Interneuronal Nitric Oxide Signaling Mediates Post-synaptic Long-Term Depression of Striatal Glutamatergic Synapses

SummaryExperience-driven plasticity of glutamatergic synapses on striatal spiny projection neurons (SPNs) is thought to be essential to goal-directed behavior and habit formation. One major form of striatal plasticity, long-term depression (LTD), has long appeared to be expressed only pre-synaptically. Contrary to this view, nitric oxide (NO) generated by striatal interneurons was found to induce a post-synaptically expressed form of LTD at SPN glutamatergic synapses. This form of LTD was dependent on signaling through guanylyl cyclase and protein kinase G, both of which are abundantly expressed by SPNs. NO-LTD was unaffected by local synaptic activity or antagonism of endocannabinoid (eCb) and dopamine receptors, all of which modulate canonical, pre-synaptic LTD. Moreover, NO signaling disrupted induction of this canonical LTD by inhibiting dendritic Ca2+ channels regulating eCb synthesis. These results establish an interneuron-dependent, heterosynaptic form of post-synaptic LTD that could act to promote stability of the striatal network during learning

Optically Selected BL Lacertae Candidates from the Sloan Digital Sky Survey Data Release Seven

We present a sample of 723 optically selected BL Lac candidates from the SDSS DR7 spectroscopic database encompassing 8250 deg^2 of sky; our sample constitutes one of the largest uniform BL Lac samples yet derived. Each BL Lac candidate has a high-quality SDSS spectrum from which we determine spectroscopic redshifts for ~60% of the objects. Redshift lower limits are estimated for the remaining objects utilizing the lack of host galaxy flux contamination in their optical spectra; we find that objects lacking spectroscopic redshifts are likely at systematically higher redshifts. Approximately 80% of our BL Lac candidates match to a radio source in FIRST/NVSS, and ~40% match to a ROSAT X-ray source. The homogeneous multiwavelength coverage allows subdivision of the sample into 637 radio-loud BL Lac candidates and 86 weak-featured radio-quiet objects. The radio-loud objects broadly support the standard paradigm unifying BL Lac objects with beamed radio galaxies. We propose that the majority of the radio-quiet objects may be lower-redshift (z<2.2) analogs to high-redshift weak line quasars (i.e., AGN with unusually anemic broad emission line regions). These would constitute the largest sample of such objects, being of similar size and complementary in redshift to the samples of high-redshift weak line quasars previously discovered by the SDSS. However, some fraction of the weak-featured radio-quiet objects may instead populate a rare and extreme radio-weak tail of the much larger radio-loud BL Lac population. Serendipitous discoveries of unusual white dwarfs, high-redshift weak line quasars, and broad absorption line quasars with extreme continuum dropoffs blueward of rest-frame 2800 Angstroms are also briefly described.Comment: 24 pages, 14 figures, 8 tables. Accepted for publication in A

Inhibition of Toll-Like Receptor 4 Signaling Mitigates Microvascular Loss but Not Fibrosis in a Model of Ischemic Acute Kidney Injury

The development of chronic kidney disease (CKD) following an episode of acute kidney injury (AKI) is an increasingly recognized clinical problem. Inhibition of toll-like receptor 4 (TLR4) protects renal function in animal models of AKI and has become a viable therapeutic strategy in AKI. However, the impact of TLR4 inhibition on the chronic sequelae of AKI is unknown. Consequently, we examined the chronic effects of TLR4 inhibition in a model of ischemic AKI. Mice with a TLR4-deletion on a C57BL/6 background and wild-type (WT) background control mice (C57BL/6) were subjected to bilateral renal artery clamping for 19 min and reperfusion for up to 6 weeks. Despite the acute protective effect of TLR4 inhibition on renal function (serum creatinine 1.6 ± 0.4 mg/dL TLR4-deletion vs. 2.8 ± 0.3 mg/dL·WT) and rates of tubular apoptosis following ischemic AKI, we found no difference in neutrophil or macrophage infiltration. Furthermore, we observed significant protection from microvascular rarefaction at six weeks following injury with TLR4-deletion, but this did not alter development of fibrosis. In conclusion, we validate the acute protective effect of TLR4 signal inhibition in AKI but demonstrate that this protective effect does not mitigate the sequential fibrogenic response in this model of ischemic AKI

Single-stage combined urethroplasty for extended strictures of the anterior urethra of tuberculous origin

