CrystalExplorer is a native cross‐platform program supported on Windows, MacOS and Linux with the primary function of visualization and investigation of molecular crystal structures, especially ...through the decorated Hirshfeld surface and its corresponding two‐dimensional fingerprint, and through the visualization of void spaces in the crystal via isosurfaces of the promolecule electron density. Over the past decade, significant changes and enhancements have been incorporated into the program, such as the capacity to accurately and quickly calculate and visualize quantitative intermolecular interactions and, perhaps most importantly, the ability to interface with the Gaussian and NWChem programs to calculate quantum‐mechanical properties of molecules. The current version, CrystalExplorer21, incorporates these and other changes, and the software can be downloaded and used free of charge for academic research.
CrystalExplorer is a native cross‐platform program for the visualization and investigation of molecular crystal structures.
Ankle sprains are the most common orthopaedic pathologic condition, and more concerning is the high percentage of persons who develop chronic ankle instability (CAI). Researchers have reported that ...patients with CAI are restricted occupationally, have more functional limitations, and have a poorer health-related quality of life. We do not know if these limitations decrease physical activity levels.
To assess total weekly steps taken between persons with CAI and persons with healthy ankles.
Case-control study.
University research laboratory.
A total of 20 participants with unilateral CAI (9 men, 11 women; age = 21.2 ± 1.9 years, height = 174.3 ± 6.9 cm, mass = 71.9 ± 11.7 kg) and 20 healthy participants (9 men, 11 women; age = 20.4 ± 2.1 years, height = 172.1 ± 5.5 cm, mass = 73.1 ± 13.4 kg) volunteered.
We provided all participants with a pedometer and instructed them to wear it every day for 7 days and to complete a daily step log. They also completed the Foot and Ankle Ability Measure (FAAM), the FAAM Sport version, and the International Physical Activity Questionnaire. A 2-way analysis of variance (group × sex) was used to determine if differences existed in the total number of weekly steps, ankle laxity, and answers on the International Physical Activity Questionnaire between groups and between sexes.
We found no group × sex interaction for step count (F range = 0.439-2.108, P = .08). A main effect for group was observed (F(1,38) = 10.45, P = .04). The CAI group took fewer steps than the healthy group (P = .04). The average daily step count was 6694.47 ± 1603.35 for the CAI group and 8831.01 ± 1290.01 for the healthy group. The CAI group also scored lower on the FAAM (P = .01) and the FAAM Sport version (P = .01).
The decreased step count that the participants with CAI demonstrated is concerning. This decreased physical activity may be secondary to the functional limitations reported. If this decrease in physical activity level continues for an extended period, CAI may potentially be a substantial health risk if not treated appropriately.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a pandemic with millions of human infections. One limitation to the evaluation of potential therapies and vaccines to inhibit ...SARS-CoV-2 infection and ameliorate disease is the lack of susceptible small animals in large numbers. Commercially available laboratory strains of mice are not readily infected by SARS-CoV-2 because of species-specific differences in their angiotensin-converting enzyme 2 (ACE2) receptors. Here, we transduced replication-defective adenoviruses encoding human ACE2 via intranasal administration into BALB/c mice and established receptor expression in lung tissues. hACE2-transduced mice were productively infected with SARS-CoV-2, and this resulted in high viral titers in the lung, lung pathology, and weight loss. Passive transfer of a neutralizing monoclonal antibody reduced viral burden in the lung and mitigated inflammation and weight loss. The development of an accessible mouse model of SARS-CoV-2 infection and pathogenesis will expedite the testing and deployment of therapeutics and vaccines.
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•Adenovirus transduction of human ACE2 enables SARS-CoV-2 infection of BALB/c mice•High levels of viral RNA and infectious SARS-CoV-2 accumulate in lungs•Mice transduced with human ACE2 develop viral pneumonia after SARS-CoV-2 infection•Neutralizing mAbs protect from SARS-CoV-2-induced lung infection and inflammation
Laboratory mice transduced with adenoviruses encoding human ACE2 are permissive for SARS-CoV-2 and develop pneumonia. Passive transfer of a neutralizing monoclonal antibody reduces lung infection, inflammation, and disease.
