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Background/Objectives: Neural retina leucine zipper (NRL) is a transcription factor involved in the differentiation of rod photoreceptors. Pathogenic variants in the gene encoding NRL have been associated with autosomal dominant retinitis pigmentosa and autosomal recessive clumped pigmentary retinal degeneration. Only a dozen unrelated families affected by recessive NRL-related retinal dystrophy have been described. The purpose of this study was to expand the genotypic spectrum of this disease by reporting clinical and genetic findings of two unrelated families. Methods: Index patients affected by retinal dystrophy were genetically tested by whole-exome sequencing (WES) and whole-genome sequencing (WGS). Segregation analysis within the families was performed for candidate variants. A minigene assay was performed to functionally characterize a variant suspected to affect splicing. Results: Variant filtering revealed homozygous NRL variants in both families. The variant in patient A was a small deletion encompassing the donor splice site of exon 1 of transcript NM_006177.3. The minigene assay revealed that this variant led to two aberrant transcripts that used alternative cryptic donor splice sites located in intron 1. In patient B, a stop-gain variant was identified in the last exon of NRL in a homozygous state due to maternal uniparental disomy of chromosome 14. Conclusions: Our study expands the genotypic spectrum of autosomal recessive NRL-related retinal dystrophy. Moreover, it underscores the importance of actively maintaining bioinformatic pipelines for variant detection and the utility of minigene assays in functionally characterizing candidate splicing variants. [ABSTRACT FROM AUTHOR]

Aging induces systematic changes in the distribution of nucleosomes, which affect gene expression programs. Here we reconstructed nucleosome maps based on cell‐free DNA (cfDNA) extracted from blood plasma using four cohorts of people of different ages. We show that nucleosomes tend to be separated by larger genomic distances in older people, and age correlates with the nucleosome repeat length (NRL). Furthermore, we developed the first aging clock based on cfDNA nucleosomics. Machine learning based on cfDNA distance distributions allowed predicting person's age with the median absolute error of 3–3.5 years. [ABSTRACT FROM AUTHOR]

Background: Nucleosome repositioning in cancer is believed to cause many changes in genome organisation and gene expression. Understanding these changes is important to elucidate fundamental aspects of cancer. It is also important for medical diagnostics based on cell-free DNA (cfDNA), which originates from genomic DNA regions protected from digestion by nucleosomes. Results: We have generated high-resolution nucleosome maps in paired tumour and normal tissues from the same breast cancer patients using MNase-assisted histone H3 ChIP-seq and compared them with the corresponding cfDNA from blood plasma. This analysis has detected single-nucleosome repositioning at key regulatory regions in a patient-specific manner and common cancer-specific patterns across patients. The nucleosomes gained in tumour versus normal tissue were particularly informative of cancer pathways, with ~ 20-fold enrichment at CpG islands, a large fraction of which marked promoters of genes encoding DNA-binding proteins. The tumour tissues were characterised by a 5–10 bp decrease in the average distance between nucleosomes (nucleosome repeat length, NRL), which is qualitatively similar to the differences between pluripotent and differentiated cells. This effect was correlated with gene activity, differential DNA methylation and changes in local occupancy of linker histone variants H1.4 and H1X. Conclusions: Our study offers a novel resource of high-resolution nucleosome maps in breast cancer patients and reports for the first time the effect of systematic decrease of NRL in paired tumour versus normal breast tissues from the same patient. Our findings provide a new mechanistic understanding of nucleosome repositioning in tumour tissues that can be valuable for patient diagnostics, stratification and monitoring. [ABSTRACT FROM AUTHOR]

