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Throughout the isolation process, human islets are subjected to destruction of the islet basement membrane (BM) and reduced oxygen supply. Reconstruction of the BM represents an option to improve islet function and survival post-transplant and may particularly be relevant for islet encapsulation devices and scaffolds. In the present study, we assessed whether Perlecan, used alone or combined with the BM proteins (BMPs) Collagen-IV and Laminin-521, has the ability to protect isolated human islets from hypoxia-induced damage. Islets isolated from the pancreas of seven different organ donors were cultured for 4–5 days at 2% oxygen in plain CMRL (sham-treated controls) or in CMRL supplemented with BMPs used either alone or in combination. Postculture, islets were characterized regarding survival, in vitro function and production of chemokines and reactive oxygen species (ROS). Individually added BMPs significantly doubled islet survival and increased in vitro function. Combining BMPs did not provide a synergistic effect. Among the tested BMPs, Perlecan demonstrated the significantly strongest inhibitory effect on chemokine and ROS production when compared with sham-treatment (p < 0.001). Perlecan may be useful to improve islet survival prior to and after transplantation. Its anti-inflammatory potency should be considered to optimise encapsulation and scaffolds to protect isolated human islets post-transplant. [ABSTRACT FROM AUTHOR]

Pancreatic adenocarcinoma is one of the most lethal types of gastrointestinal cancer despite the latest medical advances. Its incidence has continuously increased in recent years in developed countries. The location of the pancreas can result in the initial symptoms of neoplasia being overlooked, which can lead to a delayed diagnosis and a subsequent reduction in the spectrum of available therapeutic options. The role of modifiable risk factors in pancreatic cancer has been extensively studied in recent years, with smoking and alcohol consumption identified as key contributors. However, the few screening programs that have been developed focus exclusively on genetic factors, without considering the potential impact of modifiable factors on disease occurrence. Thus, fully understanding and detecting the risk factors for pancreatic cancer represents an important step in the prevention and early diagnosis of this type of neoplasia. This review reports the available evidence on different risk factors and identifies the areas that could benefit the most from additional studies. [ABSTRACT FROM AUTHOR]

Accurately identifying the dynamic interaction effects and network structure characteristics of air pollution is essential for effective collaborative governance. This study investigates the spatial dynamic interactions of air pollution among 30 cities in the Central Plains Urban Agglomeration using convergent cross mapping. Social network analysis is applied to assess the overall and node characteristics of the spatial interaction network, while key driving factors are analyzed using an exponential random graph model. The findings reveal that air pollution levels in the Central Plains Urban Agglomeration initially increase before they decrease, with heavily polluted cities transitioning from centralized to sporadic distribution. Among the interactions, Heze's air pollution impact on Kaifeng was the strongest, while Xinxiang's impact on Changzhi was the weakest. The emission and receiving effects peaked during 2010–2012. The air pollution interactions among cities exhibit significant network characteristics, with block model results indicating that emitting and receiving relationships are primarily concentrated in the bidirectional spillover plate. Natural factors such as temperature and precipitation significantly influence the spatial interaction network. Economic and social factors like economic level and industrial sector proportion also have a significant impact. However, population density does not influence the spatial interaction network. This study contributes to understanding the spatial network of air pollution, thereby enhancing strategies for optimizing regional collaborative governance efforts to address air pollution. [ABSTRACT FROM AUTHOR]

Bamboo is an economically important crop that has gained prominence as an alternative to wood to reduce deforestation and ecosystem destruction. Diseases of bamboo that typically occur on leaves and stems can cause significant loss, reducing the quality and yield of the bamboo. However, there are few reports identifying the fungal species diversity and potential pathogens of bamboo. Here, we describe four new species of plant fungi from the leaves of bamboo within Fujian provinces, China. Fungi were isolated from diseased leaves collected within Fujian province and identified based on their morphological characteristics and multilocus phylogenies using nucleotide sequences derived from combined datasets of the intervening 5.8S nrRNA gene (ITS), the 28S large subunit of nuclear ribosomal RNA gene (LSU), the large subunit of RNA polymerase I (rpb1), the translation elongation factor 1-α gene (tef1-α), and the partial beta-tubulin gene (tub2). These analyses helped reveal and clarify taxonomic relationships in the family Magnaporthaceae. The new species of bambusicolous fungi identified include two species of Bifusisporella, described as B. fujianensis sp. nov. and B. bambooensis sp. nov., and two species of Apiospora, described as A. fujianensis sp. nov. and A. fuzhouensis sp. nov. This study further expands the characterization and distribution of fungi associated with bamboo. [ABSTRACT FROM AUTHOR]

