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Pain is significantly impacted by the increasing epidemic of obesity and the metabolic syndrome. Our understanding of how these features impact pain is only beginning to be developed. Herein, we have investigated how small genetic differences among C57BL/6 mice from 2 different commercial vendors lead to important differences in the development of high-fat diet-induced mechanical sensitivity. Two substrains of C57BL/6 mice from Jackson Laboratories (Bar Harbor, ME; C57BL/6J and C57BL/6NIH), as well as C57BL/6 from Charles Rivers Laboratories (Wilmington, MA; C57BL/6CR) were placed on high-fat diets and analyzed for changes in metabolic features influenced by high-fat diet and obesity, as well as measures of pain-related behaviors. All 3 substrains responded to the high-fat diet; however, C57BL/6CR mice had the highest weights, fat mass, and impaired glucose tolerance of the 3 substrains. In addition, the C57BL/6CR mice were the only strain to develop significant mechanical sensitivity over the course of 8 weeks. Importantly, the C57BL/6J mice were protected from mechanical sensitivity, which may be based on increased physical activity compared with the other 2 substrains. These findings suggest that activity may play a powerful role in protecting metabolic changes associated with a high-fat diet and that these may also be protective in pain-associated changes as a result of a high-fat diet. These findings also emphasize the importance of selection and transparency in choosing C57BL/6 substrains in pain-related research. PERSPECTIVE: Obesity and the metabolic syndrome play an important role in pain. This study identifies key differences in the response to a high-fat diet among substrains of C57BL/6 mice and differences in intrinsic physical activity that may influence pain sensitivity. The results emphasize physical activity as a powerful modulator of obesity-related pain sensitivity.

Pumped-storage hydropower plants can contribute to a better integration of intermittent renewable energy and to balance generation and demand in real time by providing rapid response generation. The utilisation of variable-speed pump-turbine units with a doubly fed induction machine is being progressively applied due to its overall efficiency and high level of operating flexibility. This study presents state-of-the-art pumped energy storage system technology and its AC–DC interface topology, modelling, simulation and control analysis. It also provides information on the existing global capacities, technological development, topologies and control strategies of the pumped-storage system. This report also outlines the analysis of dynamic performances of the system. It also attempts to recommend the future works in this area. This study concludes that pumped storage is the most suitable technology for small autonomous island grids and massive energy storage, where the energy efficiency of pumped storage varies in practice. Around the world, the size of the pumped-storage plant mostly lies in the range of a small size to 3060 MW. The back-to-back voltage source converter topology is mostly conducted due to its significant features. Due to its imperative features, the vector control strategy is widely used. The pumped-storage plant is dedicated to power management and stability regulation of grid and isolated power systems.

Elevated Microsatellite Alterations at Selected Tetranucleotide repeats (EMAST) occur in up to 60% of colorectal cancers and may associate with aggressive and advanced disease in patients. Although EMAST occurs in many cancer types, current understanding is limited due to the lack of an animal model. Reported here is the design and implementation of an algorithm for detecting EMAST repeats in mice. This algorithm incorporates properties of known human EMAST sequences to identify repeat sequences in animal genomes and was able to identify EMAST-like sequences in the mouse. Seven of the identified repeats were analyzed further in a colon cancer mouse model and six of the seven displayed EMAST instability characteristic of that seen in human colorectal cancers. In conclusion, the algorithm developed successfully identified EMAST repeats in an animal genome and, for the first time, EMAST has been shown to occur in a mouse model of colon cancer.

Current experiments investigated whether a ketogenic diet impacts neuropathy associated with obesity and prediabetes. Mice challenged with a ketogenic diet were compared to mice fed a high-fat diet or a high-fat diet plus exercise. Additionally, an intervention switching to a ketogenic diet following 8 weeks of high-fat diet was performed to compare how a control diet, exercise, or a ketogenic diet affects metabolic syndrome-induced neural complications. When challenged with a ketogenic diet, mice had reduced bodyweight and fat mass compared to high-fat-fed mice, and were similar to exercised, high-fat-fed mice. High-fat-fed, exercised and ketogenic-fed mice had mildly elevated blood glucose; conversely, ketogenic diet-fed mice were unique in having reduced serum insulin levels. Ketogenic diet-fed mice never developed mechanical allodynia contrary to mice fed a high-fat diet. Ketogenic diet fed mice also had increased epidermal axon density compared all other groups. When a ketogenic diet was used as an intervention, a ketogenic diet was unable to reverse high-fat fed-induced metabolic changes but was able to significantly reverse a high-fat diet-induced mechanical allodynia. As an intervention, a ketogenic diet also increased epidermal axon density. In vitro studies revealed increased neurite outgrowth in sensory neurons from mice fed a ketogenic diet and in neurons from normal diet-fed mice given ketone bodies in the culture medium. These results suggest a ketogenic diet can prevent certain complications of prediabetes and provides significant benefits to peripheral axons and sensory dysfunction.

