Production and bioprocessing of Taxol from Aspergillus niger, an endophyte of Encephalartos whitelockii, with a plausible biosynthetic stability: antiproliferative activity and cell cycle analysis.

The biosynthetic potency of Taxol by fungi raises their prospective to be a platform for commercial production of Taxol, nevertheless, the attenuation of its productivity with the fungal storage, is the challenge. Thus, screening for a novel fungal isolate inhabiting ethnopharmacological plants, with a plausible metabolic stability for Taxol production could be one of the most affordable approaches. Aspergillus niger OR414905.1, an endophyte of Encephalartos whitelockii, had the highest Taxol productivity (173.9 µg/L). The chemical identity of the purified Taxol was confirmed by HPLC, FTIR, and LC-MS/MS analyses, exhibiting the same molecular mass (854.5 m/z) and molecular fragmentation pattern of the authentic Taxol. The purified Taxol exhibited a potent antiproliferative activity against HepG-2, MCF-7 and Caco-2, with IC50 values 0.011, 0.016, and 0.067 µM, respectively, in addition to a significant activity against A. flavus, as a model of human fungal pathogen. The purified Taxol displayed a significant effect against the cellular migration of HepG-2 and MCF-7 cells, by ~ 52-59% after 72 h, compared to the control, confirming its interference with the cellular matrix formation. Furthermore, the purified Taxol exhibited a significant ability to prompt apoptosis in MCF-7 cells, by about 11-fold compared to control cells, suppressing their division at G2/M phase. Taxol productivity by A. niger has been optimized by the response surface methodology with Plackett-Burman Design and Central Composite Design, resulting in a remarkable ~ 1.6-fold increase (279.8 µg/L), over the control. The biological half-life time of Taxol productivity by A. niger was ~ 6 months of preservation at 4 â„ƒ, however, the Taxol yield by A. niger was partially restored in response to ethyl acetate extracts of E. whitelockii, ensuring the presence of plant-derived signals that triggers the cryptic Taxol encoding genes.

Production and bioprocessing of epothilone B from Aspergillus niger, an endophyte of Latania loddegesii, with a conceivable biosynthetic stability: anticancer, anti-wound healing activities and cell cycle analysis.

Epothilones are one of the common prescribed anticancer drugs for solid tumors, for their exceptional binding affinity with ß-tubulin microtubule, stabilizing their disassembly, causing an ultimate arrest to the cellular growth. Epothilones were initially isolated from Sornagium cellulosum, however, their extremely slow growth rate and low yield of epothilone is the challenge. So, screening for a novel fungal endophyte dwelling medicinal plants, with higher epothilone productivity and feasibility of growth manipulation was the objective. Aspergillus niger EFBL-SR OR342867, an endophyte of Latania loddegesii, has been recognized as the heady epothilone producer (140.2 µg/L). The chemical structural identity of the TLC-purified putative sample of A. niger was resolved from the HPLC, FTIR and LC-ESI-MS/MS analyses, with an identical molecular structure of the authentic epothilone B. The purified A. niger epothilone B showed a resilient activity against MCF-7 (0.022 µM), HepG-2 (0.037 µM), and HCT-116 (0.12 µM), with selectivity indices 21.8, 12.9 and 4, respectively. The purified epothilone B exhibited a potential anti-wound healing activity to HepG-2 and MCF-7 cells by ~ 54.07 and 60.0%, respectively, after 24 h, compared to the untreated cells. The purified epothilone has a significant antiproliferative effect by arresting the cellular growth of MCF-7 at G2/M phase by ~ 2.1 folds, inducing the total apoptosis by ~ 12.2 folds, normalized to the control cells. The epothilone B productivity by A. niger was optimized by the response surface methodology, with ~ 1.4 fold increments (266.9 µg/L), over the control. The epothilone productivity by A. niger was reduced by ~ 2.4 folds by 6 months storage as a slope culture at 4 °C, however, the epothilone productivity was slightly restored with ethylacetate extracts of L. loddegesii, confirming the plant-derived chemical signals that partially triggers the biosynthetic genes of A. niger epothilones. So, this is the first report emphasizing the metabolic potency of A. niger, an endophyte of L. loddegesii, to produce epothilone B, that could be a new platform for industrial production of this drug.

