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Several hydroxysteroid dehydrogenase 17-beta 13 variants have previously been identified as protective against metabolic dysfunction-associated steatohepatitis (MASH) fibrosis, ballooning and inflammation, and as such this target holds significant therapeutic potential. However, over 5 years later, the function of 17B-HSD13 remains unknown. Structure-aided design enables the development of potent and selective sulfonamide-based 17B-HSD13 inhibitors. In order to probe their inhibitory potency in endogenous expression systems like primary human hepatocytes, inhibitors are transformed into synthetic surrogate substrates with distinct selectivity advantages over substrates previously published. Their application to cells endogenously expressing 17B-HSD13 enables quantitative measures of enzymatic inhibition in primary human hepatocytes which has never been reported to date. Application to multiple cellular systems expressing the protective human variants reveals that the most prevalent IsoD variant maintains NAD-dependent catalytic activity towards some but not all substrates, contradicting reports that the truncation results in loss-of-function. Several 17B-HSD13 variants have been identified as protective against NASH/MASH. However the protein’s endogenous function is unknown. Here authors describe sulfonamide-based inhibitors and synthetic substrates, then apply to multiple cellular systems revealing that the most prevalent IsoD variant maintains NAD-dependent catalytic activity.

If the Guardian could \"find no allies\" of Julian Assange (Report, 24 January), it did not look very hard. They could be found among the appreciative audience at the Oxford Union, and in our group seated at the front: the Sam Adams Associates for Integrity in Intelligence.

Continuing to learn is universally accepted and expected by professionals and other stakeholders across all professions. However, despite changes in response to research findings about how professionals learn, many professional development practices still focus on delivering content rather than enhancing learning. In exploring reasons for the continuation of didactic practices in professional development, this article critiques the usual conceptualization of professional development through a review of recent literature across professions. An alternative conceptualization is proposed, based on philosophical assumptions congruent with evidence about professional learning from seminal educational research of the past two decades. An argument is presented for a shift in discourse and focus from delivering and evaluating professional development programs to understanding and supporting authentic professional learning.

Early-career researchers (ECRs) make up a large portion of the academic workforce and their experiences often reflect the wider culture of the research system. Here we surveyed 658 ECRs working in Australia to better understand the needs and challenges faced by this community. Although most respondents indicated a ‘love of science’, many also expressed an intention to leave their research position. The responses highlight how job insecurity, workplace culture, mentorship and ‘questionable research practices’ are impacting the job satisfaction of ECRs and potentially compromising science in Australia. We also make recommendations for addressing some of these concerns.

Automated analysis of MRI data of the subregions of the hippocampus requires computational atlases built at a higher resolution than those that are typically used in current neuroimaging studies. Here we describe the construction of a statistical atlas of the hippocampal formation at the subregion level using ultra-high resolution, ex vivo MRI. Fifteen autopsy samples were scanned at 0.13mm isotropic resolution (on average) using customized hardware. The images were manually segmented into 13 different hippocampal substructures using a protocol specifically designed for this study; precise delineations were made possible by the extraordinary resolution of the scans. In addition to the subregions, manual annotations for neighboring structures (e.g., amygdala, cortex) were obtained from a separate dataset of in vivo, T1-weighted MRI scans of the whole brain (1mm resolution). The manual labels from the in vivo and ex vivo data were combined into a single computational atlas of the hippocampal formation with a novel atlas building algorithm based on Bayesian inference. The resulting atlas can be used to automatically segment the hippocampal subregions in structural MRI images, using an algorithm that can analyze multimodal data and adapt to variations in MRI contrast due to differences in acquisition hardware or pulse sequences. The applicability of the atlas, which we are releasing as part of FreeSurfer (version 6.0), is demonstrated with experiments on three different publicly available datasets with different types of MRI contrast. The results show that the atlas and companion segmentation method: 1) can segment T1 and T2 images, as well as their combination, 2) replicate findings on mild cognitive impairment based on high-resolution T2 data, and 3) can discriminate between Alzheimer's disease subjects and elderly controls with 88% accuracy in standard resolution (1mm) T1 data, significantly outperforming the atlas in FreeSurfer version 5.3 (86% accuracy) and classification based on whole hippocampal volume (82% accuracy). [Display omitted] •A highly detailed computational atlas of the human hippocampus built upon ex vivo MRI.•Volumes of hippocampal subregions agree well with prior histological studies.•Application to Bayesian segmentation of hippocampal subregions from in vivo MRI•The segmentation method is adaptive to MRI contrast and resolution.•The atlas and segmentation code will be released as part of FreeSurfer 6.0.

