Cytomegalovirus replication kinetics in solid organ transplant recipients managed by preemptive therapy.

After allotransplantation, cytomegalovirus (CMV) may be transmitted from the donor organ, giving rise to primary infection in a CMV negative recipient or reinfection in one who is CMV positive. In addition, latent CMV may reactivate in a CMV positive recipient. In this study, serial blood samples from 689 kidney or liver transplant recipients were tested for CMV DNA by quantitative PCR. CMV was managed using preemptive antiviral therapy and no patient received antiviral prophylaxis. Dynamic and quantitative measures of viremia and treatment were assessed. Median peak viral load, duration of viremia and duration of treatment were highest during primary infection, followed by reinfection then reactivation. In patients who experienced a second episode of viremia, the viral replication rate was significantly slower than in the first episode. Our data provide a clear demonstration of the immune control of CMV in immunosuppressed patients and emphasize the effectiveness of the preemptive approach for prevention of CMV syndrome and end organ disease. Overall, our findings provide quantitative biomarkers which can be used in pharmacodynamic assessments of the ability of novel CMV vaccines or antiviral drugs to reduce or even interrupt such transmission

Early diastolic filling dynamics in diastolic dysfunction

BACKGROUND: The aim of the study was to determine the relationship between the rate of peak early mitral inflow velocity and the peak early diastolic mitral annular tissue velocities in normal controls and to compare them with subjects with diastolic dysfunction. METHODS: The relationship between early passive diastolic transmitral flow and peak early mitral annular velocity in the normal and in diastolic dysfunction was studied. Two groups comprising 22 normal controls and 25 patients with diastolic dysfunction were studied. RESULTS: Compared with the normal group, those with diastolic dysfunction had a lower E/A ratio (0.7 ± 0.2 vs. 1.9 ± 0.5, p < 0.001), a higher time-velocity integral of the atrial component (11.7 ± 3.2 cm vs. 5.5 ± 2.1 cm, p < 0.0001), a longer isovolumic relaxation time 73 ± 12 ms vs. 94 ± 6 ms, p < 0.01 and a lower rate of acceleration of blood across the mitral valve (549.2 ± 151.9 cm/sec(2 )vs. 871 ± 128.1 cm/sec(2), p < 0.001). They also had a lower mitral annular relaxation velocity (Ea) (6.08 ± 1.6 cm/sec vs 12.8 ± 0.67 cm/sec, p < 0.001), which was positively correlated to the acceleration of early diastolic filling (R = 0.66), p < 0.05. CONCLUSIONS: This investigation provides information on the acceleration of early diastolic filling and its relationship to mitral annular peak tissue velocity (Ea) recorded by Doppler tissue imaging. It supports not only the premise that recoil is an important mechanism for rapid early diastolic filling but also the existence of an early diastolic mechanism in normal

KCC2 is required for the survival of mature neurons but not for their development

The K+/Cl- co-transporter KCC2 (SLC12A5) allows mature neurons in the CNS to maintain low intracellular Cl- levels that are critical in mediating fast hyperpolarizing synaptic inhibition via type A γ-aminobutyric acid receptors (GABAARs). In accordance with this, compromised KCC2 activity results in seizures, but whether such deficits directly contribute to the subsequent changes in neuronal structure and viability that lead to epileptogenesis, remains to be assessed. Canonical hyperpolarizing GABAAR currents develop postnatally which reflect a progressive increase in KCC2 expression levels and activity. To investigate the role that KCC2 plays in regulating neuronal viability and architecture we have conditionally ablated KCC2 expression in developing and mature neurons. Decreasing KCC2 expression in mature neurons resulted in the rapid activation of the extrinsic apoptotic pathway. Intriguingly, direct pharmacological inhibition of KCC2 in mature neurons was sufficient to rapidly induce apoptosis, an effect that was not abrogated via blockade of neuronal depolarization using Tetrodotoxin (TTX). In contrast, ablating KCC2 expression in immature neurons had no discernable effects on their subsequent development, arborization or dendritic structure. However, removing KCC2 in immature neurons was sufficient to ablate the subsequent postnatal development of hyperpolarizing GABAAR currents. Collectively, our results demonstrate that KCC2 plays a critical role in neuronal survival by limiting apoptosis, and mature neurons are highly sensitive to the loss of KCC2 function. In contrast, KCC2 appears to play a minimal role in mediating neuronal development or architecture

Safety and efficacy of umbilical cord-derived Wharton's jelly compared to hyaluronic acid and saline for knee osteoarthritis: study protocol for a randomized, controlled, single-blind, multi-center trial.