Orbital Mass Identified With Point-of-Care Ultrasound in a Child Presenting With Eyelid Swelling.

ABSTRACT: Point-of-care ultrasound was used in a child presenting to the emergency department with progressively worsening left eyelid swelling. The early use of ultrasound was helpful in detecting a soft tissue mass that is exhibiting pressure effect on the eyeball. Point-of-care ultrasound helped expedite advanced imaging and consultation with the specialist. The patient eventually had a biopsy and was diagnosed with idiopathic orbital inflammation.

Epidemiological associations of asthma status and tobacco use, substance use, and substance misuse among adults in the United States, 2015-2019.

Objective: Adults with asthma have a higher prevalence of substance use. However, knowledge is scarce regarding the associations between adults with asthma and tobacco use, substance use, and substance misuse. This study aimed to use national samples of United States adults to assess the comprehensive use and misuse of substances in adults with asthma.Method: This cross-sectional study comprised data drawn from the 2015 to 2019 National Survey on Drug Use and Health. Weighted logistic regressions were used to measure the associations of asthma status (lifetime and current) with last month's tobacco use; substance use (alcohol, marijuana, cocaine, crack, heroin, hallucinogens, inhalants); and substance misuse (pain relievers, tranquilizers, stimulants, sedatives). All regression models were controlled for sociodemographic characteristics, comorbidity, last-month serious psychological distress, and co-substance use and misuse. Results: Adults with lifetime asthma (Nweighted = 115,600,887) were less likely to use cigarettes, cigars, smokeless tobacco, inhalants, and polyuse of any substance. In contrast, adults with current asthma (Nweighted = 765,096,31) were more likely to use pipe tobacco, cocaine, non-prescribed tranquilizers, and less likely to use polytobacco products. Adults with lifetime asthma were associated with fewer last-month tobacco and inhalant use than those without lifetime asthma. However, adults with current asthma were associated with greater last month's pipe tobacco, cocaine, and non-prescribed tranquilizers. Conclusion: Thus, further longitudinal studies are recommended among adults with asthma to effectively design tailored treatment and prevention interventions.

CT in the detection of latent tuberculosis: a systematic review.

AIM: To evaluate the use of computed tomography (CT) and low-dose CT in the detection of latent tuberculosis (TB). MATERIALS AND METHODS: A systematic search of literature in adherence with the PRISMA guidelines was carried out. Quality assessment of the included studies was conducted. RESULTS: The search strategy identified a total of 4,621 studies. Sixteen studies were considered eligible and included in the review. There was high heterogeneity among all studies. CT was identified as much more sensitive for the detection of latent TB in all studies despite chest radiography often being recommended in guidelines to assess patients for latent TB. Low-dose CT showed promising results in four of the studies; however, these results were limited due to small sample sizes. CONCLUSION: CT is much superior to chest radiography consistently identifying additional cases of latent TB. There are limited high-quality publications available using low-dose CT but findings thus far suggest low-dose CT could be used as an alternative to standard-dose CT for the detection of latent TB. It is recommended that a randomised controlled trial investigating low-dose CT should be carried out.

Global mapping of herpesvirus-host protein complexes reveals a transcription strategy for late genes.

Mapping host-pathogen interactions has proven instrumental for understanding how viruses manipulate host machinery and how numerous cellular processes are regulated. DNA viruses such as herpesviruses have relatively large coding capacity and thus can target an extensive network of cellular proteins. To identify the host proteins hijacked by this pathogen, we systematically affinity tagged and purified all 89 proteins of Kaposi's sarcoma-associated herpesvirus (KSHV) from human cells. Mass spectrometry of this material identified over 500 virus-host interactions. KSHV causes AIDS-associated cancers, and its interaction network is enriched for proteins linked to cancer and overlaps with proteins that are also targeted by HIV-1. We found that the conserved KSHV protein ORF24 binds to RNA polymerase II and brings it to viral late promoters by mimicking and replacing cellular TATA-box-binding protein (TBP). This is required for herpesviral late gene expression, a complex and poorly understood phase of the viral lifecycle.