As a flagship of the Europe's Beating Cancer Plan, the European Commission supports EU member states' efforts to strengthen and expand the routine vaccination of girls and boys against human papillomavirus (HPV). Populations across Europe have grown in diversity, and health systems must adapt to meet the specific needs of increasing diversity. Healthcare professionals (HCPs) must strive to communicate HPV vaccine information in a culturally sensitive manner and address specific concerns related to cultural beliefs, trust in health systems and perceived risks. The objectives of this exploratory study are to identify which themes are most frequently raised during the recommendation of vaccination to minors based on the characteristics of the population (religion, region of origin, gender, level of education and language proficiency) and to collect strategies to improve communication with a diverse population. A survey was distributed through various European public health institutions to HCPs in the region and their networks. The survey included multi-response questions (themes addressed during vaccination recommendation based on population characteristics) and open-ended questions (own qualitative comments and strategies). The most common issues that arise during vaccine recommendation are a lack of knowledge, followed by misinformation. Differences were detected according to the population characteristics. Suggested strategies to improve HPV vaccine recommendation focused on the following aspects: affordability; sexuality and gender; communication platforms; multilingualism; quality of care; school collaboration. HCPs report differences according to the characteristics of the population receiving the recommendation. Personalisation of the recommendations would help to optimise the decision-making process for some groups. [ABSTRACT FROM AUTHOR]

Deploying onshore wind energy as a cornerstone of future global energy systems challenges societies and decision-makers worldwide. Expanding wind energy should contribute to a more sustainable electricity generation without harnessing humans and their environment. Opponents often highlight the negative environmental impacts of wind energy to impede its expansion. This study reviews 152 studies to synthesize, summarize, and discuss critically the current knowledge, research gaps, and mitigation strategies on the environmental impacts of onshore wind energy. The investigated effects comprise impacts on the abiotic and biotic environment, with birds and bats in particular, noise and visual impacts. Effects are discussed in the context of social acceptance, other energy technologies, and wind energy expansion in forests. This review illustrates that many effects are highly case-specific and must be more generalizable. Studies are biased regarding the research focus and areas, needing more standardized research methods and long-term measurements. Most studies focus on the direct mortality of birds and bats at wind farms and are concentrated in Europe and North America. Knowledge gaps persist for many impact categories, and the efficacy of mitigation strategies has yet to be proven. More targeted, unbiased research is required that allows for an objective evaluation of the environmental impacts of wind energy and strategies to mitigate them. Impacts, such as those on biodiversity, need to be addressed in the context of other anthropogenic influences and the benefits of wind energy. This forms the basis for a socially acceptable, efficient, and sustainable expansion of wind energy. [ABSTRACT FROM AUTHOR]

Background: Postoperative pancreatic fistula (POPF) after pancreaticoduodenectomy (PD) is associated with major postoperative morbidity and mortality. Several scoring systems have been described to stratify patients into risk groups according to the risk of POPF. The aim of this study was to compare scoring systems in patients who underwent a PD. Methods: A total of 196 patients undergoing PD from July 2019 to June 2022 were identified from a prospectively maintained database of the University Hospital Ghent. After performing a literature search, four validated, solely preoperative risk scores and the intraoperative Fistula Risk Score (FRS) were included in our analysis. Furthermore, we eliminated the variable blood loss (BL) from the FRS and created an additional score. Univariate and multivariate analyses were performed for all risk factors, followed by a ROC analysis for the six scoring systems. Results: All scores showed strong prognostic stratification for developing POPF (p < 0.001). FRS showed the best predictive accuracy in general (AUC 0.862). FRS without BL presented the best prognostic value of the scores that included solely preoperative variables (AUC 0.783). Soft pancreatic texture, male gender, and diameter of the Wirsung duct were independent prognostic factors on multivariate analysis. Conclusions: Although all predictive scoring systems stratify patients accurately by risk of POPF, preoperative risk stratification could improve clinical decision-making and implement preventive strategies for high-risk patients. Therefore, the preoperative use of the FRS without BL is a potential alternative. [ABSTRACT FROM AUTHOR]

