Radioprotective Effect of American Ginseng on Human Lymphocytes at 90 Minutes Post-irradiation: A Study of 40 Cases

Backgroundâ Ionizing radiation (IR) initiates intracellular oxidative stress through enhanced formation of reactive oxygen species (ROS) that attack DNA leading to cell death. As the diversity of IR applied in medicine, agriculture, industry, and the growing threats of global terrorism, the acquisition of radioprotectors is an urgent need for the nation. However, the applicability of radioprotectors currently under investigation is limited due to their inherent toxicity. Objectiveâ This study investigated the effect of a standardized North American ginseng extract (NAGE, total ginsenoside content: 11.7%) on DNA damage in human lymphocytes at 90 min postirradiation. Designâ With the application of NAGE (250 â 1000 μg mlâ 1) at 90 min post-irradiation (1 and 2 Gy), DNA damage in lymphocytes obtained from 40 healthy individuals was evaluated by cytokinesis-block micronucleus (CBMN) assay. Similar experiments were also performed in lymphocytes treated with WR-1065 (1 mM or 3mM). In addition, before and after irradiation, lymphocytes obtained from 10 individuals were measured for their total antioxidant capacity (TAC) and the reactive oxygen species (ROS). Resultsâ The significant effect of NAGE against 137Cs-induced MN in lymphocytes is concentration-dependent. NAGE (750 μg mlâ 1) reduced MN yield by 50.7% after 1 Gy and 35.9% after 2 Gy exposures, respectively; these results were comparable to that of WR-1065. Further, we also found that NAGE reduces MN yield and ROS but increases TAC in lymphocytes. Conclusionsâ Our results suggest that NAGE is a relatively non-toxic natural compound that holds radioprotective potential in human lymphocytes even when applied at 90 min post-irradiation. One of the radioprotective mechanisms may be mediated through the scavenging of free radicals and enhancement of the intracellular TAC. Originally published Journal of Alternative and Complementary Medicine Vol. 16, No. 5 2010

H2A.Z Acidic Patch Couples Chromatin Dynamics to Regulation of Gene Expression Programs during ESC Differentiation

The histone H2A variant H2A.Z is essential for embryonic development and for proper control of developmental gene expression programs in embryonic stem cells (ESCs). Divergent regions of amino acid sequence of H2A.Z likely determine its functional specialization compared to core histone H2A. For example, H2A.Z contains three divergent residues in the essential C-terminal acidic patch that reside on the surface of the histone octamer as an uninterrupted acidic patch domain; however, we know little about how these residues contribute to chromatin structure and function. Here, we show that the divergent amino acids Gly92, Asp97, and Ser98 in the H2A.Z C-terminal acidic patch (H2A.Z[superscript AP3]) are critical for lineage commitment during ESC differentiation. H2A.Z is enriched at most H3K4me3 promoters in ESCs including poised, bivalent promoters that harbor both activating and repressive marks, H3K4me3 and H3K27me3 respectively. We found that while H2A.Z[superscript AP3] interacted with its deposition complex and displayed a highly similar distribution pattern compared to wild-type H2A.Z, its enrichment levels were reduced at target promoters. Further analysis revealed that H2A.Z[superscript AP3] was less tightly associated with chromatin, suggesting that the mutant is more dynamic. Notably, bivalent genes in H2A.Z[superscript AP3] ESCs displayed significant changes in expression compared to active genes. Moreover, bivalent genes in H2A.Z[superscript AP3] ESCs gained H3.3, a variant associated with higher nucleosome turnover, compared to wild-type H2A.Z. We next performed single cell imaging to measure H2A.Z dynamics. We found that H2A.Z[superscript AP3] displayed higher mobility in chromatin compared to wild-type H2A.Z by fluorescent recovery after photobleaching (FRAP). Moreover, ESCs treated with the transcriptional inhibitor flavopiridol resulted in a decrease in the H2A.Z[superscript AP3] mobile fraction and an increase in its occupancy at target genes indicating that the mutant can be properly incorporated into chromatin. Collectively, our work suggests that the divergent residues in the H2A.Z acidic patch comprise a unique domain that couples control of chromatin dynamics to the regulation of developmental gene expression patterns during lineage commitment.Massachusetts Life Sciences Center (David H. Koch Institute for Integrative Cancer Research at MIT Core Grant P30-CA14051)National Science Foundation (U.S.). Emergent Behaviors of Integrated Cellular Systems (Grant CBET-0939511)MIT Faculty Start-up FundMassachusetts Institute of Technology. Computational and Systems Biology Initiative (Merck & Co. Postdoctoral Fellowship

Self-oligomerization regulates stability of survival motor neuron protein isoforms by sequestering an SCF^Slmb degron