Background. Urethral strictures are currently one of the most complex pathologies in reconstructive urology. The most promising direction in this area is the development of single-stage surgical interventions that meets modern requirements for the quality of life of patients.The aim of the study. To evaluate the possibility and the effectiveness of surgical treatment of extended recurrent tuberculous urethral strictures in men using a combination of a skin flap and a buccal graft. In the literature, there is no description of the use of this technique in patients with urethral tuberculosis.Materials and methods. We observed 44 patients with urethral tuberculosis. Three men from this group of patients were diagnosed with tuberculous (post-tuberculous) extended recurrent stricture of the anterior urethra and they underwent combined single-stage urethroplasty with a ventral fasciocutaneous flap and a buccal graft using the inlay method in the penile region and with a buccal graft using the ventral onlay method in the bulbous urethra. Ultrasound of the urethra served as a method that determines the possibility of performing this surgery in case of maintaining a sufficient width of the urethral plate with a moderate degree of spongiofibrosis.Results. Patients were under observation for 34, 50 and 54 months and have good long-term functional results – all patients have unassisted urination and no residual urine. Post-micturition dribbling persists in 1 patient. The overall effectiveness of the treatment of these strictures, taking into account the treatment of repeated cases of the disease recurrence, is high.Conclusion. This technique demonstrates the possibility of performing a single-stage reconstruction of the anterior urethra in patients with extended recurrent tuberculous (post-tuberculous) urethral strictures and is also applicable for the surgical treatment of urethral strictures of other origins

Introduction to protein folding for physicists

The prediction of the three-dimensional native structure of proteins from the knowledge of their amino acid sequence, known as the protein folding problem, is one of the most important yet unsolved issues of modern science. Since the conformational behaviour of flexible molecules is nothing more than a complex physical problem, increasingly more physicists are moving into the study of protein systems, bringing with them powerful mathematical and computational tools, as well as the sharp intuition and deep images inherent to the physics discipline. This work attempts to facilitate the first steps of such a transition. In order to achieve this goal, we provide an exhaustive account of the reasons underlying the protein folding problem enormous relevance and summarize the present-day status of the methods aimed to solving it. We also provide an introduction to the particular structure of these biological heteropolymers, and we physically define the problem stating the assumptions behind this (commonly implicit) definition. Finally, we review the 'special flavor' of statistical mechanics that is typically used to study the astronomically large phase spaces of macromolecules. Throughout the whole work, much material that is found scattered in the literature has been put together here to improve comprehension and to serve as a handy reference.Comment: 53 pages, 18 figures, the figures are at a low resolution due to arXiv restrictions, for high-res figures, go to http://www.pabloechenique.co

listening to what matters for the patients and health professionals

Funding Information: The authors would like to acknowledge the members of the medical and patient committees for the input, advice and experiences shared for the guidance of this study. Namely, to AM, SP, JP, LR, MC, RF, TR and JB for being part of the patient committee and to JJ, EM, LB, DCo, DCa, CTL, RA, CL and AE for integrating the medical committee. We also want to acknowledge the volunteers from the NOVA Sci & Tech Volunteer program that helped with the organisation of this project. Funding Information: This work was supported by the CDG & Allies—Professionals and Patient Associations International Network (CDG&Allies-PPAIN) and by national funds from FCT—Fundação para a Ciência e a Tecnologia, I.P., in the scope of the Project UIDP/04378/2020 and UIDB/04378/2020 of the Research Unit on Applied Molecular Biosciences—UCIBIO, the Project LA/P/0140/2020 of the Associate Laboratory Institute for Health and Bioeconomy—i4HB C.P. and R.F. were funded by Fundação para a Ciência e Tecnologia with the Grants SFRH/BD/138647/2018 and (SFRH/BD/124326/2016) respectively. Publisher Copyright: © 2022, The Author(s).Background: Congenital disorders of glycosylation (CDG) are a growing group of rare genetic disorders. The most common CDG is phosphomannomutase 2 (PMM2)-CDG which often has a severe clinical presentation and life-limiting consequences. There are no approved therapies for this condition. Also, there are no validated disease-specific quality of life (QoL) scales to assess the heterogeneous clinical burden of PMM2-CDG which presents a challenge for the assessment of the disease severity and the impact of a certain treatment on the course of the disease. Aim and methods: This study aimed to identify the most impactful clinical signs and symptoms of PMM2-CDG, and specific patient and observer reported outcome measures (PROMs and ObsROMs, respectively) that can adequately measure such impact on patients’ QoL. The most burdensome signs and symptoms were identified through input from the CDG community using a survey targeting PMM2-CDG families and experts, followed by family interviews to understand the real burden of these symptoms in daily life. The list of signs and symptoms was then verified and refined by patient representatives and medical experts in the field. Finally, a literature search for PROMs and ObsROMs used in other rare or common diseases with similar signs and symptoms to those of PMM2-CDG was performed. Results: Twenty-four signs/symptoms were identified as the most impactful throughout PMM2-CDG patients’ lifetime. We found 239 articles that included tools to measure those community-selected PMM2-CDG symptoms. Among them, we identified 80 QoL scales that address those signs and symptoms and, subsequently, their psychometric quality was analysed. These scales could be applied directly to the PMM2-CDG population or adapted to create the first PMM2-CDG-specific QoL questionnaire. Conclusion: Identifying the impactful clinical manifestations of PMM2-CDG, along with the collection of PROMs/ObsROMs assessing QoL using a creative and community-centric methodology are the first step towards the development of a new, tailored, and specific PMM2-CDG QoL questionnaire. These findings can be used to fill a gap in PMM2-CDG clinical development. Importantly, this methodology is transferable to other CDG and rare diseases with multiple signs and symptoms.publishersversionpublishe

