Gain-of-Sensitivity Mutations in a Trim5-Resistant Primary Isolate of Pathogenic SIV Identify Two Independent Conserved Determinants of Trim5α Specificity

Retroviral capsid recognition by Trim5 blocks productive infection. Rhesus macaques harbor three functionally distinct Trim5 alleles: Trim5αQ, Trim5αTFP and Trim5CypA. Despite the high degree of amino acid identity between Trim5αQ and Trim5αTFP alleles, the Q/TFP polymorphism results in the differential restriction of some primate lentiviruses, suggesting these alleles differ in how they engage these capsids. Simian immunodeficiency virus of rhesus macaques (SIVmac) evolved to resist all three alleles. Thus, SIVmac provides a unique opportunity to study a virus in the context of the Trim5 repertoire that drove its evolution in vivo. We exploited the evolved rhesus Trim5α resistance of this capsid to identify gain-of-sensitivity mutations that distinguish targets between the Trim5αQ and Trim5αTFP alleles. While both alleles recognize the capsid surface, Trim5αQ and Trim5αTFP alleles differed in their ability to restrict a panel of capsid chimeras and single amino acid substitutions. When mapped onto the structure of the SIVmac239 capsid N-terminal domain, single amino acid substitutions affecting both alleles mapped to the β-hairpin. Given that none of the substitutions affected Trim5αQ alone, and the fact that the β-hairpin is conserved among retroviral capsids, we propose that the β-hairpin is a molecular pattern widely exploited by Trim5α proteins. Mutations specifically affecting rhesus Trim5αTFP (without affecting Trim5αQ) surround a site of conservation unique to primate lentiviruses, overlapping the CPSF6 binding site. We believe targeting this site is an evolutionary innovation driven specifically by the emergence of primate lentiviruses in Africa during the last 12 million years. This modularity in targeting may be a general feature of Trim5 evolution, permitting different regions of the PRYSPRY domain to evolve independent interactions with capsid

Smoking Policies of Outpatient and Residential Substance Use Disorder Treatment Facilities in the United States

Tobacco use is associated with morbidity and mortality. Many individuals who present to treatment facilities with substance use disorders (SUDs) other than tobacco use disorder also smoke cigarettes or have a concomitant tobacco use disorder. Despite high rates of smoking among those with an SUD, and numerous demonstrated benefits of comprehensive SUD treatment for tobacco use in addition to co-occurring SUDs, not all facilities address the treatment of comorbid tobacco use disorder. In addition, facilities vary widely in terms of tobacco use policies on campus. This study examined SUD facility smoking policies in a national sample of N = 16,623 SUD treatment providers in the United States in 2021. Most facilities with outpatient treatment (52.1%) and facilities with residential treatment (67.8%) had a smoking policy that permitted smoking in designated outdoor area(s). A multinomial logistic regression model found that among facilities with outpatient treatment (n = 13,778), those located in a state with laws requiring tobacco free grounds at SUD facilities, those with tobacco screening/education/counseling services, and those with nicotine pharmacotherapy were less likely to have an unrestrictive tobacco smoking policy. Among facilities with residential treatment (n = 3449), those with tobacco screening/education/counseling services were less likely to have an unrestrictive tobacco smoking policy. There is variability in smoking policies and tobacco use treatment options in SUD treatment facilities across the United States. Since tobacco use is associated with negative biomedical outcomes, more should be done to ensure that SUD treatment also focuses on reducing the harms of tobacco use

