Notes

Syncope because First Indication of any Late-Stage Renal Cellular Carcinoma Along with Metastasis for the Human brain.
This article is a part of the "Neglected Tropical Diseases and other Infectious Diseases affecting the Heart" project (the NET-Heart Project); its purpose is to review all the information available regarding cardiac implications of this disease and its treatment and to add knowledge to this field of study, focusing on the barriers for diagnosis and treatment, and how to adopt strategies to overcome them.
Gender-based differences among cardiology professionals have been reported in North America and Europe. However, the perspective of Latin American cardiologists remains unexplored.

The objectives of the study were to analyze the gender gap perspective among cardiologists from Latin America.

A cross-sectional study using an online survey directed to Latin American cardiologists from five different cardiology societies. The survey included questions on demographic data, professional development in the field of cardiology, and perceived barriers in clinical practice.

A total of 240 professionals were surveyed, of which 41.7% were women (100) and 58.3% were men (140). The majority of women tend to work in the subfields of clinical cardiology and cardiovascular imaging. Women were underrepresented as heads of departments, earn less, and report less work satisfaction than men. The barriers that female cardiologists face at their workplace include labor discrimination, sexual harassment, family-related concerns, and lack of career development.

The survey points toward the prevalence of a gender gap among cardiologists in Latin America, which is primarily driven by labor discrimination, sexual harassment, family-related concerns, and lack of career development among female cardiologists. Actions aimed at addressing this issue should be considered by different parties.
The survey points toward the prevalence of a gender gap among cardiologists in Latin America, which is primarily driven by labor discrimination, sexual harassment, family-related concerns, and lack of career development among female cardiologists. Actions aimed at addressing this issue should be considered by different parties.Intellectual disability and autism spectrum disorder (ASD) are common, and genetic testing is increasingly performed in individuals with these diagnoses to inform prognosis, refine management and provide information about recurrence risk in the family. For neurogenetic conditions associated with intellectual disability and ASD, data on natural history in adults are scarce; however, as older adults with these disorders are identified, it is becoming clear that some conditions are associated with both neurodevelopmental problems and neurodegeneration. Moreover, emerging evidence indicates that some neurogenetic conditions associated primarily with neurodegeneration also affect neurodevelopment. In this Perspective, we discuss examples of diseases that have developmental and degenerative overlap. We propose that neurogenetic disorders should be studied continually across the lifespan to understand the roles of the affected genes in brain development and maintenance, and to inform strategies for treatment.Cerebral small vessel disease (cSVD) is a leading cause of ischaemic and haemorrhagic stroke and a major contributor to dementia. Covert cSVD, which is detectable with brain MRI but does not manifest as clinical stroke, is highly prevalent in the general population, particularly with increasing age. Advances in technologies and collaborative work have led to substantial progress in the identification of common genetic variants that are associated with cSVD-related stroke (ischaemic and haemorrhagic) and MRI-defined covert cSVD. In this Review, we provide an overview of collaborative studies - mostly genome-wide association studies (GWAS) - that have identified >50 independent genetic loci associated with the risk of cSVD. We describe how these associations have provided novel insights into the biological mechanisms involved in cSVD, revealed patterns of shared genetic variation across cSVD traits, and shed new light on the continuum between rare, monogenic and common, multifactorial cSVD. We consider how GWAS summary statistics have been leveraged for Mendelian randomization studies to explore causal pathways in cSVD and provide genetic evidence for drug effects, and how the combination of findings from GWAS with gene expression resources and drug target databases has enabled identification of putative causal genes and provided proof-of-concept for drug repositioning potential. We also discuss opportunities for polygenic risk prediction, multi-ancestry approaches and integration with other omics data.During conversation, people take turns speaking by rapidly responding to their partners while simultaneously avoiding interruption1,2. Such interactions display a remarkable degree of coordination, as gaps between turns are typically about 200 milliseconds3-approximately the duration of an eyeblink4. These latencies are considerably shorter than those observed in simple word-production tasks, which indicates that speakers often plan their responses while listening to their partners2. Although a distributed network of brain regions has been implicated in speech planning5-9, the neural dynamics underlying the specific preparatory processes that enable rapid turn-taking are poorly understood. Here we use intracranial electrocorticography to precisely measure neural activity as participants perform interactive tasks, and we observe a functionally and anatomically distinct class of planning-related cortical dynamics. We localize these responses to a frontotemporal circuit centred on the language-critical caudal inferior frontal cortex10 (Broca's region) and the caudal middle frontal gyrus-a region not normally implicated in speech planning11-13. Using a series of motor tasks, we then show that this planning network is more active when preparing speech as opposed to non-linguistic actions. Finally, we delineate planning-related circuitry during natural conversation that is nearly identical to the network mapped with our