Investigating the Origin of Epimerization Attenuation during Pd-Catalyzed Cross-Coupling Reactions.

Palladium-catalyzed cross-couplings remain among the most robust methodologies to form carbon-carbon and carbon-heteroatom bonds. In particular, carbon-nitrogen (C-N) couplings (Buchwald-Hartwig aminations) find widespread use in fine chemicals industries. The use of base in these reactions is critical for catalyst activation and proton sequestration. Base selection also plays an important role in process design, as strongly basic conditions can impact sensitive stereocenters and result in erosion of stereochemical purity. Herein we investigate the role of a Pd catalyst in suppressing base-mediated epimerization of a sultam stereocenter during a C-N cross-coupling reaction to access the RORγ inhibitor GDC-0022. Online high-performance liquid chromatography-mass spectrometry (HPLC-MS) was employed to acquire reaction time course profiles and to delineate epimerization behavior, identify decomposition pathways, and monitor Pd-containing species. Our ability to monitor organopalladium complexes in real time by HPLC-MS provided strong evidence that the degree of epimerization was correlated to the Pd speciation in solution. Specifically, Pd(II) complexes were associated with mitigating epimerization of six-membered sultams. Additional studies showed that the suppression of epimerization in the presence of Pd(II) can impact Pd-catalyzed reactions of other substrates such as enolizable ketones, thus providing practical insight on the execution and optimization of such processes.

Level Up Your Residency: Can a Novel Two-Week Simulation Rotation Really Make a Difference?

INTRODUCTION: This study describes a unique two-week simulation-based medical education (SBME) rotation for transitional year (TY) residents. During the rotation, residents are fully integrated into the simulation team, actively participating in clinically based interprofessional scenarios, procedural techniques, and mixed reality experiences. Residents also created and ran their own simulations while receiving content expert feedback. We evaluated the rotation's effectiveness in preparing TY graduates for their specific advanced residency track. METHODS: A retrospective survey evaluated the experiences of 11 TY residents who participated in a unique two-week simulation rotation. The survey assessed residents' perceptions of the program's value and skill development, course design, scenario relevance to future practice, and preparedness to develop future scenarios. RESULTS: Residents (11 out of 12 residents, 92% response rate) overwhelmingly endorsed the simulation rotation (100% positive, 45.45% extremely valuable). The program demonstrably improved core clinical skills (100% reported improvement) and fostered self-efficacy for future practice. Scenario relevance was high (81.82% highly relevant). Collaboration and communication skills showed promise (72.73% positive) while highlighting a potential area for future refinement. Residents unanimously agreed on effective time allocation and the program's value for debriefing skills. Notably, 91% strongly supported residency-specific simulation training. DISCUSSION: The two-week simulation was perceived by prior TY residents as valuable, with a majority finding the experience highly valuable across multiple survey questions. Residents overwhelmingly expressed a preference for residency-specific training, suggesting future development of specialty-tailored modules and enhanced debriefing sessions. The findings highlight the program's effectiveness and successful implementation into a TY residency curriculum.

Cancer research provides a model for advancing clinical trials in dementia in the era of disease-modifying Alzheimer's-type dementia therapies.

Dementia and cancer are multifactorial, widely-feared, age-associated clinical syndromes that are increasing in prevalence. There have been major breakthroughs in clinical cancer research leading to some effective treatments, whereas the field of dementia has achieved comparatively limited success in clinical research. The lessons of cancer research may help those in the dementia research field in confronting some of the dilemmas faced when the clinical care regimen is not entirely safe or efficacious. Cancer clinical trials have assumed that untreated individuals with cancer are at high risk for morbidity and mortality after primary diagnoses. Thus, patients deserve a choice of clinical interventions, either standard of care or experimental, even if the benefits are not certain and the therapy's side effects are potentially severe. The prognosis for many individuals at risk for dementia carries a correspondingly high level of risk for both mortality and severe morbidity, particularly if one focuses on "health-span" rather than lifespan. Caregivers and patients can be strongly impacted by dementia and the many troubling associated symptoms that often go well beyond amnesia. Polls, surveys, and a literature on "dementia worry" strongly underscore that the public fears dementia. While there are institutional and industry hurdles that complicate enrollment in randomized trials, the gravity of the future morbidity and mortality inherent in a dementia diagnosis may require reconsideration of the current protective stance that limits the freedom of at-risk individuals (either symptomatic or asymptomatic) to participate and potentially benefit from ongoing clinical research. There is also evidence from both cancer and dementia research that individuals enrolled in the placebo arms of clinical trials have unexpectedly good outcomes, indicating that participation in clinical trial can have medical benefits to enrollees. To highlight aspects of cancer clinical research that may inform present and future dementia clinical research, this review highlights three main themes: the risk of side effects should be weighed against the often dire consequences of non-treatment; the desirability of long-term incremental (rather than "magic bullet") clinical advances; and, the eventual importance of combination therapies, reflecting that the dementia clinical syndrome has many underlying biological pathways.

