Building C(sp)-rich complexity by combining cycloaddition and C-C cross-coupling reactions.

Prized for their ability to rapidly generate chemical complexity by building new ring systems and stereocentres, cycloaddition reactions have featured in numerous total syntheses and are a key component in the education of chemistry students. Similarly, carbon-carbon (C-C) cross-coupling methods are integral to synthesis because of their programmability, modularity and reliability. Within the area of drug discovery, an overreliance on cross-coupling has led to a disproportionate representation of flat architectures that are rich in carbon atoms with orbitals hybridized in an sp manner.

Kinetically guided radical-based synthesis of C(sp)-C(sp) linkages on DNA.

DNA-encoded libraries (DEL)-based discovery platforms have recently been widely adopted in the pharmaceutical industry, mainly due to their powerful diversity and incredible number of molecules. In the two decades since their disclosure, great strides have been made to expand the toolbox of reaction modes that are compatible with the idiosyncratic aqueous, dilute, and DNA-sensitive parameters of this system. However, construction of highly important C(sp)-C(sp) linkages on DNA through cross-coupling remains unexplored.

Development and validation of the 25-item Hikikomori Questionnaire (HQ-25).

Aim: Hikikomori, a form of severe social withdrawal, is an emerging issue in mental health, for which validated measurement tools are lacking. The object was to develop a self-report scale of hikikomori, and assess its psychometric properties and diagnostic accuracy.

Methods: A sample of 399 participants from clinical and community settings completed measures.

Leveraging the Knorr Pyrazole Synthesis for the Facile Generation of Thioester Surrogates for use in Native Chemical Ligation.

Facile synthesis of C-terminal thioesters is integral to native chemical ligation (NCL) strategies for chemical protein synthesis. We introduce a new method of mild peptide activation, which leverages solid-phase peptide synthesis (SPPS) on an established resin linker and classical heterocyclic chemistry to convert C-terminal peptide hydrazides into their corresponding thioesters via an acyl pyrazole intermediate. Peptide hydrazides, synthesized on established trityl chloride resins, can be activated in solution with stoichiometric acetyl acetone (acac), readily proceed to the peptide acyl pyrazoles.

CIP2A facilitates the G1/S cell cycle transition via B-Myb in human papillomavirus 16 oncoprotein E6-expressing cells.

Infection with high-risk human papillomaviruses (HR-HPVs, including HPV-16, HPV-18, HPV-31) plays a central aetiologic role in the development of cervical carcinoma. The transforming properties of HR-HPVs mainly reside in viral oncoproteins E6 and E7. E6 protein degrades the tumour suppressor p53 and abrogates cell cycle checkpoints.

Delayed-Onset Seizure in a Mild Quetiapine Overdose: Report of a Case and Review of the Literature.

Among atypical antipsychotics, quetiapine is commonly prescribed and considered to have a favorable side effect and safety profile. Here, we report the case of a patient who developed a generalized tonic-clonic seizure 28 hours following ingestion of 1,400 mg of quetiapine. Review of the literature identifies delayed-onset seizure as a potential complication of quetiapine overdose.

Regulator of chromatin condensation 1 abrogates the G1 cell cycle checkpoint via Cdk1 in human papillomavirus E7-expressing epithelium and cervical cancer cells.

Regulator of chromatin condensation 1 (RCC1) is a major guanine-nucleotide exchange factor for Ran GTPase and plays key roles in nucleo-cytoplasmic transport, mitosis, and nuclear envelope assembly. RCC1 is known to be a critical cell cycle regulator whose loss causes G1 phase arrest, but the molecular basis for this regulation is poorly understood. Furthermore, little is known about the relationship between RCC1 and carcinomas.

Establishing the Transient Mass Balance of Thrombosis: From Tissue Factor to Thrombin to Fibrin Under Venous Flow.

Objective: We investigated the coregulation of thrombin and fibrin as blood flows over a procoagulant surface.

Approach And Results: Using microfluidic perfusion of factor XIIa-inhibited human whole blood (200 s wall shear rate) over a 250-μm long patch of collagen/TF (tissue factor; ≈1 molecule per μm) and immunoassays of the effluent for F1.2 (prothrombin fragment 1.

Human cytomegalovirus infection-induced autophagy was associated with the biological behavioral changes of human umbilical vein endothelial cell (HUVEC).

In this study, we investigated the enacted role of autophagy in biological behavioral changes of human umbilical vein endothelial cell (HUVEC) infected with human cytomegalovirus (HCMV). It was found that in HCMV-infected cells, the number of punctuate structures increased from 24 h to 48 h p.i.

Predictors of viewing progress notes among users of VA's electronic health portal who receive mental health care.

