Neurogenesis Drives Stimulus Decorrelation in a Model of the Olfactory Bulb

The reshaping and decorrelation of similar activity patterns by neuronal networks can enhance their discriminability, storage, and retrieval. How can such networks learn to decorrelate new complex patterns, as they arise in the olfactory system? Using a computational network model for the dominant neural populations of the olfactory bulb we show that fundamental aspects of the adult neurogenesis observed in the olfactory bulb -- the persistent addition of new inhibitory granule cells to the network, their activity-dependent survival, and the reciprocal character of their synapses with the principal mitral cells -- are sufficient to restructure the network and to alter its encoding of odor stimuli adaptively so as to reduce the correlations between the bulbar representations of similar stimuli. The decorrelation is quite robust with respect to various types of perturbations of the reciprocity. The model parsimoniously captures the experimentally observed role of neurogenesis in perceptual learning and the enhanced response of young granule cells to novel stimuli. Moreover, it makes specific predictions for the type of odor enrichment that should be effective in enhancing the ability of animals to discriminate similar odor mixtures

Photochemical activation of TRPA1 channels in neurons and animals

Optogenetics is a powerful research tool because it enables high-resolution optical control of neuronal activity. However, current optogenetic approaches are limited to transgenic systems expressing microbial opsins and other exogenous photoreceptors. Here, we identify optovin, a small molecule that enables repeated photoactivation of motor behaviors in wild type animals. Surprisingly, optovin's behavioral effects are not visually mediated. Rather, photodetection is performed by sensory neurons expressing the cation channel TRPA1. TRPA1 is both necessary and sufficient for the optovin response. Optovin activates human TRPA1 via structure-dependent photochemical reactions with redox-sensitive cysteine residues. In animals with severed spinal cords, optovin treatment enables control of motor activity in the paralyzed extremities by localized illumination. These studies identify a light-based strategy for controlling endogenous TRPA1 receptors in vivo, with potential clinical and research applications in non-transgenic animals, including humans

Expanding the <em>HPSE2</em> Genotypic Spectrum in Urofacial Syndrome, A Disease Featuring a Peripheral Neuropathy of the Urinary Bladder

Copyright \ua9 2022 Beaman, Lopes, Hofmann, Roesch, Promm, Bijlsma, Patel, Akinci, Burgu, Knijnenburg, Ho, Aufschlaeger, Dathe, Voelckel, Cohen, Yue, Stuart, Mckenzie, Elvin, Roberts, Woolf and Newman. Urofacial (also called Ochoa) syndrome (UFS) is an autosomal recessive congenital disorder of the urinary bladder featuring voiding dysfunction and a grimace upon smiling. Biallelic variants in HPSE2, coding for the secreted protein heparanase-2, are described in around half of families genetically studied. Hpse2 mutant mice have aberrant bladder nerves. We sought to expand the genotypic spectrum of UFS and make insights into its pathobiology. Sanger sequencing, next generation sequencing and microarray analysis were performed in four previously unreported families with urinary tract disease and grimacing. In one, the proband had kidney failure and was homozygous for the previously described pathogenic variant c.429T&gt;A, p.(Tyr143*). Three other families each carried a different novel HPSE2 variant. One had homozygous triplication of exons 8 and 9; another had homozygous deletion of exon 4; and another carried a novel c.419C&gt;G variant encoding the missense p.Pro140Arg in trans with c.1099-1G&gt;A, a previously reported pathogenic splice variant. Expressing the missense heparanase-2 variant in vitro showed that it was secreted as normal, suggesting that 140Arg has aberrant functionality after secretion. Bladder autonomic neurons emanate from pelvic ganglia where resident neural cell bodies derive from migrating neural crest cells. We demonstrated that, in normal human embryos, neuronal precursors near the developing hindgut and lower urinary tract were positive for both heparanase-2 and leucine rich repeats and immunoglobulin like domains 2 (LRIG2). Indeed, biallelic variants of LRIG2 have been implicated in rare UFS families. The study expands the genotypic spectrum in HPSE2 in UFS and supports a developmental neuronal pathobiology