Harmonious naming across nomenclature codes exemplified by the description of bacterial isolates from the mammalian gut.

A dual system for naming prokaryotes is currently in place based on the well-established International Code of Nomenclature of Prokaryotes (ICNP) and the newly created Code of Nomenclature of Prokaryotes Described from Sequence Data (SeqCode). Whilst recent creation of the SeqCode opened an avenue to accelerate the naming of uncultured taxa, the existence of two codes increases the risk of species being assigned multiple validly published names. In this work we present a workflow that aims to limit conflicts by firstly naming novel cultured taxa under the SeqCode, and secondly under the ICNP, enhancing the traceability of the taxa across the two codes. To exemplify this workflow, we describe four novel taxa isolated from the intestine of pigs: Intestinicryptomonas porci gen. nov., sp. nov. (strain CLA-KB-P66T, genome accession GCA_033971905.1TS) within a novel family, Intestinicryptomonaceae; Grylomicrobium aquisgranensis gen. nov., sp. nov. (CLA-KB-P133T, GCA_033971865.1TS); Absicoccus intestinalis sp. nov. (CLA-KB-P134T, GCA_033971885.1TS); and Mesosutterella porci sp. nov. (oilRF-744- wt-GAM-9T, GCF_022134585.1TS).

BRCA1 secondary splice-site mutations drive exon-skipping and PARP inhibitor resistance.

PARP inhibitor (PARPi) therapy has transformed outcomes for patients with homologous recombination DNA repair (HRR) deficient ovarian cancers, for example those with BRCA1 or BRCA2 gene defects. Unfortunately, PARPi resistance is common. Multiple resistance mechanisms have been described, including secondary mutations that restore the HR gene reading frame. BRCA1 splice isoforms △11 and △11q can contribute to PARPi resistance by splicing out the mutation-containing exon, producing truncated, partially functional proteins. However, the clinical impacts and underlying drivers of BRCA1 exon skipping are not fully understood.We analyzed nine ovarian and breast cancer patient derived xenografts (PDX) with BRCA1 exon 11 frameshift mutations for exon skipping and therapy response, including a matched PDX pair derived from a patient pre- and post-chemotherapy/PARPi. BRCA1 exon 11 skipping was elevated in PARPi resistant PDX tumors. Two independent PDX models acquired secondary BRCA1 splice site mutations (SSMs) that drive exon skipping, confirmed using qRT-PCR, RNA sequencing, immunoblotting and minigene modelling. CRISPR/Cas9-mediated disruption of splicing functionally validated exon skipping as a mechanism of PARPi resistance. SSMs were also enriched in post-PARPi ovarian cancer patient cohorts from the ARIEL2 and ARIEL4 clinical trials.Few PARPi resistance mechanisms have been confirmed in the clinical setting. While secondary/reversion mutations typically restore a gene's reading frame, we have identified secondary mutations in patient cohorts that hijack splice sites to enhance mutation-containing exon skipping, resulting in the overexpression of BRCA1 hypomorphs, which in turn promote PARPi resistance. Thus, BRCA1 SSMs can and should be clinically monitored, along with frame-restoring secondary mutations.

Cardiac Molecular Analysis Reveals Aging-Associated Metabolic Alterations Promoting Glycosaminoglycans Accumulation via Hexosamine Biosynthetic Pathway.

