Early Events in G-quadruplex Folding Captured by Time-Resolved Small-Angle X-Ray Scattering.

Time-resolved small-angle X-ray experiments (TR-SAXS) are reported here that capture and quantify a previously unknown rapid collapse of the unfolded oligonucleotide as an early step in G4 folding of hybrid 1 and hybrid 2 telomeric G-quadruplex structures. The rapid collapse, initiated by a pH jump, is characterized by an exponential decrease in the radius of gyration from 20.6 to 12.

Heat-induced structural and chemical changes to a computationally designed miniprotein.

The de novo design of miniprotein inhibitors has recently emerged as a new technology to create proteins that bind with high affinity to specific therapeutic targets. Their size, ease of expression, and apparent high stability makes them excellent candidates for a new class of protein drugs. However, beyond circular dichroism melts and hydrogen/deuterium exchange experiments, little is known about their dynamics, especially at the elevated temperatures they seemingly tolerate quite well.

Intramuscular Exposure to a Lethal Dose of Ricin Toxin Leads to Endothelial Glycocalyx Shedding and Microvascular Flow Abnormality in Mice and Swine.

Ricin toxin isolated from the castor bean () is one of the most potent and lethal molecules known. While the pathophysiology and clinical consequences of ricin poisoning by the parenteral route, i.e.

Dynamics in natural and designed elastins and their relation to elastic fiber structure and recoil.

Elastin fibers assemble in the extracellular matrix from the precursor protein tropoelastin and provide the flexibility and spontaneous recoil required for arterial function. Unlike many proteins, a structure-function mechanism for elastin has been elusive. We have performed detailed NMR relaxation studies of the dynamics of the minielastins 24x' and 20x' using solution NMR, and of purified bovine elastin fibers in the presence and absence of mechanical stress using solid state NMR.

Pathophysiological profile of awake and anesthetized pigs following systemic exposure to the highly lethal ricin toxin.

Ricin, a plant-derived toxin originating from the seeds of (castor bean plant), is one of the most lethal toxins known. To date, no in-depth study of systemic exposure to ricin in a standardized large animal model has been reported. This study details for the first time the pathophysiological hemodynamic profile following systemic/intramuscular exposure to the ricin toxin in a porcine model by comprehensive cardiorespiratory monitoring of awake and anesthetized pigs.

Mice with induced pulmonary morbidities display severe lung inflammation and mortality following exposure to SARS-CoV-2.

Mice are normally unaffected by SARS coronavirus 2 (SARS-CoV-2) infection since the virus does not bind effectively to the murine version of the angiotensin-converting enzyme 2 (ACE2) receptor molecule. Here, we report that induced mild pulmonary morbidities rendered SARS-CoV-2-refractive CD-1 mice susceptible to this virus. Specifically, SARS-CoV-2 infection after application of low doses of the acute lung injury stimulants bleomycin or ricin caused severe disease in CD-1 mice, manifested by sustained body weight loss and mortality rates greater than 50%.

ACTA2 leukovasculopathy: A rare pediatric white matter disorder.

A 3-year-old girl presented with ataxia, dilated pupils, and behavioral change prompting work up for stroke. Her medical history included chronic mydriasis and patent ductus arteriosus requiring aortoplasty. Magnetic resonance imaging of the brain demonstrated confluent white matter signal abnormality concerning for leukodystrophy.

The low density receptor-related protein 1 plays a significant role in ricin-mediated intoxication of lung cells.

Ricin, a highly lethal plant-derived toxin, is a potential biological threat agent due to its high availability, ease of production and the lack of approved medical countermeasures for post-exposure treatment. To date, no specific ricin receptors were identified. Here we show for the first time, that the low density lipoprotein receptor-related protein-1 (LRP1) is a major target molecule for binding of ricin.

Post-Exposure Anti-Ricin Treatment Protects Swine Against Lethal Systemic and Pulmonary Exposures.

