Biochemical, structural, and cellular characterization of S-but-3-yn-2-ylglycine as a mechanism-based covalent inactivator of the flavoenzyme proline dehydrogenase.

The mitochondrial flavoenzymes proline dehydrogenase (PRODH) and hydroxyproline dehydrogenase (PRODH2) catalyze the first steps of proline and hydroxyproline catabolism, respectively. The enzymes are targets for chemical probe development because of their roles in cancer cell metabolism (PRODH) and primary hyperoxaluria (PRODH2). Mechanism-based inactivators of PRODH target the FAD by covalently modifying the N5 atom, with N-propargylglycine (NPPG) being the current best-in-class of this type of probe.

Prenol production in a microbial host via the "Repass" Pathways.

Prenol and isoprenol are promising advanced biofuels and serve as biosynthetic precursors for pharmaceuticals, fragrances, and other industrially relevant compounds. Despite engineering improvements that circumvent intermediate cytotoxicity and lower energy barriers, achieving high titer 'mevalonate (MVA)-derived' prenol has remained elusive. Difficulty in selective prenol production stems from the necessary isomerization of isopentenyl diphosphate (IPP) to dimethylallyl diphosphate (DMAPP) as well as the intrinsic toxicity of these diphosphate precursors.

Role of institutional and state policies in management of pregnancies of unknown location: a 2024 online survey of Ryan Programs in the United States.

Objective: To assess the perceived impact of state and institutional policies on managing pregnancies of unknown location (PUL) at U.S. Ryan residency programs.

Pitfalls and practical suggestions for using local field potential recordings in DBS clinical practice and research.

Local field potential (LFP) recordings using chronically implanted sensing-enabled stimulators are a powerful tool for indexing symptom presence and severity in neurological and neuropsychiatric disorders, and for enhancing our neurophysiological understanding of brain processes. LFPs have gained interest as input signals for closed-loop deep brain stimulation (DBS) and can be used to inform DBS parameter selection. LFP recordings using chronically implanted sensing-enabled stimulators have various implementational challenges.

Leveraging Artificial Intelligence to Develop a Decision-Support Tool for Visual Symptom Assessment of Grapevine Leafroll and Red Blotch Diseases.

The timely detection of viral pathogens in vineyards is a critical aspect of management. Diagnostic methods can be labor-intensive and may require specialized training or facilities. The emergence of artificial intelligence (AI) has the potential to provide innovative solutions for disease detection but requires a significant volume of high-quality data as input.

Evaluating oomycete pathogen and community responses to chemical- and Slow Sand Filtration-based water treatment strategies to enable water recycling in nursery production systems.

While recycling irrigation water can reduce water use constraints and costs in nurseries, adoption is hindered by the associated risk of recirculating and spreading waterborne pathogens. To enable regional water re-use, this study assessed oomycete re-circulation risks and recycled water treatment efficacy at organismal and community scales. In culture-based analysis of recycled pond water at two Mid-Atlantic nurseries across three years, diverse oomycetes (12+ species) were detected using culture-based analysis, with Phytopythium helicoides as the dominant species; MiSeq analysis detected eight of these species, plus 24 additional taxa.

Health Expenditures of Patients With Diabetes After Bariatric Surgery: Comparing Gastric Bypass and Sleeve Gastrectomy.

Background: Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) differ in their effects on body weight and risk for reoperation. However, it is unclear whether long-term health expenditures differ by procedure type in patients with diabetes.

Objective: To compare health expenditures 3 years before and 5.

Methods to Adjust for Confounding in Test-Negative Design COVID-19 Effectiveness Studies: Simulation Study.

Background: Real-world COVID-19 vaccine effectiveness (VE) studies are investigating exposures of increasing complexity accounting for time since vaccination. These studies require methods that adjust for the confounding that arises when morbidities and demographics are associated with vaccination and the risk of outcome events. Methods based on propensity scores (PS) are well-suited to this when the exposure is dichotomous, but present challenges when the exposure is multinomial.

Multimodal Pain Recognition in Postoperative Patients: Machine Learning Approach.

Background: Acute pain management is critical in postoperative care, especially in vulnerable patient populations that may be unable to self-report pain levels effectively. Current methods of pain assessment often rely on subjective patient reports or behavioral pain observation tools, which can lead to inconsistencies in pain management. Multimodal pain assessment, integrating physiological and behavioral data, presents an opportunity to create more objective and accurate pain measurement systems.

Designing the First Pregnancy Guaranteed Income Program in the United States: Qualitative Needs Assessment and Human-Centered Design to Develop the Abundant Birth Project.

Background: Racial inequities in pregnancy outcomes persist despite investments in clinical, educational, and behavioral interventions, indicating that a new approach is needed to address the root causes of health disparities. Guaranteed income during pregnancy has the potential to narrow racial health inequities for birthing people and infants by alleviating financial stress.