Objective: Consistent with the movement, the Veterans Health Administration (VHA) offers patients online access to their clinical notes through the feature in its electronic patient health portal, My HealthVet. We identified demographic, diagnostic, and knowledge-related predictors of viewing clinical notes among veterans receiving VHA mental health care who recently used My HealthVet.

Materials And Methods: Three hundred and thirty-eight patients receiving mental health care from 1 VHA medical center who had logged into My HealthVet in the prior 6 months completed self-report questionnaires assessing their viewing of clinical notes.

Patients' Positive and Negative Responses to Reading Mental Health Clinical Notes Online.

Objective: This study describes responses to OpenNotes, clinical notes available online, among patients receiving mental health care and explores whether responses vary by patient demographic or clinical characteristics.

Methods: Survey data from 178 veterans receiving mental health treatment at a large Veterans Affairs medical center included patient-reported health self-efficacy, health knowledge, alliance with clinicians, and negative emotional responses after reading OpenNotes. Health care data were extracted from the patient care database.

Neurodegenerative disease biomarkers Aβ, Aβ, tau, and p-tau in the vervet monkey cerebrospinal fluid: Relation to normal aging, genetic influences, and cerebral amyloid angiopathy.

Background: The Caribbean vervet monkey () is a potentially valuable animal model of neurodegenerative disease. However, the trajectory of aging in vervets and its relationship to human disease is incompletely understood.

Methods: To characterize biomarkers associated with neurodegeneration, we measured cerebrospinal fluid (CSF) concentrations of Aβ, Aβ, total tau, and p-tau in 329 members of a multigenerational pedigree.

The KCa3.1 blocker TRAM34 reverses renal damage in a mouse model of established diabetic nephropathy.

Despite optimal control of hyperglycaemia, hypertension, and dyslipidaemia, the number of patients with diabetic nephropathy (DN) continues to grow. Strategies to target various signaling pathways to prevent DN have been intensively investigated in animal models and many have been proved to be promising. However, targeting these pathways once kidney disease is established, remain unsatisfactory.

Haploinsufficiency leads to neurodegeneration in C9ORF72 ALS/FTD human induced motor neurons.

An intronic GGGGCC repeat expansion in C9ORF72 is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), but the pathogenic mechanism of this repeat remains unclear. Using human induced motor neurons (iMNs), we found that repeat-expanded C9ORF72 was haploinsufficient in ALS. We found that C9ORF72 interacted with endosomes and was required for normal vesicle trafficking and lysosomal biogenesis in motor neurons.

Metformin attenuates folic-acid induced renal fibrosis in mice.

Progressive tubulointerstitial fibrosis has been recognized as a common pathological process that leads to the progression of all chronic kidney disease (CKD). Innovative strategies are needed to both prevent and treat CKD. Inflammatory and fibrotic signaling pathways play central roles in the progression of CKD regardless of aetiology.

Patient and social characteristics contributing to disparities in outcomes after burn injury: application of database research to minority health in the burn population.

Background: Although racial disparities have been well described in trauma and medical literature, less is known about disparities in the burn population, especially the Native American, Hispanic, Black, and Asian minority groups. This study seeks to identify at-risk populations for differences in patient and social characteristics that may link certain race groups to disparate burn outcomes.

Methods: Data was reviewed from the National Burn Repository.

Bioinformatics and genomic databases.

High-throughput, low-cost sequencing technologies have begun to yield new insights into biology and medicine. New data enable the interrogation of the molecular biology of disease from DNA to RNA to protein, charting the central dogma. This chapter reviews some of the key advances and resources in the application of bioinformatics to understanding, and ultimately diagnosing and treating, diseases of the nervous system.

Reference ranges for rotational thromboelastometry in male Sprague Dawley rats.

Background: A functional coagulation assay was used to investigate the extrinsic pathway of coagulation on citrated whole blood samples from healthy adult male Sprague Dawley rats using the mini cup and pin system.

Methods: Reference values for coagulation parameters from forty-three animals were calculated using data obtained from the ROTEM® hemostasis analyzer with the EXTEM test.

Results: The following ranges, presented as the 2.

Inhibition of arginase by CB-1158 blocks myeloid cell-mediated immune suppression in the tumor microenvironment.

Background: Myeloid cells are an abundant leukocyte in many types of tumors and contribute to immune evasion. Expression of the enzyme arginase 1 (Arg1) is a defining feature of immunosuppressive myeloid cells and leads to depletion of L-arginine, a nutrient required for T cell and natural killer (NK) cell proliferation. Here we use CB-1158, a potent and orally-bioavailable small-molecule inhibitor of arginase, to investigate the role of Arg1 in regulating anti-tumor immunity.