Characterization of Olive Oil Volatile Compounds after Elution through Selected Bleaching Materials-Gas Chromatography-Mass Spectrometry Analysis.

Using different bleaching materials to eliminate or reduce organic volatiles in deteriorated olive oils will positively affect its characteristics. This study aims to identify the volatiles of oxidized olive oil after physical bleaching using selected immobilized adsorbents. Oxidized olive oil was eluted using open-column chromatography packed with silica gel, bentonite, resin, Arabic gum, and charcoal at a 1:5 eluent system (w/v, adsorbent: oxidized olive oil). The smoke point was determined. The collected distilled vapor was injected into GC-MS to identify the volatiles eluted after partial refining with each of these bleaching compounds. The results showed that volatile compounds were quantitatively and qualitatively affected by the type of adsorbents used for the elution of olive oil and the smoking points of eluted oils. The most prominent detected volatile compounds were limonene (14.53%), piperitone (10.35%), isopropyl-5-methyl-(2E)-hexenal (8.6%), methyl octadecenoate (6.57%), and citronellyl acetate (5.87%). Both bentonite and resin were superior in decreasing the ratio of volatile compounds compared with other bleaching materials used. Resin immobilized medium was significantly affected (p < 0.05), raising the smoke point. These results highlighted some information regarding the characteristics of volatile compounds that result after the physical elution of olive oil through selected adsorbents.

MP-NeRF: A massively parallel method for accelerating protein structure reconstruction from internal coordinates.

The conversion of proteins between internal and cartesian coordinates is a limiting step in many pipelines, such as molecular dynamics simulations and machine learning models. This conversion is typically carried out by sequential or parallel applications of the Natural extension of Reference Frame (NeRF) algorithm. This work proposes a massively parallel NeRF implementation which, depending on the polymer length, achieves speedups between 400 and 1200× over the previous state-of-the-art. It accomplishes this by dividing the conversion into three main phases: parallel composition of the monomer backbone, assembly of backbone subunits, and parallel elongation of sidechains; and by batching these computations into a minimal number of efficient matrix operations. Special emphasis is placed on reusability and ease of use. We open source the code (available at https://github.com/EleutherAI/mp_nerf) and provide a corresponding python package.

Creation of a protective space between the rectum and prostate prior to prostate radiotherapy using a hydrogel spacer.

The placement of a polyethylene glycol (PEG) hydrogel spacer is a recently developed technique employed to reduce the radiation dose administered to the rectum during prostate radiotherapy. This procedure has been adopted by urologists and radiation oncologists involved in transperineal prostate biopsy and brachytherapy, and more recently by radiologists with experience in transperineal prostate procedures. Radiologists should be familiar with the product, which may be encountered on computed tomography (CT) or magnetic resonance imaging (MRI). Radiologists may wish to become involved in the delivery of this increasingly utilised procedure. This review familiarises radiologists with the technique and risks and benefits of the use of transperineal delivery of hydrogel spacers with imaging examples.

Vaginal preparation with different antiseptic solutions before cesarean section for preventing postoperative infections: A systematic review and network meta-analysis.

AIMS: We aimed to investigate the effect of various vaginal wash solutions on reducing risks of post-cesarean endometritis, wound infections, fever, and hospital stay duration. METHODS: Scopus, Web of Science, PubMed, and Cochrane Library were searched for randomized clinical trials that compared different vaginal wash solutions to each other or to "no vaginal cleaning"; without restriction on the age of parturients or site where trials were conducted. We analyzed this frequentist network meta-analysis using the netmeta package in R software version 4.1.2; synthesized data as mean difference or risk ratio with their 95% confidence intervals. RESULTS: Our network meta-analysis included 29 RCTs with a total sample size of 9311 women undergoing CS. Regarding post-cesarean endometritis, we found that povidone-iodine had the highest significant risk reduction compared to "no vaginal cleaning" (RR = 0.08, 95% CI [0.01, 0.69]). While regarding post-cesarean reduction of wound infection, fever, and hospital stay duration, we found that chlorhexidine 4% (RR = 0.17, 95% CI [0.05, 0.65]), saline 0.9% (RR = 0.12, 95% CI [0.03; 0.48]), and saline 0.9% (MD = -1.29, 95% CI [-2.18; -0.39]), respectively, had the highest significant risk reduction compared to "no vaginal cleaning." CONCLUSION: Vaginal wash solutions were associated with a significant reduction of post-cesarean endometritis, wound infection, fever, and hospital stay duration. Since povidone-iodine had the highest significant reduction of post-cesarean endometritis, we recommend setting povidone-iodine as the standard practice as pre cesarean vaginal wash solution; consistent practice guidelines of Enhanced Recovery After Surgery (ERAS).

