The novel coronavirus SARS-CoV-2 (coronavirus disease 19, or COVID-19) primarily causes pulmonary injury, but has been implicated to cause hepatic injury, both by serum markers and histologic ...evaluation. The histologic pattern of injury has not been completely described. Studies quantifying viral load in the liver are lacking. Here we report the clinical and histologic findings related to the liver in 40 patients who died of complications of COVID-19. A subset of liver tissue blocks were subjected to polymerase chain reaction (PCR) for viral ribonucleic acid (RNA). Peak levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were elevated; median ALT peak 68 U/l (normal up to 46 U/l) and median AST peak 102 U/l (normal up to 37 U/l). Macrovesicular steatosis was the most common finding, involving 30 patients (75%). Mild lobular necroinflammation and portal inflammation were present in 20 cases each (50%). Vascular pathology, including sinusoidal microthrombi, was infrequent, seen in six cases (15%). PCR of liver tissue was positive in 11 of 20 patients tested (55%). In conclusion, we found patients dying of COVID-19 had biochemical evidence of hepatitis (of variable severity) and demonstrated histologic findings of macrovesicular steatosis and mild acute hepatitis (lobular necroinflammation) and mild portal inflammation. We also identified viral RNA in a sizeable subset of liver tissue samples.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was demonstrated in the placenta; however, the data on the prevalence of placental infection and associated histopathology are limited. To ...identify the frequency and features of SARS-CoV-2 involvement, we performed a clinicopathologic analysis of 75 placental cases from women infected at the time of delivery and 75 uninfected controls. Placental samples were studied with anti–SARS-CoV-2 immunohistochemistry and/or in situ hybridization. Positive results were confirmed by electron microscopy and quantitative reverse-transcription polymerase chain reaction (qRT-PCR). During delivery, only one woman had symptoms of coronavirus disease 2019, six women reported previous symptoms, and 68 women were asymptomatic. All neonates tested negative for SARS-CoV-2 as per nasopharyngeal swab PCR results. Obstetric histories were unremarkable in 29 of 75 SARS-CoV-2–positive and 8 of 75 SARS-CoV-2–negative women. Placental examination was normal in 12 of 75 infected and 3 of 75 uninfected subjects, respectively. In the remaining cases, placental pathology correlated with obstetric comorbidities without significant differences between SARS-CoV-2–positive and SARS-CoV-2–negative women. SARS-CoV-2 was identified in one placenta of an infected, but asymptomatic, parturient. Viral staining was predominantly localized to the syncytiotrophoblast (STB) which demonstrated marked damage accompanied by perivillous fibrin deposition and mixed intervillositis. A significant decrease of viral titers was detected in the attached umbilical cord compared with the villous parenchyma as per qRT-PCR. SARS-CoV-2 is seldom identified in placentas of infected women. Placental involvement by the virus is characterized by STB damage disrupting the placental barrier and can be seen in asymptomatic mothers without evidence of vertical transmission.
-Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) placental invasion is detected seldom at the time of delivery.-SARS-CoV-2 invades the villous trophoblast and disrupts placental barrier.-SARS-CoV-2 is associated with acute and chronic intervillositis.-SARS-CoV-2 placental invasion can be seen in asymptomatic infection.-SARS-CoV-2–caused disruption of the placental barrier is not always associated with vertical transmission of the infection to offspring.
