The predisposition for scleroderma, defined as fibrosis and hardening of the skin, is poorly understood. We report that stiff skin syndrome (SSS), an autosomal dominant congenital form of ...scleroderma, is caused by mutations in the sole Arg-Gly-Asp sequence-encoding domain of fibrillin-1 that mediates integrin binding. Ordered polymers of fibrillin-1 (termed microfibrils) initiate elastic fiber assembly and bind to and regulate the activation of the profibrotic cytokine transforming growth factor-beta (TGFbeta). Altered cell-matrix interactions in SSS accompany excessive microfibrillar deposition, impaired elastogenesis, and increased TGFbeta concentration and signaling in the dermis. The observation of similar findings in systemic sclerosis, a more common acquired form of scleroderma, suggests broad pathogenic relevance.
The disconnected (disco)‐interacting protein 2 (DIP2) gene was first identified in D. melanogaster and contains a DNA methyltransferase‐associated protein 1 (DMAP1) binding domain, Acyl‐CoA ...synthetase domain and AMP‐binding sites. DIP2 regulates axonal bifurcation of the mushroom body neurons in D. melanogaster and is required for axonal regeneration in the neurons of C. elegans. The DIP2 homologues in vertebrates, Disco‐interacting protein 2 homolog A (DIP2A), Disco‐interacting protein 2 homolog B (DIP2B), and Disco‐interacting protein 2 homolog C (DIP2C), are highly conserved and expressed widely in the central nervous system. Although there is evidence that DIP2C plays a role in cognition, reports of pathogenic variants in these genes are rare and their significance is uncertain. We present 23 individuals with heterozygous DIP2C variants, all manifesting developmental delays that primarily affect expressive language and speech articulation. Eight patients had de novo variants predicting loss‐of‐function in the DIP2C gene, two patients had de novo missense variants, three had paternally inherited loss of function variants and six had maternally inherited loss‐of‐function variants, while inheritance was unknown for four variants. Four patients had cardiac defects (hypertrophic cardiomyopathy, atrial septal defects, and bicuspid aortic valve). Minor facial anomalies were inconsistent but included a high anterior hairline with a long forehead, broad nasal tip, and ear anomalies. Brainspan analysis showed elevated DIP2C expression in the human neocortex at 10–24 weeks after conception. With the cases presented herein, we provide phenotypic and genotypic data supporting the association between loss‐of‐function variants in DIP2C with a neurocognitive phenotype.
The presence of microvascular obstruction (MO) within infarcted regions may adversely influence left ventricular (LV) remodeling after acute myocardial infarction. This study examined whether the ...extent of MO directly alters the mechanical properties of the infarcted myocardium.
Seventeen dogs underwent 90 minutes of balloon occlusion of the left anterior descending coronary artery, followed by reperfusion. Gadolinium-enhanced perfusion MRI and 3D-tagging were performed 4 to 6 and 48 hours (8 animals) and 10 days (9 animals) after reperfusion. Early increase in LV end-diastolic volume (from 42+/-9 to 54+/-14 mL, P<0.05) between 4 to 6 and 48 hours after reperfusion was predicted by both extent of MO (r=0.89, P<0.01) and infarct size (r=0.83, P<0.01), defined as MRI hypoenhanced and hyperenhanced regions, respectively. Multivariate analysis demonstrated that extent of MO had better and independent value to predict LV volume than overall infarct size. A strong inverse relationship existed between magnitude of first principal strain (r=-0.80, P<0.001) and relative extent of MO within infarcted myocardium. Also, infarcted myocardium involved by extensive areas of MO demonstrated reductions of circumferential (r=-0.61, P<0.01) and longitudinal (r=-0.53, P<0. 05) stretching. Furthermore, significant reductions of radial thickening (9+/-6% versus 14+/-3%, P<0.01) occurred in noninfarcted regions adjacent to infarcts that had increased (>35%) amounts of MO.
In the early healing phase of acute myocardial infarction, the extent of MO in infarcted tissue relates to reduced local myocardial deformation and dysfunction of noninfarcted adjacent myocardium. Such strain alterations might explain the increased remodeling observed in patients with large regions of MO.
In this multicenter, double-blind trial of convalescent plasma for early, symptomatic SARS-CoV-2 infection, 1225 patients were randomly assigned to receive convalescent plasma or control plasma ...within 9 days after the onset of symptoms. Significantly fewer recipients of convalescent plasma had progression of Covid-19–associated illness leading to hospitalization.
1 Division of Physiology, Department of Medicine, University of California, San Diego, La Jolla, California 92093-0623
2 Department of Molecular Oncology, Genentech, Incorporated, South San ...Francisco, California
Skeletal muscle angiogenesis is an important physiological adaptation to increased metabolic demand, possibly dependent on vascular endothelial growth factor (VEGF), the increased expression of which is a known early response to exercise. To test the hypothesis that VEGF is essential to muscle capillary maintenance, we evaluated the consequences of targeted skeletal muscle inhibition of VEGF expression in postnatal, cage-confined VEGF loxP (+/+) mice. To delete VEGF, cre recombinase expression was accomplished using direct intramuscular injection of a recombinant adeno-associated cre recombinase expressing viral vector. Four weeks postinfection, VEGF-inactivated regions revealed 64% decreases in capillary density and capillary-to-fiber ratio. Substantial apoptosis was also observed in VEGF-depleted regions. There was no evidence of rescue at 8 wk, with a persistent 67% reduction in capillary-to-fiber ratio and a 69% decrease in capillary density. These data implicate VEGF as an essential survival factor for muscle capillarity and also demonstrate insufficient VEGF-dependent signaling leads to apoptosis in mouse skeletal muscle.