Spinal muscular atrophy (SMA) is caused by homozygous mutations in human SMN1. Expression of a duplicate gene (SMN2) primarily results in skipping of exon 7 and production of an unstable protein isoform, SMNΔ7. Although SMN2 exon skipping is the principal contributor to SMA severity, mechanisms governing stability of survival motor neuron (SMN) isoforms are poorly understood. We used a Drosophila model system and label-free proteomics to identify the SCFSlmb ubiquitin E3 ligase complex as a novel SMN binding partner. SCFSlmb interacts with a phosphor degron embedded within the human and fruitfly SMN YG-box oligomerization domains. Substitution of a conserved serine (S270A) interferes with SCFSlmb binding and stabilizes SMNΔ7. SMA-causing missense mutations that block multimerization of full-length SMN are also stabilized in the degron mutant background. Overexpression of SMNΔ7S270A, but not wild-type (WT) SMNΔ7, provides a protective effect in SMA model mice and human motor neuron cell culture systems. Our findings support a model wherein the degron is exposed when SMN is monomeric and sequestered when SMN forms higher-order multimers

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

Patient preferences for the allocation of deceased donor kidneys for transplantation: a mixed methods study

<p>Abstract</p> <p>Background</p> <p>Deceased donor kidneys are a scarce health resource, yet patient preferences for organ allocation are largely unknown. The aim of this study was to determine patient preferences for how kidneys should be allocated for transplantation.</p> <p>Methods</p> <p>Patients on dialysis and kidney transplant recipients were purposively selected from two centres in Australia to participate in nominal/focus groups in March 2011. Participants identified and ranked criteria they considered important for deceased donor kidney allocation. Transcripts were thematically analysed to identify reasons for their rankings.</p> <p>Results</p> <p>From six groups involving 37 participants, 23 criteria emerged. Most agreed that matching, wait-list time, medical urgency, likelihood of surviving surgery, age, comorbidities, duration of illness, quality of life, number of organs needed and impact on the recipient's life circumstances were important considerations. Underpinning their rankings were four main themes: enhancing life, medical priority, recipient valuation, and deservingness. These were predominantly expressed as achieving equity for all patients, or priority for specific sub-groups of potential recipients regarded as more "deserving".</p> <p>Conclusions</p> <p>Patients believed any wait-listed individual who would gain life expectancy and quality of life compared with dialysis should have access to transplantation. Equity of access to transplantation for all patients and justice for those who would look after their transplant were considered important. A utilitarian rationale based on maximizing health gains from the allocation of a scarce resource to avoid "wastage," were rarely expressed. Organ allocation organisations need to seek input from patients who can articulate preferences for allocation and advocate for equity and justice in organ allocation.</p

Spatially controlled cell adhesion on three-dimensional substrates

The microenvironment of cells in vivo is defined by spatiotemporal patterns of chemical and biophysical cues. Therefore, one important goal of tissue engineering is the generation of scaffolds with defined biofunctionalization in order to control processes like cell adhesion and differentiation. Mimicking extrinsic factors like integrin ligands presented by the extracellular matrix is one of the key elements to study cellular adhesion on biocompatible scaffolds. By using special thermoformable polymer films with anchored biomolecules micro structured scaffolds, e.g. curved and µ-patterned substrates, can be fabricated. Here, we present a novel strategy for the fabrication of µ-patterned scaffolds based on the “Substrate Modification and Replication by Thermoforming” (SMART) technology: The surface of a poly lactic acid membrane, having a low forming temperature of 60°C and being initially very cell attractive, was coated with a photopatterned layer of poly(L-lysine) (PLL) and hyaluronic acid (VAHyal) to gain spatial control over cell adhesion. Subsequently, this modified polymer membrane was thermoformed to create an array of spherical microcavities with diameters of 300 µm for 3D cell culture. Human hepatoma cells (HepG2) and mouse fibroblasts (L929) were used to demonstrate guided cell adhesion. HepG2 cells adhered and aggregated exclusively within these cavities without attaching to the passivated surfaces between the cavities. Also L929 cells adhering very strongly on the pristine substrate polymer were effectively patterned by the cell repellent properties of the hyaluronic acid based hydrogel. This is the first time cell adhesion was controlled by patterned functionalization of a polymeric substrate with UV curable PLL-VAHyal in thermoformed 3D microstructures

Simultaneous Recruitment of Drug Users and Men Who Have Sex with Men in the United States and Russia Using Respondent-Driven Sampling: Sampling Methods and Implications

The Sexual Acquisition and Transmission of HIV Cooperative Agreement Program (SATHCAP) examined the role of drug use in the sexual transmission of the human immunodeficiency virus (HIV) from traditional high-risk groups, such as men who have sex with men (MSM) and drug users (DU), to lower risk groups in three US cities and in St. Petersburg, Russia. SATHCAP employed respondent-driven sampling (RDS) and a dual high-risk group sampling approach that relied on peer recruitment for a combined, overlapping sample of MSM and DU. The goal of the sampling approach was to recruit an RDS sample of MSM, DU, and individuals who were both MSM and DU (MSM/DU), as well as a sample of sex partners of MSM, DU, and MSM/DU and sex partners of sex partners. The approach efficiently yielded a sample of 8,355 participants, including sex partners, across all four sites. At the US sites—Los Angeles, Chicago, and Raleigh–Durham—the sample consisted of older (mean age = 41 years), primarily black MSM and DU (both injecting and non-injecting); in St. Petersburg, the sample consisted of primarily younger (mean age = 28 years) MSM and DU (injecting). The US sites recruited a large proportion of men who have sex with men and with women, an important group with high potential for establishing a generalized HIV epidemic involving women. The advantage of using the dual high-risk group approach and RDS was, for the most part, the large, efficiently recruited samples of MSM, DU, and MSM/DU. The disadvantages were a recruitment bias by race/ethnicity and income status (at the US sites) and under-enrollment of MSM samples because of short recruitment chains (at the Russian site)