BACKGROUND: Osteoarthritis (OA) is the most common joint disorder in the United States of America (USA) with a fast-rising prevalence. Current treatment modalities are limited, and total knee replacement surgeries have shown disadvantages, especially for grade II/III OA. The interest in the use of biologics, including umbilical cord (UC)-derived Wharton's jelly (WJ), has grown in recent years. The results from a preliminary study demonstrated the presence of essential components of regenerative medicine, namely growth factors, cytokines, hyaluronic acid (HA), and extracellular vesicles, including exosomes, in WJ. The proposed study aims to evaluate the safety and efficacy of intra-articular injection of UC-derived WJ for the treatment of knee OA symptoms. METHODS: A randomized, controlled, single-blind, multi-center, prospective study will be conducted in which the safety and efficacy of intra-articular administration of UC-derived WJ are compared to HA (control) and saline (placebo control) in patients suffering from grade II/III knee OA. A total of 168 participants with grade II or III knee OA on the KL scale will be recruited across 53 sites in the USA with 56 participants in each arm and followed for 1 year post-injection. Patient satisfaction, Numeric Pain Rating Scale, Knee Injury and Osteoarthritis Outcome Score, 36-Item Short Form Survey (SF-36), and 7-point Likert Scale will be used to assess the participants. Physical exams, X-rays, and MRI with Magnetic Resonance Observation of Cartilage Repair Tissue score will be used to assess improvement in associated anatomy. DISCUSSION: The study results will provide valuable information into the safety and efficacy of intra-articular administration of Wharton's jelly for grade II/III knee osteoarthritis. The results of this study will also add to the treatment options available for grade II/III OA as well as help facilitate the development of a more focused treatment strategy for patients. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04711304 . Registered on January 15, 2021

Combined In Silico, In Vivo, and In Vitro Studies Shed Insights into the Acute Inflammatory Response in Middle-Aged Mice

We combined in silico, in vivo, and in vitro studies to gain insights into age-dependent changes in acute inflammation in response to bacterial endotoxin (LPS). Time-course cytokine, chemokine, and NO2-/NO3- data from "middle-aged" (6-8 months old) C57BL/6 mice were used to re-parameterize a mechanistic mathematical model of acute inflammation originally calibrated for "young" (2-3 months old) mice. These studies suggested that macrophages from middle-aged mice are more susceptible to cell death, as well as producing higher levels of pro-inflammatory cytokines, vs. macrophages from young mice. In support of the in silico-derived hypotheses, resident peritoneal cells from endotoxemic middle-aged mice exhibited reduced viability and produced elevated levels of TNF-α, IL-6, IL-10, and KC/CXCL1 as compared to cells from young mice. Our studies demonstrate the utility of a combined in silico, in vivo, and in vitro approach to the study of acute inflammation in shock states, and suggest hypotheses with regard to the changes in the cytokine milieu that accompany aging. © 2013 Namas et al

Genomic Expansion of Magnetotactic Bacteria Reveals an Early Common Origin of Magnetotaxis with Lineage-specific Evolution

The origin and evolution of magnetoreception, which in diverse prokaryotes and protozoa is known as magnetotaxis and enables these microorganisms to detect Earth’s magnetic field for orientation and navigation, is not well understood in evolutionary biology. The only known prokaryotes capable of sensing the geomagnetic field are magnetotactic bacteria (MTB), motile microorganisms that biomineralize intracellular, membrane-bounded magnetic single-domain crystals of either magnetite (Fe3O4) or greigite (Fe3S4) called magnetosomes. Magnetosomes are responsible for magnetotaxis in MTB. Here we report the first large-scale metagenomic survey of MTB from both northern and southern hemispheres combined with 28 genomes from uncultivated MTB. These genomes expand greatly the coverage of MTB in the Proteobacteria, Nitrospirae, and Omnitrophica phyla, and provide the first genomic evidence of MTB belonging to the Zetaproteobacteria and “Candidatus Lambdaproteobacteria” classes. The gene content and organization of magnetosome gene clusters, which are physically grouped genes that encode proteins for magnetosome biosynthesis and organization, are more conserved within phylogenetically similar groups than between different taxonomic lineages. Moreover, the phylogenies of core magnetosome proteins form monophyletic clades. Together, these results suggest a common ancient origin of iron-based (Fe3O4 and Fe3S4) magnetotaxis in the domain Bacteria that underwent lineage-specific evolution, shedding new light on the origin and evolution of biomineralization and magnetotaxis, and expanding significantly the phylogenomic representation of MTB

Computer vision and machine learning for robust phenotyping in genome-wide studies

Traditional evaluation of crop biotic and abiotic stresses are time-consuming and labor-intensive limiting the ability to dissect the genetic basis of quantitative traits. A machine learning (ML)-enabled image-phenotyping pipeline for the genetic studies of abiotic stress iron deficiency chlorosis (IDC) of soybean is reported. IDC classification and severity for an association panel of 461 diverse plant-introduction accessions was evaluated using an end-to-end phenotyping workflow. The workflow consisted of a multi-stage procedure including: (1) optimized protocols for consistent image capture across plant canopies, (2) canopy identification and registration from cluttered backgrounds, (3) extraction of domain expert informed features from the processed images to accurately represent IDC expression, and (4) supervised ML-based classifiers that linked the automatically extracted features with expert-rating equivalent IDC scores. ML-generated phenotypic data were subsequently utilized for the genome-wide association study and genomic prediction. The results illustrate the reliability and advantage of ML-enabled image-phenotyping pipeline by identifying previously reported locus and a novel locus harboring a gene homolog involved in iron acquisition. This study demonstrates a promising path for integrating the phenotyping pipeline into genomic prediction, and provides a systematic framework enabling robust and quicker phenotyping through ground-based systems