Composite analogue bone models provide consistent geometric and structural properties that represent a valuable asset in a range of biomechanical analyses and testing procedures. The objective of ...this study was to evaluate the diaphyseal structural properties of the large-size Fourth-Generation composite analogue femur and tibia models concentrated on mechanical behaviors under axial compression, bending and torsion. Thirty of each large-size composite analogue models (femora and tibiae) were tested under medial-lateral four-point bending, anterior-posterior four-point bending, axial compression and external rotational torque to evaluate flexural rigidity, axial stiffness, torsional rigidity and ultimate failure strength. The composite femur was tested under torsion at both the femoral neck and the mid-diaphyseal areas. Large-size Fourth-Generation composite replicate bones exhibited intra-specimen variations under 10% for all cases and was also found to perform within the biological range of healthy adult bones (age: <80 years old) range with respect to flexural rigidity (<8%) and torsional rigidity (<12%). The failure modes of these composite models were close to published findings for human bones (four-point bending: butterfly fragment fracture; torsional: spiral fracture; and compression: transverse fracture). The large-size composite analogue femur and tibia are close to ideal replicas for standardization in biomechanical analyses. One advantage of these analogue models is that their variability is significantly lower than that of cadaveric specimens for all loading regimens. Published results vary widely in cadaveric studies, which is likely due to the high anatomic variability among cadaveric specimens. This study evaluated and advanced our overall understanding of the capacity of composite analogue bone models mimic the structural properties of average healthy adult human bones.
To expand the clinical phenotype of autosomal dominant congenital spinal muscular atrophy with lower extremity predominance (SMA-LED) due to mutations in the dynein, cytoplasmic 1, heavy chain 1 ...(DYNC1H1) gene.
Patients with a phenotype suggestive of a motor, non-length-dependent neuronopathy predominantly affecting the lower limbs were identified at participating neuromuscular centers and referred for targeted sequencing of DYNC1H1.
We report a cohort of 30 cases of SMA-LED from 16 families, carrying mutations in the tail and motor domains of DYNC1H1, including 10 novel mutations. These patients are characterized by congenital or childhood-onset lower limb wasting and weakness frequently associated with cognitive impairment. The clinical severity is variable, ranging from generalized arthrogryposis and inability to ambulate to exclusive and mild lower limb weakness. In many individuals with cognitive impairment (9/30 had cognitive impairment) who underwent brain MRI, there was an underlying structural malformation resulting in polymicrogyric appearance. The lower limb muscle MRI shows a distinctive pattern suggestive of denervation characterized by sparing and relative hypertrophy of the adductor longus and semitendinosus muscles at the thigh level, and diffuse involvement with relative sparing of the anterior-medial muscles at the calf level. Proximal muscle histopathology did not always show classic neurogenic features.
Our report expands the clinical spectrum of DYNC1H1-related SMA-LED to include generalized arthrogryposis. In addition, we report that the neurogenic peripheral pathology and the CNS neuronal migration defects are often associated, reinforcing the importance of DYNC1H1 in both central and peripheral neuronal functions.
We report severe acute respiratory syndrome coronavirus 2 in semen by using quantitative reverse transcription PCR during the late convalescent phase. Virus was associated with adequate humoral and ...cell-mediated responses, suggesting possible seeding of the immune-privileged testes. We provide longitudinal semen quality data for 6 other men, including 3 who had oligozoospermia.
Treatment of BRAF(V600E) mutant melanoma by small molecule drugs that target the BRAF or MEK kinases can be effective, but resistance develops invariably. In contrast, colon cancers that harbour the ...same BRAF(V600E) mutation are intrinsically resistant to BRAF inhibitors, due to feedback activation of the epidermal growth factor receptor (EGFR). Here we show that 6 out of 16 melanoma tumours analysed acquired EGFR expression after the development of resistance to BRAF or MEK inhibitors. Using a chromatin-regulator-focused short hairpin RNA (shRNA) library, we find that suppression of sex determining region Y-box 10 (SOX10) in melanoma causes activation of TGF-β signalling, thus leading to upregulation of EGFR and platelet-derived growth factor receptor-β (PDGFRB), which confer resistance to BRAF and MEK inhibitors. Expression of EGFR in melanoma or treatment with TGF-β results in a slow-growth phenotype with cells displaying hallmarks of oncogene-induced senescence. However, EGFR expression or exposure to TGF-β becomes beneficial for proliferation in the presence of BRAF or MEK inhibitors. In a heterogeneous population of melanoma cells having varying levels of SOX10 suppression, cells with low SOX10 and consequently high EGFR expression are rapidly enriched in the presence of drug, but this is reversed when the drug treatment is discontinued. We find evidence for SOX10 loss and/or activation of TGF-β signalling in 4 of the 6 EGFR-positive drug-resistant melanoma patient samples. Our findings provide a rationale for why some BRAF or MEK inhibitor-resistant melanoma patients may regain sensitivity to these drugs after a 'drug holiday' and identify patients with EGFR-positive melanoma as a group that may benefit from re-treatment after a drug holiday.
