Amorphous solids lack long-range order. Therefore identifying structural defects -- akin to dislocations in crystalline solids -- that carry plastic flow in these systems remains a daunting ...challenge. By comparing many different structural indicators in computational models of glasses, under a variety of conditions we carefully assess which of these indicators are able to robustly identify the structural defects responsible for plastic flow in amorphous solids. We further demonstrate that the density of defects changes as a function of material preparation and strain in a manner that is highly correlated with the macroscopic material response. Our work represents an important step towards predicting how and when an amorphous solid will fail from its microscopic structure.
To better understand the surprising low-frequency vibrational modes in structural glasses, we study the spectra of a large ensemble of sparse random matrices where disorder is controlled by the ...distribution of bond weights and network coordination. We find \(D(\omega)\) has three regimes: a very-low-frequency regime that can be predicted analytically using extremal statistics, an intermediate regime with quasi-localized modes, and a plateau with \(D(\omega) \sim \omega^0\). In the special case of uniform bond weights, the intermediate regime displays \(D(\omega) \sim \omega^4\), independent of network coordination and system size, just as recently discovered in simulations of structural glasses.
Amorphous solids lack long-range order. Therefore identifying structural defects -- akin to dislocations in crystalline solids -- that carry plastic flow in these systems remains a daunting ...challenge. By comparing many different structural indicators in computational models of glasses, under a variety of conditions we carefully assess which of these indicators are able to robustly identify the structural defects responsible for plastic flow in amorphous solids. We further demonstrate that the density of defects changes as a function of material preparation and strain in a manner that is highly correlated with the macroscopic material response. Our work represents an important step towards predicting how and when an amorphous solid will fail from its microscopic structure.
This article presents a literature review of the evaluation and management of open fractures. A case report of a patient having sustained a type II open fracture of the hallux is presented. ...Debridement, tetanus prophylaxis, reduction and stabilization, and intravenous antibiosis are the hallmarks for prompt and appropriate treatment.
Congenital hallux varus is uncommon as an isolated deformity. Many authors cite this deformity in conjunction with metatarsus varus or talipes equino varus deformities. An unusual case of bilateral ...congenital hallux varus is presented in a 9-month-old. A review of etiologies and treatment methods are given.
It is not well understood why diabetic individuals are more prone to develop severe COVID-19. To this, we here established a human kidney organoid model promoting early hallmarks of diabetic kidney ...disease development. Upon SARS-CoV-2 infection, diabetic-like kidney organoids exhibited higher viral loads compared with their control counterparts. Genetic deletion of the angiotensin-converting enzyme 2 (ACE2) in kidney organoids under control or diabetic-like conditions prevented viral detection. Moreover, cells isolated from kidney biopsies from diabetic patients exhibited altered mitochondrial respiration and enhanced glycolysis, resulting in higher SARS-CoV-2 infections compared with non-diabetic cells. Conversely, the exposure of patient cells to dichloroacetate (DCA), an inhibitor of aerobic glycolysis, resulted in reduced SARS-CoV-2 infections. Our results provide insights into the identification of diabetic-induced metabolic programming in the kidney as a critical event increasing SARS-CoV-2 infection susceptibility, opening the door to the identification of new interventions in COVID-19 pathogenesis targeting energy metabolism.
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•ACE2 is upregulated in hyperglycemia in kidney organoids and patient renal cells•Metabolic changes and increased ACE2 boost cellular infection by SARS-CoV-2•Targeting of energy metabolism in patient renal cells lowers SARS-CoV-2 infection
Garreta et al. developed a human kidney organoid system mirroring early hallmarks of diabetic kidney disease development. This resulted in higher SARS-CoV-2 infections, which were critically dependent on ACE2. Diabetic patient renal cells also showed elevated ACE2 and altered energy metabolism that following chemical targeting resulted in a reduction of SARS-CoV-2 infection.
Combinations of direct-acting antivirals are needed to minimize drug resistance mutations and stably suppress replication of RNA viruses. Currently, there are limited therapeutic options against the ...severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and testing of a number of drug regimens has led to conflicting results. Here, we show that cobicistat, which is an FDA-approved drug booster that blocks the activity of the drug-metabolizing proteins cytochrome P450-3As (CYP3As) and P-glycoprotein (P-gp), inhibits SARS-CoV-2 replication. Two independent cell-to-cell membrane fusion assays showed that the antiviral effect of cobicistat is exerted through inhibition of spike protein-mediated membrane fusion. In line with this, incubation with low-micromolar concentrations of cobicistat decreased viral replication in three different cell lines including cells of lung and gut origin. When cobicistat was used in combination with remdesivir, a synergistic effect on the inhibition of viral replication was observed in cell lines and in a primary human colon organoid. This was consistent with the effects of cobicistat on two of its known targets, CYP3A4 and P-gp, the silencing of which boosted the
antiviral activity of remdesivir in a cobicistat-like manner. When administered
to Syrian hamsters at a high dose, cobicistat decreased viral load and mitigated clinical progression. These data highlight cobicistat as a therapeutic candidate for treating SARS-CoV-2 infection and as a potential building block of combination therapies for COVID-19.
The lack of effective antiviral treatments against SARS-CoV-2 is a significant limitation in the fight against the COVID-19 pandemic. Single-drug regimens have so far yielded limited results, indicating that combinations of antivirals might be required, as previously seen for other RNA viruses. Our work introduces the drug booster cobicistat, which is approved by the FDA and typically used to potentiate the effect of anti-HIV protease inhibitors, as a candidate inhibitor of SARS-CoV-2 replication. Beyond its direct activity as an antiviral, we show that cobicistat can enhance the effect of remdesivir, which was one of the first drugs proposed for treatment of SARS-CoV-2. Overall, the dual action of cobicistat as a direct antiviral and a drug booster can provide a new approach to design combination therapies and rescue the activity of compounds that are only partially effective in monotherapy.
Lung volume reduction surgery (LVRS) as means to improve the pulmonary function and quality of life of patients with chronic obstructive pulmonary disease (COPD) can be traced back to the 1950's and ...early work by Otto Brantigan. Joel Cooper revived this concept with pioneering work in the 1990's. His work, along with others, led to the National Emphysema Treatment Trial (NETT) which demonstrated a quality of life and survival benefit for certain subsets of patients with emphysema. While the outcomes of carefully selected patients are excellent, with proven benefits in both quality of life and overall survival, the volume of LVRS being performed remains low. The procedure is highly regulated in the United States and is only performed in Centers for Medicare and Medicaid Services (CMS) approved programs. Programs are required to follow the NETT selection criteria. The program at Columbia University Medical Center/New York Presbyterian Hospital remains active. Utilizing the NETT criteria, we continue to perform LVRS with no operative mortality and excellent long-term outcomes.
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