Synthetic adhesives used in the production of plywood are a matter of concern because of the emission of carcinogenic gas formaldehyde, increased environmental pollution, and the depletion of fossil fuels. In this study, a bioadhesive composed of natural rubber latex (NRL) and rice starch was developed. However, rice starch has low moisture resistance, resulting in low adhesion. Thus, to enhance the effectiveness of NRL-blended rice starch-based bioadhesive, rice starch was cross-linked with polymeric 4,4″-diphenylmethane diisocyanate (pMDI) resin, which is an environment-friendly, formaldehyde free, and moisture resistant that is highly compatible with starch. The chemical interaction, viscosity, solid content, and gel time of the developed NRL-isocyanate cross-linked rice starch-based bioadhesive was investigated. The efficacy of the formulated bioadhesive was demonstrated by the fabrication of plywood. The presence of isocyanate and urethane capabilities in the bioadhesive formulations was confirmed by Fourier transform infrared spectroscopy (FTIR). The bioadhesive type Iso-A was discovered to have the highest viscosity of 8270 mPa.s, whereas Iso-B has the shortest gel time of 3.46 min and the highest solid content of 44%; the higher solid content accelerates the gel time. In terms of physical and mechanical properties of plywood, Iso-B has the lowest thickness swelling (TS) value of 13%, lowest water absorption (WA) value of 52% and shear strength value of 1.92 MPa, which corresponds to the ISO 12466–2-2007 standard requirements. Based on the results, NRL-blended isocyanate starch-based bioadhesive could be a good potential raw material for eco-friendly plywood industries with adequate accuracy. [ABSTRACT FROM AUTHOR]

Retinitis pigmentosa (RP) is an inherited retinal dystrophy (IRD) with a prevalence of 1:4000, characterized by initial rod photoreceptor loss and subsequent cone photoreceptor loss with accompanying nyctalopia, visual field deficits, and visual acuity loss. A diversity of causative mutations have been described with autosomal dominant, autosomal recessive, and X-linked inheritance and sporadic mutations. The diversity of mutations makes gene therapy challenging, highlighting the need for mutation-agnostic treatments. Neural leucine zipper (NRL) and NR2E3 are factors important for rod photoreceptor cell differentiation and homeostasis. Germline mutations in NRL or NR2E3 leads to a loss of rods and an increased number of cones with short wavelength opsin in both rodents and humans. Multiple groups have demonstrated that inhibition of NRL or NR2E3 activity in the mature retina could endow rods with certain properties of cones, which prevents cell death in multiple rodent RP models with diverse mutations. In this review, we summarize the literature on NRL and NR2E3, therapeutic strategies of NRL/NR2E3 modulation in preclinical RP models, as well as future directions of research. In summary, inhibition of the NRL/NR2E3 pathway represents an intriguing mutation agnostic and disease-modifying target for the treatment of RP.

We report a patient with enhanced S-cone syndrome because of pathogenic (p.Arg309Gly), and likely pathogenic (p.Arg77Trp) variants in the NR2E3 gene with atypical electroretinogram responses and atypical double hyperautofluorescent ring in both eyes. Purpose: To describe the clinical phenotype and molecular diagnosis of a patient with atypical presentation of enhanced S-cone syndrome. Methods: This is a case report of a patient who underwent best-corrected visual acuity, slit-lamp exam, fundus examination, autofluorescence, optical coherence tomography, kinetic perimetry, and full-field electroretinography. Genetic testing was performed via next-generation sequencing. Results: A 33-year-old female patient presented with mild nyctalopia, but normal rod function measured by electroretinogram and foveoschisis on optical coherence tomography. She also presented a double hyperautofluorescent ring on autofluorescence. Genetic testing found a pathogenic variant c.925C>G (p.Arg309Gly) and a likely pathogenic variant c.299C>T (p.Arg77Trp) in NR2E3 gene. Conclusion: Enhanced S-cone syndrome may present without the pathognomonic findings of decreased rod function on electroretinogram, suggesting the importance of genetic testing in retinal diseases for diagnosis. [ABSTRACT FROM AUTHOR]

The voltage-gated calcium channel, Cav1.4 is localized to photoreceptor ribbon synapses and functions both in molecular organization of the synapse and in regulating release of synaptic vesicles. Mutations in Cav1.4 subunits typically present as either incomplete congenital stationary night blindness or a progressive cone-rod dystrophy in humans. We developed a cone-rich mammalian model system to further study how different Cav1.4 mutations affect cones. RPE65 R91W KI; Nrl KO "Conefull" mice were crossed to Cav1.4 α1F or α2δ4 KO mice to generate the "Conefull:α1F KO" and "Conefull:α2δ4 KO" lines. Animals were assessed using a visually guided water maze, electroretinogram (ERG), optical coherence tomography (OCT), and histology. Mice of both sexes and up to six-months of age were used. Conefull: α1F KO mice could not navigate the visually guided water maze, had no b-wave in the ERG, and the developing all-cone outer nuclear layer reorganized into rosettes at the time of eye opening with degeneration progressing to 30% loss by 2-months of age. In comparison, the Conefull: α2δ4 KO mice successfully navigated the visually guided water maze, had a reduced amplitude b-wave ERG, and the development of the all-cone outer nuclear layer appeared normal although progressive degeneration with 10% loss by 2-months of age was observed. In summary, new disease models for studying congenital synaptic diseases due to loss of Cav1.4 function have been created. [ABSTRACT FROM AUTHOR]