Aptamers: Potential Diagnostic and Therapeutic Agents for Blood Diseases.

Aptamers are RNA/DNA oligonucleotide molecules that specifically bind to a targeted complementary molecule. As potential recognition elements with promising diagnostic and therapeutic applications, aptamers, such as monoclonal antibodies, could provide many treatment and diagnostic options for blood diseases. Aptamers present several superior features over antibodies, including a simple in vitro selection and production, ease of modification and conjugation, high stability, and low immunogenicity. Emerging as promising alternatives to antibodies, aptamers could overcome the present limitations of monoclonal antibody therapy to provide novel diagnostic, therapeutic, and preventive treatments for blood diseases. Researchers in several biomedical areas, such as biomarker detection, diagnosis, imaging, and targeted therapy, have widely investigated aptamers, and several aptamers have been developed over the past two decades. One of these is the pegaptanib sodium injection, an aptamer-based therapeutic that functions as an anti-angiogenic medicine, and it is the first aptamer approved by the U.S. Food and Drug Administration (FDA) for therapeutic use. Several other aptamers are now in clinical trials. In this review, we highlight the current state of aptamers in the clinical trial program and introduce some promising aptamers currently in pre-clinical development for blood diseases.

In vitro study of the effect of high temperature on erythrocytes in sickle cell trait.

Background: Although, sickle cell trait (SCT) was considered a benign condition with most patients being asymptomatic, however, there is an impressive increase in the number of sudden deaths in the military recruits and athletes, which has led to SCT as a rapidly emerging medical issue. Genetic factors have been extensively investigated in the etiopathogenesis of SCT but, environmental factors have not been studied in depth. Aims: The main aim of this study was to investigate the effect of high temperature on the red blood cells (RBCs) in those with SCT and compare this to a control group lacking SCT. Patients and Methods: Heat stress to RBCs was induced by in vitro incubation of freshly drawn blood at high temperatures (45°C for 35 min). Additional information such as hemoglobin (Hb) level, RBC count, mean corpuscular volume (MCV), and hemoglobin S level was obtained from the medical record of the case and control groups. Data were entered in Statistical Package for Social Sciences version 22.0 (IBM Corp, Armonk, NY, United States) and analyzed to examine the research hypothesis. Results: A total of 17 blood samples from SCT (HbAS subjects) labeled as cases and 16 samples from controls (HbAA subjects) were included in this study. The results of this study showed no significant change in sickled erythrocytes in SCT in response to in vitro heat stress. Conclusion: This study's findings appear to suggest that hyperthermia could be excluded as one of the major factors inducing sickling complications during exhausting exercise. Long-term studies in the future are recommended in this area, particularly to assess the effect of high temperature and sudden death in SCT.

The Utility of Carbohydrate-Deficient Transferrin in Identifying Chronic Alcohol Users in the Injured Patient: Expanding the Toolkit.

