Can Prenatal Malaria Exposure Produce an Immune Tolerant Phenotype?: A Prospective Birth Cohort Study in Kenya

In a prospective cohort study of newborns residing in a malaria holoendemic area of Kenya, Christopher King and colleagues find a subset of children born to malaria-infected women who acquire a tolerant phenotype, which persists into childhood and is associated with increased susceptibility to malarial infection and anemia

Microplastic burden in invasive signal crayfish (Pacifastacus leniusculus) increases along a stream urbanization gradient

Microplastics are a globally pervasive pollutant with the potential to directly impact species and accumulate in ecosystems. However, there remains a relative paucity of research addressing their accumulation in freshwater ecosystems and a near absence of work in crayfish, despite their high ecological and economic importance. This study investigated the presence of microplastics in the invasive signal crayfish Pacifastacus leniusculus along a stream urbanization gradient. The results demonstrate a ubiquitous presence of microplastics in crayfish digestive tracts at all sites and provide the first evidence of microplastic accumulation in tail tissue. Evidence of a positive linear trend was demonstrated between microplastic concentration in crayfish and upstream urban area size in generalized linear models. Evidence for a positive effect of the upstream urban area and a negative effect of crayfish length on microplastic concentrations in crayfish was demonstrated in multiple generalized linear regression models. Our results extend the current understanding of microplastics presence in freshwater ecosystems and demonstrate their presence in crayfish in the wild for the first time

[Pemetrexed + Sorafenib] lethality is increased by inhibition of ERBB1/2/3-PI3K-NFκB compensatory survival signaling

In the completed phase I trial NCT01450384 combining the anti-folate pemetrexed and the multi-kinase inhibitor sorafenib it was observed that 20 of 33 patients had prolonged stable disease or tumor regression, with one complete response and multiple partial responses. The pre-clinical studies in this manuscript were designed to determine whether [pemetrexed + sorafenib] –induced cell killing could be rationally enhanced by additional signaling modulators. Multiplex assays performed on tumor material that survived and re-grew after [pemetrexed + sorafenib] exposure showed increased phosphorylation of ERBB1 and of NFκB and IκB; with reduced IκB and elevated G-CSF and KC protein levels. Inhibition of JAK1/2 downstream of the G-CSF/KC receptors did not enhance [pemetrexed + sorafenib] lethality whereas inhibition of ERBB1/2/4 using kinase inhibitory agents or siRNA knock down of ERBB1/2/3 strongly promoted killing. Inhibition of ERBB1/2/4 blocked [pemetrexed + sorafenib] stimulated NFκB activation and SOD2 expression; and expression of IκB S32A S36A significantly enhanced [pemetrexed + sorafenib] lethality. Sorafenib inhibited HSP90 and HSP70 chaperone ATPase activities and reduced the interactions of chaperones with clients including c-MYC, CDC37 and MCL-1. In vivo, a 5 day transient exposure of established mammary tumors to lapatinib or vandetanib significantly enhanced the anti-tumor effect of [pemetrexed + sorafenib], without any apparent normal tissue toxicities. Identical data to that in breast cancer were obtained in NSCLC tumors using the ERBB1/2/4 inhibitor afatinib. Our data argue that the combination of pemetrexed, sorafenib and an ERBB1/2/4 inhibitor should be explored in a new phase I trial in solid tumor patients

Evidence for hierarchical black hole mergers in the second LIGO--Virgo gravitational-wave catalog

We study the population properties of merging binary black holes in the second LIGO--Virgo Gravitational-Wave Transient Catalog assuming they were all formed dynamically in gravitationally bound clusters. Using a phenomenological population model, we infer the mass and spin distribution of first-generation black holes, while self-consistently accounting for hierarchical mergers. Considering a range of cluster masses, we see compelling evidence for hierarchical mergers in clusters with escape velocities $\gtrsim 100~\mathrm{km\,s^{-1}}$. For our most probable cluster mass, we find that the catalog contains at least one second-generation merger with $99\%$ credibility. We find that the hierarchical model is preferred over an alternative model with no hierarchical mergers (Bayes factor $\mathcal{B} > 1400$) and that GW190521 is favored to contain two second-generation black holes with odds $\mathcal{O}>700$, and GW190519, GW190602, GW190620, and GW190706 are mixed-generation binaries with $\mathcal{O} > 10$. However, our results depend strongly on the cluster escape velocity, with more modest evidence for hierarchical mergers when the escape velocity is $\lesssim 100~\mathrm{km\,s^{-1}}$. Assuming that all binary black holes are formed dynamically in globular clusters with escape velocities on the order of tens of $\mathrm{km\,s^{-1}}$, GW190519 and GW190521 are favored to include a second-generation black hole with odds $\mathcal{O}>1$. In this case, we find that $99\%$ of black holes from the inferred total population have masses that are less than $49\,M_{\odot}$, and that this constraint is robust to our choice of prior on the maximum black hole mass.Comment: 15 pages, 11 figures, 1 appendi