To inform the study and regulation of emerging tobacco products, we sought to identify sensitive biomarkers of tobacco-induced subclinical cardiovascular damage by testing the cross-sectional ...associations of smoking with 17 biomarkers of inflammation in 2,702 GENOA study participants belonging to sibships ascertained on the basis of hypertension. Cigarette smoking was assessed by status, intensity (number of cigarettes per day), burden (pack-years of smoking), and time since quitting. We modeled biomarkers as geometric mean (GM) ratios using generalized estimating equations (GEE). The mean age of participants was 61 ±10 years; 64.5% were women and 54.4% African American. The prevalence of smoking was 12.2%. After adjusting for potential confounders, 6 of 17 biomarkers were significantly higher among current smokers at a Bonferroni adjusted p-value threshold (p<0.003). High sensitivity C-reactive protein was the most elevated biomarker among current smokers when compared to never smokers GM ratio = 1.39 (95% CI: 1.23, 1.57); p <0.001. Among former smokers, each pack-year of cigarettes smoked was associated with a 0.4% higher serum level of hsCRP GM ratio = 1.004 (95% CI: 1.001, 1.006); p = 0.002 and each 5-year lapsed since quitting was associated with a 4% lower serum level of hsCRP GM ratio = 0.96 (95% CI: 0.93, 0.99); p = 0.006. However, we found no significant association of smoking intensity or burden with biomarkers of inflammation among current smokers. HsCRP appears to be the most sensitive biomarker of inflammation associated with cigarette smoking of those investigated, and could be a useful biomarker of smoking-related injury for the study and regulation of emerging tobacco products.
The energy of interaction between molecules is commonly expressed in terms of four key components: electrostatic, polarization, dispersion, and exchange-repulsion. Using monomer wave functions to ...obtain accurate estimates of electrostatic, polarization, and repulsion energies along with Grimme’s dispersion corrections, a series of energy models are derived by fitting to dispersion-corrected DFT energies for a large number of molecular pairs extracted from organic and inorganic molecular crystals. The best performing model reproduces B3LYP-D2/6-31G(d,p) counterpoise-corrected energies with a mean absolute deviation (MAD) of just over 1 kJ mol–1 but in considerably less computation time. It also performs surprisingly well against benchmark CCSD(T)/CBS energies, with a MAD of 2.5 kJ mol–1 for a combined data set including Hobza’s X40, S22, A24, and S66 dimers. Two of these energy models, the most accurate and the fastest, are expected to find widespread application in investigations of molecular crystals.
At the start of the 20th century, cesarean section (CS) was uncommon in obstetrics. By the end of the century, CS rates had increased dramatically worldwide. Although the explanation for the increase ...is multifactorial, a major driver in the ongoing escalation is the increase in women who are delivered by repeat CS. This is due, in part, to the fact that there has been a sharp fall in vaginal birth after CS (VBAC) rates as fewer women are offered a trial of labor after CS (TOLAC), due principally to fears of a catastrophic intrapartum uterine rupture. This paper reviewed international VBAC policies and trends. A number of themes emerged. The risk of intrapartum rupture and its associated complications is low and may sometimes be overestimated. Individual maternity hospitals in both developed and developing countries are inadequately resourced to safely supervise a TOLAC. Efforts to mitigate the risks of TOLAC by careful patient selection and good clinical practices may be underutilized. Given the serious short‐term and long‐term consequences of rising CS rates for women and for maternity services generally, a review of TOLAC policies worldwide should be prioritized and consideration given to convening a Global Consensus Development Conference on Delivery after CS.
Synopsis
The dramatic fall in trial of labor after cesarean section rates globally may reflect overestimation of risks and underestimation of benefits associated with vaginal birth.
Resistance to tyrosine kinase inhibitors in patients with chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL) is frequently caused by ...mutations in the BCR-ABL kinase domain. Ponatinib (AP24534) is a potent oral tyrosine kinase inhibitor that blocks native and mutated BCR-ABL, including the gatekeeper mutant T315I, which is uniformly resistant to tyrosine kinase inhibitors.
In this phase 1 dose-escalation study, we enrolled 81 patients with resistant hematologic cancers, including 60 with CML and 5 with Ph-positive ALL. Ponatinib was administered once daily at doses ranging from 2 to 60 mg. Median follow-up was 56 weeks (range, 2 to 140).
Dose-limiting toxic effects included elevated lipase or amylase levels and pancreatitis. Common adverse events were rash, myelosuppression, and constitutional symptoms. Among Ph-positive patients, 91% had received two or more approved tyrosine kinase inhibitors, and 51% had received all three approved tyrosine kinase inhibitors. Of 43 patients with chronic-phase CML, 98% had a complete hematologic response, 72% had a major cytogenetic response, and 44% had a major molecular response. Of 12 patients who had chronic-phase CML with the T315I mutation, 100% had a complete hematologic response and 92% had a major cytogenetic response. Of 13 patients with chronic-phase CML without detectable mutations, 100% had a complete hematologic response and 62% had a major cytogenetic response. Responses among patients with chronic-phase CML were durable. Of 22 patients with accelerated-phase or blast-phase CML or Ph-positive ALL, 36% had a major hematologic response and 32% had a major cytogenetic response.
