Gene Therapy Using Recombinant AAV Type 8 Vector Encoding TNAP-D Improves the Skeletal Phenotypes in Murine Models of Osteomalacia.

Hypophosphatasia (HPP), caused by loss-of-function mutations in the gene encoding tissue-nonspecific alkaline phosphatase (TNAP), is characterized by skeletal and dental hypomineralization that can vary in severity from life-threatening to milder manifestations only in adulthood. PHOSPHO1 deficiency leads to early-onset scoliosis, osteomalacia, and fractures that mimic pseudo-HPP. Asfotase alfa, a life-saving enzyme replacement therapy approved for pediatric-onset HPP, requires subcutaneous injections 3 to 6 times per week.

Protein quaternary structures in solution are a mixture of multiple forms.

Over half the proteins in the cytoplasm form homo or hetero-oligomeric structures. Experimentally determined structures are often considered in determining a protein's oligomeric state, but static structures miss the dynamic equilibrium between different quaternary forms. The problem is exacerbated in homo-oligomers, where the oligomeric states are challenging to characterize.

Differential Patterns and Outcomes of 20.6 Million Cardiovascular Emergency Department Encounters for Men and Women in the United States.

Background We describe sex-differential disease patterns and outcomes of >20.6 million cardiovascular emergency department encounters in the United States. Methods and Results We analyzed primary cardiovascular encounters from the Nationwide Emergency Department Sample between 2016 and 2018.

Patent Ductus Arteriosus: A Contemporary Perspective for the Pediatric and Adult Cardiac Care Provider.

The burden of patent ductus arteriosus (PDA) continues to be significant. In view of marked differences in preterm infants versus more mature, term counterparts (viewed on a continuum with adolescent and adult patients), mechanisms regulating ductal patency, genetic contributions, clinical consequences, and diagnostic and treatment thresholds are discussed separately, when appropriate. Among both preterm infants and older children and adults, a range of hemodynamic profiles highlighting the markedly variable consequences of the PDA are provided.

Permutation tests for hypothesis testing with animal social network data: Problems and potential solutions.

Permutation tests are widely used to test null hypotheses with animal social network data, but suffer from high rates of type I and II error when the permutations do not properly simulate the intended null hypothesis.Two common types of permutations each have limitations. Pre-network (or datastream) permutations can be used to control 'nuisance effects' like spatial, temporal or sampling biases, but only when the null hypothesis assumes random social structure.

Quantification of Cardiac Adipose Tissue in Failing and Nonfailing Human Myocardium.

Background Because body mass index (BMI) is generally used clinically to define obesity and to estimate body adiposity, BMI likely is positively correlated with epicardial adipose tissue (EAT) level. Based on echocardiography, previous outcomes on this matter have varied from almost absent to rather strong correlations between BMI and EAT. The purpose of our study was to unambiguously examine EAT content and determine if correlations exist between EAT content and BMI, cause of heart failure, or contractile force.

The Abundance of Trace Elements in Human Bone Relative to Bone Type and Bone Pathology.

As the global population ages and the proportion of individuals afflicted with musculoskeletal disease spirals upward, there is an increasing interest in understanding and preventing bone-related diseases. Bone diseases, such as osteoporosis and osteoarthritis, are known to be influenced by a variety of factors including age, gender, nutrition, and genetics, but are also inherently linked to the human body's ability to produce biominerals of suitable quality. Because the crystal lattice structure and mineralogy of bone hydroxyapatite is surprisingly analogous to geological hydroxyapatite, trace element levels and exposure have long been proposed to influence the structure of biominerals as they do geological minerals (e.

Synthesis of a fluorinated pyronin that enables blue light to rapidly depolarize mitochondria.

Fluorinated analogues of the fluorophore pyronin B were synthesized as a new class of amine-reactive drug-like small molecules. In water, 2,7-difluoropyronin B was found to reversibly react with primary amines to form covalent adducts. When this fluorinated analogue is added to proteins, these adducts undergo additional oxidation to yield fluorescent 9-aminopyronins.

Association of Vascular Properties With the Brain White Matter Hyperintensity in Middle-Aged Population.

Background The periventricular white matter is more sensitive to the systemic hemodynamic alterations than the deep white matter because of differences in its vascular structure and systemic circulation relationship. We hypothesize that periventricular white matter hyperintensity (PVWMH) volume shows greater association than deep white matter hyperintensity (DWMH) volume with vascular properties (VPs) reflecting arterial stiffness and cardiovascular remodeling, indicators of the systemic circulation. Methods and Results A total of 426 participants (age, 59.

Photocytotoxicity and photoinduced phosphine ligand exchange in a Ru(ii) polypyridyl complex.

Two new tris-heteroleptic Ru(ii) complexes with triphenylphosphine (PPh) coordination, -[Ru(phen)(PPh)(CHCN)] (1a, phen = 1,10-phenanthroline) and -[Ru(biq)(phen)(PPh)(CHCN)] (2a, biq = 2,2'-biquinoline), were synthesized and characterized for photochemotherapeutic applications. Upon absorption of visible light, 1a exchanges a CHCN ligand for a solvent water molecule. Surprisingly, the steady-state irradiation of 2a followed by electronic absorption and NMR spectroscopies reveals the photosubstitution of the PPh ligand.

In-Hospital Complications in Pregnancies Conceived by Assisted Reproductive Technology.