With a diverse network of substrates, NUDIX hydrolases have emerged as a key family of nucleotide-metabolizing enzymes. NUDT5 (also called NUDIX5) has been implicated in ADP-ribose and 8-oxo-guanine metabolism and was recently identified as a rheostat of hormone-dependent gene regulation and proliferation in breast cancer cells. Here, we further elucidate the physiological relevance of known NUDT5 substrates and underscore the biological requirement for NUDT5 in gene regulation and proliferation of breast cancer cells. We confirm the involvement of NUDT5 in ADP-ribose metabolism and dissociate a relationship to oxidized nucleotide sanitation. Furthermore, we identify potent NUDT5 inhibitors, which are optimized to promote maximal NUDT5 cellular target engagement by CETSA. Lead compound, TH5427, blocks progestin-dependent, PAR-derived nuclear ATP synthesis and subsequent chromatin remodeling, gene regulation and proliferation in breast cancer cells. We herein present TH5427 as a promising, targeted inhibitor that can be used to further study NUDT5 activity and ADP-ribose metabolism. NUDIX hydrolases are an important family of nucleotide-metabolizing enzymes. Here, the authors identify potent, small molecule inhibitors of NUDT5, which is implicated in ADP-ribose and 8-oxo-guanine metabolism, and confirm its role in gene regulation and proliferation in breast cancer cells.

This multiwave longitudinal study investigated potential transactional and accumulating influences among corumination, interpersonal stressors, and internalizing symptoms among a sample of early and middle adolescents (N = 350; 6th–10th graders). Youth completed self-report measures of corumination at Times 1, 2, and 4, and negative life events, internalizing symptoms (general depressive, specific anhedonic depressive, anxious arousal, general internalizing), and externalizing problems at all four time points (5 weeks between each assessment across 4 months). Results supported hypotheses. First, baseline corumination predicted prospective trajectories of all forms of internalizing symptoms but not externalizing problems. Second, baseline corumination predicted generation of interpersonal-dependent, but not interpersonal-independent or noninterpersonal stressors. Third, interpersonal-dependent events partially mediated the longitudinal association between baseline corumination and prospective internalizing symptoms. Fourth, a transactional, bidirectional set of associations was supported in that initial internalizing symptoms and stressors predicted later elevations in corumination, and in turn, corumination predicted later symptoms through the mediating role of interpersonal stressors to complete both streams in the transactional chain of influence. Fifth, girls and older adolescents exhibited higher corumination, but neither age nor sex moderated any associations. These findings are discussed within a transactional, developmental cascade model.

\"Parrots of the Wildis an exhaustive compendium of information about parrots, from their evolutionary history to their behavior to present-day conservation issues. A must-have for anyone interested in these amazing creatures.\" -Irene M. Pepperberg, Professor at Harvard University and author ofAlex & Me: How a Scientist and a Parrot Discovered a Hidden World of Animal Intelligence-and Formed a Deep Bond in the Process\"If you like parrots then you'll love this book. From their evolutionary past to their modern-day love lives,Parrots of the Wildpresents a suitably captivating read. I thought I knew a lot about parrots--until I delved into these pages.\" -Tony Juniper, author ofWhat Has Nature Ever Done for Us?andSpix's Macaw: The Race to Save the World's Rarest Bird Parrots of the Wildexplores recent scientific discoveries and what they reveal about the lives of wild parrots, which are among the most intelligent and rarest of birds. Catherine A. Toft and Tim Wright discuss the evolutionary history of parrots and how this history affects perceptual and cognitive abilities, diet and foraging patterns, and mating and social behavior. The authors also discuss conservation status and the various ways different populations are adapting to a world that is rapidly changing. The book focuses on general patterns across the 350-odd species of parrots, as well as what can be learned from interesting exceptions to these generalities.A synthetic account of the diversity and ecology of wild parrots, this book distills knowledge from the authors' own research and from their review of more than 2,400 published scientific studies. The book is enhanced by an array of illustrations, including nearly ninety color photos of wild parrots represented in their natural habitats.Parrots of the Wildmelds scientific exploration with features directed at the parrot enthusiast to inform and delight a broad audience.

LGR5 is known to be a stem cell marker in the murine small intestine and colon, however the localization of LGR5 in human adenoma samples has not been examined in detail and previous studies have been limited by the lack of specific antibodies. Here we used in situ hybridization to specifically examine LGR5 mRNA expression in a panel of human adenoma and carcinoma samples (n = 66). We found that a small number of cells express LGR5 at the base of normal colonic crypts. We then showed that conventional adenomas widely express high levels of LGR5 and there is no evidence of stereotypic cellular hierarchy. In contrast, serrated lesions display basal localization of LGR5 and the cellular hierarchy resembles that of a normal crypt. Moreover, ectopic crypts found in traditional serrated adenomas show basal LGR5 mRNA, indicating that they replicate the stem cell organization of normal crypts with the development of a cellular hierarchy. These data imply differences in the stem cell dynamics between the serrated and conventional pathways of colorectal carcinogenesis. Furthermore we noted high LGR5 expression in invading cells, with later development of a stem cell niche in adenocarcinomas of all stages.

Antibiotic resistance is an important public health problem. One potential solution is the development of synergistic antibiotic combinations, in which the combination is more effective than the component drugs. However, experimental progress in this direction is severely limited by the number of samples required to exhaustively test for synergy, which grows exponentially with the number of drugs combined. We introduce a new metric for antibiotic synergy, motivated by the popular Fractional Inhibitory Concentration Index and the Highest Single Agent model. We also propose a new experimental design that samples along all appropriately normalized diagonals in concentration space, and prove that this design identifies all synergies among a set of drugs while only sampling a small fraction of the possible combinations. We applied our method to screen two- through eight-way combinations of eight antibiotics at 10 concentrations each, which requires sampling only 2,560 unique combinations of antibiotic concentrations.