/g volatile solids (VS) was recorded in the first reactor (R1) containing 100% SWW, while the maximum cumulative biogas yield of 579 ml/g VS was obtained in the fourth reactor (R4) consisting of 30% SWW and 70% PPPW. Results from conventional kinetic models indicated that mono-digestion processes (R1 and R5) were best fitted with the modified Gompertz model (R2 ≥ 0.9890), while the logistic model best described the co-digestion systems (R2: R2 = 0.9767; R3: R2 = 0.9854; R4: R2 = 0.9966). However, comparative analysis of empirical data with surrogate model predictions illustrated the stability and high accuracy of the surrogate model (0.9921 ≥ R2 ≥ 0.9789) over other kinetic models in simulating both mono and co-digestions of SWW and PPPW. Using the proposed model as objective function in numerical optimization, an optimum biogas yield of 580.55 mg/l VS was obtained in R4 operating for 25 days.

The 3 MeV proton irradiation effects on SiGe low noise amplifier (LNA) (NXP BGU7005) performance under different voltage supply VCC (0 V, 2.5 V) conditions were firstly experimental studied in this present work. The S parameters including S11, S22, S21, 1 dB compression point and noise figure (NF) of the test samples under different bias voltage supply were measured and compared before and after 3 MeV proton irradiation. The total proton irradiation fluence was 1 × 1015 protons/cm2. The maximum degradation quantities of the gain S21 and NF of the test samples under zero bias are measured respectively 1.6 dB and 1.2 dB. Compared with the samples under 2.5 V bias supply, the maximum degradation of S21 and NF are respectively 1.1 dB and 0.8 dB in the whole frequency band. It is noteworthy that the gain and NF of SiGe LNAs under zero-bias mode suffer enhanced degradation compared with those under normal bias supply. The key influence factors are discussed based on the correlation of the SiGe device and the LNA circuit. Different process of the ionization damage and displacement damage under zero-bias and 2.5 V bias voltage supply contributed to the degradation difference. The underlying physical mechanisms are analyzed and investigated.

Abstract Background Blood-based markers of cognitive functioning might provide an accessible way to track neurodegeneration years prior to clinical manifestation of cognitive impairment and dementia. Results Using blood-based epigenome-wide analyses of general cognitive function, we show that individual differences in DNA methylation (DNAm) explain 35.0% of the variance in general cognitive function (g). A DNAm predictor explains ~4% of the variance, independently of a polygenic score, in two external cohorts. It also associates with circulating levels of neurology- and inflammation-related proteins, global brain imaging metrics, and regional cortical volumes. Conclusions As sample sizes increase, the ability to assess cognitive function from DNAm data may be informative in settings where cognitive testing is unreliable or unavailable.