Mass Spectrometry Based Imaging of Labile Glucosides in Plants

Mass spectrometry based imaging is a powerful tool to investigate the spatial distribution of a broad range of metabolites across a variety of sample types. The recent developments in instrumentation and computing capabilities have increased the mass range, sensitivity and resolution and rendered sample preparation the limiting step for further improvements. Sample preparation involves sectioning and mounting followed by selection and application of matrix. In plant tissues, labile small molecules and specialized metabolites are subject to degradation upon mechanical disruption of plant tissues. In this study, the benefits of cryo-sectioning, stabilization of fragile tissues and optimal application of the matrix to improve the results from MALDI mass spectrometry imaging (MSI) is investigated with hydroxynitrile glucosides as the main experimental system. Denatured albumin proved an excellent agent for stabilizing fragile tissues such as Lotus japonicus leaves. In stem cross sections of Manihot esculenta, maintaining the samples frozen throughout the sectioning process and preparation of the samples by freeze drying enhanced the obtained signal intensity by twofold to fourfold. Deposition of the matrix by sublimation improved the spatial information obtained compared to spray. The imaging demonstrated that the cyanogenic glucosides (CNglcs) were localized in the vascular tissues in old stems of M. esculenta and in the periderm and vascular tissues of tubers. In MALDI mass spectrometry, the imaged compounds are solely identified by their m/z ratio. L. japonicus MG20 and the mutant cyd1 that is devoid of hydroxynitrile glucosides were used as negative controls to verify the assignment of the observed masses to linamarin, lotaustralin, and linamarin acid

Analysis of acute vascular damage after photodynamic therapy using benzoporphyrin derivative (BPD)

Benzoporphyrin derivative monoacid ring A (BPD-MA, verteporfin) is currently under investigation as a photosensitizer for photodynamic therapy (PDT). Since BPD exhibits rapid pharmacokinetics in plasma and tissues, we assessed damage to tumour and muscle microvasculature when light treatment for PDT was given at short times after injection of photosensitizer. Groups of rats with chondrosarcoma were given 2 mg kg−1 of BPD intravenously 5 min to 180 min before light treatment of 150 J cm−2 690 nm. Vascular response was monitored using intravital microscopy and tumour cure was monitored by following regrowth over 42 days. For treatment at 5 or 30 min after BPD injection, blood flow stasis was limited to tumour microvasculature with lesser response in the surrounding normal microvasculature, indicating selective targeting for damage. No acute changes were observed in vessels when light was given 180 min after BPD injection. Tumour regression after light treatment occurred in all animals given PDT with BPD. Long-term tumour regression was greater in animals treated 5 min after BPD injection and least in animals given treatment 180 min after drug injection. The correlation between the timing for vascular damage and cure implies that blood flow stasis plays a significant role in PDT-induced tumour destruction. © 1999 Cancer Research Campaig

Rumen bacterial composition in lambs is affected by β-adrenergic agonist supplementation and heat stress at the phylum level

The rumen has several important physiological functions, including absorption, transport, metabolic activity, and host protection (Roh et al., 2007). The rumen is extensively researched due to the importance of ruminants in agriculture and the major role played by rumen microbes in nutrient utilization and health of the ruminant animal. The microbial community of the rumen is altered by diet (McCann et al., 2014), age (Jami et al., 2013), and environment

Region-Resolved Quantitative Proteome Profiling Reveals Molecular Dynamics Associated With Chronic Pain in the PNS and Spinal Cord

To obtain a thorough understanding of chronic pain, large-scale molecular mapping of the pain axis at the protein level is necessary, but has not yet been achieved. We applied quantitative proteome profiling to build a comprehensive protein compendium of three regions of the pain neuraxis in mice: the sciatic nerve (SN), the dorsal root ganglia (DRG), and the spinal cord (SC). Furthermore, extensive bioinformatics analysis enabled us to reveal unique protein subsets which are specifically enriched in the peripheral nervous system (PNS) and SC. The immense value of these datasets for the scientific community is highlighted by validation experiments, where we monitored protein network dynamics during neuropathic pain. Here, we resolved profound region-specific differences and distinct changes of PNS-enriched proteins under pathological conditions. Overall, we provide a unique and validated systems biology proteome resource (summarized in our online database painproteome.em.mpg.de), which facilitates mechanistic insights into somatosensory biology and chronic pain—a prerequisite for the identification of novel therapeutic targets

Why I tense up when you watch me: inferior parietal cortex mediates an audience’s influence on motor performance