The International Society for Clinical Electrophysiology of Vision (ISCEV) standard for full-field electroretinography (ERG) describes a minimum procedure, but encourages more extensive testing. This ISCEV extended protocol describes an extension to the ERG standard, namely the photopic On-Off ERG, and outlines common clinical applications. A light stimulus duration of 150-200 ms is used in the presence of a rod-suppressing background to elicit cone-driven On- and Off-system ERG components. The On-response occurs after the stimulus onset and has a negative a-wave and positive b-wave. The Off d-wave is a positive component evoked by stimulus offset. Common diagnoses that may benefit from additional photopic On-Off ERG testing include retinal dystrophies and retinal disorders that cause dysfunction at a level that is post-phototransduction or post-receptoral. On-Off ERGs assess the relative involvement of On- and Off-systems and may be of use in the diagnosis of disorders such as complete and incomplete congenital stationary night blindness (complete and incomplete CSNB), melanoma-associated retinopathy, and some forms of autoimmune retinopathy. The photopic On-Off ERGs may also be useful in X-linked retinoschisis, Batten disease, Duchenne muscular dystrophy, spinocerebellar degeneration, quinine toxicity, and other retinal disorders.

The management of acute pain for the phenotypically different patient who suffers from chronic pain is challenging. The care of these patients is expensive and siloed. The physician-led, multidisciplinary, patient-centric, care coordination framework of the perioperative surgical home is an optimal vehicle for the management of these patients. The engagement of physician anesthesiologists in the optimization, in-hospital management, and postdischarge care of the patient with chronic pain will lead to improved outcomes, reduced health care expenditures, and improve the health of this challenging population.

Purpose To investigate the prevalence of peripheral pigmented retinal lesions and associated clinical findings in patients with Stargardt disease. Design Retrospective case series. Methods Records at a single academic institution were reviewed for patients with genetically confirmed Stargardt disease with peripheral pigmented retinal lesions on wide-field retinal imaging. For this cohort we described demographics, clinical features, and pathogenic variants. Results Out of 62 patients with Stargardt disease and wide-field retinal imaging, 14 had peripheral pigmented retinal lesions. These flat, subretinal lesions were located in the mid or far periphery and had well-defined borders, resembling congenital hypertrophy of retinal pigment epithelium (CHRPE) lesions. For this group of 14 patients, median age at initial diagnosis of Stargardt disease was 9.5 years, and the median duration of disease was 21.5 years. Median Snellen visual acuity was 20/200, and median central scotoma size was 20.0 degrees. All 14 patients had electroretinographic abnormalities. Four out of 14 patients developed new lesions during clinical follow-up. Conclusions Wide-field retinal imaging revealed the presence of peripheral pigmented retinal lesions resembling CHRPE lesions in a subset of patients with genetically confirmed Stargardt disease. Presence of these lesions may be associated with severe phenotypes of the disease.

It is human nature that we tend to stereotype certain individuals and groups based on their ethnicity, race, religion, and even looks, among other attributes. That is the case with Pakhtuns as well. Non-Pakhtuns, within and outside Pakistan, do not have a very positive notion about them; more so about their treatment of women. In this paper, I demonstrate that there is no doubt that the Pakhtuns are restricted, in some cases, by their cultural boundaries but then everyone, irrespective of their ethnic, racial, and/or religious backgrounds have their limitations. In order to prove my stance I have first of all interviewed some native Pashto speakers to get a general understanding about and usage of Pashto tappa and contemporary poetry composed by women. Using Althusser’s framework of ideology and Ideological State Apparatus, as the theoretical foundation, I argue that Pakhtun women are culturally interpellated but they have their own ways of practicing their agency. These women may not be able to totally challenge structural and cultural norms but they definitely know how to use their quotidian agency. Finally, I conclude that agency should not be understood in the narrow sense; it can have different meanings for different people in different contexts.