The thymus is a central lymphoid organ primarily responsible for the development of T cells. A small proportion of B cells, however, also reside in the thymus to assist negative selection of ...self-reactive T cells. Here we show that the thymus of human neonates contains a consistent contingent of CD138
plasma cells, producing all classes and subclasses of immunoglobulins with the exception of IgD. These antibody-secreting cells are part of a larger subset of B cells that share the expression of signature genes defining mouse B1 cells, yet lack the expression of complement receptors CD21 and CD35. Data from single-cell transcriptomic, clonal correspondence and in vitro differentiation assays support the notion of intrathymic CD138
plasma cell differentiation, alongside other B cell subsets with distinctive molecular phenotypes. Lastly, neonatal thymic plasma cells also include clones reactive to commensal and pathogenic bacteria that commonly infect children born with antibody deficiency. Thus, our findings point to the thymus as a source of innate humoral immunity in human neonates.
BRAF mutations are frequent in cutaneous melanomas, and BRAF inhibitors (BRAFi) have shown remarkable clinical efficacy in BRAF mutant melanoma patients. However, acquired drug resistance can occur ...rapidly and tumor(s) often progresses thereafter. Various mechanisms of BRAFi resistance have recently been described; however, the mechanism of resistance remains controversial. In this study, we developed BRAFi-resistant melanoma cell lines and found that metastasis-related epithelial to mesenchymal transition properties of BRAFi-resistant cells were enhanced significantly. Upregulation of EGFR was observed in BRAFi-resistant cell lines and patient tumors because of demethylation of EGFR regulatory DNA elements. EGFR induced PI3K/AKT pathway activation in BRAFi-resistant cells through epigenetic regulation. Treatment of EGFR inhibitor was effective in BRAFi-resistant melanoma cell lines. The study demonstrates that EGFR epigenetic activation has important implications in BRAFi resistance in melanoma.
The development of nanoplasmonic devices, such as plasmonic circuits and metamaterial superlenses in the visible to ultraviolet frequency range, is hampered by the lack of low-loss plasmonic media. ...Recently, strong plasmonic response was reported in a certain class of topological insulators. Here, we present a first-principles density functional theory analysis of the dielectric functions of topologically insulating quaternary (Bi,Sb)2 (Te,Se)3 trichalcogenide compounds. Bulk plasmonic properties, dominated by interband transitions, are observed from 2 to 3 eV and extend to higher frequencies. Moreover, trichalcogenide compounds are better plasmonic media than gold and silver at blue and UV wavelengths. By analyzing thin slabs, we also show that these materials exhibit topologically protected surface states, which are capable of supporting propagating plasmon polariton modes over an extremely broad spectral range, from the visible to the mid-infrared and beyond, owing to a combination of inter- and intra-surface band transitions.
The worldwide annual production volume of textiles is nearly one hundred million metric tons. Most of these undergo treatments to achieve specific properties, such as color, hydrophobicity, ...antimicrobial, or UV protection, using chemicals that lead to collateral environmental consequences. There is great interest in developing alternative and sustainable strategies to achieve textile functionality that do not involve chemical treatment. Here we present a thermal drawing approach to achieve fiber surface gratings on a rectangular cross‐section. We demonstrate directional wetting properties as well as structural coloration based on the gratings. Periods down to ≈ 600 nm were established on the surface of a fiber. Fabrics displaying higher‐order diffraction peaks in the visible regime were produced from surface‐patterned fibers using convetional weaving machinery.
An all‐structural‐fiber surface functionalization technique combining conventional macromachining and thermal fiber drawing is reported. Ribbon fibers with a variety of sub‐micrometer surface features extending uniformly over kilometer lengths are produced at rates of tens of meters per minute, enabling a nonchemical, environmentally friendly approach toward functional textiles.
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