Preliminary safety assessment of a membrane-bound delta 9 desaturase candidate protein for transgenic oilseed crops

AbstractA gene encoding delta 9 desaturase (D9DS), an integral membrane protein, is being considered for incorporation into oilseed crops to reduce saturated fatty acids and thus improve human nutritional value. Typically, a safety assessment for transgenic crops involves purifying heterologously produced transgenic proteins in an active form for use in safety studies. Membrane-bound proteins have been very difficult to isolate in an active form due to their inherent physicochemical properties. Described here are methods used to derive enriched preparations of the active D9DS protein for use in early stage safety studies. Results of these studies, in combination with bioinformatic results and knowledge of the mode of action of the protein, along with a history of safe consumption of related proteins, provides a weight of evidence supporting the safety of the D9DS protein in food and feed

Broadly reactive antibodies specific for Plasmodium falciparum MSP-119 are associated with the protection of naturally exposed children against infection

BACKGROUND: The 19 kDa C-terminal region of Plasmodium falciparum Merozoite Surface Protein-1 is a known target of naturally acquired humoral immunity and a malaria vaccine candidate. MSP- 119 has four predominant haplotypes resulting in amino acid changes labelled EKNG, QKNG, QTSR and ETSR. IgG antibodies directed against all four variants have been detected, but it is not known if these variant specific antibodies are associated with haplotype-specific protection from infection. METHODS: Blood samples from 201 healthy Kenyan adults and children who participated in a 12-week treatment time-to-infection study were evaluated. Venous blood drawn at baseline (week 0) was examined for functional and serologic antibodies to MSP-119 and MSP-142 variants. MSP-119 haplotypes were detected by a multiplex PCR assay at baseline and weekly throughout the study. Generalized linear models controlling for age, baseline MSP-119 haplotype and parasite density were used to determine the relationship between infecting P. falciparum MSP-119 haplotype and variant-specific antibodies. RESULTS: A total of 964 infections resulting in 1,533 MSP-119 haplotypes detected were examined. The most common haplotypes were EKNG and QKNG, followed by ETSR and QTSR. Children had higher parasite densities, greater complexity of infection (\u3e1 haplotype), and more frequent changes in haplotypes over time compared to adults. Infecting MSP-119 haplotype at baseline (week 0) had no influence on haplotypes detected over the subsequent 11 weeks among children or adults. Children but not adults with MSP-119 and some MSP-142 variant antibodies detected by serology at baseline had delayed time-to-infection. There was no significant association of variant-specific serology or functional antibodies at baseline with infecting haplotype at baseline or during 11 weeks of follow up among children or adults. CONCLUSIONS: Variant transcending IgG antibodies to MSP-119 are associated with protection from infection in children, but not adults. These data suggest that inclusion of more than one MSP-119 variant may not be required in a malaria blood stage vaccine

Obesity Is Not Associated with Antimicrobial Treatment Failure for Intra-Abdominal Infection