Background: Patients with heterozygous signal transducer and activator of transcription 1 (STAT1) gain-of-function (GOF) pathogenic variants exhibit an array of clinical phenotypes including susceptibility to multiple infections, autoimmunity, and cancer predisposition. Previous studies to characterize the pathways involved and explore therapeutic interventions have been constrained by the technology to perform in-depth immunophenotyping. Mass cytometry has allowed us to perform extensive immune profiling of patients with inborn errors of immunity (IEI) to help gain a better understanding of disease pathology. STAT1 gain-of-function (GOF) mutations have demonstrated higher levels of phosphorylated STAT1 in response to type I and II interferons, but the response to other cytokines is less understood. Using advanced cytometry, we demonstrate a unique pattern of STAT1 phosphorylation in response to IL-6 stimulation in T-cell subsets and this differential pattern may play a role in T-cell differentiation and memory in STAT1 GOF patients. Cases: We report two patients with heterozygous STAT1 GOF mutations in the coiled-coil domain. For both patients, the clinical phenotype was largely consistent with other STAT1 GOF patients, one (P1, c.800C>T; p.ala267Val) presented with secondary HLH due to histoplasmosis, and the second (P2, c.866A>G; p.Tyr289Cys) presented with presumed vaccine strain varicella zoster virus (VZV) meningitis and subsequent history of recurrent herpes simplex virus (HSV) skin lesions. Patient peripheral blood mononuclear cells (PBMCs) were evaluated by fluorescence flow cytometry and cytometry by time of flight (CyTOF) as previously described (Roussel et al. J Leukoc Biol. 2017) to evaluate the impact of STAT1 GOF mutations on T-cell immunophenotype and cytokine signaling. Results: Utilizing cytometric data, we were able to identify similar patterns of T cell distribution on t-distributed stochastic neighbor embedding (t-SNE) plots for both patients with STAT1 GOF that were distinct compared to healthy controls (Fig 1a). In the T-cell compartment, both patients had decreased Th17 and Treg populations and an increased Th1/Th2 ratio compared to healthy donor (Fig 1b). In response to stimulation with IFNg or IL-6, there were also clear patterns with the two patients compared to healthy controls. Levels of p-STAT1 and p-STAT3 were assessed in STAT1 GOF and health donor PBMCs at several times points between 15 and 120 minutes, after stimulation with either IFNg or IL-6. Using fluorescence flow, we found that IL-6 stimulation led to greater than anticipated p-STAT1 response at all timepoints compared to a much more muted response to IFNg. The cell subsets highlighted in the t-SNE after IL-6 stimulation differ from the cell subsets that respond to IFNg stimulation in patients and healthy control (Fig 2a), suggesting that distinct cell populations are driving the response to IL-6. By evaluating these IL-6 responsive subsets in comparison with healthy control by CyTOF, we identified an exaggerated p-STAT1 response to IL-6 in the memory T-cell populations in P2 (Fig 2b). Conclusions: These two unique clinical presentations demonstrate that with similar mutations in the coiled-coil domain of STAT1, yet largely differing clinical presentations, the immune profiling patterns of the patients compared to healthy controls can drive further work on disease characterization and therapeutic interventions. This is relevant for this patient cohort, as treatment recommendations for STAT1 GOF are not well established. Long-term outcomes with JAK inhibition are lacking and transplant survival rates to date have been very poor compared to other immune diseases including familial HLH. With identification of IL-6 signaling playing a potential role in T-cell maturation, further studies will need to be performed to determine if IL-6 modulation could be used as a treatment modality. We conclude that performing deep immunophenotyping of patients with inborn errors of immunity (IEIs) such as STAT1 GOF can point to new disease mechanisms of human immunity and inflammation and lead to improved understanding of the role of cytokine and cellular signaling in normal hematopoiesis and cellular maturation. Figure 1 Figure 1. Disclosures Rathmell: Sitryx: Consultancy, Current equity holder in publicly-traded company, Research Funding; Caribou: Consultancy, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company; Nirogy: Consultancy, Current holder of stock options in a privately-held company; Merck: Speakers Bureau; Pfizer: Speakers Bureau; Mitobridge: Consultancy; Incyte: Research Funding; Calithera: Research Funding; Tempest: Research Funding.