Ricin, a plant-derived toxin originating from the seeds of (castor bean plant), is one of the most lethal toxins known. To date, there is no approved post-exposure therapy for ricin exposures. This work demonstrates for the first time the therapeutic efficacy of equine-derived anti-ricin F(ab') antibodies against lethal pulmonary and systemic ricin exposures in swine.

Mapping Immunodominant Antibody Epitopes of Abrin.

Abrin, a toxin isolated from the seeds of (jequirity pea) is considered a biological threat agent by the Center for Disease Control and Prevention. To date, there is no effective postexposure treatment for abrin poisoning, and efforts are being made to develop an efficient vaccine and measures for postexposure therapy. Epitope mapping is widely applied as an efficient tool for discovering the antigenic moieties of toxins, thus providing invaluable information needed for the development of vaccines and therapies.

Estimation of passive gastrointestinal absorption and membrane retention using PAMPA test, quantitative structure-permeability and quantitative structure-retention relationship analyses of ethylenediamine-N,N'-di-2-(3-cyclohexyl)propanoic acid and 1,3-propanediamine-N,N'-di-2-(3-cyclohexyl)propanoic acid derivatives.

Passive gastrointestinal absorption and membrane retention of twelve esters of (S,S)-ethylenediamine-N,N'-di-2-(3-cyclohexyl)propanoic acid (EDCP) and (S,S)-1,3-propanediamine-N,N'-di-2-(3-cyclohexyl)propanoic acid (PDCP), as well as of these two non-esterified acids were estimated using PAMPA test. Artificial PAMPA membrane used in this study for the simulation of gastrointestinal barrier was solution of egg lecithin in dodecane (1 % w/v). All tested compounds belong to class III (high membrane retention and low permeation), whereas EDCP, dipentyl ester of PDCP (DPE-PDCP) and diisopentyl ester of PDCP (DIPE-PDCP) belong to class I (negligible membrane retention and low permeation).

The hTERT core promoter forms three parallel G-quadruplexes.

The structure of the 68 nt sequence with G-quadruplex forming potential within the hTERT promoter is disputed. One model features a structure with three stacked parallel G-quadruplex units, while another features an unusual duplex hairpin structure adjoined to two stacked parallel and antiparallel quadruplexes. We report here the results of an integrated structural biology study designed to distinguish between these possibilities.

Equal Neutralization Potency of Antibodies Raised against Abrin Subunits.

Abrin and ricin are potent AB toxins, which are considered biological threats. To date, there are no approved treatments against abrin or ricin intoxications. Previously, we showed that the administration of polyclonal anti-abrin antibodies to mice that were intranasally exposed to abrin, even very late post-exposure, conferred an exceedingly high-level of protection, while following ricin intoxication, similar treatment with anti-ricin antibodies resulted in negligible survival rates.

The North Texas Concussion Registry (ConTex).

Purpose: The North Texas Concussion Registry (ConTex) was established in 2015 as a multi-institutional collaboration intended to study risk factors, recovery patterns and clinical outcomes associated with concussion across the lifespan, with a particular emphasis on sport-related concussion.

Participants: Prospective enrolment of individuals who sustained a concussion within the past 6 months who were seen at one of four North Texas ConTex concussion clinics which employ common diagnostic criteria and assessment metrics to evaluate effects of a concussion as well as longitudinal tracking of recovery.

Findings To Date: The ConTex database and multidisciplinary oversight team has been established, and over 1700 participants aged 5-88 years have been enrolled.

Recombinant expression and purification of AF1q and its interaction with T-cell Factor 7.

The protein ALL1 fused from chromosome 1q (AF1q) is overexpressed in a variety of cancers and acts to activate several signaling pathways that lead to oncogenesis. For example, AF1q has been shown to interact with T-cell Factor 7 (TCF7; also known as TCF1) from the Wnt/β-catenin pathway resulting in the transcriptional activation of the CD44 and the enhancement of breast cancer metastasis. Despite the importance of AF1q in facilitating oncogenesis and metastasis, the structural and biophysical properties of AF1q remain largely unexplored due to the absence of a viable method for producing recombinant protein.

