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Brain function depends on synaptic connections between specific neuron types, yet systematic descriptions of synaptic networks and their molecular properties are not readily available. Here, we introduce SBARRO ( S ynaptic B arcode A nalysis by R etrograde R abies Read O ut), a method that uses single-cell RNA sequencing to reveal directional, monosynaptic relationships based on the paths of a barcoded rabies virus from its “starter” postsynaptic cell to that cell’s presynaptic partners. Thousands of these partner relationships can be ascertained in a single experiment, alongside genome-wide RNAs. We use SBARRO to describe synaptic networks formed by diverse mouse brain cell types in vitro, finding that different cell types have presynaptic networks with differences in average size and cell type composition. Patterns of RNA expression suggest that functioning synapses are critical for rabies virus uptake. By tracking individual rabies clones across cells, SBARRO offers new opportunities to map the synaptic organization of neural circuits. Synaptic connections are critical for brain function but are hard to measure systematically. Here, authors present a method which uses rabies virus barcoding and single-cell RNAseq to parallelize monosynaptic network reconstruction from molecularly-profiled single cells.

Phenotypic variation among species is a product of evolutionary changes to developmental programs 1 , 2 . However, how these changes generate novel morphological traits remains largely unclear. Here we studied the genomic and developmental basis of the mammalian gliding membrane, or patagium—an adaptative trait that has repeatedly evolved in different lineages, including in closely related marsupial species. Through comparative genomic analysis of 15 marsupial genomes, both from gliding and non-gliding species, we find that the Emx2 locus experienced lineage-specific patterns of accelerated cis -regulatory evolution in gliding species. By combining epigenomics, transcriptomics and in-pouch marsupial transgenics, we show that Emx2 is a critical upstream regulator of patagium development. Moreover, we identify different cis -regulatory elements that may be responsible for driving increased Emx2 expression levels in gliding species. Lastly, using mouse functional experiments, we find evidence that Emx2 expression patterns in gliders may have been modified from a pre-existing program found in all mammals. Together, our results suggest that patagia repeatedly originated through a process of convergent genomic evolution, whereby regulation of Emx2 was altered by distinct cis -regulatory elements in independently evolved species. Thus, different regulatory elements targeting the same key developmental gene may constitute an effective strategy by which natural selection has harnessed regulatory evolution in marsupial genomes to generate phenotypic novelty. Patagia—the mammalian gliding membrane—repeatedly originated through a process of convergent genomic evolution, whereby the regulation of Emx2 was altered by distinct cis -regulatory elements in independently evolved species.

Objective To evaluate the safety and efficacy of BI 1467335 in patients with non-proliferative diabetic retinopathy (NPDR). Methods ROBIN is a Phase IIa, double-masked, randomised, placebo-controlled study (NCT03238963). Patients with NPDR and without centre-involved diabetic macular oedema were included; all had a best corrected visual acuity letter score of ≥70 Early Treatment Diabetic Retinopathy Study letters in the study eye at screening. Patients received oral BI 1467335 10 mg or placebo once daily for 12 weeks. Post-treatment follow-up was 12 weeks. The primary endpoint was the proportion of patients over the 24 weeks with ocular adverse events (AEs). Secondary endpoints were the proportion of patients with ≥2-step improvement from baseline in DRSS severity level at Week 12 and the proportion of patients with non-ocular AEs at 24 weeks. Results Seventy-nine patients entered the study (BI 1467335, n  = 40; placebo, n  = 39). The proportion of patients with ocular AEs over 24 weeks was greater in the BI 1467335 versus the placebo group (35.0% vs 23.1%, respectively). Treatment-related AEs were reported for similar numbers of patients in the placebo and BI 1467335 group (7.7% vs 7.5%, respectively). At Week 12, 5.7% ( n  = 2) of patients in the BI 1467335 group had a 2-step improvement in DRSS severity level from baseline, compared with 0% in the placebo group. Conclusions BI 1467335 was well tolerated by patients with NPDR. There was a high variability in DRSS levels for individual patients over time, with no clear efficacy signal.

Brain function depends on forming and maintaining connections between neurons of specific types, ensuring neural function while allowing the plasticity necessary for cellular and behavioral dynamics. However, systematic descriptions of how brain cell types organize into synaptic networks and which molecules instruct these relationships are not readily available. Here, we introduce SBARRO (Synaptic Barcode Analysis by Retrograde Rabies ReadOut), a method that uses single-cell RNA sequencing to reveal directional, monosynaptic relationships based on the paths of a barcoded rabies virus from its \"starter\" postsynaptic cell to that cell's presynaptic partners1. Thousands of these partner relationships can be ascertained in a single experiment, alongside genome-wide RNA profiles - and thus cell identities and molecular states - of each host cell. We used SBARRO to describe synaptic networks formed by diverse mouse brain cell types in vitro, leveraging a system similar to those used to identify synaptogenic molecules. We found that the molecular identity (cell type/subtype) of the starter cell predicted the number and types of cells that had synapsed onto it. Rabies transmission tended to occur into cells with RNA-expression signatures related to developmental maturation and synaptic transmission. The estimated size of a cell's presynaptic network, relative to that of other cells of the same type, associated with increased expression of Arpp21 and Cdh13. By tracking individual virions and their clonal progeny as they travel among host cells, single-cell, single-virion genomic technologies offer new opportunities to map the synaptic organization of neural circuits in health and disease. Competing Interest Statement The authors have declared no competing interest.