Photoreceptors are sensory neurons that capture light within their outer segment, a narrow cylindrical organelle stacked with disc-shaped membranes housing the visual pigment. Photoreceptors are the most abundant neurons in the retina and are tightly packed to maximize the capture of incoming light. As a result, it is challenging to visualize an individual cell within a crowded photoreceptor population. To address this limitation, we developed a rod-specific mouse model that expresses tamoxifen-inducible cre recombinase under the control of the Nrl promoter. We characterized this mouse using a farnyslated GFP (GFPf) reporter mouse and found mosaic rod expression throughout the retina. The number of GFPf-expressing rods stabilized within 3 days post tamoxifen injection. At that time, the GFPf reporter began to accumulate in basal disc membranes. Using this new reporter mouse, we attempted to quantify the time course of photoreceptor disc renewal in WT and Rd9 mice, a model of X-linked retinitis pigmentosa previously proposed to have a reduced disc renewal rate. We measured GFPf accumulation in individual outer segments at 3 and 6 days post-induction and found that basal accumulation of the GFPf reporter was unchanged between WT and Rd9 mice. However, rates of renewal based on the GFPf measurements were inconsistent with historical calculations from radiolabeled pulse-chase experiments. By extending GFPf reporter accumulation to 10 and 13 days we found that this reporter had an unexpected distribution pattern that preferentially labeled the basal region of the outer segment. For these reasons the GFPf reporter cannot be used for measuring rates of disc renewal. Therefore, we used an alternative method that labels newly forming discs with a fluorescent dye to measure disc renewal rates directly in the Rd9 model and found it was not significantly different from WT. Our study finds that the Rd9 mouse has normal rates of disc renewal and introduces a novel Nrl:CreERT2 mouse for gene manipulation of individual rods. [ABSTRACT FROM AUTHOR]

Photoreceptors are sensory neurons that capture light within their outer segment, a narrow cylindrical organelle stacked with disc-shaped membranes housing the visual pigment. Photoreceptors are the most abundant neurons in the retina and are tightly packed to maximize the capture of incoming light. As a result, it is challenging to visualize an individual cell within a crowded photoreceptor population. To address this limitation, we developed a rod-specific mouse model that expresses tamoxifen-inducible cre recombinase under the control of the Nrl promoter. We characterized this mouse using a farnyslated GFP (GFPf) reporter mouse and found mosaic rod expression throughout the retina. The number of GFPf-expressing rods stabilized within 3 days post tamoxifen injection. At that time, the GFPf reporter began to accumulate in basal disc membranes. Using this new reporter mouse, we attempted to quantify the time course of photoreceptor disc renewal in WT and Rd9 mice, a model of X-linked retinitis pigmentosa previously proposed to have a reduced disc renewal rate. We measured GFPf accumulation in individual outer segments at 3 and 6 days post-induction and found that basal accumulation of the GFPf reporter was unchanged between WT and Rd9 mice. However, rates of renewal based on the GFPf measurements were inconsistent with historical calculations from radiolabeled pulse-chase experiments. By extending GFPf reporter accumulation to 10 and 13 days we found that this reporter had an unexpected distribution pattern that preferentially labeled the basal region of the outer segment. For these reasons the GFPf reporter cannot be used for measuring rates of disc renewal. Therefore, we used an alternative method that labels newly forming discs with a fluorescent dye to measure disc renewal rates directly in the Rd9 model and found it was not significantly different from WT. Our study finds that the Rd9 mouse has normal rates of disc renewal and introduces a novel Nrl:CreERT2 mouse for gene manipulation of individual rods.