Cellulose hydrogels, formed either through physical or chemical cross-linking into a three-dimensional network from cellulose or its derivatives, are renowned for their exceptional water absorption capacities and biocompatibility. Rising demands for sustainable materials have spurred interest in cellulose hydrogels, attributed to their abundant supply, biodegradability, and non-toxic nature. These properties highlight their extensive potential across various sectors including biomedicine, the food industry, and environmental protection. Cellulose hydrogels are particularly advantageous in applications such as drug delivery, wound dressing, and water treatment. Recent large-scale studies have advanced our understanding of cellulose preparation and its applications. This review delves into the fundamental concepts, preparation techniques, and current applications of cellulose hydrogels in diverse fields. It also discusses the latest advances in nano-lignin-based hydrogels, providing a comprehensive overview of this promising material and offering insights and guidance for future research and development. [ABSTRACT FROM AUTHOR]

A series of hybrid compounds with triazole and thiazolidine nuclei connected by a linker has been synthesized and extensively studied. Various synthetic methods for the target compounds have been tested. A microbiological assessment of the obtained compounds was carried out on strains of pathogenic fungi C. albicans, C. non-albicans, multidrug-resistant C. auris, Rhizopus arrhizus, Aspergillus spp. and some dermatophytes and other yeasts. The lowest obtained MIC values for target compounds lie between 0.003 µg/mL and 0.5 µg/mL and therefore the compounds are not inferior or several times better than commercial azole drugs. The length of the acylpiperazine linker has a limited effect on antifungal activity. Some bioisosteric analogues were tested in microbiological analysis, but turned out to be weaker than the leader in activity. The highest activity was demonstrated by a compound with para-chlorobenzylidene substituent in the thiazolidine fragment. Molecular modelling was used to predict binding modes of synthesized molecules and rationalize experimentally observed SAR. The leader compound is twice more effective in inhibiting the formation of germ tubes by Candida albicans yeast cells compared to voriconazole. An increased level of Pdr5, an azoles drug efflux pump was observed, but the increase is lower than that caused by azoles. The results can be useful for further development of more powerful and safe antifungal agents. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic underscores the significance of vaccine hesitancy in shaping vaccination outcomes. Understanding the factors underpinning COVID-19 vaccination hesitancy is crucial for tailoring effective vaccination strategies. This cross-sectional study, conducted in three communities across the United States and Lebanon, employed surveys to assess respondents' knowledge, attitudes, and perceptions regarding COVID-19 infection and vaccination. Among the 7196 participants, comprising 6775 from the US and 422 from Lebanon, vaccine hesitancy rates were comparable at 12.2% and 12.8%, respectively. Notably, a substantial proportion of respondents harbored misconceptions, such as attributing the potential to alter DNA (86.4%) or track individuals (92.8%) to COVID-19 vaccines and believing in the virus's artificial origins (81%). US participants had more misconceptions about the COVID-19 vaccine, such as altering DNA or causing infertility. Lebanese participants were more likely to question the origins of the virus and the speed of vaccine development. Additionally, US respondents were less worried about infection, while Lebanese respondents were more indecisive but less likely to outright reject the vaccine. Primary determinants of hesitancy included perceptions that the vaccine poses a greater risk than the infection itself (aOR = 8.7 and 9.4, respectively) and negative recommendations from healthcare providers (aOR = 6.5 and 5.4, respectively). Conversely, positive endorsements from healthcare providers were associated with reduced hesitancy (aOR = 0.02 and 0.4, respectively). Targeting healthcare providers to dispel misinformation and elucidate COVID-19 vaccine risks holds promise for enhancing vaccination uptake. [ABSTRACT FROM AUTHOR]