Background. South Africa (SA) has a shortage of dedicated neonatal critical care services, which are mostly concentrated in urban areas, thus illustrating the need for neonatal critical care transport (CCT) services. Neonates who are transported by teams without the requisite experience and knowledge in neonatal care are at risk of severe adverse events during transport. This has led to the development of dedicated CCT teams by some emergency medical services. There is a paucity of national literature describing the neonatal population who undergo CCT in dedicated services. Objectives. To describe a sample of neonates who underwent CCT transfer by dedicated CCT services in the private sector in SA. Methods. This observational cohort study with a retrospective descriptive design sampled all neonatal transfers completed during 1 year (1 January 2017 - 31 December 2017) from the dedicated CCT of the two largest national emergency medical services in SA. Data were extracted from patient report forms by trained data extractors, and subjected to descriptive analysis. Results. A total of 444 neonates were transferred between the two services. A total of 760 diagnoses were recorded, yielding an average of ~2 diagnoses per patient. The most prevalent diagnosis was respiratory distress syndrome ( n =139, 31%), followed by congenital heart defects ( n =123, 28%) and prematurity ( n =81, 18%). Patients had an average of ~4 attachments, with the most prevalent being patient monitoring ( n =677, 152%). Just under half ( n =182, 41%) of patients required ventilatory support. A total of 422 medications were required during transport, yielding a rate of ~1 medication or infusion per neonate transported. The most common infusion was maintenance ( n =199, 45%), while almost 1 in 10 neonates required inotropic support ( n =33, 7%). Conclusions. This study provides insight into the demographics, most prevalent diagnoses, and interfacility transfer monitoring needs of neonates being transported in SA by two private dedicated CCT services. The results of this study should be used to inform future specialised neonatal CCT courses and qualifications, as well as the scopes of practice of providers transporting neonates.

Objective Vascular dementia (VaD) is the second most common cause of dementia and a major health concern worldwide. A comprehensive review on VaD is warranted for better understanding and guidance for the practitioner. We provide an updated overview of the epidemiology, pathophysiological mechanisms, neuroimaging patterns as well as current diagnostic and therapeutic approaches. Materials and methods A narrative review of current literature in VaD was performed based on publications from the database of PubMed, Scopus and Google Scholar up to January, 2021. Results VaD can be the result of ischemic or hemorrhagic tissue injury in a particular region of the brain which translates into clinically significant cognitive impairment. For example, a cerebral infarct in the speech area of the dominant hemisphere would translate into clinically significant impairment as would involvement of projection pathways such as the arcuate fasciculus. Specific involvement of the angular gyrus of the dominant hemisphere, with resultant Gerstman's syndrome, could have a pronounced effect on functional ability despite being termed a “minor stroke”. Small vessel cerebrovascular disease can have a cumulate effect on cognitive function over time. It is unfortunately well recognized that “good” functional recovery in acute ischemic or haemorrhagic stroke, including subarachnoid haemorrhage, does not necessarily translate into good cognitive recovery. The victim may often be left unable to have gainful employment, drive a car safely or handle their affairs independently. Conclusions This review should serve as a compendium of updated information on VaD and provide guidance in terms of newer diagnostic and potential therapeutic approaches.

The transcription factor signal activator and transducer or transcription (STAT)3, which regulates genes controlling proliferation, survival, and invasion, is activated inappropriately in many human cancers, including breast cancer. Activation of STAT3 can lead to both malignant cellular behavior, as well as to suppression of immune cell function in the tumor microenvironment. Through a chemical-biology screen, pyrimethamine (PYR), an FDA approved anti-microbial drug, was identified as an inhibitor of STAT3 function at concentrations known to be achieved safely in humans. We report that PYR shows therapeutic activity in two independent mouse models of breast cancer, with both direct tumor inhibitory and immune stimulatory effects. PYR inhibited STAT3 activity in TUBO and TM40D-MB metastatic breast cancer cells in vitro and inhibited tumor cell proliferation and invasion into Matrigel basement membrane matrix. In tumor-transplanted mice, PYR had both direct and indirect tumor inhibitory effects. Tumor bearing mice treated with PYR showed reduced STAT3 activation in tumor cells, attenuated tumor growth, and reduced tumor-associated inflammation. In addition, expression of Lamp1 by tumor infiltrating CD8+ T-cells was elevated, indicating enhanced release of cytotoxic granules. These findings suggest that PYR may have beneficial effects in the treatment of breast cancer.