Background: Obesity and commonly associated comorbidities are known risk factors for the development of infections. However, the intensity and duration of antimicrobial treatment are rarely conditioned on body mass index (BMI). In particular, the influence of obesity on failure of antimicrobial treatment for intra-abdominal infection (IAI) remains unknown. We hypothesized that obesity is associated with recurrent infectious complications in patients treated for IAI. Methods: Five hundred eighteen patients randomized to treatment in the Surgical Infection Society Study to Optimize Peritoneal Infection Therapy (STOP-IT) trial were evaluated. Patients were stratified by obese (BMI ≥30) versus non-obese (BMI≥30) status. Descriptive comparisons were performed using Chi-square test, Fisher exact test, or Wilcoxon rank-sum tests as appropriate. Multivariable logistic regression using a priori selected variables was performed to assess the independent association between obesity and treatment failure in patients with IAI. Results: Overall, 198 (38.3%) of patients were obese (BMI ≥30) versus 319 (61.7%) who were non-obese. Mean antibiotic d and total hospital d were similar between both groups. Unadjusted outcomes of surgical site infection (9.1% vs. 6.9%, p?=?0.36), recurrent intra-abdominal infection (16.2% vs. 13.8, p?=?0.46), death (1.0% vs. 0.9%, p?=?1.0), and a composite of all complications (25.3% vs. 19.8%, p?=?0.14) were also similar between both groups. After controlling for appropriate demographics, comorbidities, severity of illness, treatment group, and duration of antimicrobial therapy, obesity was not independently associated with treatment failure (c-statistic: 0.64). Conclusions: Obesity is not associated with antimicrobial treatment failure among patients with IAI. These results suggest that obesity may not independently influence the need for longer duration of antimicrobial therapy in treatment of IAI versus non-obese patients.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/140219/1/sur.2015.213.pd

Resistance exercise initiates mechanistic target of rapamycin (mTOR) translocation and protein complex co-localisation in human skeletal muscle

The mechanistic target of rapamycin (mTOR) is a central mediator of protein synthesis in skeletal muscle. We utilized immunofluorescence approaches to study mTOR cellular distribution and protein-protein co-localisation in human skeletal muscle in the basal state as well as immediately, 1 and 3 h after an acute bout of resistance exercise in a fed (FED; 20 g Protein/40 g carbohydrate/1 g fat) or energy-free control (CON) state. mTOR and the lysosomal protein LAMP2 were highly co-localised in basal samples. Resistance exercise resulted in rapid translocation of mTOR/LAMP2 towards the cell membrane. Concurrently, resistance exercise led to the dissociation of TSC2 from Rheb and increased in the co-localisation of mTOR and Rheb post exercise in both FED and CON. In addition, mTOR co-localised with Eukaryotic translation initiation factor 3 subunit F (eIF3F) at the cell membrane post-exercise in both groups, with the response significantly greater at 1 h of recovery in the FED compared to CON. Collectively our data demonstrate that cellular trafficking of mTOR occurs in human muscle in response to an anabolic stimulus, events that appear to be primarily influenced by muscle contraction. The translocation and association of mTOR with positive regulators (i.e. Rheb and eIF3F) is consistent with an enhanced mRNA translational capacity after resistance exercise

Recent developments in frailty identification, management, risk factors and prevention : A narrative review of leading journals in geriatrics and gerontology

Funding The Frailty Epidemiology Research Network (EPI-FRAIL) is an international collaborative project aimed at filling knowledge gaps in the field of frailty epidemiology. The network was established as part of a NWO/ZonMw Veni fellowship awarded to E.O. Hoogendijk (Grant no. 91618067). P. Hanlon is funded through a Clinical Research Training Fellowship from the Medical Research Council (Grant reference: MR/S021949/1). Z. Liu was supported by the Soft Science Research Program of Zhejiang Province (2023KXCX-KT011). J. Jylhävä has received grant support from the Swedish Research Council (grant no. 2018-02077), the Academy of Finland (grant no. 349335), the Sigrid Jusélius Foundation, the Yrjö Jahnsson Foundation and the Instrumentarium Science Foundation. M. Sim is supported by a Royal Perth Hospital Research Foundation Career Advancement Fellowship and an Emerging Leader Fellowship from the Future Health Research and Innovation Fund (Department of Health, Western Australia). R. Ambagtsheer receives funding from the Australian Medical Research Future Fund (grant #MRF2016140). D. L. Vetrano receives financial support from the Swedish Research Council (2021-03324). S. Shi reports funding from the National Institute of Aging, R03AG078894-01. None of the funding agencies had any role in the conduct of the study; collection, management, analysis, or interpretation of the data; or preparation, review, or approval of the manuscript.Peer reviewedPublisher PD