Background Assisted reproductive technology (ART) has emerged as a common treatment option for infertility, a problem that affects an estimated 48 million couples worldwide. Advancing maternal age with increasing prepregnancy cardiovascular risk factors, such as chronic hypertension, obesity, and diabetes, has raised concerns about pregnancy complications associated with ART. However, in-hospital complications following pregnancies conceived by ART are poorly described.

Social Isolation and Incident Heart Failure Hospitalization in Older Women: Women's Health Initiative Study Findings.

Background The association of social isolation or lack of social network ties in older adults is unknown. This knowledge gap is important since the risk of heart failure (HF) and social isolation increase with age. The study examines whether social isolation is associated with incident HF in older women, and examines depressive symptoms as a potential mediator and age and race and ethnicity as effect modifiers.

Trifluoromethyl substitution enhances photoinduced activity against breast cancer cells but reduces ligand exchange in Ru(ii) complex.

A series of five ruthenium complexes containing triphenyl phosphine groups known to enhance both cellular penetration and photoinduced ligand exchange, -[Ru(bpy)(P(-R-Ph))(CHCN)], where bpy = 2,2'-bipyridine and P(-R-Ph) represent -substituted triphenylphosphine ligands with R = -OCH (), -CH () -H (), -F (), and -CF (), were synthesized and characterized. The photolysis of in water with visible light ( ≥ 395 nm) results in the substitution of the coordinated acetonitrile with a solvent molecule, generating the corresponding aqua complex as the single photoproduct. A 3-fold variation in quantum yield was measured with 400 nm irradiation, , where is the most efficient with a = 0.

Murine cancer cachexia models replicate elevated catabolic pembrolizumab clearance in humans.

Background: Monoclonal antibody (mAb) immune checkpoint inhibitor (ICI) therapies have dramatically impacted oncology this past decade. However, only about one-third of patients respond to treatment, and biomarkers to predict responders are lacking. Recent ICI clinical pharmacology data demonstrate high baseline drug clearance (CL) significantly associates with shorter overall survival, independent of ICI exposure, in patients receiving ICI mAb therapies.

Association of Adiposity With Incident Diabetes Among Black Adults in the Jackson Heart Study.

Background The prognostic value of anthropometric, adipokine, and computed tomography measures of adiposity to predict diabetes in Black, specifically by normoglycemia versus prediabetes, remains incompletely understood. Methods and Results Among Black participants without diabetes in the JHS (Jackson Heart Study), waist circumference [WC], body mass index, adiponectin, leptin, and leptin:adiponectin ratio were standardized in sample 1 (2422 participants at baseline [2000-2004]) and WC, body mass index, visceral adipose tissue (VAT), subcutaneous adipose tissue, and liver attenuation in 1537 participants at examination 2 (2005-2008) (sample 2). Hazard ratios (HRs) for diabetes were estimated using interval-censored Cox modeling adjusting for traditional risk factors and validated with the C index.

Towards Wind Vector and Wave Height Retrievals Over Inland Waters Using CYGNSS.

GNSS Reflectometry (GNSS-R) measurements over inland water bodies, such as lakes, rivers, and wetlands exhibit strong coherent signals. The strength of the coherent reflections is highly sensitive to small-scale surface roughness. For inland waters, this roughness is primarily due to wind-driven surface waves.

Potential local adaptation in populations of invasive reed canary grass () across an urbanization gradient.

Urban stressors represent strong selective gradients that can elicit evolutionary change, especially in non-native species that may harbor substantial within-population variability. To test whether urban stressors drive phenotypic differentiation and influence local adaptation, we compared stress responses of populations of a ubiquitous invader, reed canary grass (). Specifically, we quantified responses to salt, copper, and zinc additions by reed canary grass collected from four populations spanning an urbanization gradient (natural, rural, moderate urban, and intense urban).

Advances in viral oncolytics for treatment of multiple myeloma - a focused review.

Introduction: Oncolytic viruses are genetically engineered viruses that target myeloma-affected cells by detecting specific cell surface receptors (CD46, CD138), causing cell death by activating the signaling pathway to induce apoptosis or by immune-mediated cellular destruction.

Areas Covered: This article summarizes oncolytic virotherapy advancements such as the therapeutic use of viruses by targeting cell surface proteins of myeloma cells as well as the carriers to deliver viruses to the target tissues safely. The major classes of viruses that have been studied for this include measles, myxoma, adenovirus, reovirus, vaccinia, vesicular-stomatitis virus, coxsackie, and others.

Avoidance and early diagnosis of erroneous permanent pacemaker placement into the left ventricle: A case report.

Diagnosis of a pacemaker inserted through the subclavian artery is essential due to risk of thromboembolism. Fluoroscopy, ECG, and other imaging techniques must be used to diagnose the condition, and appropriate treatment path must be administered.

SARS-CoV-2 infection and paediatric endocrine disorders: Risks and management considerations.

Background: Coronavirus-19 (COVID-19) is a disease caused by the SARS-CoV-2 virus, the seventh coronavirus identified as causing disease in humans. The SARS-CoV-2 virus has multiple potential pathophysiologic interconnections with endocrine systems, potentially causing disturbances in glucose metabolism, hypothalamic and pituitary function, adrenal function and mineral metabolism. A growing body of data is revealing both the effects of underlying endocrine disorders on COVID-19 disease outcome and the effects of the SARS-CoV-2 virus on endocrine systems.