The effect of a brief social intervention on the examination results of UK medical students: a cluster randomised controlled trial

Background: Ethnic minority (EM) medical students and doctors underperform academically, but little evidence exists on how to ameliorate the problem. Psychologists Cohen et al. recently demonstrated that a written self-affirmation intervention substantially improved EM adolescents' school grades several months later. Cohen et al.'s methods were replicated in the different setting of UK undergraduate medical education.Methods: All 348 Year 3 white (W) and EM students at one UK medical school were randomly allocated to an intervention condition (writing about one's own values) or a control condition (writing about another's values), via their tutor group. Students and assessors were blind to the existence of the study. Group comparisons on post-intervention written and OSCE (clinical) assessment scores adjusted for baseline written assessment scores were made using two-way analysis of covariance. All assessment scores were transformed to z-scores (mean = 0 standard deviation = 1) for ease of comparison. Comparisons between types of words used in essays were calculated using t-tests. The study was covered by University Ethics Committee guidelines.Results: Groups were statistically identical at baseline on demographic and psychological factors, and analysis was by intention to treat [intervention group EM n = 95, W n = 79; control group EM n = 77; W n = 84]. As predicted, there was a significant ethnicity by intervention interaction [F(4,334) = 5.74; p = 0.017] on the written assessment. Unexpectedly, this was due to decreased scores in the W intervention group [mean difference = 0.283; (95% CI = 0.093 to 0.474] not improved EM intervention group scores [mean difference = -0.060 (95% CI = -0.268 to 0.148)]. On the OSCE, both W and EM intervention groups outperformed controls [mean difference = 0.261; (95% CI = -0.047 to -0.476; p = 0.013)]. The intervention group used more optimistic words (p < 0.001) and more "I" and "self" pronouns in their essays (p < 0.001), whereas the control group used more "other" pronouns (p < 0.001) and more negations (p < 0.001).Discussion: Cohen et al.'s finding that a brief self-affirmation task narrowed the ethnic academic achievement gap was replicated on the written assessment but against expectations, this was due to reduced performance in the W group. On the OSCE, the intervention improved performance in both W and EM groups. In the intervention condition, participants tended to write about themselves and used more optimistic words than in the control group, indicating the task was completed as requested. The study shows that minimal interventions can have substantial educational outcomes several months later, which has implications for the multitude of seemingly trivial changes in teaching that are made on an everyday basis, whose consequences are never formally assessed

Linkage study of 14 candidate genes and loci in four large Dutch families with vesico-ureteral reflux

Vesico-ureteral reflux (VUR) is a major contributing factor to end-stage renal disease in paediatric patients. Primary VUR is a familial disorder, but little is known about its genetic causes. To investigate the involvement of 12 functional candidate genes and two reported loci in VUR, we performed a linkage study in four large, Dutch, multi-generational families with multiple affected individuals. We were unable to detect linkage to any of the genes and loci and could exclude the GDNF, RET, SLIT2, SPRY1, PAX2, AGTR2, UPK1A and UPK3A genes and the 1p13 and 20p13 loci from linkage to VUR. Our results provide further evidence that there appears to be genetic heterogeneity in VUR

The IGNITE (investigation to guide new insight into translational effectiveness) trial: Protocol for a translational study of an evidenced-based wellness program in fire departments

<p>Abstract</p> <p>Background</p> <p>Worksites are important locations for interventions to promote health. However, occupational programs with documented efficacy often are not used, and those being implemented have not been studied. The research in this report was funded through the American Reinvestment and Recovery Act Challenge Topic 'Pathways for Translational Research,' to define and prioritize determinants that enable and hinder translation of evidenced-based health interventions in well-defined settings.</p> <p>Methods</p> <p>The IGNITE (investigation to guide new insights for translational effectiveness) trial is a prospective cohort study of a worksite wellness and injury reduction program from adoption to final outcomes among 12 fire departments. It will employ a mixed methods strategy to define a translational model. We will assess decision to adopt, installation, use, and outcomes (reach, individual outcomes, and economic effects) using onsite measurements, surveys, focus groups, and key informant interviews. Quantitative data will be used to define the model and conduct mediation analysis of each translational phase. Qualitative data will expand on, challenge, and confirm survey findings and allow a more thorough understanding and convergent validity by overcoming biases in qualitative and quantitative methods used alone.</p> <p>Discussion</p> <p>Findings will inform worksite wellness in fire departments. The resultant prioritized influences and model of effective translation can be validated and manipulated in these and other settings to more efficiently move science to service.</p