Reduced heart rate variability and lower cerebral blood flow associated with poor cognition during recovery following concussion.

Although physiological deficits such as altered cerebral blood flow (CBF), and autonomic nervous system (ANS) dysregulation have been reported following a concussion, the relationship between CBF and ANS with functional outcome post-injury remains unclear. Our present study was designed to examine heart-rate variability (HRV) using percentage of successive NN intervals (pNN50) and CBF on day-3 (T1), day-21 (T2), and day-90 (T3) following a concussion in collegiate athletes (N = 31) in comparison to non-injured controls (N = 31). Continuous RR-interval (3-lead electrocardiogram), middle cerebral artery blood velocity (MCAV; transcranial Doppler ultrasonography), mean arterial pressure (MAP; finger photoplethysmography) were obtained at rest.

Solution structure and functional investigation of human guanylate kinase reveals allosteric networking and a crucial role for the enzyme in cancer.

Human guanylate kinase (hGMPK) is the only known enzyme responsible for cellular GDP production, making it essential for cellular viability and proliferation. Moreover, hGMPK has been assigned a critical role in metabolic activation of antiviral and antineoplastic nucleoside-analog prodrugs. Given that hGMPK is indispensable for producing the nucleotide building blocks of DNA, RNA, and cGMP and that cancer cells possess elevated GTP levels, it is surprising that a detailed structural and functional characterization of hGMPK is lacking.

Chronic effects of platinum(IV) complex and its diamine ligand on rat heart function: comparison with cisplatin.

The aim of the present study was to compare the cardiodynamic parameters in the isolated rat heart in animals chronically treated with cisplatin, platinum(IV) complex and its diamine ligand. Sixty Wistar albino rats (8 weeks old) were divided into five groups: three experimental and two control groups. Animals in all groups were treated with a dose of 4 mg/kg body weight once a week for 4 weeks with different substances; experimental groups received cisplatin, ligand and octahedral platinum(IV) complex, and control groups received saline and dimethyl sulfoxide.

Impaired Cerebral Vasoreactivity Despite Symptom Resolution in Sports-Related Concussion.

Traumatic brain injury (TBI) is associated with increased risk of later-life neurodegeneration and dementia. However, the underpinning mechanisms are poorly understood, and secondary injury resulting from perturbed physiological processes plays a significant role. Cerebral vasoreactivity (CVR), a measure of hemodynamic reserve, is known to be impaired in TBI.

Thrombin Exosite Maturation and Ligand Binding at ABE II Help Stabilize PAR-Binding Competent Conformation at ABE I.

Thrombin, derived from zymogen prothrombin (ProT), is a serine protease involved in procoagulation, anticoagulation, and platelet activation. Thrombin's actions are regulated through anion-binding exosites I and II (ABE I and ABE II) that undergo maturation during activation. Mature ABEs can utilize exosite-based communication to fulfill thrombin functions.

Toxicity study of DE-EDCP as a potential drug for cancer therapy: Toxicity profile of DE-EDCP.

It was reported that novel O, O'-diethyl-(S, S)-ethylenediamine- N, N'-di-2-(3-cyclohexyl) propanoate dihydrochloride (DE-EDCP) displayed in vitro antiproliferative activity on several human and mouse cancer cell lines, which was comparable to that of the prototypical anticancer drug cisplatin. In order to reveal its toxicity profile, acute and repeated-dose toxicity studies were performed in Naval Medical Research Institute (NMRI) Han mice. The intravenous LD values of DE-EDCP were found to be 95.

Generation of Highly Efficient Equine-Derived Antibodies for Post-Exposure Treatment of Ricin Intoxications by Vaccination with Monomerized Ricin.

Ricin, a highly lethal toxin derived from the seeds of (castor beans) is considered a potential biological threat agent due to its high availability, ease of production, and to the lack of any approved medical countermeasure against ricin exposures. To date, the use of neutralizing antibodies is the most promising post-exposure treatment for ricin intoxication. The aim of this work was to generate anti-ricin antitoxin that confers high level post-exposure protection against ricin challenge.