BACKGROUND: Alcohol use remains abundant in patients with traumatic injury. Previous studies have suggested that serum carbohydrate-deficient transferrin (%dCDT) levels, relative to blood alcohol levels (BALs), may better differentiate episodic binge drinkers from sustained heavy consumers in admitted patients with traumatic injury. We characterized %dCDT levels and BAL levels to differentiate binge drinkers from sustained heavy consumers in admitted trauma patients and their associations with outcomes. METHODS: This prospective, cross-sectional, observational study assessed %dCDT and BAL levels in admitted male and female patients with traumatic injury (≥18 y) at an American College of Surgeons Committee on Trauma level-1 center from July 2014 to June 2016. We designated patients with %dCDT levels ≥1.7% (CDT+) as chronic alcohol users and dichotomized acutely intoxicated patients using three different BAL-level thresholds. Primary outcomes included in-hospital complications, along with prolonged ventilation and intensive care unit length of stay, both defined as the top decile. Secondary outcomes included rates of drug or alcohol withdrawal and all-cause mortality. Analyses were adjusted for clinical factors. RESULTS: We studied 715 patients (77.5% men, 60.6% ≤ 40 y of age, median Injury Severity Score: 14, 41.7% motor vehicle crashes, 17.9% gunshot wounds, 11.1% falls). While 31.0% were CDT+, 48.7% were BAL>0. After adjusting for CDT levels, BAL levels >0, >100, or >200 were not associated with adverse outcomes. However, CDT+ relative to patients with CDT were associated with complications (adjusted odds ratio: 1.96 [1.24-3.09]), prolonged ventilation days (3.23 [1.08-9.65]), and prolonged intensive care unit stays (2.83 [1.20-6.68]). CONCLUSIONS: In this 2-year prospective, cross-sectional, and observational study, we found that %dCDT levels, relative to BAL levels, may better stratify admitted patients with traumatic injury into acute versus chronic alcohol users, identifying those at higher risk for in-hospital complications.

Efficacy of ferumoxytol versus sodium ferric gluconate in anemia management in outpatient hemodialysis patients: A prospective cohort study.

BACKGROUND: Intravenous iron is one of the main therapies for anemia management in hemodialysis-dependent patients. Data comparing the efficacy of ferumoxytol versus other parenteral iron supplements are scarce. The objective of the study was to compare the efficacy of ferumoxytol with that of sodium ferric gluconate in outpatient hemodialysis patients. MATERIALS AND METHODS: A prospective, observational study was conducted in outpatients receiving ferumoxytol 510 mg once or twice quarterly compared to sodium ferric gluconate 125 mg weekly in a single center hemodialysis center in Ontario, Canada. Patient demographics, hemoglobin levels, iron indices, iron doses, and erythropoiesis-stimulating agent (ESA) doses were collected. RESULTS: The study sample consisted of 291 observations from 173 patients. Generalized estimating equations of multiple linear regression modeling were conducted to compare the outcomes while adjusting for baseline scores. Approximately 25% of the study participants received ferumoxytol while 75% received sodium ferric gluconate. Patients treated were mainly males (58.4%), and the mean age was 68.73 (SD ± 13.03) years. Both groups did not show significant differences in their hemoglobin levels (Wald z = 0.54; p = 0.46), ESA utilization at 3 months (Wald z = 0.20; p = 0.65), and TSAT levels (Wald z = 3.45; p = 0.06). However, the iron levels (Wald z = 4.24; p = 0.04) and ferritin levels (Wald z = 5.14; p = 0.02) were higher in the ferric gluconate group (Wald z = 58.78; p ≤ 0.001), and patients who received ferumoxytol received more blood transfusions as compared to those who received sodium ferric gluconate (χ2 = 16.71; p ≤ 0.001). CONCLUSION: Both iron products maintained hemoglobin levels, but patients receiving ferumoxytol had lower iron indices and received more blood transfusions compared to patients who received sodium ferric gluconate.

Ultra-low-dose thoracic CT with model-based iterative reconstruction (MBIR) in cystic fibrosis patients undergoing treatment with cystic fibrosis transmembrane conductance regulators (CFTR).