interactive tasks, and we find this circuit to be most active before participant speech during unconstrained turn-taking. Therefore, we have identified a speech planning network that is central to natural language generation during social interaction.Gram-negative bacteria are responsible for an increasing number of deaths caused by antibiotic-resistant infections1,2. The bacterial natural product colistin is considered the last line of defence against a number of Gram-negative pathogens. The recent global spread of the plasmid-borne mobilized colistin-resistance gene mcr-1 (phosphoethanolamine transferase) threatens the usefulness of colistin3. Bacteria-derived antibiotics often appear in nature as collections of similar structures that are encoded by evolutionarily related biosynthetic gene clusters. This structural diversity is, at least in part, expected to be a response to the development of natural resistance, which often mechanistically mimics clinical resistance. Here we propose that a solution to mcr-1-mediated resistance might have evolved among naturally occurring colistin congeners. Bioinformatic analysis of sequenced bacterial genomes identified a biosynthetic gene cluster that was predicted to encode a structurally divergent colistin congener. Chemical synthesis of this structure produced macolacin, which is active against Gram-negative pathogens expressing mcr-1 and intrinsically resistant pathogens with chromosomally encoded phosphoethanolamine transferase genes. These Gram-negative bacteria include extensively drug-resistant Acinetobacter baumannii and intrinsically colistin-resistant Neisseria gonorrhoeae, which, owing to a lack of effective treatment options, are considered among the highest level threat pathogens4. In a mouse neutropenic infection model, a biphenyl analogue of macolacin proved to be effective against extensively drug-resistant A. baumannii with colistin-resistance, thus providing a naturally inspired and easily produced therapeutic lead for overcoming colistin-resistant pathogens.Maternal morbidity and mortality continue to rise, and pre-eclampsia is a major driver of this burden1. Yet the ability to assess underlying pathophysiology before clinical presentation to enable identification of pregnancies at risk remains elusive. Here we demonstrate the ability of plasma cell-free RNA (cfRNA) to reveal patterns of normal pregnancy progression and determine the risk of developing pre-eclampsia months before clinical presentation. Our results centre on comprehensive transcriptome data from eight independent prospectively collected cohorts comprising 1,840 racially diverse pregnancies and retrospective analysis of 2,539 banked plasma samples. The pre-eclampsia data include 524 samples (72 cases and 452 non-cases) from two diverse independent cohorts collected 14.5 weeks (s.d., 4.5 weeks) before delivery. We show that cfRNA signatures from a single blood draw can track pregnancy progression at the placental, maternal and fetal levels and can robustly predict pre-eclampsia, with a sensitivity of 75% and a positive predictive value of 32.3% (s.d., 3%), which is superior to the state-of-the-art method2. cfRNA signatures of normal pregnancy progression and pre-eclampsia are independent of clinical factors, such as maternal age, body mass index and race, which cumulatively account for less than 1% of model variance. Further, the cfRNA signature for pre-eclampsia contains gene features linked to biological processes implicated in the underlying pathophysiology of pre-eclampsia.The discovery of antibiotics more than 80 years ago has led to considerable improvements in human and animal health. Although antibiotic resistance in environmental bacteria is ancient, resistance in human pathogens is thought to be a modern phenomenon that is driven by the clinical use of antibiotics1. Here we show that particular lineages of methicillin-resistant Staphylococcus aureus-a notorious human pathogen-appeared in European hedgehogs in the pre-antibiotic era. Subsequently, these lineages spread within the local hedgehog populations and between hedgehogs and secondary hosts, including livestock and humans. We also demonstrate that the hedgehog dermatophyte Trichophyton erinacei produces two β-lactam antibiotics that provide a natural selective environment in which methicillin-resistant S. aureus isolates have an advantage over susceptible isolates. selleck inhibitor Together, these results suggest that methicillin resistance emerged in the pre-antibiotic era as a co-evolutionary adaptation of S. aureus to the colonization of dermatophyte-infected hedgehogs. The evolution of clinically relevant antibiotic-resistance genes in wild animals and the connectivity of natural, agricultural and human ecosystems demonstrate that the use of a One Health approach is critical for our understanding and management of antibiotic resistance, which is one of the biggest threats to global health, food security and development.The DNA-dependent protein kinase catalytic subunit (DNA-PKcs) has a central role in non-homologous end joining, one of the two main pathways that detect and repair DNA double-strand breaks (DSBs) in humans1,2. DNA-PKcs is of great importance in repairing pathological DSBs, making DNA-PKcs inhibitors attractive therapeutic agents for cancer in combination with DSB-inducing radiotherapy and chemotherapy3. Many of the selective inhibitors of DNA-PKcs that have been developed exhibit potential as treatment for various cancers4. Here we report cryo-electron microscopy (cryo-EM) structures of human DNA-PKcs natively purified from HeLa cell nuclear extracts, in complex with adenosine-5'-(γ-thio)-triphosphate (ATPγS) and four inhibitors (wortmannin, NU7441, AZD7648 and M3814), including drug candidates undergoing clinical trials. The structures reveal molecular details of ATP binding at the active site before catalysis and provide insights into the modes of action and specificities of the competitive inhibitors. Of note, binding of the ligands causes movement of the PIKK regulatory domain (PRD), revealing a connection between the p-loop and PRD conformations.
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