The impact of US-China tensions on US science: Evidence from the NIH investigations.

Amid the discourse on foreign influence investigations in research, this study examines the impact of NIH-initiated investigations starting in 2018 on U.S. scientists' productivity, focusing on those collaborating with Chinese peers. Using publication data from 2010 to 2021, we analyze over 113,000 scientists and find that investigations coincide with reduced productivity for those with China collaborations compared to those with other international collaborators, especially when accounting for publication impact. The decline is particularly pronounced in fields that received greater preinvestigation NIH funding and engaged more in U.S.-China collaborations. Indications of scientist migration and broader scientific progress implications also emerge. We also offer insights into the underlying mechanisms via qualitative interviews.

Association between Dietary Diversity and Weight Status of Aboriginal Primary School Children in Negeri Sembilan, Malaysia.

Background: The purpose of this study is to determine the association between dietary diversity and weight status of aboriginal primary school children. Methods: Dietary diversity measures food intake diversity in food groups, whereas weight status indicates nutritional status. Dietary serving score (DSS) method was used to determine dietary diversity status, while weight status was assessed using BMI-for-Age (BAZ). Results: Results reported that 51.9% and 54.2% were male and 10 years old-12 years old children, respectively. A total of 36.4% of children consumed cereal/grains diversely while fruits were not diversely consumed by 96.4% of them. Approximately 60.8% of children were reported to have normal weight status, which was followed by overweight (17.7%), obese (16.7%) and thinness to severe-thinness (4.8%). There was an association between DSS of fruits, meat/fish/ eggs, legumes/lentils and milk/dairy products with age group, vegetables DSS with gender and BAZ with parental employment status (P < 0.05). The association between DSS of all food groups and total with BAZ were reported to be insignificant, indicating no association between both variables (0.00 < r < 0.30; P > 0.05). Conclusion: Children from this study were shown to practice a monotonous diet, although the majority of them were within normal weight status.

Discovery of Clinical Candidate PF-06648671: A Potent γ-Secretase Modulator for the Treatment of Alzheimer's Disease.

Herein, we describe the design and synthesis of γ-secretase modulator (GSM) clinical candidate PF-06648671 (22) for the treatment of Alzheimer's disease. A key component of the design involved a 2,5-cis-tetrahydrofuran (THF) linker to impart conformational rigidity and lock the compound into a putative bioactive conformation. This effort was guided using a pharmacophore model since crystallographic information was not available for the membrane-bound γ-secretase protein complex at the time of this work. PF-06648671 achieved excellent alignment of whole cell in vitro potency (Aß42 IC50 = 9.8 nM) and absorption, distribution, metabolism, and excretion (ADME) parameters. This resulted in favorable in vivo pharmacokinetic (PK) profile in preclinical species, and PF-06648671 achieved a human PK profile suitable for once-a-day dosing. Furthermore, PF-06648671 was found to have favorable brain availability in rodent, which translated into excellent central exposure in human and robust reduction of amyloid ß (Aß) 42 in cerebrospinal fluid (CSF).

Influences and trends of various shape-capture methods on outcomes in trans-tibial prosthetics: A systematic review.

INTRODUCTION: In trans-tibial prosthetics, shape-capture methods are employed to create a representation of the residuum. Shape-capture methods can be grouped into the categories of 'hands-on', 'hands-off' and computer-aided design. OBJECTIVE: This review examines the influences and trends of shape-capture methods on the outcomes of quality, comfort of user and clinical efficiency, in the population of trans-tibial prosthesis users. STUDY DESIGN: Systematic Review. METHOD: Databases and relevant journals were searched. Participants included trans-tibial prosthetics users/limb models. Interventions included shape-capture methods. Outcomes included quality, comfort of user and clinical efficiency. RESULTS: Overall, 22 papers were evaluated; 8 papers evaluated hands-on and hands-off methods, 2 evaluated computer-aided design and 12 evaluated measurement systems used with shape capture. No papers relating to clinical efficiency were found. CONCLUSION: Overall evidence was weak in suggesting that effects on outcomes were due to the sole influences of shape capture. However, studies suggest that hands-on methods are dependent on a prosthetist's skill. Hands-off methods, although repeatable, might still require experience to attain a good fit. Computer-aided design studies were mostly done on theoretical models. Shape-capture measurements require more consistent 'gold standards'. The relation between socket fit and comfort is still unclear. Overall, more research is required in each area. CLINICAL RELEVANCE: A good fitting prosthetic socket is crucial for efficient and comfortable use of a prosthesis. To attain the best chances of a good fit, it is important that the characteristics of the residuum are captured as accurately as possible during the initial "shape capture" stage. This paper attempts to categorize and evaluate the existing shape capture methods on their influence and trends on various outcomes - Quality of shape capture, comfort of user and clinical efficiency.

Discovery of Potent and Selective Periphery-Restricted Quinazoline Inhibitors of the Cyclic Nucleotide Phosphodiesterase PDE1.

We disclose the discovery and X-ray cocrystal data of potent, selective quinazoline inhibitors of PDE1. Inhibitor ( S)-3 readily attains free plasma concentrations above PDE1 IC50 values and has restricted brain access. The racemic compound 3 inhibits >75% of PDE hydrolytic activity in soluble samples of human myocardium, consistent with heightened PDE1 activity in this tissue. These compounds represent promising new tools to probe the value of PDE1 inhibition in the treatment of cardiovascular disease.

Discovery of cyclopropyl chromane-derived pyridopyrazine-1,6-dione γ-secretase modulators with robust central efficacy.

Herein we describe the discovery of a novel series of cyclopropyl chromane-derived pyridopyrazine-1,6-dione γ-secretase modulators for the treatment of Alzheimer's disease (AD). Using ligand-based design tactics such as conformational analysis and molecular modeling, a cyclopropyl chromane unit was identified as a suitable heterocyclic replacement for a naphthyl moiety that was present in the preliminary lead 4. The optimized lead molecule 44 achieved good central exposure resulting in robust and sustained reduction of brain amyloid-ß42 (Aß42) when dosed orally at 10 mg kg-1 in a rat time-course study. Application of the unpaced isolated heart Langendorff model enabled efficient differentiation of compounds with respect to cardiovascular safety, highlighting how minor structural changes can greatly impact the safety profile within a series of compounds.

Design of Pyridopyrazine-1,6-dione γ-Secretase Modulators that Align Potency, MDR Efflux Ratio, and Metabolic Stability.

Herein we describe the design and synthesis of a series of pyridopyrazine-1,6-dione γ-secretase modulators (GSMs) for Alzheimer's disease (AD) that achieve good alignment of potency, metabolic stability, and low MDR efflux ratios, while also maintaining favorable physicochemical properties. Specifically, incorporation of fluorine enabled design of metabolically less liable lipophilic alkyl substituents to increase potency without compromising the sp(3)-character. The lead compound 21 (PF-06442609) displayed a favorable rodent pharmacokinetic profile, and robust reductions of brain Aß42 and Aß40 were observed in a guinea pig time-course experiment.

Synthesis of α,α-difluoroethyl aryl and heteroaryl ethers.

Fluorine plays a critical role in modern medicinal chemistry due to its unique properties, and new methods for its incorporation into target molecules are of high interest. An efficient new method for the preparation of aryl-α,α-difluoroethyl ethers (4) via addition of aryl and heteroaryl alcohols (1) to commercially available 2-bromo-1,1-difluoroethene (2) and subsequent hydrogenolysis is presented. This procedure is an attractive alternative to existing methods that employ harshly reactive fluorinating systems such as xenon difluoride and hydrogen fluoride.