Enhanced S-cone syndrome (ESCS) is a rare autosomal recessive retinal degeneration mainly associated with pathogenic variations in the NR2E3 gene. Only a few pathogenic variations in the NRL gene associated with ESCS have been reported to date. Here, we describe the clinical and genetic findings of two unrelated pediatric patients with a novel frameshift homozygous variant in the NRL gene. Fundus examinations showed signs of peripheral degeneration in both patients, more severe in Proband 2, with relative sparing of the macular area. Spectral domain optical coherence tomography (SD-OCT) revealed a significant macular involvement with cysts in Proband 1, and minimal foveal alteration with peripheral retina involvement in Proband 2. Visual acuity was abnormal in both patients, but more severely affected in Proband 1 than Proband 2. The electroretinogram recordings showed reduced scotopic, mixed and single flash cone responses, with a typical supernormal S-cone response, meeting the criteria for a clinical diagnosis of ESCS in both patients. The present report expands the clinical and genetic spectrum of NRL-associated ESCS, and confirms the age-independent variability of phenotypic presentation already described in the NR2E3-associated ESCS. [ABSTRACT FROM AUTHOR]

Introduction. Multiple sclerosis (MS) is one of the main chronic inflammatory diseases of the central nervous system that causes functional disability in people. Assessment of the state of the immune system begins with an analysis of the total number of blood leukocytes and their population composition (the number of neutrophils and lymphocytes). The ratio of neutrophils and lymphocytes (NRL) is a marker of inflammation.The aim of the study. The aim of this study was to investigate the WBC and neutrophil-to-lymphocyte ratio in patients with different forms of MS. Results. In patients with MS in 23.5% of cases the WBC is higher than 9×109/L. In 5.9% of МS cases leukopenia is observed, and in the vast majority of cases (70, 6%) the level of blood leukocytes was in the range of 4-9×109/L. Leukopenia and leukocytosis are more common in women than in men (pConclusions. NRL is an inexpensive and affordable indicator, which is determined by the automatic determination of the total number of leukocytes in the blood. It can be an additional informative indicator of inflammation against the background of normal leukocyte levels.

Nanocomposites have received voluminous interest due to the combination of unique properties of organic and inorganic component in one material. In this class, magnetic polymer nanocomposites are of particular interest because of the combination of excellent magnetic properties, stability, and good biocompatibility. This paper reports the preparation and characterization of nanocomposites films based on natural rubber in latex state (NRL) loaded with different concentrations of semiconducting magnetite nanoparticles (Fe3O4) (MNPs) (5, 10, 15, 20, and 30%). NRL (100%) and NRL/Fe3O4 nanocomposites were prepared by solution casting technique then, exposed to various irradiation doses (50, 70, 100 kGy).The nanocomposite's morphological, and physical properties were investigated through various spectroscopic techniques such as Fourier-transformed infrared, X-ray diffraction, scanning electron, and transmission electron microscopies. The mechanical properties, including the tensile strength and elongation at break percentage (Eb%) of the nanocomposites were also studied and compared with the 100% NRL films. Based on the results obtained from the mechanical study, it is found that the NRL/20% Fe3O4 nanocomposite film exhibited the highest tensile strength at 100 kGy. On the other hand, based on the conductivity study, it is found that, NRL/Fe3O4 nanocomposite with 10% magnetite exhibit the highest conductivity as the content of magnetite plays an important and effective role based on the high and homogeneous dispersity. [ABSTRACT FROM AUTHOR]