Sooty moulds are a widespread group of saprophytic ascomycetes that obtain nutrients from honeydew excreted by sap-feeding insects and coat plant tissue with mycelia. Research on sooty moulds has focused on fungal morphology and phylogeny-based taxonomy, but little research has been conducted on the community structure. In this study, the PacBio sequencing platform was used to systematically analyse the fungal and bacterial diversity of the sooty mould community on camphor trees at two sampling sites. Six dominant sooty mould genera were identified, of which three genera of Dothideomycetes were enriched only in diseased samples, while three genera of Eurotiomycetes were present in both healthy and diseased samples. Bacterial diversity and co-occurrence network analysis indicated that the sooty moulds had an effect on the leaf surface bacterial communities but not on the endophyte communities. There was a close correlation between the six dominant pathogenic groups and bacteria in the soot layer. Transcriptomic data from Cinnamomum camphora samples showed that the sooty moulds that did not penetrate plant cells not only affected plant photosynthesis but also induced plant defence responses. This study systematically studied the microbial community of sooty moulds, indicating the close relationship between sooty moulds and the bacterial communities., (© 2022 Applied Microbiology International and John Wiley & Sons Ltd.)

Acetylcholine-activated receptors are divided broadly into two major structurally distinct classes: ligand-gated ion channel nicotinic and G-protein-coupled muscarinic receptors. Each class encompasses several structurally related receptor subtypes with distinct patterns of tissue expression and post-receptor signal transduction mechanisms. The activation of both nicotinic and muscarinic cholinergic receptors has been associated with the induction and progression of gastrointestinal neoplasia. Herein, after briefly reviewing the classification of acetylcholine-activated receptors and the role that nicotinic and muscarinic cholinergic signaling plays in normal digestive function, we consider the mechanics of acetylcholine synthesis and release by neuronal and non-neuronal cells in the gastrointestinal microenvironment, and current methodology and challenges in measuring serum and tissue acetylcholine levels accurately. Then, we critically evaluate the evidence that constitutive and ligand-induced activation of acetylcholine-activated receptors plays a role in promoting gastrointestinal neoplasia. We focus primarily on adenocarcinomas of the stomach, pancreas, and colon, because these cancers are particularly common worldwide and, when diagnosed at an advanced stage, are associated with very high rates of morbidity and mortality. Throughout this comprehensive review, we concentrate on identifying novel ways to leverage these observations for prognostic and therapeutic purposes. [ABSTRACT FROM AUTHOR]

Auxins are chemical compounds of wide interest, mostly due to their role in plant metabolism and development. Synthetic auxins have been used as herbicides for more than 75 years and low toxicity in humans is one of their most advantageous features. Extensive studies of natural and synthetic auxins have been made in an effort to understand their role in plant growth. However, molecular details of the binding and recognition process are still an open question. Herein, we present a comprehensive in silico pipeline for the assessment of TIR1 ligands using several structure-based methods. Our results suggest that subtle dynamics within the binding pocket arise from water–ligand interactions. We also show that this trait distinguishes effective binders. Finally, we construct a database of putative ligands and decoy compounds, which can aid further studies focusing on synthetic auxin design. To the best of our knowledge, this study is the first of its kind focusing on TIR1. [ABSTRACT FROM AUTHOR]

Type 2 diabetes is a chronic disease marked by hyperglycemia; impaired insulin secretion by pancreatic β-cells is a hallmark of this disease. Recent studies have shown that hypoxia occurs in the β-cells of patients with type 2 diabetes and hypoxia, in turn, contributes to the insulin secretion defect and β-cell loss through various mechanisms, including the activation of hypoxia-inducible factors, induction of transcriptional repressors, and activation of AMP-activated protein kinase. This review focuses on advances in our understanding of the contribution of β-cell hypoxia to the development of β-cell dysfunction in type 2 diabetes. A better understanding of β-cell hypoxia might be useful in the development of new strategies for treating type 2 diabetes. [ABSTRACT FROM AUTHOR]