Ponatinib was highly active in heavily pretreated patients with Ph-positive leukemias with resistance to tyrosine kinase inhibitors, including patients with the BCR-ABL T315I mutation, other mutations, or no mutations. (Funded by Ariad Pharmaceuticals and others; ClinicalTrials.gov number, NCT00660920.).
Cytoplasmic accumulation of TDP-43 is a disease hallmark for many cases of amyotrophic lateral sclerosis (ALS), associated with a neuroinflammatory cytokine profile related to upregulation of nuclear ...factor κB (NF-κB) and type I interferon (IFN) pathways. Here we show that this inflammation is driven by the cytoplasmic DNA sensor cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS) when TDP-43 invades mitochondria and releases DNA via the permeability transition pore. Pharmacologic inhibition or genetic deletion of cGAS and its downstream signaling partner STING prevents upregulation of NF-κB and type I IFN induced by TDP-43 in induced pluripotent stem cell (iPSC)-derived motor neurons and in TDP-43 mutant mice. Finally, we document elevated levels of the specific cGAS signaling metabolite cGAMP in spinal cord samples from patients, which may be a biomarker of mtDNA release and cGAS/STING activation in ALS. Our results identify mtDNA release and cGAS/STING activation as critical determinants of TDP-43-associated pathology and demonstrate the potential for targeting this pathway in ALS.
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•TDP-43 enters mitochondria, triggers mtDNA release via the mPTP•TDP-43-induced cytosolic mtDNA accumulation activates the cGAS/STING pathway•Evidence of cytoplasmic mtDNA was found in ALS patient cells and disease models•Blocking STING prevents inflammation and neurodegeneration in vitro and in vivo
TDP-43 causes inflammation in ALS by stimulating mitochondrial DNA release, which is subsequently sensed by the cytosolic cGAS/STING pathway, suggesting that inhibition of cGAS/STING could help alleviate inflammation-related damage in ALS.
This article presents the revised consensus criteria for the diagnosis of frontotemporal dysfunction in amyotrophic lateral sclerosis (ALS) based on an international research workshop on ...frontotemporal dementia (FTD) and ALS held in London, Canada in June 2015. Since the publication of the Strong criteria, there have been considerable advances in the understanding of the neuropsychological profile of patients with ALS. Not only is the breadth and depth of neuropsychological findings broader than previously recognised -
- including deficits in social cognition and language - but mixed deficits may also occur. Evidence now shows that the neuropsychological deficits in ALS are extremely heterogeneous, affecting over 50% of persons with ALS. When present, these deficits significantly and adversely impact patient survival. It is the recognition of this clinical heterogeneity in association with neuroimaging, genetic and neuropathological advances that has led to the current re-conceptualisation that neuropsychological deficits in ALS fall along a spectrum. These revised consensus criteria expand upon those of 2009 and embrace the concept of the frontotemporal spectrum disorder of ALS (ALS-FTSD).
We performed whole-genome sequencing (WGS) of 208 genomes from 53 families affected by simplex autism. For the majority of these families, no copy-number variant (CNV) or candidate de novo ...gene-disruptive single-nucleotide variant (SNV) had been detected by microarray or whole-exome sequencing (WES). We integrated multiple CNV and SNV analyses and extensive experimental validation to identify additional candidate mutations in eight families. We report that compared to control individuals, probands showed a significant (p = 0.03) enrichment of de novo and private disruptive mutations within fetal CNS DNase I hypersensitive sites (i.e., putative regulatory regions). This effect was only observed within 50 kb of genes that have been previously associated with autism risk, including genes where dosage sensitivity has already been established by recurrent disruptive de novo protein-coding mutations (ARID1B, SCN2A, NR3C2, PRKCA, and DSCAM). In addition, we provide evidence of gene-disruptive CNVs (in DISC1, WNT7A, RBFOX1, and MBD5), as well as smaller de novo CNVs and exon-specific SNVs missed by exome sequencing in neurodevelopmental genes (e.g., CANX, SAE1, and PIK3CA). Our results suggest that the detection of smaller, often multiple CNVs affecting putative regulatory elements might help explain additional risk of simplex autism.
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