Age is a prominent risk factor for cardiometabolic disease, often leading to heart structural and functional changes. However, precise molecular mechanisms underlying cardiac remodeling and dysfunction exclusively resulting from physiological aging remain elusive. Previous research demonstrated age-related functional alterations in baboons, analogous to humans. The goal of this study is to identify early cardiac molecular alterations preceding functional adaptations, shedding light on the regulation of age-associated changes. Unbiased transcriptomics of left ventricle samples are performed from female baboons aged 7.5-22.1 years (human equivalent ≈30-88 years). Weighted-gene correlation network and pathway enrichment analyses are performed, with histological validation. Modules of transcripts negatively correlated with age implicated declined metabolism-oxidative phosphorylation, tricarboxylic acid cycle, glycolysis, and fatty-acid ß-oxidation. Transcripts positively correlated with age suggested a metabolic shift toward glucose-dependent anabolic pathways, including hexosamine biosynthetic pathway (HBP). This shift is associated with increased glycosaminoglycan synthesis, modification, precursor synthesis via HBP, and extracellular matrix accumulation, verified histologically. Upregulated extracellular matrix-induced signaling coincided with glycosaminoglycan accumulation, followed by cardiac hypertrophy-related pathways. Overall, these findings revealed a transcriptional shift in metabolism favoring glycosaminoglycan accumulation through HBP before cardiac hypertrophy. Unveiling this metabolic shift provides potential targets for age-related cardiac diseases, offering novel insights into early age-related mechanisms.

Protein surface chemistry encodes an adaptive resistance to desiccation.

Cellular desiccation - the loss of nearly all water from the cell - is a recurring stress in an increasing number of ecosystems that can drive proteome-wide protein unfolding and aggregation. For cells to survive this stress, at least some of the proteome must disaggregate and resume function upon rehydration. The molecular determinants that underlie the ability of proteins to do this remain largely unknown. Here, we apply quantitative and structural proteomic mass spectrometry to desiccated and rehydrated yeast extracts to show that some proteins possess an innate capacity to survive extreme water loss. Structural analysis correlates the ability of proteins to resist desiccation with their surface chemistry. Remarkably, highly resistant proteins are responsible for the production of the cell's building blocks - amino acids, metabolites, and sugars. Conversely, those proteins that are most desiccation-sensitive are involved in ribosome biogenesis and other energy consuming processes. As a result, the rehydrated proteome is preferentially enriched with metabolite and small molecule producers and depleted of some of the cell's heaviest consumers. We propose this functional bias enables cells to kickstart their metabolism and promote cell survival following desiccation and rehydration.

Sleep Composition of Patients With Colorectal Cancer and Their Sleep-Partner Caregivers: Physical Health Correlates of Sleep Diary and Actigraphy Measurements.

BACKGROUND: Disturbed sleep is frequently identified in adult patients with cancer and their caregivers, with detrimental impact on physical health. Less known is the extent to which self-reported and actigraph-measured sleep patterns are similar between patients and their sleep-partner caregivers, and how these different modes of sleep measurements are related to physical health. METHODS: Patients diagnosed with colorectal cancer and their sleep-partner caregivers (81 dyads) completed a questionnaire for physical functioning and collected saliva samples for seven consecutive days, from which cortisol slope was quantified. Additionally, participants completed a daily sleep diary and wore actigraph for 14 consecutive days, from which sleep duration, sleep onset latency (SOL), and duration of wake after sleep onset (WASO) were calculated. RESULTS: Participants reported sleep patterns that fell within or close to the optimal range, which were similar between patients and their caregivers. Self-reported and actigraph-measured sleep duration had moderate levels of agreement (ICC = 0.604), whereas SOL and WASO had poor agreement (ICC = 0.269). Among patients, longer self-reported WASO was associated with poorer physical health and flatter cortisol slope (p ≤ 0.013). Among caregivers, longer self-reported SOL was associated with poorer physical functioning, actigraph-measured WASO was associated with steeper cortisol slope, and longer self-reported sleep markers studied than actigraph-measured were associated with poorer physical functioning (p ≤ 0.042). CONCLUSION: Findings suggest that employing multiple assessment modes for sleep and physical health is vital for comprehensive understanding of sleep health. Furthermore, when addressing patients' sleep health, it may be beneficial to include their sleep-partner caregivers who may experience similar disturbed sleep.