Simple Summary: Pancreatic ductal adenocarcinoma (PDAC) accounts for 90% of pancreatic cancers. It is considered one of the deadliest cancers due to its high metastatic potential and drug resistance. This review discusses various targets and nanoparticle-based delivery systems developed, tested, and approved for the effective diagnosis and targeted treatment of PDAC. Pancreatic ductal adenocarcinoma (PDAC), one of the deadliest cancers, presents significant challenges in diagnosis and treatment due to its aggressive, metastatic nature and lack of early detection methods. A key obstacle in PDAC treatment is the highly complex tumor environment characterized by dense stroma surrounding the tumor, which hinders effective drug delivery. Nanotechnology can offer innovative solutions to these challenges, particularly in creating novel drug delivery systems for existing anticancer drugs for PDAC, such as gemcitabine and paclitaxel. By using customization methods such as incorporating conjugated targeting ligands, tumor-penetrating peptides, and therapeutic nucleic acids, these nanoparticle-based systems enhance drug solubility, extend circulation time, improve tumor targeting, and control drug release, thereby minimizing side effects and toxicity in healthy tissues. Moreover, nanoparticles have also shown potential in precise diagnostic methods for PDAC. This literature review will delve into targeted mechanisms, pathways, and approaches in treating pancreatic cancer. Additional emphasis is placed on the study of nanoparticle-based delivery systems, with a brief mention of those in clinical trials. Overall, the overview illustrates the significant advances in nanomedicine, underscoring its role in transcending the constraints of conventional PDAC therapies and diagnostics. [ABSTRACT FROM AUTHOR]

Islets of Langerhans are anatomically dispersed within the pancreas and exhibit regulatory coordination between islets in response to nutritional and inflammatory stimuli. However, within individual islets, there is also multi-faceted coordination of function between individual beta-cells, and between beta-cells and other endocrine and vascular cell types. This is mediated partly through circulatory feedback of the major secreted hormones, insulin and glucagon, but also by autocrine and paracrine actions within the islet by a range of other secreted products, including somatostatin, urocortin 3, serotonin, glucagon-like peptide-1, acetylcholine, and ghrelin. Their availability can be modulated within the islet by pericyte-mediated regulation of microvascular blood flow. Within the islet, both endocrine progenitor cells and the ability of endocrine cells to trans-differentiate between phenotypes can alter endocrine cell mass to adapt to changed metabolic circumstances, regulated by the within-islet trophic environment. Optimal islet function is precariously balanced due to the high metabolic rate required by beta-cells to synthesize and secrete insulin, and they are susceptible to oxidative and endoplasmic reticular stress in the face of high metabolic demand. Resulting changes in paracrine dynamics within the islets can contribute to the emergence of Types 1, 2 and gestational diabetes. [ABSTRACT FROM AUTHOR]

Background: The incidence of colorectal cancer (CRC) is decreasing in individuals >50 years due to organised screening but has increased for younger individuals. We characterized symptoms and their timing before diagnosis in young individuals. Methods: We identified all patients diagnosed with CRC between 1990–2017 in British Columbia, Canada. Individuals <50 years (n = 2544, EoCRC) and a matched cohort >50 (n = 2570, LoCRC) underwent chart review to identify CRC related symptoms at diagnosis and determine time from symptom onset to diagnosis. Results: Across all stages of CRC, EoCRC presented with significantly more symptoms than LoCRC (Stage 1 mean ± SD: 1.3 ± 0.9 vs. 0.7 ± 0.9, p = 0.0008; Stage 4: 3.3 ± 1.5 vs. 2.3 ± 1.7, p < 0.0001). Greater symptom burden at diagnosis was associated with worse survival in both EoCRC (p < 0.0001) and LoCRC (p < 0.0001). When controlling for cancer stage, both age (HR 0.87, 95% CI 0.8–1.0, p = 0.008) and increasing symptom number were independently associated with worse survival in multivariate models. Conclusions: Patients with EoCRC present with a greater number of symptoms of longer duration than LoCRC; however, time from patient reported symptom onset was not associated with worse outcomes. [ABSTRACT FROM AUTHOR]