AIM: To assess the utility of a volumetric low-dose computed tomography (CT) thorax (LDCTT) protocol at a dose equivalent to a posteroanterior (PA) and lateral chest radiograph for surveillance of cystic fibrosis (CF) patients. MATERIALS AND METHODS: A prospective study was undertaken of 19 adult patients with CF that proceeded to LDCTT at 12 and 24 months following initiation of ivacaftor. A previously validated seven-section, low-dose axial CT protocol was used for the 12-month study. A volumetric LDCTT protocol was developed for the 24-month study and reconstructed with hybrid iterative reconstruction (LD-ASIR) and pure iterative reconstruction (model-based IR [LD-MBIR]). Radiation dose was recorded for each scan. Image quality was assessed quantitatively and qualitatively, and disease severity was assessed using a modified Bhalla score. Statistical analysis was performed and p-values of <0.05 were considered statistically significant. RESULTS: Volumetric LD-MBIR studies were acquired at a lower radiation dose than the seven-section studies (0.08 ± 0.01 versus 0.10 ± 0.02 mSv; p=0.02). LD-MBIR and seven-section ASIR images had significantly lower levels of image noise compared with LD-ASIR images (p<0.0001). Diagnostic acceptability scores and depiction of bronchovascular structures were found to be acceptable for axial and coronal LD-MBIR images. LD-MBIR images were superior to LD-ASIR images for all qualitative parameters assessed (p<0.0001). No significant change was observed in mean Bhalla score between 1-year and 2-year studies (p=0.84). CONCLUSIONS: The use of a volumetric LDCTT protocol (reconstructed with pure IR) enabled acquisition of diagnostic quality CT images, which were considered extremely useful for surveillance of CF patients, at a dose equivalent to a PA and lateral chest radiograph.

Epidemiology of pediatric sepsis in the pediatric intensive care unit of king Abdulaziz Medical City, Jeddah, Saudi Arabia.

BACKGROUND: Pediatric sepsis remains a significant cause of morbidity and mortality worldwide. This study aimed to identify the incidence of sepsis and septic shock among patients admitted to the pediatric intensive care unit (PICU) of a tertiary center in Saudi Arabia.  Patients' demographics and risk factors associated with sepsis-related mortality were also investigated. METHODS: A retrospective cohort study was conducted in the PICU of King Abdulaziz Medical City, Jeddah (KAMC-J). KAMC-J is a tertiary care hospital in the western region of Saudi Arabia. A total of 2389 patients admitted to the PICU of KAMC-J between January 1, 2013 and December 31, 2017 were screened and evaluated for sepsis using The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). RESULTS: Of the 2389 total admissions to the PICU, 113 patients (4.9%) met the definition of Sepsis-3; 50.4% of the 113 patients met the definition of septic shock. Most patients (66.3%) were less than 6 years old, and 52.2% were male. Eight-five patients (75.2%) had underlying comorbidities. The respiratory system was the most common primary site of infection (57.5%). Bacterial and viral infections were the most common infectious etiology with reported rates of 29.2 and 21.2%, respectively. The median duration of PICU stay was 8 days and the 28-day PICU mortality rate was 23.9%. A Pediatric Sequential Organ Failure Assessment (pSOFA) Score greater than four and a pre-existing percutaneous central venous catheter were associated with a significant increase in mortality, with adjusted odds ratios of 3.6 (95% confidence interval: 1.30-9.93) and 9.27 (95% confidence interval: 1.28-67.29), respectively. CONCLUSIONS: The incidence of sepsis in our institution is comparable to that reported internationally; however, the mortality rate is higher than that of developed countries. Nationwide studies identifying sepsis epidemiology are needed to improve the outcome of pediatric sepsis. Following international guidelines for central-line insertion and maintenance is of paramount importance.

Efficacy of alteplase 1 versus 2 mg dose in restoring haemodialysis catheter function (Alte-dose 2): A randomized double-blind controlled study.

AIM: Data about the optimal alteplase dose required to treat haemodialysis catheter occlusion (HDC) are scarce. The purpose of the clinical trial was to examine the effectiveness of alteplase 2 mg as compared with 1 mg in restoring HDC function. METHODS: A double-blind, randomized, controlled clinical trial was conducted in a single-centre in southwestern Ontario, Canada. Rate of clot resolution, catheter replacements, catheter stripping, and mean catheter survival time were assessed using Kaplan-Meier, Cox-proportional hazard and clustered logic regression analyses. RESULTS: On a sample of 48 haemodialysis patients who provided 252 catheter occlusion events, the rate of clot resolution at the catheter site in the 2 mg group was 85.7% as opposed to 84.9% in the 1 mg group. There were only six catheter removals and 10 catheter stripping events. Cox regression analysis revealed no difference between the two groups in the hazard of occlusion on the primary 48 observations after the initial alteplase management (P = 0.267; hazard ratio = 0.72; 95% confidence interval 0.40-1.3). Correlated logistic regression on all 252 observations indicated no difference in the rate of post alteplase clot resolution (P = 0.336; odds ratio = 2.4, 95% confidence interval 0.399-14.6) between the two groups. CONCLUSION: Alteplase 1 mg is as effective as 2 mg in restoring HDC malfunction and may result in cost reduction in haemodialysis units.

