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Highly dispersed Cobalt doped ZnS nanostructures were successfully fabricated on the surfaces of graphene sheets via a simple hydrothermal method. X-ray diffraction (XRD), X-ray photocurrent spectroscopy (XPS), Raman spectroscopy (RS), Fourier transform infrared spectroscopy (FTIR) and Scanning electron microscopy (SEM) were utilized to analyze the structural characteristics of the cobalt doped ZnS decorated with graphene Co x Zn 1 - x S rGO nanostructures (NSs). UV-visible optical absorption (UV-vis) studies were conducted to investigate their optical properties. In laboratory studies utilizing water and visible light, the photocatalytic activity of Co x Zn 1 - x S rGO NSs at (x = 0, 1, 2, 4 and 6 atm.%) were evaluated. Graphite Oxide (GO) was successfully transformed into sheets of graphene and Co x Zn 1 - x S rGO NSs possessed a crystalline structure according to the findings of XRD, RS and FTIR analysis. SEM investigation showed graphene sheets enhanced with ZnS NSs possessed cuboidal, spheroidal form of structure and displayed a paper like appearance. UV-vis confirmed a noticeable rapid increase in transmittance along the UV wavelength area and confirmed a highly transparent NSs in the wavelength range of (180-800 nm). Calculations using density functional theory (DFT) revealed that the Co NSs have more negative conduction bands than ZnS, allowing for effective electron transfer from cobalt to ZnS and exhibiting a band gap decrease as Co content increased. The Co 0.04 Zn 0.96 S rGO NSs sample had the highest photocatalytic activity, measured at 7648.9 µ mol h - 1 . A combination of improved dispersion properties, greater surface area, increased absorption and enhanced transfer of photogenerated electrons, Co x Zn 1 - x S rGO NSs increased the photocatalytic hydrogen generation activity.

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Striga hermonthica (Del.) Benth., a parasitic weed, causes substantial yield losses in maize production in sub-Saharan Africa (SSA). Breeding for Striga resistance in maize is constrained by limited genetic diversity for Striga resistance within the elite germplasm and phenotyping capacity under artificial Striga infestation. Genomics-enabled approaches have the potential to accelerate identification of Striga resistant lines for hybrid development. The objectives of this study were to evaluate the accuracy of genomic selection for traits associated with Striga resistance and grain yield (GY) and to predict genetic values of tested and untested doubled haploid (DH) maize lines. We genotyped 606 DH lines with 8,439 rAmpSeq markers. A training set of 116 DH lines crossed to two testers was phenotyped under artificial Striga infestation at three locations in Kenya. Heritability for Striga resistance parameters ranged from 0.38‒0.65 while that for GY was 0.54. The prediction accuracies for Striga resistance-associated traits across locations, as determined by cross validation (CV) were 0.24 to 0.53 for CV0 and from 0.20 to 0.37 for CV2. For GY, the prediction accuracies were 0.59 and 0.56 for CV0 and CV2, respectively. The results revealed 300 DH lines with desirable genomic estimated breeding values (GEBVs) for reduced number of emerged Striga plants (STR) at 8, 10, and 12 weeks after planting. The GEBVs of DH lines for Striga resistance associated traits in the training and testing sets were similar in magnitude. These results highlight the potential application of genomic selection in breeding for Striga resistance in maize. The integration of genomic-assisted strategies and DH technology for line development coupled with forward breeding for major adaptive traits will enhance genetic gains in breeding for Striga resistance in maize.