Sirt5 regulates chondrocyte metabolism and osteoarthritis development through protein lysine malonylation.

Objectives: Chondrocyte metabolic dysfunction plays an important role in osteoarthritis (OA) development during aging and obesity. Protein post-translational modifications (PTMs) have recently emerged as an important regulator of cellular metabolism. We aim to study one type of PTM, lysine malonylation (MaK) and its regulator Sirt5 in OA development. Methods: Human and mouse cartilage tissues were used to measure SIRT5 and MaK levels. Both systemic and cartilage-specific conditional knockout mouse models were subject to high-fat diet (HFD) treatment to induce obesity and OA. Proteomics analysis was performed in Sirt5 -/- and WT chondrocytes. SIRT5 mutation was identified in the Utah Population Database (UPDB). Results: We found that SIRT5 decreases while MAK increases in the cartilage during aging. A combination of Sirt5 deficiency and obesity exacerbates joint degeneration in a sex dependent manner in mice. We further delineate the malonylome in chondrocytes, pinpointing MaK's predominant impact on various metabolic pathways such as carbon metabolism and glycolysis. Lastly, we identified a rare coding mutation in SIRT5 that dominantly segregates in a family with OA. The mutation results in substitution of an evolutionally invariant phenylalanine (Phe-F) to leucine (Leu-L) (F101L) in the catalytic domain. The mutant protein results in higher MaK level and decreased expression of cartilage ECM genes and upregulation of inflammation associated genes. Conclusions: We found that Sirt5 mediated MaK is an important regulator of chondrocyte cellular metabolism and dysregulation of Sirt5-MaK could be an important mechanism underlying aging and obesity associated OA development.

Retrospective Radiology Research: Do We Need Informed Patient Consent?

While knowledge of the population's view on the need for informed consent for retrospective radiology research may provide valuable insight into how an optimal balance can be achieved between patient rights versus an expedited advancement of radiology science, this is a topic that has been ignored in the literature so far. To investigate the view of the general population, survey data were collected from 2407 people representative of the Dutch population. The results indicate that for non-commercial institutions, especially hospitals (97.4 per cent), respondents agree with the retrospective use of imaging data, although they generally indicate that their explicit consent is required. However, most respondents (63.5 per cent) would never allow commercial firms to retrospectively use their imaging data. When including only respondents who completed the minimally required reading time of 12.3 s to understand the description about retrospective radiology research given in the survey (n = 770), almost all (98.9 per cent) mentioned to have no objections for their imaging data to be used by hospitals for retrospective research, with 57.9 per cent indicating their consent to be required and 41.0 per cent indicating that explicit patient consent to be unnecessary. We conclude that the general population permits retrospective radiology research by hospitals, and a substantial proportion indicates explicit patient consent to be unnecessary when understanding what retrospective radiology research entails. However, the general population's support for the unrestricted retrospective use of imaging data for research purposes without patient consent decreases for universities not linked to hospitals, other non-commercial institutions, government agencies, and particularly commercial firms.

A refined reweighing technique for nondiscriminatory classification.

Discrimination-aware classification methods remedy socioeconomic disparities exacerbated by machine learning systems. In this paper, we propose a novel data pre-processing technique that assigns weights to training instances in order to reduce discrimination without changing any of the inputs or labels. While the existing reweighing approach only looks into sensitive attributes, we refine the weights by utilizing both sensitive and insensitive ones. We formulate our weight assignment as a linear programming problem. The weights can be directly used in any classification model into which they are incorporated. We demonstrate three advantages of our approach on synthetic and benchmark datasets. First, discrimination reduction comes at a small cost in accuracy. Second, our method is more scalable than most other pre-processing methods. Third, the trade-off between fairness and accuracy can be explicitly monitored by model users. Code is available at https://github.com/frnliang/refined_reweighing.

Nanometer-resolution tracking of single cargo reveals dynein motor mechanisms.