Linkage study of 14 candidate genes and loci in four large Dutch families with vesico-ureteral reflux

Vesico-ureteral reflux (VUR) is a major contributing factor to end-stage renal disease in paediatric patients. Primary VUR is a familial disorder, but little is known about its genetic causes. To investigate the involvement of 12 functional candidate genes and two reported loci in VUR, we performed a linkage study in four large, Dutch, multi-generational families with multiple affected individuals. We were unable to detect linkage to any of the genes and loci and could exclude the GDNF, RET, SLIT2, SPRY1, PAX2, AGTR2, UPK1A and UPK3A genes and the 1p13 and 20p13 loci from linkage to VUR. Our results provide further evidence that there appears to be genetic heterogeneity in VUR

Local Translation in Primary Afferent Fibers Regulates Nociception

Recent studies have demonstrated the importance of local protein synthesis for neuronal plasticity. In particular, local mRNA translation through the mammalian target of rapamycin (mTOR) has been shown to play a key role in regulating dendrite excitability and modulating long-term synaptic plasticity associated with learning and memory. There is also increased evidence to suggest that intact adult mammalian axons have a functional requirement for local protein synthesis in vivo. Here we show that the translational machinery is present in some myelinated sensory fibers and that active mTOR-dependent pathways participate in maintaining the sensitivity of a subpopulation of fast-conducting nociceptors in vivo. Phosphorylated mTOR together with other downstream components of the translational machinery were localized to a subset of myelinated sensory fibers in rat cutaneous tissue. We then showed with electromyographic studies that the mTOR inhibitor rapamycin reduced the sensitivity of a population of myelinated nociceptors known to be important for the increased mechanical sensitivity that follows injury. Behavioural studies confirmed that local treatment with rapamycin significantly attenuated persistent pain that follows tissue injury, but not acute pain. Specifically, we found that rapamycin blunted the heightened response to mechanical stimulation that develops around a site of injury and reduced the long-term mechanical hypersensitivity that follows partial peripheral nerve damage - a widely used model of chronic pain. Our results show that the sensitivity of a subset of sensory fibers is maintained by ongoing mTOR-mediated local protein synthesis and uncover a novel target for the control of long-term pain states

Platelet rich plasma injection grafts for musculoskeletal injuries: a review

In Europe and the United States, there is an increasing prevalence of the use of autologous blood products to facilitate healing in a variety of applications. Recently, we have learned more about specific growth factors, which play a crucial role in the healing process. With that knowledge there is abundant enthusiasm in the application of concentrated platelets, which release a supra-maximal quantity of these growth factors to stimulate recovery in non-healing injuries. For 20 years, the application of autologous PRP has been safely used and documented in many fields including; orthopedics, sports medicine, dentistry, ENT, neurosurgery, ophthalmology, urology, wound healing, cosmetic, cardiothoracic, and maxillofacial surgery. This article introduces the reader to PRP therapy and reviews the current literature on this emerging treatment modality. In summary, PRP provides a promising alternative to surgery by promoting safe and natural healing. However, there are few controlled trials, and mostly anecdotal or case reports. Additionally the sample sizes are frequently small, limiting the generalization of the findings. Recently, there is emerging literature on the beneficial effects of PRP for chronic non-healing tendon injuries including lateral epicondylitis and plantar fasciitis and cartilage degeneration (Mishra and Pavelko, The American Journal of Sports Medicine 10(10):1–5, 2006; Barrett and Erredge, Podiatry Today 17:37–42, 2004). However, as clinical use increases, more controlled studies are needed to further understand this treatment