Objective: We describe community-driven formative research to design the first pregnancy-guaranteed income program in the United States-the Abundant Birth Project (ABP).

Elective Discontinuation of Larotrectinib in Pediatric Patients With TRK Fusion Sarcomas and Related Mesenchymal Tumors.

Larotrectinib is a highly selective tropomyosin receptor kinase (TRK) inhibitor with efficacy in children with TRK fusion tumors. We evaluated patient outcomes after elective discontinuation of larotrectinib in the absence of disease progression in a protocol-defined wait-and-see subset analysis of eligible patients where treatment resumption with larotrectinib was allowed if disease progressed. We also assessed the safety and efficacy of larotrectinib in all pediatric patients with sarcoma.

Integrative genomic analysis of DLBCL identifies immune environments associated with bispecific antibody response.

Most diffuse large B-cell lymphoma (DLBCL) patients treated with immunotherapies such as bispecific antibodies (BsAb) or chimeric antigen receptor (CAR) T cells fail to achieve durable treatment responses, underscoring the need for a deeper understanding of mechanisms that regulate the immune environment and response to treatment. Here, an integrative, multi-omic approach was applied to multiple large independent datasets in order to characterize DLBCL immune environments, and to define their association with tumor cell-intrinsic genomic alterations and outcomes to CD19-directed CAR T-cell and CD20 x CD3 BsAb therapies. This approach effectively segregated DLBCLs into four immune quadrants (IQ) defined by cell-of-origin and immune-related gene set expression scores.

Botensilimab (Fc-enhanced anti-cytotoxic lymphocyte-association protein-4 antibody) Plus Balstilimab (anti-PD-1 antibody) in Patients With Relapsed/Refractory Metastatic Sarcomas.

Purpose: Outcomes for patients with advanced sarcomas are poor and there is a high unmet need to develop novel therapies. The purpose of this phase I study was to define the safety and efficacy of botensilimab (BOT), an Fc-enhanced anti-cytotoxic lymphocyte-association protein-4 antibody, plus balstilimab (BAL), an anti-PD-1 antibody, in advanced sarcomas.

Methods: BOT was administered intravenously (IV) at 1 mg/kg or 2 mg/kg once every 6 weeks in combination with BAL IV at 3 mg/kg once every 2 weeks for up to 2 years.

Alternative models of funding curiosity-driven research.

Funding of curiosity-driven science is the lifeblood of scientific and technological innovation. Various models of funding allocation became institutionalized in the 20th century, shaping the present landscape of research funding. There are numerous reasons for scientists to be dissatisfied with current funding schemes, including the imbalance between funding for curiosity-driven and mission-directed research, regional and country disparities, path-dependency of who gets funded, gender and race disparities, low inter-reviewer reliability, and the trade-off between the effort and time spent on writing or reviewing proposals and doing research.

How can we make sound replication decisions?

Replication and the reported crises impacting many fields of research have become a focal point for the sciences. This has led to reforms in publishing, methodological design and reporting, and increased numbers of experimental replications coordinated across many laboratories. While replication is rightly considered an indispensable tool of science, financial resources and researchers' time are quite limited.

No gender differences in attraction to young partners: A study of 4500 blind dates.

In mixed-gender couples, men are older than women on average. Scholars and laypeople presume that this arrangement reflects mirrored preferences such that men desire younger partners and women desire older partners. Nevertheless, relevant published data on in-person romantic evaluations-that is, studies where adults interact in person and report their initial attraction to each other-are nearly nonexistent.

Is Ockham's razor losing its edge? New perspectives on the principle of model parsimony.

The preference for simple explanations, known as the parsimony principle, has long guided the development of scientific theories, hypotheses, and models. Yet recent years have seen a number of successes in employing highly complex models for scientific inquiry (e.g.

The misalignment of incentives in academic publishing and implications for journal reform.

For most researchers, academic publishing serves two goals that are often misaligned-knowledge dissemination and establishing scientific credentials. While both goals can encourage research with significant depth and scope, the latter can also pressure scholars to maximize publication metrics. Commercial publishing companies have capitalized on the centrality of publishing to the scientific enterprises of knowledge dissemination and academic recognition to extract large profits from academia by leveraging unpaid services from reviewers, creating financial barriers to research dissemination, and imposing substantial fees for open access.

14-3-3 promotes sarcolemmal expression of cardiac Ca1.2 and nucleates isoproterenol-triggered channel superclustering.

The L-type Ca channel (Ca1.2) is essential for cardiac excitation-contraction coupling. To contribute to the inward Ca flux that drives Ca-induced-Ca-release, Ca1.

How should the advancement of large language models affect the practice of science?

Large language models (LLMs) are being increasingly incorporated into scientific workflows. However, we have yet to fully grasp the implications of this integration. How should the advancement of large language models affect the practice of science? For this opinion piece, we have invited four diverse groups of scientists to reflect on this query, sharing their perspectives and engaging in debate.