Cytoplasmic dynein is essential for intracellular transport. Despite extensive in vitro characterizations, how the dynein motors transport vesicles by processive steps in live cells remains unclear. To dissect the molecular mechanisms of dynein, we develop optical probes that enable long-term single-particle tracking in live cells with high spatiotemporal resolution. We find that the number of active dynein motors transporting cargo switches stochastically between one and five dynein motors during long-range transport in neuronal axons. Our very bright optical probes allow the observation of individual molecular steps. Strikingly, these measurements reveal that the dwell times between steps are controlled by two temperature-dependent rate constants in which two ATP molecules are hydrolyzed sequentially during each dynein step. Thus, our observations uncover a previously unknown chemomechanical cycle of dynein-mediated cargo transport in living cells.

Transforming environmental health datasets from the comparative toxicogenomics database into chord diagrams to visualize molecular mechanisms.

In environmental health, the specific molecular mechanisms connecting a chemical exposure to an adverse endpoint are often unknown, reflecting knowledge gaps. At the public Comparative Toxicogenomics Database (CTD; https://ctdbase.org/), we integrate manually curated, literature-based interactions from CTD to compute four-unit blocks of information organized as a potential step-wise molecular mechanism, known as "CGPD-tetramers," wherein a chemical interacts with a gene product to trigger a phenotype which can be linked to a disease. These computationally derived datasets can be used to fill the gaps and offer testable mechanistic information. Users can generate CGPD-tetramers for any combination of chemical, gene, phenotype, and/or disease of interest at CTD; however, such queries typically result in the generation of thousands of CGPD-tetramers. Here, we describe a novel approach to transform these large datasets into user-friendly chord diagrams using R. This visualization process is straightforward, simple to implement, and accessible to inexperienced users that have never used R before. Combining CGPD-tetramers into a single chord diagram helps identify potential key chemicals, genes, phenotypes, and diseases. This visualization allows users to more readily analyze computational datasets that can fill the exposure knowledge gaps in the environmental health continuum.

NCI SEER-Linked Virtual Tissue Repository Pilot.

BACKGROUND: The Surveillance, Epidemiology, and End Results (SEER) Program with the National Cancer Institute tested whether population-based cancer registries can serve as honest brokers to acquire tissue and data in the SEER-Linked Virtual Tissue Repository (VTR) Pilot. METHODS: We collected formalin-fixed, paraffin-embedded tissue and clinical data from patients with pancreatic ductal adenocarcinoma (PDAC) and breast cancer (BC) for two studies comparing cancer cases with highly unusual survival (≥5 years for PDAC and ≤30 months for BC) to pair-matched controls with usual survival (≤2 years for PDAC and ≥5 years for BC). Success was defined as the ability for registries to acquire tissue and data on cancer cases with highly unusual outcomes. RESULTS: Of 98 PDAC and 103 BC matched cases eligible for tissue collection, sources of attrition for tissue collection were tissue being unavailable, control paired with failed case, second control that was not requested, tumor necrosis ≥20%, and low tumor cellularity. In total, tissue meeting the study criteria was obtained for 70 (71%) PDAC and 74 (72%) BC matched cases. For patients with tissue received, clinical data completeness ranged from 59% for CA-19-9 after treatment to >95% for margin status, whether radiation therapy and chemotherapy were administered, and comorbidities. CONCLUSIONS: The VTR Pilot demonstrated the feasibility of using SEER cancer registries as honest brokers to provide tissue and clinical data for secondary use in research. Studies using this program should oversample by 45% to 50% to obtain sufficient sample size and targeted population representation and involve subspecialty matter expert pathologists for tissue selection.

The panzootic spread of highly pathogenic avian influenza H5N1 sublineage 2.3.4.4b: a critical appraisal of One Health preparedness and prevention.

Changes in the epidemiology and ecology of H5N1 highly pathogenic avian influenza are devastating wild bird and poultry populations, farms and communities, and wild mammals worldwide. Having originated in farmed poultry, H5N1 viruses are now spread globally by wild birds, with transmission to many mammal and avian species, resulting in 2024 in transmission among dairy cattle with associated human cases. These ecological changes pose challenges to mitigating the impacts of H5N1 highly pathogenic avian influenza on wildlife, ecosystems, domestic animals, food security, and humans. H5N1 highly pathogenic avian influenza highlights the need for One Health approaches to pandemic prevention and preparedness, emphasising multisectoral collaborations among animal, environmental, and public health sectors. Action is needed to reduce future pandemic risks by preventing transmission of highly pathogenic avian influenza among domestic and wild animals and people, focusing on upstream drivers of outbreaks, and ensuring rapid responses and risk assessments for zoonotic outbreaks. Political commitment and sustainable funding are crucial to implementing and maintaining prevention programmes, surveillance, and outbreak responses.