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BACKGROUND: During pseudoglandular stage of the human lung development the primitive bronchial buds are initially conformed by simple tubules lined by endoderm-derived epithelium surrounded by mesenchyme, which will progressively branch into airways and start to form distal epithelial saculles. For first time alveolar type II (AT2) pneumocytes appears. This study aims to characterize the genes and microRNAs involved in this differentiation process and decipher its role in the starting alveolar differentiation. METHODS: Gene and microRNA profiling was performed in human embryonic lungs from 7 to 12 post conception weeks (pcw). Protein expression location of candidate genes were analyzed by immunofluorescense in embryonic lung tissue sections. mRNA/miRNA target pairs were identified using computational approaches and their expression was studied in purified epithelial/mesenchymal cell populations and in isolated tips and stalks from the bronchial tree. Additionally, silencing experiments in human embryonic lung mesenchymal cells and in human embryonic tip-derived lung organoids were performed, as well as organoid differentiation studies. AT2 cell markers were studied by qRT-PCR and by immunofluorescence. The TGFB-ß phosphorylated pathways was analyzed with membrane protein arrays. Lung explants were cultured in air/liquid interface with/without peptides. RESULTS: We identified 88 differentially expressed genes, including IGFBP3. Although IGFBP3 mRNA was detected in both epithelial and mesenchymal populations, the protein was restricted to the epithelium, indicating post-transcriptional regulation preventing IGFBP3 protein expression in the mesenchyme. MicroRNA profiling identified miR-34a as an IGFBP3 regulator. miR-34a was up-regulated in mesenchymal cells, and its silencing in human embryonic lung mesenchymal cells increased IGFBP3 levels. Additionally, IGFBP3 expression showed a marked downregulation from 7 to 12 pcw, suggesting its involvement in the differentiation process. The differentiation of human tip-derived lung embryonic organoids showed a drastic reduction in IGFBP3, supported by the scRNAseq data. IGFBP3 silencing in organoids activated an alveolar-like differentiation process characterized by stem cell markers downregulation and upregulation of AT2 markers. This process was mediated by TGFß signalling inhibition and BMP pathway activation. CONCLUSIONS: The IGFBP3/miR-34a axis restricts IGFBP3 expression in the embryonic undifferentiated lung epithelium, and the progressive downregulation of IGFBP3 during the pseudoglandular stage is required for alveolar differentiation.

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BACKGROUND AND PURPOSE: A novel Cone-Beam Computed Tomography (CBCT) named HyperSight provides superior CBCT image quality compared to conventional ring gantry CBCT imaging, and it is suitable for dose calculations for prostate cancer, but it comes with considerable additional costs. The aim of this study was to determine the added value of HyperSight CBCT imaging compared to conventional CBCT imaging in terms of organ visibility in the male pelvic region. MATERIALS AND METHODS: Twenty prostate cancer patients were included in this prospective clinical study. For each patient three CBCT pairs, consisting of HyperSight and conventional CBCT scans acquired on consecutive days, were included. CBCT scans were evaluated by four observers in terms of visibility of the prostate, bladder, rectum and seminal vesicles. Visibility was scored on a 1-to-5 scale and by annotating axial slices where the organs were hard to delineate. Lastly, observers indicated whether the CBCT scans were of sufficient quality for an online adaptive radiation therapy workflow. RESULTS: All four organs were better visible on HyperSight CBCT scans compared to conventional CBCT scans. The mean visibility scores increased from 3.1 to 4.5 on a 1--5 scale of and the mean number of annotated slices reduced from 4.5 to 1.1. 99% Of the HyperSight CBCT scans were considered suitable for an online adaptive workflow vs 25-83% for the conventional CBCT scans. CONCLUSION: HyperSight CBCT scans yielded a visibility of prostate, bladder, rectum and seminal vesicles comparable to planning CT scans and, can replace a repeat planning CT scan in case of anatomical changes requiring a new treatment plan.

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Using nonequilibrium computer simulations, we study the response of ferromagnetic nanofilaments, consisting of stabilized one dimensional chains of ferromagnetic nanoparticles, under external rotating magnetic fields. In difference with their analogous microscale and stiff counterparts, which have been actively studied in recent years, nonequilibrium properties of rather flexible nanoparticle filaments remain mostly unexplored. By progressively increasing the modeling details, we are able to evidence the qualitative impact of main interactions that can not be neglected at the nanoscale, showing that filament flexibility, thermal fluctuations and hydrodynamic interactions contribute independently to broaden the range of synchronous frequency response in this system. Furthermore, we also show the existence of a limited set of characteristic dynamic filament configurations and discuss in detail the asynchronous response, which at finite temperature becomes probabilistic.