We describe a 13-year-old boy who presented with blurred vision, vitreous cells, cystoid macular edema refractory response to steroid treatment, and a negative uveitic workup. He was diagnosed with enhanced S-cone syndrome after a complex course. We present a novel mutation and multimodal imaging analysis. Purpose: To describe in detail the phenotype of a patient with enhanced S-cone syndrome. Methods: We describe a 13-year-old boy who presented with blurred vision, vitreous cells, cystoid macular edema refractory to steroid treatment, and a negative uveitic workup. The patient underwent a complete ophthalmic examination, full-field electroretinograms (ffERG), automatic static perimetry and multimodal imaging with spectral domain optical coherence tomography, and adaptive optics scanning laser ophthalmoscopy (AOSLO). Results: Spectral domain optical coherence tomography demonstrated cystoid macular edema and a hyperthick, delaminated midperipheral retina. Fluorescein angiography did not demonstrate macular leakage. Rod-mediated ffERGs were undetectable, and there was a supernormal response to short-wavelength stimuli compared with photopically matched longer wavelengths of light consistent with enhanced S-cone syndrome. Gene screening was positive for compound heterozygous mutations NR2E3 : a known (c.119-2 A>C) and a novel (c.119-1G>A) mutation. By perimetry, sensitivities were normal or above normal for short-wavelength stimuli; there was no detectable rod-mediated vision. AOSLO demonstrated higher than normal cone densities in the perifoveal retina and evidence for smaller outer segment cone diameters. Conclusion: Evidence for supernumerary cones (at least twice the normal complement) by AOSLO and spectral domain optical coherence tomography was associated with supernormal S-cone sensitivities and electroretinogram responses confirming previous in vivo findings in postmortem human specimens. Smaller than normal cones in enhanced S-cone syndrome may represent "hybrid" photoreceptors analogous to the rd7/rd7 murine model of the disease. [ABSTRACT FROM AUTHOR]

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Organoid cultures represent a unique tool to investigate the developmental complexity of tissues like the human retina. NRL is a transcription factor required for the specification and homeostasis of mammalian rod photoreceptors. In Nrl-deficient mice, photoreceptor precursor cells do not differentiate into rods, and instead follow a default photoreceptor specification pathway to generate S-cone-like cells. To investigate whether this genetic switch mechanism is conserved in humans, we used CRISPR/Cas9 gene editing to engineer an NRL-deficient embryonic stem cell (ESC) line (NRL-/-), and differentiated it into retinal organoids. Retinal organoids self-organize and resemble embryonic optic vesicles (OVs) that recapitulate the natural histogenesis of rods and cone photoreceptors. NRL-/- OVs develop comparably to controls, and exhibit a laminated, organized retinal structure with markers of photoreceptor synaptogenesis. Using immunohistochemistry and quantitative polymerase chain reaction (qPCR), we observed that NRL-/- OVs do not express NRL, or other rod photoreceptor markers directly or indirectly regulated by NRL. On the contrary, they show an abnormal number of photoreceptors positive for S-OPSIN, which define a primordial subtype of cone, and overexpress other cone genes indicating a conserved molecular switch in mammals. This study represents the first evidence in a human in vitro ESC-derived organoid system that NRL is required to define rod identity, and that in its absence S-cone-like cells develop as the default photoreceptor cell type. It shows how gene edited retinal organoids provide a useful system to investigate human photoreceptor specification, relevant for efforts to generate cells for transplantation in retinal degenerative diseases. [ABSTRACT FROM AUTHOR]

Work-life balance has become an increasingly pervasive concern for all the level of Human resources of all organizations. An efficient employee with better education, nourished skills, innovations, and competency is an inevitable asset for an organization. Engagement and retention of these employees requires the application of best strategies on the part of the employers or management. The respective study is concentrated with the refinery employees and it has been attempted to understand the organizational effort to enable its employees specially the management staff to enjoy a balanced life. It has been found that the Numaligarh Refinery Limited is striving to provide various compensation and employee benefits and services for the upliftment of its staff and enabling them to balance their different spheres of life. [ABSTRACT FROM AUTHOR]

This work aims to develop the routing capability of GPSR in MANETs. A new GPSR improvement described as Advanced GPSR (AGPSR) is proposed with enhanced greedy forwarding and efficient routing decision. AGPSR greedy forwarding model consists of three major phases; initialization, finding target neighbor, weight value computation and next hop selection. The weight value encounters a set of network metrics including node density, network size, congestion level, transmission range, node speed and movement direction. An intensive evaluation methodology was implemented in order to evaluate the performance of proposed AGPSR in MANET. Results confirm that proposed GPSR has surpassed several MANET environmental challenges and outperformed conventional GPSR in terms of PDR, E2E delay, routing overhead, and power consumption. The delay is reduced by AGPSR of up-to 10% compared to conventional GPSR. In addition, 5% increase in PDR and more than 7% decrease in routing overhead and in power consumption was achieved by AGPSR. [ABSTRACT FROM AUTHOR]

This research note outlines advances in the development of shipborne radar in Britain, Germany, the US and the Soviet Union. It focuses on the inventions and innovations in electronic and radars techniques for military and commercial applications on the eve of the Second World War, during the war and in the post-war period. [ABSTRACT FROM AUTHOR]