The presence of an evaluative audience can alter skilled motor performance through changes in force output. To investigate how this is mediated within the brain, we emulated real-time social monitoring of participants’ performance of a fine grip task during functional magnetic resonance neuroimaging. We observed an increase in force output during social evaluation that was accompanied by focal reductions in activity within bilateral inferior parietal cortex. Moreover, deactivation of the left inferior parietal cortex predicted both inter- and intra-individual differences in socially-induced change in grip force. Social evaluation also enhanced activation within the posterior superior temporal sulcus, which conveys visual information about others’ actions to the inferior parietal cortex. Interestingly, functional connectivity between these two regions was attenuated by social evaluation. Our data suggest that social evaluation can vary force output through the altered engagement of inferior parietal cortex; a region implicated in sensorimotor integration necessary for object manipulation, and a component of the action-observation network which integrates and facilitates performance of observed actions. Social-evaluative situations may induce high-level representational incoherence between one’s own intentioned action and the perceived intention of others which, by uncoupling the dynamics of sensorimotor facilitation, could ultimately perturbe motor output

The effect of water immersion on short-latency somatosensory evoked potentials in human

<p>Abstract</p> <p>Background</p> <p>Water immersion therapy is used to treat a variety of cardiovascular, respiratory, and orthopedic conditions. It can also benefit some neurological patients, although little is known about the effects of water immersion on neural activity, including somatosensory processing. To this end, we examined the effect of water immersion on short-latency somatosensory evoked potentials (SEPs) elicited by median nerve stimuli. Short-latency SEP recordings were obtained for ten healthy male volunteers at rest in or out of water at 30°C. Recordings were obtained from nine scalp electrodes according to the 10-20 system. The right median nerve at the wrist was electrically stimulated with the stimulus duration of 0.2 ms at 3 Hz. The intensity of the stimulus was fixed at approximately three times the sensory threshold.</p> <p>Results</p> <p>Water immersion significantly reduced the amplitudes of the short-latency SEP components P25 and P45 measured from electrodes over the parietal region and the P45 measured by central region.</p> <p>Conclusions</p> <p>Water immersion reduced short-latency SEP components known to originate in several cortical areas. Attenuation of short-latency SEPs suggests that water immersion influences the cortical processing of somatosensory inputs. Modulation of cortical processing may contribute to the beneficial effects of aquatic therapy.</p> <p>Trial Registration</p> <p>UMIN-CTR (UMIN000006492)</p

A secondary ionization mass spectrometry calibration of Cibicidoides pachyderma Mg/Ca with temperature

Author Posting. © American Geophysical Union, 2008. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Geochemistry Geophysics Geosystems 9 (2008): Q04009, doi:10.1029/2007GC001620.An evaluation of C. pachyderma Mg/Ca using a new suite of warm water multicores from the Florida Straits shows that the slope of Mg/Ca with temperature is shallower than previously thought. Using secondary ionization mass spectrometry, we have documented that the distribution of magnesium within the polished walls of foraminiferal tests is Gaussian, suggesting that the Mg/Ca in these samples is not affected by the addition of a secondary high-magnesium calcite in the walls. The Mg/Ca within a typical C. pachyderma test varies by about ±20% (1σ/μ · 100), and the variability increases slightly in tests with higher Mg/Ca. The regression of C. pachyderma Mg/Ca with temperature has a slope of 0.13 ± 0.05 mmol mol−1 per °C, indistinguishable from the slope observed in inductively coupled plasma–mass spectrometry measurements from a different subset of the same multicores, but about one half the slope of previously published calibrations. The largest differences between the calibrations comes at the warm water end of the regression, where previously published C. pachyderma Mg/Ca values from Little Bahama Bank are at least 3 mmol mol−1 higher than observed in these new cores. The reasons for this difference are not fully known but are most likely related to diagenesis at Little Bahama Bank.This research was supported by several grants from the National Science Foundation: OCE0096469 to W.B.C. for cruise support to collect the Florida Straits cores; ATM0502428 and OCE0550271 to W. B. C. for support to obtain the Mg/Ca data on the ion probe; and OCE0425522 and OCE0550150 to T. M. for the core top calibration study using ICP-MS