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Ctenophores are marine organisms attracting significant attention from evolutionary biology, molecular biology, and ecological research. Here, we describe an easy and affordable setup to maintain a stable culture of the ctenophore Mnemiopsis leidyi. The challenging delicacy of the lobate ctenophores can be met by monitoring the water quality, providing the right nutrition, and adapting the handling and tank set-up to their fragile gelatinous body plan. Following this protocol allows stable laboratory lines, a continuous supply of embryos for molecular biological studies, and independence from population responses to environmental fluctuations.

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This article reviews the geographical distribution, ethnomedicinal applications, and phytochemistry of the genus Monanthotaxis Baill, tribe Uvariae of the family Annonaceae. The reviewed works of literature were collected from various electronic databases including Google Scholar, PubMed, Science Direct, The International Plant Names Index (IPNI), and Research Gate. During this review, ninety-eight species of the genus Monanthotaxis were found to be widely distributed in tropical Africa. Some of those species are used in folkloric medicine by various communities to manage diseases and disease conditions such as fever, vomiting, headache, stomach-ache, malaria, helminthiasis, and hysteria. In the past 44 years (1979 to 2023), one hundred and nineteen secondary metabolites with different biomedical potentials have been reported from this genus. The reported compounds are categorised into flavonoids, alkaloids, terpenoids, polyoxygenated cyclohexane, and cyclohexene derivatives, benzyl derivatives, cinnamic acid derivatives, and stilbenoids. Most of the reported compounds showed an array of bioactivities corroborating the use of some members of the genus in folkloric medicine.

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Karst aquifers are globally prized freshwater sources, posing a significant preservation challenge. These aquifers typically exhibit dual or even triple porosities, encompassing matrix, fractures-fissures and conduits, rendering them highly responsive to variations in chemical characteristics and hydraulic head. In coastal regions, these aquifers often possess extensive subsurface conduit networks intricately linked to the rock matrix, facilitating groundwater discharge into the sea. Therefore, they display acute sensitivity to seawater intrusion, swiftly reacting to changes in precipitation and pumping regimes. This makes them exceptionally vulnerable to short-term meteorological fluctuations and long-term climate change. Their high heterogeneity leads to uneven penetration of the freshwater-seawater interface, causing rapid seawater intrusion inland over significant distances. The Mediterranean region, characterized by water deficit and water stress, faces strong impacts from climate change, featuring a warming atmospheric trend exceeding the global average, along with diminished rainfall exacerbating water scarcity. Increasing water demands for agriculture, urban development, and the growing tourism industry, because of global change, are worsening water stress. Our primary research objectives were analyzing the environmental consequences of global and climate change on seawater intrusion in Mediterranean coastal karst aquifers, with a focus on the role of the double-flow model, thus contributing to the understanding of the processes involved. To achieve this, we selected a study region on Mallorca Island in the western Mediterranean, where a karst aquifer system discharges into the sea. We employed various study methods, notably hydrochemical techniques and multi-isotopic analysis, encompassing the examination of 2H and 18O isotopes in water, 87Sr/86Sr ratio, Sr and B concentrations, and δ11B in water. A key finding is the rebound effect, wherein aquifers recontaminate due to solute molecular back-diffusion following cessation of extractions and the retreat of marine intrusion, providing insight into the impact of climate and global change on Mediterranean karst aquifers.

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Primary hyperaldosteronism (PAH) is an important cause of secondary hypertension (HTN). The study of the same requires a high clinical suspicion in addition to a hormonal study that confirms hormonal hypersecretion. It is important to start the appropriate treatment once the diagnosis is confirmed, and for this is necessary to demonstrate whether the hormonal hypersecretion is unilateral (patients who could be candidates for surgical treatment) or bilateral (patients who are candidates for pharmacological treatment only). At the Hospital del Mar since 2016 there has been a multidisciplinary work team in which Nephrologists, Endocrinologists, Radiologists and Surgeons participate to evaluate cases with suspected hyperaldosteronism and agree on the best diagnostic-therapeutic approach for these patients, including the need for adrenal vein sampling, which is a technique that in recent years has become the gold standard for the study of PAH. In the present study we collect the experience of our centre in performing AVC and its usefulness for the management of these patients.