A Large Specific Deterrent Effect of Arrest for Patronizing a Prostitute

BACKGROUND: Prior research suggests that arrest, compared with no police detection, of some types of offenders does not decrease the chances they will reoffend. METHODOLOGY/PRINCIPAL FINDINGS: We assessed the specific deterrent effect of arrest for patronizing a street prostitute in Colorado Springs by comparing the incidence of arrest for clients of prostitutes first detected through public health surveillance with the incidence of rearrest for clients first detected by police arrest. Although these sets of clients were demographically and behaviorally similar, arrest reduced the likelihood of a subsequent arrest by approximately 70%. In other areas of the United States, arrest did not appear to displace a client's patronizing. CONCLUSIONS/SIGNIFICANCE: Our results suggest that apprehending clients decreases their patronizing behavior substantially

Plant Trait Diversity Buffers Variability in Denitrification Potential over Changes in Season and Soil Conditions

BACKGROUND: Denitrification is an important ecosystem service that removes nitrogen (N) from N-polluted watersheds, buffering soil, stream, and river water quality from excess N by returning N to the atmosphere before it reaches lakes or oceans and leads to eutrophication. The denitrification enzyme activity (DEA) assay is widely used for measuring denitrification potential. Because DEA is a function of enzyme levels in soils, most ecologists studying denitrification have assumed that DEA is less sensitive to ambient levels of nitrate (NO(3)(-)) and soil carbon and thus, less variable over time than field measurements. In addition, plant diversity has been shown to have strong effects on microbial communities and belowground processes and could potentially alter the functional capacity of denitrifiers. Here, we examined three questions: (1) Does DEA vary through the growing season? (2) If so, can we predict DEA variability with environmental variables? (3) Does plant functional diversity affect DEA variability? METHODOLOGY/PRINCIPAL FINDINGS: The study site is a restored wetland in North Carolina, US with native wetland herbs planted in monocultures or mixes of four or eight species. We found that denitrification potentials for soils collected in July 2006 were significantly greater than for soils collected in May and late August 2006 (p<0.0001). Similarly, microbial biomass standardized DEA rates were significantly greater in July than May and August (p<0.0001). Of the soil variables measured--soil moisture, organic matter, total inorganic nitrogen, and microbial biomass--none consistently explained the pattern observed in DEA through time. There was no significant relationship between DEA and plant species richness or functional diversity. However, the seasonal variance in microbial biomass standardized DEA rates was significantly inversely related to plant species functional diversity (p<0.01). CONCLUSIONS/SIGNIFICANCE: These findings suggest that higher plant functional diversity may support a more constant level of DEA through time, buffering the ecosystem from changes in season and soil conditions

Association of genetic variants of the histamine H1 and muscarinic M3 receptors with BMI and HbA1c values in patients on antipsychotic medication

Rationale: Antipsychotic affinity for the histamine H1 receptor and the muscarinic M3 receptor have been associated with the side effects weight gain, and development of diabetes, respectively. Objectives: We investigated polymorphisms of the histamine H1 (HRH1) and muscarinic acetylcholine receptor M3 (CHRM3) receptor genes for an association with body mass index (BMI) and glycated hemoglobin (HbA1c). Methods: We included 430 Caucasian patients with a non-affective psychotic disorder using antipsychotics for at least 3 months. Primary endpoints of the study were cross-sectionally measured BMI and HbA1c; secondary endpoints were obesity and hyperglycaemia. Two single-nucleotide polymorphisms (SNPs) in the HRH1 gene, rs346074 and rs346070, and one SNP in the CHRM3 gene, rs3738435, were genotyped. Our primary hypothesis in this study was an interaction between genotype on BMI and antipsychotic affinity for the H1 and M3 receptor. Results: A significant association of interaction between haplotype rs346074-rs346070 and BMI (p value 0.025) and obesity (p value 0.005) in patients using high-H1 affinity antipsychotics versus patients using low-H1 affinity antipsychotics was found. There was no association of CHRM3 gene variant rs3738435 with BMI, and we observed no association with HbA1c or hyperglycaemia in any of the variants. Conclusions: This study, for the first time, demonstrates a significant association between HRH1 variants and BMI in patients with a psychotic disorder using antipsychotics. In future, genotyping of HRH1 variants may help predicting weight gain in patients using antipsychotics