PURPOSE: An electronegative electroretinogram (ERG), defined as having a b:a wave ratio ≤1 in the scotopic flash ERG response, indicates relative inner retinal dysfunction. Causes vary depending upon the study population. In the Arabian Gulf, where inherited retinal disease is relatively prevalent, common diagnoses associated with electronegative ERGs have not been described. In this study, we report the frequency and causes of electronegative ERGs in a cohort of Emirati patients with inherited retinal disease. METHODS: A retrospective review was performed of all full-field ERGs done for Emirati patients in the Ocular Genetics Service of Cleveland Clinic Abu Dhabi from January 2017 to December 2019. Those who had an electronegative ERG in at least one eye were included in the study. RESULTS: Out of 137 patients, 9 probands (6.6%) had an electronegative ERG. The mean age at presentation was 24 years (range 5–48 years), and five patients (55.6%) were male. The final clinical diagnoses were congenital stationary night blindness (CSNB) (two TRPM1-related and one Oguchi disease), X-linked retinoschisis (XLRS) (one genetically confirmed and two not genetically tested), cone-rod dystrophy (one CRX-related and one not genetically tested), and enhanced S-cone syndrome (ESCS) (one NRL-related). The one patient who did not have bilateral electronegative ERGs was a male with XLRS whose fellow eye had an unrecordable ERG. CONCLUSIONS: In this series of Emirati patients, an electronegative ERG was most commonly associated with the inherited retinal diseases recessive CSNB and XLRS. An electronegative ERG was noted in a case of NRL-related ESCS. [ABSTRACT FROM AUTHOR]

Introduction: In 2013, the National Tuberculosis (TB) Program of Armenia introduced GeneXpert MTB/RIF (Xpert) assay to address World Health Organization (WHO) target of 80% (2020) of notified new and relapse TB cases to be tested with WHO recommended rapid diagnostic methods. This study aimed to assess the change in laboratory diagnostic profile of Mycobacterium tuberculosis after introduction of the Xpert assay from 2013 to 2017. Methodology: Retrospective cohort analysis of all presumptive TB patients' records retrieved from the National Reference Laboratory database was performed. Results: This study showed increased trend of Xpert coverage for suspected TB cases from 25% in 2013 to 86% in 2017 which is in line with WHO TB global strategy's target of 80% in 2020. In 4.7% cases, Xpert tested positive while microscopy showed negative results. There was also an improved detection of Rifampicin resistance with increased concordance from 99.1% to 99.4% and decreased discordance from 6.7% to 1.4% between culture and Xpert results. Conclusion: Armenia has achieved the 2020 target; in terms of utilizing the GeneXpert it is on track to achieve the End TB strategy target of 100% by 2025. The next step of this research will be assessment of the impact of GeneXpert and other TB tests utilization on the treatment outcomes in Armenia. [ABSTRACT FROM AUTHOR]

Introduction: A one of the step towards achieving TB related targets is to ensure early and quality diagnosis of TB in national laboratories. WHO recommends that all national reference laboratories in TB burden countries strive to reach accreditation by 2025, based on ISO15189:2012 quality management system standard. To identify gaps, progress and evaluated the evolution in implementation QMS we performed a formal assessment of the national TB reference laboratory of Armenia, as well as estimates the specific quality indicators of NRL activity. Methodology: This is retrospective study cross-sectional study using laboratory data from the National TB Reference Laboratory in Armenia. Quality Management System assessments was conducted twice a year, using TB SLMTA assessment checklist. The sputum rejection and culture rates for quality indicators are calculated and assessed monthly. Results: Compared to the baseline in 2016, there was a quality improvement reflecting the progress from zero to a "one star" in 2018. Areas that reached half of the target score included document and records, management review and responsibilities, evaluation and audits. Sections as "client management and customer service" and "evaluation and audits" stagnated in terms of progress. In terms of NRL performace, all indicators improved except for culture positivity in smear negative tuberculosis. Conclusion: Although a quality management system was introduced in the NRL there is now an urgent need to develop and implement an adapted roadmap for Armenia. This will be vital to hasten the much-needed pace towards accreditation. [ABSTRACT FROM AUTHOR]