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The target of rapamycin (TOR) signalling pathway plays a key role in the coordination between cellular growth and the cell cycle machinery in eukaryotes. The underlying molecular mechanisms by which TOR might regulate events after anaphase remain unknown. We show for the first time that one of the 2 TOR complexes in budding yeast, TORC1, blocks the separation of cells following cytokinesis by phosphorylation of a member of the NDR (nuclear Dbf2-related) protein-kinase family, the protein Cbk1. We observe that TORC1 alters the phosphorylation pattern of Cbk1 and we identify a residue within Cbk1 activation loop, T574, for which a phosphomimetic substitution makes Cbk1 catalytically inactive and, indeed, reproduces TORC1 control over cell separation. In addition, we identify the exocyst component Sec3 as a key substrate of Cbk1, since Sec3 activates the SNARE complex to promote membrane fusion. TORC1 activity ultimately compromises the interaction between Sec3 and a t-SNARE component. Our data indicate that TORC1 negatively regulates cell separation in budding yeast by participating in Cbk1 phosphorylation, which in turn controls the fusion of secretory vesicles transporting hydrolase at the site of division.

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Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by the progressive loss of motor neurons in the spinal cord. Glial cells, including astrocytes and microglia, have been shown to contribute to neurodegeneration in ALS, and metabolic dysfunction plays an important role in the progression of the disease. Glycogen is a soluble polymer of glucose found at low levels in the central nervous system that plays an important role in memory formation, synaptic plasticity, and the prevention of seizures. However, its accumulation in astrocytes and/or neurons is associated with pathological conditions and aging. Importantly, glycogen accumulation has been reported in the spinal cord of human ALS patients and mouse models. In the present work, using the SOD1G93A mouse model of ALS, we show that glycogen accumulates in the spinal cord and brainstem during symptomatic and end stages of the disease and that the accumulated glycogen is associated with reactive astrocytes. To study the contribution of glycogen to ALS progression, we generated SOD1G93A mice with reduced glycogen synthesis (SOD1G93A GShet mice). SOD1G93A GShet mice had a significantly longer life span than SOD1G93A mice and showed lower levels of the astrocytic pro-inflammatory cytokine Cxcl10, suggesting that the accumulation of glycogen is associated with an inflammatory response. Supporting this, inducing an increase in glycogen synthesis reduced life span in SOD1G93A mice. Altogether, these results suggest that glycogen in reactive astrocytes contributes to neurotoxicity and disease progression in ALS.

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Chondrosarcomas are the most common malignancy of cartilage and are associated with somatic mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 genes. Somatic IDH mutations are also found in its benign precursor lesion, enchondromas, suggesting that IDH mutations are early events in malignant transformation. Human mutant IDH chondrosarcomas and mutant Idh mice that develop enchondromas investigated in our studies display glycogen deposition exclusively in mutant cells from IDH mutant chondrosarcomas and Idh1 mutant murine growth plates. Pharmacologic blockade of glycogen utilization induces changes in tumor cell behavior, downstream energetic pathways, and tumor burden in vitro and in vivo. Mutant IDH1 interacts with hypoxia-inducible factor 1α (HIF1α) to regulate expression of key enzymes in glycogen metabolism. Here, we show a critical role for glycogen in enchondromas and chondrosarcomas, which is likely mediated through an interaction with mutant IDH1 and HIF1α.