Predicting the impact of Lynch syndrome-causing missense mutations from structural calculations.

Accurate methods to assess the pathogenicity of mutations are needed to fully leverage the possibilities of genome sequencing in diagnosis. Current data-driven and bioinformatics approaches are, however, limited by the large number of new variations found in each newly sequenced genome, and often do not provide direct mechanistic insight. Here we demonstrate, for the first time, that saturation mutagenesis, biophysical modeling and co-variation analysis, performed in silico, can predict the abundance, metabolic stability, and function of proteins inside living cells. As a model system, we selected the human mismatch repair protein, MSH2, where missense variants are known to cause the hereditary cancer predisposition disease, known as Lynch syndrome. We show that the majority of disease-causing MSH2 mutations give rise to folding defects and proteasome-dependent degradation rather than inherent loss of function, and accordingly our in silico modeling data accurately identifies disease-causing mutations and outperforms the traditionally used genetic disease predictors. Thus, in conclusion, in silico biophysical modeling should be considered for making genotype-phenotype predictions and for diagnosis of Lynch syndrome, and perhaps other hereditary diseases.

Identification of individuals by trait prediction using whole-genome sequencing data.

Prediction of human physical traits and demographic information from genomic data challenges privacy and data deidentification in personalized medicine. To explore the current capabilities of phenotype-based genomic identification, we applied whole-genome sequencing, detailed phenotyping, and statistical modeling to predict biometric traits in a cohort of 1,061 participants of diverse ancestry. Individually, for a large fraction of the traits, their predictive accuracy beyond ancestry and demographic information is limited. However, we have developed a maximum entropy algorithm that integrates multiple predictions to determine which genomic samples and phenotype measurements originate from the same person. Using this algorithm, we have reidentified an average of >8 of 10 held-out individuals in an ethnically mixed cohort and an average of 5 of either 10 African Americans or 10 Europeans. This work challenges current conceptions of personal privacy and may have far-reaching ethical and legal implications.

Five-Coordinated Geometries from Molecular Structures to Solutions in Copper(II) Complexes Generated from Polydentate-N-Donor Ligands and Pseudohalides.

A novel series of mononuclear five-coordinated pseudohalido-Cu(II) complexes displaying distorted square bipyramidal: [Cu(L1)(NCS)2] (1), [Cu(L2)(NCS)2] (2) and [Cu(L3)(NCS)]ClO4 (5) as well as distorted trigonal bipyramidal: [Cu(isp3tren)(N3)]ClO4 (3), [Cu(isp3tren)(dca)]ClO4 (4) and [Cu(tedmpza)(dca)]ClO4·0.67H2O (6) geometries had been synthesized and structurally characterized using X-ray single crystal crystallography, elemental microanalysis, IR and UV-vis spectroscopy, and molar conductivity measurements. Different N-donor amine skeletons including tridentate: L1 = [(2-pyridyl)-2-ethyl)-(3,4-dimethoxy)-2-methylpyridyl]methylamine and L2 = [(2-pyridyl)-2-ethyl)-(3,5-dimethyl-4-methoxy)-2-methyl-pyridyl]methylamine, and tetradentate: L3 = bis(2-ethyl-di(3,5-dimethyl-1H-pyrazol-1-yl)-[2-(3,4-dimethoxy-pyridylmethyl)]amine, tedmpza = tris[(2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]amine and isp3tren = tris[(2-isopropylamino)ethyl)]amine ligands were employed. Molecular structural parameters such as nature of coligand, its chelate ring size and steric environment incorporated into its skeleton, which lead to adopting one of the two limiting geometries in these complexes and other reported compounds are analyzed and correlated to their assigned geometries in solutions. Similar analysis were extended to other five-coordinated halido-Cu(II) complexes.