Vehicular Ad-hoc network (VANET) is a self-organized ad hoc network. VANET becomes a most challenging research area as it has several issues related to routing protocols, quality of service, security, etc. Vehicular communication is critically unsafe to several kinds of active and passive routing attacks. This paper analyzes the impact of a compromised node (vehicle) on zone routing protocol and ad-hoc on-demand distance vector, and recommends a suitable solution called secure vehicular on demand routing to find out and mitigate the black hole attack. The given study analyses the effect of vehicle density on the average throughput, packet delivery ratio, end-to-end delay, normalized routing load and average path length. [ABSTRACT FROM AUTHOR]

Retinal histogenesis requires coordinated and temporal functioning of factors by which different cell types are generated from multipotent progenitors. Development of rod photoreceptors is regulated by multiple transcription factors, and Nrl is one of the major factors involved in their fate specification. Presence or absence of Nrl at the postnatal stages decides the generation of cone photoreceptors or other later retinal cells. This suggests the need for regulated expression of Nrl in order to accelerate the generation of other cell types during retinal development. We found that miR cluster 143/145, comprising miR-143 and miR-145, targets and imparts a posttranscriptional inhibition of Nrl. Expression of both miRNAs was differentially regulated during retinal development and showed least expression at PN1 stage in which most of the rod photoreceptors are generated. Downregulation of rod photoreceptor regulators and markers upon miR cluster 143/145 overexpression demonstrated that this cluster indeed negatively regulates rod photoreceptors. Further, we prove that Nrl positively regulates miR cluster 143/145, thus establishing a feedback loop regulatory mechanism. This may be one possible mechanism by which Nrl is posttranscriptionally regulated to facilitate the generation of other cell types in retina. [ABSTRACT FROM AUTHOR]

Aim: We have previously described two unrelated Bukhara Jews (BJs) with a combination of oculopharyngeal muscular dystrophy (OPMD) and inherited retinal dystrophy (IRD), because of mutations in two linked genes: PABPN1 and NRL. Here we investigated the prevalence of the NRL mutation among BJs with OPMD. Materials and Methods: PABPN1 and NRL mutation testing were performed by polymerase chain reaction amplification and direct sequencing on two cohorts of Bukhara Jewish patients: OPMD patients (with or without IRD) and IRD patients (without OPMD). Results: Of 24 unrelated chromosomes from Bukhara Jewish OPMD patients, 19 (79%) harbored the NRL mutation. In contrast, the NRL mutation was not detected in Bukhara Jewish patients diagnosed with IRD but without OPMD. Conclusions: Our findings provide an explanation for the reoccurrence of IRD in Bukhara Jewish OPMD homozygotes. Moreover, they indicate that Bukhara Jewish OPMD patients are at high risk for carrying the NRL mutation, and should be offered appropriate genetic counseling and testing. [ABSTRACT FROM AUTHOR]

A number of studies have established that higher levels of strength and power, tested at the end of the preseason, distinguish between playing level in professional rugby league. How this may impact the ability of players to get selected for final payoff games some 30 weeks later has not been fully investigated. The purpose of this study was to compare measures of upper- and lower-body strength between players from the same professional club, designated as those 17 players who attained selection and played in the team that won the Grand Final of the National Rugby League competition (GF) and those who did not attain selection (NSGF). Players were tested and compared for 1 repetition maximum bench press and full squat strength levels at the end of the preparation period, 30 weeks before the GF, using traditional significance analysis of variance and effect size (ES) statistics. Furthermore, the players were analyzed according to the 2 broad positional playing groups of forwards (FWD) and backs (BL). The results demonstrated that overall, the GF players were stronger than NSGF players by approximately 10 and 15%, respectively, for the upper and lower body. When analyzed according to positional groupings, there were significant differences and large ES for GF forwards, who were significantly stronger, heavier, and older than NSGF FWD players. For the BL groups, the differences between the groups were not significant. Because of the intense physical collisions inherent in rugby league, it would appear that higher levels of strength afford players greater performance benefits, resiliency against injury, and greater likelihood of being selected in the most important games at the end of the season. [ABSTRACT FROM AUTHOR]