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BACKGROUND: RNA modifications are important regulators of transcript activity and an increasingly emerging body of data suggests that the epitranscriptome and its associated enzymes are altered in human tumors. METHODS: Combining data mining and conventional experimental procedures, NSUN7 methylation and expression status was assessed in liver cancer cell lines and primary tumors. Loss-of-function and transfection-mediated recovery experiments coupled with RNA bisulfite sequencing and proteomics determined the activity of NSUN7 in downstream targets and drug sensitivity. RESULTS: In this study, the initial screening for genetic and epigenetic defects of 5-methylcytosine RNA methyltransferases in transformed cell lines, identified that the NOL1/NOP2/Sun domain family member 7 (NSUN7) undergoes promoter CpG island hypermethylation-associated with transcriptional silencing in a cancer-specific manner. NSUN7 epigenetic inactivation was common in liver malignant cells and we coupled bisulfite conversion of cellular RNA with next-generation sequencing (bsRNA-seq) to find the RNA targets of this poorly characterized putative RNA methyltransferase. Using knock-out and restoration-of-function models, we observed that the mRNA of the coiled-coil domain containing 9B (CCDC9B) gene required NSUN7-mediated methylation for transcript stability. Most importantly, proteomic analyses determined that CCDC9B loss impaired protein levels of its partner, the MYC-regulator Influenza Virus NS1A Binding Protein (IVNS1ABP), creating sensitivity to bromodomain inhibitors in liver cancer cells exhibiting NSUN7 epigenetic silencing. The DNA methylation-associated loss of NSUN7 was also observed in primary liver tumors where it was associated with poor overall survival. Interestingly, NSUN7 unmethylated status was enriched in the immune active subclass of liver tumors. CONCLUSION: The 5-methylcytosine RNA methyltransferase NSUN7 undergoes epigenetic inactivation in liver cancer that prevents correct mRNA methylation. Furthermore, NSUN7 DNA methylation-associated silencing is associated with clinical outcome and distinct therapeutic vulnerability.

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BACKGROUND: Water insecurity and inadequate sanitation have adverse impacts on the mental health of individuals. OBJECTIVE: To review and synthesize evidence on the relationship between water insecurity, inadequate sanitation, and mental health globally. DATA SOURCES: Relevant studies were identified by searching PubMed, PsycINFO, and EMBASE databases from inception up to March 2023. STUDY ELIGIBILITY CRITERIA: Only quantitative studies were included. The exposure was water insecurity and or inadequate sanitation. The outcome was common mental disorders (CMD: depression or anxiety), mental distress, mental health or well-being. There was no restriction on geographical location. PARTICIPANTS: General population or people attending health facilities or other services. EXPOSURE: Water insecurity and/ or inadequate sanitation. RISK OF BIAS: The effective Public Health Practice Project (EPHPP) assessment tool was used to assess quality of selected studies. SYNTHESIS OF RESULTS: A meta-analysis was conducted using a random effects statistical model. RESULTS: Twenty-five studies were included, with 23,103 participants from 16 countries in three continents: Africa (Kenya, Ethiopia, Ghana, Uganda, South Africa, Malawi, Mozambique, and Lesotho), Asia (Nepal, Bangladesh, India, and Iran) and the Americas (Brazil, Haiti, Bolivia and Vietnam). There was a statistically significant association between water insecurity and CMD symptoms. Nine studies reported a continuous outcome (5,248 participants): overall standardized mean difference (SMD = 1.38; 95% CI = 0.88, 1.87). Five studies reported a binary outcome (5,776 participants): odds ratio 5.03; 95% CI = 2.26, 11.18. There was a statistically significant association between inadequate sanitation and CMD symptoms (7415 participants), overall SMD = 5.36; 95% CI = 2.51, 8.20. LIMITATIONS: Most of the included studies were cross-sectional which were unable to examine temporal relationships. CONCLUSIONS: Water insecurity and inadequate sanitation contribute to poorer mental health globally. IMPLICATIONS OF KEY FINDINGS: Interventions to provide basic water, sanitation and psychosocial support, could substantially contribute to reducing the burden of CMD alongside other health and social benefits. TRIAL REGISTRATION: PROSPERO registration number: CRD42022322528.