Simple Summary: Phytoestrogens are secondary plant metabolites that are structurally similar to endogenous estrogens and may result in adverse reproductive effects in grazing livestock. This study evaluated the key phytoestrogens in legume pastures and their effect on superovulation, embryo quantity and embryo quality. Cows grazed on legume and ryegrass pastures for a duration of 7 weeks at two timed treatments and were subjected to a conventional estrus synchronization and superovulation protocol. Coumestrol and formononetin were identified as the dominant phytoestrogens. The results from the grazing trial suggest that grazing potential estrogenic legume pastures less than 20 days before artificial insemination may affect oocyte developmental competence and contribute to early embryonic loss. Ovulation and artificial insemination rates have been observed to decrease in sheep and cows when exposed to dietary phytoestrogens at concentrations greater than 25 mg/kg DM. A grazing trial was undertaken to investigate the effects of coumestrol and other key phytoestrogens on the superovulatory response, embryo numbers and quality in beef cows grazing legume pastures. A 7-week controlled grazing trial was conducted with legume and ryegrass pasture treatments, with cows exposed to legumes at two timed treatments, 4 and 7 weeks. Twenty Angus cows were subjected to a conventional estrus synchronization and superovulation protocol. Embryos were recovered via conventional uterine body flushing 7 days post artificial insemination (AI). Numerous phytoestrogens were identified in both pasture and plasma samples, including coumestrol and formononetin. Concentrations of phytoestrogens in the pasture ranged from 0.001 to 47.5 mg/kg DM and 0 to 2.6 ng/mL in plasma. Approximately 50% of cows produced viable embryos 7 days post AI. A significant interaction between the effect of treatment groups on the embryo stage was observed (p < 0.05). The results suggest that concentrations of >25 mg/kg DM of phytoestrogens less than 20 days preceding AI may negatively affect oocyte developmental competence, reduce progesterone production and thus contribute to early embryonic loss. [ABSTRACT FROM AUTHOR]

Chronic lymphocytic leukemia, in spite of recent advancements, is still an incurable disease; the majority of patients eventually acquire resistance to treatment through relapses. In all subtypes of chronic lymphocytic leukemia, the disruption of normal B-cell homeostasis is thought to be mostly caused by the absence of apoptosis. Consequently, apoptosis induction is crucial to the management of this illness. Damaged biological components can accumulate as a result of the oxidation of intracellular lipids, proteins, and DNA by reactive oxygen species. It is possible that cancer cells are more susceptible to apoptosis because of their increased production of reactive oxygen species. An excess of reactive oxygen species can lead to oxidative stress, which can harm biological elements like DNA and trigger apoptotic pathways that cause planned cell death. In order to upset the balance of oxidative stress in cells, recent therapeutic treatments in chronic lymphocytic leukemia have focused on either producing reactive oxygen species or inhibiting it. Examples include targets created in the field of nanomedicine, natural extracts and nutraceuticals, tailored therapy using biomarkers, and metabolic targets. Current developments in the complex connection between apoptosis, particularly ferroptosis and its involvement in epigenomics and alterations, have created a new paradigm. [ABSTRACT FROM AUTHOR]

Proteolysis-targeting chimeras (PROTACs) describe compounds that bind to and induce degradation of a target by simultaneously binding to a ubiquitin ligase. More generally referred to as bifunctional degraders, PROTACs have led the way in the field of targeted protein degradation (TPD), with several compounds currently undergoing clinical testing. Alongside bifunctional degraders, single-moiety compounds, or molecular glue degraders (MGDs), are increasingly being considered as a viable approach for development of therapeutics, driven by advances in rational discovery approaches. This review focuses on drug discovery with respect to bifunctional and molecular glue degraders within the ubiquitin proteasome system, including analysis of mechanistic concepts and discovery approaches, with an overview of current clinical and pre-clinical degrader status in oncology, neurodegenerative and inflammatory disease. [ABSTRACT FROM AUTHOR]