Radio non-detection during nearly-simultaneous Swift/XRT observations of MAXI J0911-635/Swift J0911.9-6452 in NGC 2808

We report nearly-simultaneous radio and X-ray observations of the newly discovered X-ray transient MAXI J0911-635/Swift J0911.9-6452 in the globular cluster NGC 2808 (ATel #8872, #8884)

Surgical treatment of urethral tuberculosis in men – history and present (literature review)

The literature review provides data on tuberculosis of the urethra in men. This disease is rarely recorded, as a rule, at the stage of formation of the urethral stricture, which can develop many years after the onset of the disease. Urethral tuberculosis is usually secondary to other localizations of extrapulmonary tuberculosis, such as tuberculosis of the prostate, penis, kidney, and bladder, but there are also isolated forms of this disease. The most common symptoms of urethral tuberculosis are the presence of strictures, skin-urethral and recto-prostatic fistulas, and purulent urethritis. Almost always, with this disease, conservative specific therapy was carried out, which in some cases made it possible to completely eliminate the symptoms and ensure the patient’s clinical recovery. Tuberculous urethral strictures are operated on according to generally accepted rules, but there is no single algorithm for the surgical treatment of strictures of this etiology, often limiting itself only to urine diversion or urethral dilation. Of the urethroplasty, the most commonly used end-to-end urethral anastomosis. In our opinion, a promising direction is the use of various grafts for the surgical treatment of this disease

The X-ray properties of million solar mass black holes

We present new Chandra X-ray observations of seven low-mass black holes (~1e6 Msun) accreting at low Eddington ratios between -2.0<log L/Ledd<-1.5. We compare the X-ray properties of these seven low-mass active galactic nuclei (AGN) to a total of 73 other low-mass AGN in the literature with published Chandra observations (with Eddington ratios extending from -2.0<log L/Ledd<-0.1). We do not find any statistical differences between low- and high-Eddington ratio low-mass AGN in the distributions of their X-ray to ultraviolet luminosity ratios (aox), or in their X-ray spectral shapes. Furthermore, the aox distribution of low-L/Ledd AGN displays an X-ray weak tail that is also observed within high-L/Ledd objects. Our results indicate that between -2<log L/Ledd<-0.1, there is no systematic change in the structure of the accretion flow for active galaxies hosting 1e6 Msun black holes. We examine the accuracy of current bolometric luminosity estimates for our low-L/Ledd objects with new Chandra observations, and it is plausible that their Eddington ratios could be underestimated by up to an order of magnitude. If so, then in analogy with weak emission line quasars, we suggest that accretion from a geometrically thick, radiatively inefficient `slim disk' could explain their diverse properties in aox. Alternatively, if current Eddington ratios are in fact correct (or overestimated), then the X-ray weak tail would imply that there is diversity in disk/corona couplings among individual low-mass objects. Finally, we conclude by noting that the aox distribution for low-mass black holes may have favorable consequences for the epoch of cosmic reionization being driven by AGN.Comment: 14 pages, 6 figures, 6 tables. Accepted for publication in Ap