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Knowledge of life histories is crucial for understanding ecological and evolutionary processes, but for many hydrozoan species only incomplete life cycles have been described due to challenges in linking hydromedusae with their polyp stages. Using a combination of DNA barcoding, morphology, and ecological information, we describe for the first time the polyp stage of Halopsis ocellata Agassiz, 1865 and re-describe that of Mitrocomella polydiademata (Romanes, 1876). Campanulinid hydroids referable to Lafoeina tenuis Sars, 1874 and collected in the same biogeographic region as the type locality of this species are shown to be the polyp stage of these two mitrocomid hydromedusae. The nominal species L. tenuis thus is a species complex that includes the polyp stage of medusae belonging to at least two genera currently placed in a different family. Consistent morphological and ecological differences were found between the polyps linked to each of these two hydromedusae, but molecular results suggest that yet other species may have morphologically similar hydroids. Polyps morphologically identified to L. tenuis are therefore better referred to as Lafoeina tenuis-type until further associations are resolved, particularly when occurring outside of the area of distribution of H. ocellata and M. polydiademata. Molecular identification integrated with traditional taxonomy is confirmed as an effective approach to link inconspicuous stages of marine invertebrates with hitherto unknown life cycles, especially in often-overlooked taxa. Disentangling the relationships between L. tenuis, H. ocellata, and M. polydiademata lays the ground for future research aimed at resolving the taxonomy and systematics of the enigmatic families Mitrocomidae and Campanulinidae.

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The ways in which people conceptualize the human-nature relationship have significant implications for proenvironmental values and attitudes, sustainable behavior, and environmental policy measures. Human exceptionalism (HE) is one such conceptual framework, involving the belief that humans and human societies exist independently of the ecosystems in which they are embedded, promoting a sharp ontological boundary between humans and the rest of the natural world. In this paper, we introduce HE in more depth, exploring the impact of HE on perceptions of the human-nature relationship, the role of culture in HE, and speculating on the origins of HE. We consider potential implications for environmental decision-making, conservation and environmental science, and promoting proenvironmental behavior. We present empirical evidence on the pervasiveness and consequences of HE in WEIRD (Western, Educated, Industrialized, Rich and Democratic) populations, and potential interventions. Finally, we close with implications of human-exceptionalist thinking on other sustainability-related fields, including conservation practices, nature management, climate change adaptation, and environmental science. Understanding the cognitive and social drivers of this disconnect is vital on a planet now dominated by environmental change, as not only are humans increasingly impacted by natural disasters, but the choices they make can have ever more dire consequences for the sustainability of ecosystems.

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A fundamental breakthrough in neurobiology has been the formulation of the neuron doctrine by Santiago Ramón y Cajal, which stated that the nervous system is composed of discrete cells. Electron microscopy later confirmed the doctrine and allowed the identification of synaptic connections. In this work, we used volume electron microscopy and three-dimensional reconstructions to characterize the nerve net of a ctenophore, a marine invertebrate that belongs to one of the earliest-branching animal lineages. We found that neurons in the subepithelial nerve net have a continuous plasma membrane that forms a syncytium. Our findings suggest fundamental differences of nerve net architectures between ctenophores and cnidarians or bilaterians and offer an alternative perspective on neural network organization and neurotransmission.