muscle; apoptosis; capillaries; peripheral vascular disease; growth factors/cytokines
Four Cu(II) complexes Cu(HL–LH)Cl
2
.H
2
O (
1
), Cu
2
(L–L)Cl
2
n
(
2
), Cu(LH)
2
0.5H
2
O (
3
) and CuL
n
(
4
) derived from a disulfide Schiff base ligand
N
,
N
...′-(1,1′-dithio-bis(phenylene))-bis(salicylideneimine) (
HL
–
LH
) were synthesized under different reaction conditions in the absence and presence of N-donor ligands and characterized by spectral, elemental, magnetic and thermal studies. A single-crystal X-ray analysis of
4
revealed that the Cu atom is in a square planar geometry, coordinated to phenolic oxygen, azomethine nitrogen and two sulfur atoms with cleavage of the S–S bond in
HL
–
LH
. Complexes
1
–
4
were found to be better antioxidants than
HL
–
LH
. Complexes
1
and
3
, possessing free OH groups, showed higher antioxidant potentials. The interactions of the Schiff base Cu(II) complexes with DNA were investigated by UV–visible and fluorescence spectroscopies and agarose gel electrophoresis. The binding constants were in the order 10
3
–10
5
M
−1
suggesting moderate binding affinity of the complexes toward CT-DNA, with complex
1
showing the maximum binding affinity. In competitive binding experiments with ethidium bromide, complex
1
displayed the highest quenching constant, consistent with the UV binding results. Complexes
1
–
4
were found to cleave DNA efficiently in its nicked or linear forms.
Display omitted
•Five novel rhenium(I) complexes were synthesized.•All complexes were characterized fully by 1H NMR, FTIR, UV–Vis and X-ray diffraction.•A rare four-membered Re2Cl2 bridging ring was ...observed.•The ligands all coordinated in a monodentate fashion.
The reactivity of the rhenium(I) precursor fac-Re(CO)5Cl with various benzo-fused ligands were studied. 2-Aminobenzothiazole (abt), mercaptobenzimidazole (mbi), N-(1,3-benzothiazol-2-yl)-2-chloroacetamide (bct), ethyl-(1H-benzimidazol-2-yl-sulfanyl)acetate (bsa) and (dibenzothiazol-2-yl)tetraazathiapentalene (dbt) were chosen as the ligands of interest, where all ligands coordinated in a monodentate mode. The novel complexes isolated were fully characterized, with abt, mbi and dbt (L) resulting in rhenium complexes of the type fac-ReCl(L)2(CO)3. However, the ligands bct and bsa produced ReCl(bct)(CO)3(NCMe) and the bridged species (µ-Cl)2Re(bsa)(CO)3 respectively.
Summary
We explored the involvement of genomic copy number variants (CNVs) in susceptibility to recurrent airway obstruction (RAO), or heaves—an asthmalike inflammatory disease in horses. Analysis of ...16 RAO‐susceptible (cases) and six RAO‐resistant (control) horses on a custom‐made whole‐genome 400K equine tiling array identified 245 CNV regions (CNVRs), 197 previously known and 48 new, distributed on all horse autosomes and the X chromosome. Among the new CNVRs, 30 were exclusively found in RAO cases and were further analyzed by quantitative PCR, including additional cases and controls. Suggestive association (P = 0.03; corrected P = 0.06) was found between RAO and a loss on chromosome 5 involving NME7, a gene necessary for ciliary functions in lungs and involved in primary ciliary dyskinesia in humans. The CNVR could be a potential marker for RAO susceptibility but needs further study in additional RAO cohorts. Other CNVRs were not associated with RAO, although several involved genes of interest, such as SPI2/SERPINA1 from the serpin gene family, which are associated with chronic obstructive pulmonary disease and asthma in humans. The SPI2/SERPINA1 CNVR showed striking variation among horses, but it was not significantly different between RAO cases and controls. The findings provide baseline information on the relationship between CNVs and RAO susceptibility. Discovery of new CNVs and the use of a larger population of RAO‐affected and control horses are needed to shed more light on their significance in modulating this complex and heterogeneous disease.
Review of Particle Physics Barnett, R M; Beringer, J; Dahl, O ...
Progress of theoretical and experimental physics,
2020, Letnik:
2020, Številka:
8
Journal Article
Recenzirano
Odprti dostop
Abstract
The Review summarizes much of particle physics and cosmology. Using data from previous editions, plus 3,324 new measurements from 878 papers, we list, evaluate, and average measured ...properties of gauge bosons and the recently discovered Higgs boson, leptons, quarks, mesons, and baryons. We summarize searches for hypothetical particles such as supersymmetric particles, heavy bosons, axions, dark photons, etc. Particle properties and search limits are listed in Summary Tables. We give numerous tables, figures, formulae, and reviews of topics such as Higgs Boson Physics, Supersymmetry, Grand Unified Theories, Neutrino Mixing, Dark Energy, Dark Matter, Cosmology, Particle Detectors, Colliders, Probability and Statistics. Among the 120 reviews are many that are new or heavily revised, including a new review on High Energy Soft QCD and Diffraction and one on the Determination of CKM Angles from B Hadrons.
The Review is divided into two volumes. Volume 1 includes the Summary Tables and 98 review articles. Volume 2 consists of the Particle Listings and contains also 22 reviews that address specific aspects of the data presented in the Listings.
The complete Review (both volumes) is published online on the website of the Particle Data Group (pdg.lbl.gov) and in a journal. Volume 1 is available in print as the PDG Book. A Particle Physics Booklet with the Summary Tables and essential tables, figures, and equations from selected review articles is available in print and as a web version optimized for use on phones as well as an Android app.
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