BCL-xL and BCL-2 are validated therapeutic targets in small-cell lung cancer (SCLC). Targeting these proteins with navitoclax (formerly ABT263, a dual BCL-xL/2 inhibitor) induces dose-limiting thrombocytopenia through on-target BCL-xL inhibition in platelets. Therefore, platelet toxicity poses a barrier in advancing the clinical translation of navitoclax. We have developed a strategy to selectively target BCL-xL in tumors, while sparing platelets, by utilizing proteolysis-targeting chimeras (PROTACs) that hijack the cellular ubiquitin proteasome system for target ubiquitination and subsequent degradation. In our previous study, the first-in-class BCL-xL PROTAC, called DT2216, was shown to have synergistic antitumor activities when combined with venetoclax (formerly ABT199, BCL-2-selective inhibitor) in a BCL-xL/2 co-dependent SCLC cell line, NCI-H146 (hereafter referred to as H146), in vitro and in a xenograft model. Guided by these findings, we evaluated our newly developed BCL-xL/2 dual degrader, called 753b, in three BCL-xL/2 co-dependent SCLC cell lines and the H146 xenograft models. 753b was found to degrade both BCL-xL and BCL-2 in these cell lines. Importantly, it was considerably more potent than DT2216, navitoclax, or DT2216 + venetoclax in reducing the viability of BCL-xL/2 co-dependent SCLC cell lines in cell culture. In vivo, 5 mg/kg weekly dosing of 753b was found to lead to significant tumor growth delay, similar to the DT2216 + venetoclax combination in H146 xenografts, by degrading both BCL-xL and BCL-2. Additionally, 753b administration at 5 mg/kg every four days induced tumor regressions. At this dosage, 753b was well tolerated in mice, without observable induction of severe thrombocytopenia as seen with navitoclax, and no evidence of significant changes in mouse body weights. These results suggest that the BCL-xL/2 dual degrader could be an effective and safe therapeutic for a subset of SCLC patients, warranting clinical trials in future. [ABSTRACT FROM AUTHOR]

Xylariomycetidae comprises extremely diverse taxa that are widespread on decaying wood worldwide. An investigation of the diversity of microfungi on oil tree plantations in Sichuan Province was conducted during 2020–2021. Twelve saprobic taxa representing five species were identified as members of Amphisphaeriales and Xylariales through morphological comparisons. Phylogenetic analyses of combined ITS, LSU, rpb2, tub2 and tef1 sequence data indicated a distinct clade formed by three strains within Xylariomycetidae, unrelated to any currently recognized families. Thus, a novel anthostomella-like genus, Bicellulospora, is proposed and treated as Xylariales genera incertae sedis. Bicellulospora is characterized by dark brown to black, immersed, subglobose ascomata with a clypeus, cylindrical asci, and hyaline to yellowish brown, inequilaterally ellipsoidal ascospores with a large upper cell and a dwarf lower cell. Two new species of Amphisphaeria, namely A. oleae and A. verniciae, are introduced based on multi-gene phylogenetic analyses (ITS, LSU, rpb2 and tub2) coupled with morphological characteristics. Amphisphaeria micheliae and Endocalyx ptychospermatis are reported as new host records. [ABSTRACT FROM AUTHOR]

Rock-inhabiting fungi (RIF) are usually extremely tolerant or extremophilic, as they can survive on natural and artificial rocks despite being exposed to stressful conditions. RIF have serious negative effects on the appearance and cohesion of rocky substrates, causing the alteration and decomposition of building materials, but also on human and animal health, as they can act as opportunistic pathogens. Their identification is therefore of great importance, especially in urban areas. In the present study, culturing techniques for isolating fungi, and a polyphasic taxonomic approach to their identification, were used to assess the diversity of micromycetes that darken the surfaces of buildings in various villages and cities in Tarragona Province (Spain). Sixty-four species of RIF belonging to forty-one genera were identified, including a new genus (Coccodomyces) and the following six new fungal species: Coccodomyces pleiosporus, Exophiala caementiphila, Exophiala multiformis, Neocatenulostroma spinulosum, Neodevriesia longicatenispora, and Paradevriesia holothallica. Thus, we have established that building materials are ecological niches where a high biodiversity of RIF can develop. [ABSTRACT FROM AUTHOR]

Background: Antimicrobial resistance has become one of the world's most important public health problems. Accordingly, nursing strategies to manage antimicrobials in hospital environments are fundamental to promoting patient health. The aim of this study was to summarise the best evidence available on nursing strategies for the safe management of antimicrobials in hospital environments. Methods: This qualitative systematic review used meta-aggregation in accordance with the recommendations of the Joanna Briggs Institute. The protocol was registered in the data base of the Prospective Register of Systematic Reviews under No. CRD42021224804. The literature search was conducted, in April and May 2021, in the following data bases and journal repositories: Latin American and Caribbean Health Sciences Literature (LILACS) via the Virtual Health Library (VHL), Medical Literature Analysis and Retrieval System on-line (Medline) via PubMed, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Scientific Electronic Library Online (SciELO) and Excerpta Medica Database (EMBASE). The findings of each study were summarized and the results were meta-aggregated in JBI SUMARI software. Results: The search resulted in a total of 447 studies and, after selection, the review included 26 studies, in which 42 nursing strategies were identified. The strategies were first categorised as care- or stewardship-related and then into the subcategories: Screening, Administration, Monitoring and Discharge, Nursing Team, Multi-professional Teams, Patients and Institutional Leadership. The 42 strategies were meta-aggregated and represented in flow diagrams. The best evidence was synthesized related to nursing strategies in the safe management of antimicrobials in the hospital environment. Conclusions: Nurses play an indispensable function in antimicrobial stewardship in the hospital environment, because they work directly at the core of safe patient care. Significant contributions by nursing towards reducing antimicrobial resistance were found in care-related practice, education activities, research and policy. [ABSTRACT FROM AUTHOR]