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Basal cell carcinomas (BCCs) and cutaneous squamous cell carcinomas (SCCs) are the most frequent types of cancer, and both originate from the keratinocyte transformation, giving rise to the group of tumors called keratinocyte carcinomas (KCs). The invasive behavior is different in each group of KC and may be influenced by their tumor microenvironment. The principal aim of the study is to characterize the protein profile of the tumor interstitial fluid (TIF) of KC to evaluate changes in the microenvironment that could be associated with their different invasive and metastatic capabilities. We obtained TIF from 27 skin biopsies and conducted a label-free quantitative proteomic analysis comparing seven BCCs, 16 SCCs, and four normal skins. A total of 2945 proteins were identified, 511 of them quantified in more than half of the samples of each tumoral type. The proteomic analysis revealed differentially expressed TIF proteins that could explain the different metastatic behavior in both KCs. In detail, the SCC samples disclosed an enrichment of proteins related to cytoskeleton, such as Stratafin and Ladinin-1. Previous studies found their upregulation positively correlated with tumor progression. Furthermore, the TIF of SCC samples was enriched with the cytokines S100A8/S100A9. These cytokines influence the metastatic output in other tumors through the activation of NF-kB signaling. According to this, we observed a significant increase in nuclear NF-kB subunit p65 in SCCs but not in BCCs. In addition, the TIF of both tumors was enriched with proteins involved in the immune response, highlighting the relevance of this process in the composition of the tumor environment. Thus, the comparison of the TIF composition of both KCs provides the discovery of a new set of differential biomarkers. Among them, secreted cytokines such as S100A9 may help explain the higher aggressiveness of SCCs, while Cornulin is a specific biomarker for BCCs. Finally, the proteomic landscape of TIF provides key information on tumor growth and metastasis, which can contribute to the identification of clinically applicable biomarkers that may be used in the diagnosis of KC, as well as therapeutic targets.

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CONTEXT: The mental health crisis in medicine cannot be explained by burnout alone. Physicians are not immune to this crisis and are known to have higher rates of suicide and depression than the general population. A high prevalence of mental health symptoms has been observed in early medical training. OBJECTIVES: This study was completed to characterize medical students' mental well-being and provide guidance for timely intervention. METHODS: An annual prospective, voluntary, anonymous, cross-sectional survey of medical students was completed over a 4-year period in medical school from 2016 to 2019. The survey was created based on standardized psychiatric screening tools assessing symptoms of depression, anxiety, burnout, and sleep problems. In each of those years, 1,257 (2016), 1,254 (2017), 1,221 (2018), and 1,220 (2019) enrolled students, respectively, were invited to participate. Data on students' mental health were analyzed in relation to their year of school separately for each survey year utilizing SAS 9.4. RESULTS: A total of 973 students in 2016, 889 students in 2017, 547 students in 2018, and 606 students in 2019 participated in the study. For depression and burnout subscales, an increase in symptom scores were observed every survey year (2016, 2017, 2018, and 2019) by the second or third year of medical school with a clinically significant effect size. Persistently high levels of anxiety were observed throughout medical school, with significant increases after the first year noted in the 2016 and 2017 surveys, but not in the 2018 or 2019 surveys. Similarly, significant changes in sleep disturbance were found in the 2016 and 2017 surveys, but not in 2018 or 2019. CONCLUSIONS: Symptoms of burnout, depression, and anxiety were observed throughout all four years of medical school, with increases starting after the first year. Early intervention is needed to support students' mental health and increase access to care and resources.

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Six new crotofolane diterpenoids (1-6) and 13 known compounds (7-19) were isolated from the MeOH-CH2Cl2 (1:1, v/v) extracts of the leaves and stem bark of Croton kilwae. The structures of the new compounds were elucidated by extensive analysis of spectroscopic and mass spectrometric data. The structure of crotokilwaepoxide A (1) was confirmed by single-crystal X-ray diffraction, allowing for the determination of its absolute configuration. The crude extracts and the isolated compounds were investigated for antiviral activity against respiratory syncytial virus (RSV) and human rhinovirus type-2 (HRV-2) in HEp-2 and HeLa cells, respectively, for antibacterial activity against the Gram-positive Bacillus subtilis and the Gram-negative Escherichia coli, and for antimalarial activity against the Plasmodium falciparum Dd2 strain. ent-3ß,19-Dihydroxykaur-16-ene (7) and ayanin (16) displayed anti-RSV activities with IC50 values of 10.2 and 6.1 µM, respectively, while exhibiting only modest cytotoxic effects on HEp-2 cells that resulted in selectivity indices of 4.9 and 16.4. Compounds 2 and 5 exhibited modest anti-HRV-2 activity (IC50 of 44.6 µM for both compounds), while compound 16 inhibited HRV-2 with an IC50 value of 1.8 µM. Compounds 1-3 showed promising antiplasmodial activities (80-100% inhibition) at a 50 µM concentration.

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