Association between metabolic syndrome and cervical cancer among women in Southwestern Uganda: A case-control study.

Objective: To determine the association between MetS and its components with cervical cancer among women in South-western Uganda. Methods: We conducted an unmatched case-control study on 470 participants in a 1:2 case-to-control ratio among women in southwestern Uganda. We recruited 157 women with cervical cancer as cases and 313 women without cervical cancer as controls at the Mbarara Regional Referral Hospital Cervical Cancer Clinic. We assessed for MetS using the National Cholesterol Education Programme Adult Treatment Panel III (NCEP ATP III) criteria. We used a multivariable binary logistic regression analysis to determine the association between MetS and its components with cervical cancer adjusted for potential confounders. We reported the adjusted odds ratios (aOR) and 95% confidence intervals (CI). Results: Cases were significantly older than controls: 52.4 ± 13.15 versus 41.9 ± 11.9 respectively, p < 0.001. We found MetS was independently associated with cervical cancer (aOR 1.66; 95 % CI 1.07-2.57). Age ≥ 50 years (aOR-2.20; 95 % CI 1.35-3.56), HIV infection (aOR 2.51, 95 % CI 1.56-4.05), increasing parity (aOR 1.16, 95 % CI 1.06-1.26), and a lack of formal education (aOR 6.41, 95 % CI, 1.33-30.86) were also associated with cervical cancer. However, none of the components of MetS was associated with cervical cancer. Conclusion: In Ugandan women, MetS was associated with a higher likelihood of cervical cancer. We, therefore recommend combined screening for MetS and cervical cancer in order to reduce morbidity and mortality from both Mets and cervical cancer.

Association between dyslipidemia and cervical intraepithelial neoplasia: A case-control study in south-western Uganda.

Background: Altered lipid levels may be associated with the development of a number of malignancies, including cancer of the cervix. However, there is limited understanding of this relationship in the rural Ugandan context. Objective: We investigated the connection between dyslipidaemias and cervical intraepithelial neoplasia (CIN) among women attending the cervical cancer clinic at Mbarara Regional Referral Hospital in south-western Uganda. Methods: This unmatched case-control study was conducted between December 2022 and February 2023 and included women with CIN (cases) and women without intraepithelial lesions (controls) in a 1:1 ratio. Participants were selected based on cytology and/or histology results, and after obtaining written informed consent. Demographic data were collected, and venous blood was drawn for lipid profile analysis. Dyslipidaemia was defined as: total cholesterol > 200 mg/dL, low-density lipoprotein > 160 mg/dL, triglycerides > 150 mg/dL, or high-density lipoprotein < 40 mg/dL. At diagnosis, cases were categorised as either CIN1 (low grade) or CIN2+ (high grade). Results: Among the 93 cases, 81 had CIN1, while 12 had CIN2+. Controls had a 13.9% (13/93) prevalence of high triglycerides and cases had a prevalence of 3.2% (3/93; p = 0.016). Reduced high-density lipoprotein was the most prevalent dyslipidaemia among cases (40.9%; 38/93). Statistically significant associations were found between high serum triglycerides and CIN (odds ratio: 1.395, 95% confidence interval: 0.084-1.851, p = 0.007). Conclusion: A notable association was observed between triglyceride dyslipidemia and CIN. Further studies into biochemical processes and interactions between lipids and cervical carcinogenesis are recommended through prospective cohort studies. What this study adds: This research provides additional information on the potential role of lipids in cervical carcinogenesis among women in rural Uganda. It also presents the possible prevalence of multimorbidity involving cervical cancer and cardiovascular diseases, particularly in low-resource settings lacking preventive measures against the increasing prevalence of dyslipidaemia.