Corneal surgeons were surveyed with regard to their technique of suture fixation of posterior chamber intraocular lenses in the absence of posterior capsular support. Fifty-nine percent of the 260 respondents stated they perform the procedure almost exclusively during penetrating keratoplasty. Scleral fixation was marginally favored over iris fixation by these surgeons. Most intraoperative problems reported were related to the relative technical difficulty of the procedure, although transient hemorrhage from the ciliary body was also mentioned. Postoperative complications cited included mechanical problems involving the lens and iris, cystoid macular edema, glaucoma, and endophthalmitis.

The Free vibration response of the Railway track is an important area in the design of the Rail and its joints to improve the ride comfort of the passengers. In this study, the rail weld considered is alumino thermite weldment used in majority of Indian Railways network. This paper aims at the study of the vibration response of rail wheel assembly having an AT weld on as a rail joint subjected to free vibration and to find the Natural frequencies of vibration and mode shapes. The geometric model of rail and weldment with wheel and axle components is modelled using Space-claim which is a part of ANSYS package and analysed using numerical simulation package ANSYS 2020 Workbench. In this work, free vibration analysis or modal analysis of the rail weld is carried out to extract the first few modes of vibration. The Natural frequencies obtained along with the corresponding mode shapes of the rail weldment show that they are within the permissible range specified by the standards of railway department also for better ride comfort of the passenger.

At wheel track contact point, the high stress concentration, poor weld quality, and heterogeneity of weld material are the main factors that cause fatigue crack on any rail weld. Railway network agencies are concerned about the safety of the railway track when it comes to detecting and fixing weld faults to avoid vehicle derailment and loss of lives. This study analysed a numerical simulation of fatigue crack and its evolution under loaded service condition. A 3-D CAD wheel rail weld assembly model was built to study an AT welded joint under fatigue, and for stress concentration factor (SIF) calculation. The results are found by inserting a semi elliptical crack on the rail weld head surface with ANSYS, and then numerical simulation has been performed to get the different three modes of SIF at rail weld crack. The analysis findings data was recorded with critical fracture parameters of SIFs and its number of cycles to failure using LEFM technique and respective results have been plotted. With ANSYS the stress intensity on a crack will be resulted. By using numerical method, the critical crack size and number of cycle load with fatigue life of rail would be determined. The numbers of rail weld inspection per year has been determine by using the maximum number of cycle. The aim of this paper is to develop an effective inspection and maintenance frequency based on rolling contact surfaces crack propagation analyse. This will help to prevent the occurrence of rail failure by taking the required action at the right time, and extend the rail life expectancy, reduce the rail maintenance work and its cost.

Purpose: COVID-19-associated rhino-orbital-cerebral mucormycosis (ROCM) has reached epidemic proportion during India's second wave of COVID-19 pandemic, with several risk factors being implicated in its pathogenesis. This study aimed to determine the patient demographics, risk factors including comorbidities, and medications used to treat COVID-19, presenting symptoms and signs, and the outcome of management. Methods: This was a retrospective, observational study of patients with COVID-19-associated ROCM managed or co-managed by ophthalmologists in India from January 1, 2020 to May 26, 2021. Results: Of the 2826 patients, the states of Gujarat (22%) and Maharashtra (21%) reported the highest number of ROCM. The mean age of patients was 51.9 years with a male preponderance (71%). While 57% of the patients needed oxygen support for COVID-19 infection, 87% of the patients were treated with corticosteroids, (21% for > 10 days). Diabetes mellitus (DM) was present in 78% of all patients. Most of the cases showed onset of symptoms of ROCM between day 10 and day 15 from the diagnosis of COVID-19, 56% developed within 14 days after COVID-19 diagnosis, while 44% had delayed onset beyond 14 days. Orbit was involved in 72% of patients, with stage 3c forming the bulk (27%). Overall treatment included intravenous amphotericin B in 73%, functional endoscopic sinus surgery (FESS)/paranasal sinus (PNS) debridement in 56%, orbital exenteration in 15%, and both FESS/PNS debridement and orbital exenteration in 17%. Intraorbital injection of amphotericin B was administered in 22%. At final follow-up, mortality was 14%. Disease stage >3b had poorer prognosis. Paranasal sinus debridement and orbital exenteration reduced the mortality rate from 52% to 39% in patients with stage 4 disease with intracranial extension (p < 0.05). Conclusion: Corticosteroids and DM are the most important predisposing factors in the development of COVID-19-associated ROCM. COVID-19 patients must be followed up beyond recovery. Awareness of red flag symptoms and signs, high index of clinical suspicion, prompt diagnosis, and early initiation of treatment with amphotericin B, aggressive surgical debridement of the PNS, and orbital exenteration, where indicated, are essential for successful outcome.