SWI/SNF enzymes are heterogeneous multi-subunit complexes that utilize the energy from ATP hydrolysis to remodel chromatin structure, facilitating transcription, DNA replication, and repair. In mammalian cells, distinct sub-complexes, including cBAF, ncBAF, and PBAF exhibit varying subunit compositions and have different genomic functions. Alterations in the SWI/SNF complex and sub-complex functions are a prominent feature in cancer, making them attractive targets for therapeutic intervention. Current strategies in cancer therapeutics involve the use of pharmacological agents designed to bind and disrupt the activity of SWI/SNF complexes or specific sub-complexes. Inhibitors targeting the catalytic subunits, SMARCA4/2, and small molecules binding SWI/SNF bromodomains are the primary approaches for suppressing SWI/SNF function. Proteolysis-targeting chimeras (PROTACs) were generated by the covalent linkage of the bromodomain or ATPase-binding ligand to an E3 ligase-binding moiety. This engineered connection promotes the degradation of specific SWI/SNF subunits, enhancing and extending the impact of this pharmacological intervention in some cases. Extensive preclinical studies have underscored the therapeutic potential of these drugs across diverse cancer types. Encouragingly, some of these agents have progressed from preclinical research to clinical trials, indicating a promising stride toward the development of effective cancer therapeutics targeting SWI/SNF complex and sub-complex functions. [ABSTRACT FROM AUTHOR]

The development of BRD9 inhibitors involves the design and synthesis of molecules that can specifically bind the BRD9 protein, interfering with the function of the chromatin-remodeling complex ncBAF, with the main advantage of modulating gene expression and controlling cellular processes. Here, we summarize the work conducted over the past 10 years to find new BRD9 binders, with an emphasis on their structure–activity relationships, efficacies, and selectivities in preliminary studies. BRD9 is expressed in a variety of cancer forms, hence, its inhibition holds particular significance in cancer research. However, it is crucial to note that the expanding research in the field, particularly in the development of new degraders, may uncover new therapeutic potentials. [ABSTRACT FROM AUTHOR]

Research Problem: Families with children travel by car more frequently than any other household type and hence significantly contribute to transport externalities. Lift-sharing is a potential time-effective and convenient means of mitigating these effects. Whilst some research has been conducted on lift-sharing for the school run, there is little research beyond this context, particularly around lift-sharing for children's activities (e.g., sport). Study Aim: Consequently, the aim of this study was to assess the current prevalence of lift-sharing (for children's activities and other types of trips) in families with young children, the factors influencing its uptake, the experiences and attitudes of regular lift-sharers, and whether previous literature findings on reciprocity applied in this context to gain a deeper understanding of how and why families participate in activity lift-sharing. Research Design: A mixed-methods approach was applied, comprising (1) a travel survey of 474 families to establish socio-demographic and activity factors that influence lift-share prevalence for activity trips; and (2) 15 semi-structured interviews with parents to further explore how and why families participate in activity lift-sharing. Results: Factors influencing lift-sharing decisions for activity travel were number of cars owned, number of seats in the car, settlement type, income, time of day and location of the activity, number of children attending, parking availability, whether the activity is a sporting activity or not, and number of close friends of the child at the same activity. Salient motivating factors triggering lift-sharing included intentions to reduce chauffeuring and parents wanting their children to socialise. Trust was an initial imperative component of lift-share formation, and attitudes towards reciprocity supported previous literature findings relating to the variability of acceptable reciprocation and the role of fairness. [ABSTRACT FROM AUTHOR]