Clustered interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9)-mediated genome engineering technologies are sparking a new revolution in biological research. This technology efficiently induces DNA double strand breaks at the targeted genomic sequence and results in indel mutations by the error-prone process of nonhomologous end joining DNA repair or homologous recombination with a DNA repair template. The efficiency of genome editing with CRISPR/Cas9 alone in human embryonic stem cells is still low. Gene targeting with adeno-associated virus (AAV) vectors has been demonstrated in multiple human cell types with maximal targeting frequencies without engineered nucleases. However, whether CRISPR/Cas9-mediated double strand breaks and AAV based donor DNA mediated homologous recombination approaches could be combined to create a novel CRISPR/Cas9-AAV genetic tool for highly specific gene editing is not clear. Here we demonstrate that using CRISPR/Cas9-AAV, we could successfully knock-in a DsRed reporter gene at the basic motifleucine zipper transcription factor (NRL) locus in human embryonic stem cells. For the first time, this study provides the proof of principle that these two technologies can be used together. CRISPR/Cas9-AAV, a new genome editing tool, offers a platform for the manipulation of human genome.

The Inter European Union Reference Laboratories (EURLs) Working Group on Next Generation Sequencing (NGS) involves eight EURLs for microbiological food and feed hazards and has been working since 2017 to promote the adoption of NGS by the National Reference Laboratories (NRLs) in the European Union. This work illustrates the results of the first 5 years of activity. By working together, the EURLs involved have released guidance documents for assisting NRLs in all the steps of NGS, helping the transition from classical molecular methods towards whole genome sequencing while ensuring harmonization, with the final aim of improving preparedness in the use of NGS to characterize microbial hazards and trace the sources of infection.

We have approached the role of cellular stress in neurodegenerative diseases caused by polyglutamine expansion (polyQ) in the context of Spinocerebellar ataxia type 7 (SCA7) that includes retinal degeneration. Using the R7E mouse, in which polyQ-ataxin-7 is specifically over-expressed in rod photoreceptors, we previously showed that rod dysfunction correlated to moderate and prolonged activation of the JNK/c-Jun stress pathway. SCA7 retinopathy was also associated with reduced expression of rod-specific genes, including the transcription factor Nrl, which is essential for rod differentiation and function. Here, we report that R7E retinopathy is improved upon breeding with the JunAA knock-in mice, in which JNK-mediated activation of c-Jun is compromised. Expression of Nrl and its downstream targets, which are involved in phototranduction, are partially restored in the JunAA-R7E mice. We further show that c-Jun can directly repress the transcription of Nrl. Our studies suggest that polyQ-induced cellular stress leads to repression of genes necessary for neuronal fate and function.

This study explores how alcohol brands use markers of brand community (consciousness of kind, rituals and traditions, and moral responsibility) to engage existing lifestyle consumption communities. Drawing on consumption community and ethics theory, the article examines the interface between brands and a lifestyle consumption community, and explores ethical issues and implications from this phenomenon. A mixed methods research case study examining alcohol sports sponsorship of the Australian National Rugby League (NRL) is presented to generate understanding of the live context and explore the use of markers of brand community to engage adolescent members of the NRL lifestyle consumption community. Evidence of consciousness of kind, and rituals and traditions relating to brand activity, was identified, but was less evident in relation to moral responsibility. The study also identified some important theoretical, practical, and ethical implications. This research addresses a significant gap in the current literature by identifying how community markers can be used by brands to engage existing lifestyle consumption communities, and distinguishing ethical implications that warrant attention. [ABSTRACT FROM AUTHOR]

Inherited Retinal Dystrophies (IRDs) are a clinically and genetically heterogeneous group of rare disorders characterized by a significant impairment in retinal function and vision. More than 150 genes have been associated with retinal dystrophies and the genetic overlap among different IRDs renders diagnosis and prognosis challenging. In this In Focus article, we give a summary on the pathogenic role of gene expression regulators in IRDs. Emphasis is given on key transcription factors that participate to regulatory gene networks controlling photoreceptor specification and maintenance, and their possible relevance as therapeutic targets. The increasing knowledge on the composition and function of these transcriptional regulatory networks indicates that intervening on transcription factors may be instrumental for a more effective treatment of some forms of IRDs, although the development of appropriate molecular tools to target them remains a formidable challenge. [ABSTRACT FROM AUTHOR]