Objective Patients undergoing coronary artery bypass graft (CABG) are recommended to undergo carotid duplex study in presence of risk factors. Aim of the study was to quantify the relationship between risk factors and presence of carotid disease and examine if screening influenced outcomes. Methods Over a four year period in a single institution, 4364 consecutive patients presenting for primary isolated CABG were enrolled to undergo carotid duplex scanning. Patients were grouped as no significant carotid artery stenosis ( 70%). Sub group analysis of patients with severe carotid stenosis was performed. Sensitivity of risk factors thought to be associated with carotid disease was also assessed. Results Of the 4364 patients, 406 patients (9.3%) had moderate or severe carotid artery stenosis. 32 (7.88%) had bilateral disease. Age>65, hypertension, left main stem stenosis, peripheral vascular disease, and previous neurological injury were all associated with carotid artery disease (p In patients with moderate carotid artery stenosis there was no difference in the incidence of major 4 (0.98%) vs.18 (0.45%) p=0.14 or minor 8 (1.9%) vs. 56 (1.41%); p=0.38 neurological outcomes. However, severe carotid stenosis was associated with an increase in all-cause mortality but no increase in neurological events. Conclusions In the presence of risk factors carotid screening identifies at risk population. Severe carotid stenosis was associated with increased all-cause mortality. However, moderate stenosis did not influence neurological outcomes or mortality in patients undergoing coronary artery bypass grafting.

Kinetic visual field testing is used to monitor disease course in retinal dystrophy clinical care and treatment response in treatment trials, which are increasingly recruiting children. This study investigates Goldmann visual field (GVF) changes in young children with mutation-proven retinal dystrophies as they age and with progression of the retinal degeneration.Retrospective review of children ≤ 17 years old with a mutation-proven retinal dystrophy. Objective clinical disease activity was assessed by a retinal degeneration specialist masked to GVF results. Digital quantification of GVF area was performed.Twenty-nine children (58 eyes), ages 5-16, were identified. GVF area increased with age despite progression in 20 children and clinical stability in nine children. Mean ± standard error increase in GVF area/year was 333 ± 130 mmIn a substantial proportion of children with mutation-proven retinal dystrophies, there is a significant increase in GVF area with age, particularly those12 years, despite progression or stability of disease. These findings suggest that change in GVF area in children with retinal dystrophies can be an unreliable measure of response to treatment and on which to base appropriate counseling about visual impairment.

Identification of candidate genomic regions associated with target traits using conventional mapping methods is challenging and time‐consuming. In recent years, a number of single nucleotide polymorphism (SNP)‐based mapping approaches have been developed and used for identification of candidate/putative genomic regions. However, in the majority of these studies, insertion–deletion (Indel) were largely ignored. For efficient use of Indels in mapping target traits, we propose Indel‐seq approach, which is a combination of whole‐genome resequencing (WGRS) and bulked segregant analysis (BSA) and relies on the Indel frequencies in extreme bulks. Deployment of Indel‐seq approach for identification of candidate genomic regions associated with fusarium wilt (FW) and sterility mosaic disease (SMD) resistance in pigeonpea has identified 16 Indels affecting 26 putative candidate genes. Of these 26 affected putative candidate genes, 24 genes showed effect in the upstream/downstream of the genic region and two genes showed effect in the genes. Validation of these 16 candidate Indels in other FW‐ and SMD‐resistant and FW‐ and SMD‐susceptible genotypes revealed a significant association of five Indels (three for FW and two for SMD resistance). Comparative analysis of Indel‐seq with other genetic mapping approaches highlighted the importance of the approach in identification of significant genomic regions associated with target traits. Therefore, the Indel‐seq approach can be used for quick and precise identification of candidate genomic regions for any target traits in any crop species.

Summary Rust and late leaf spot (LLS) are the two major foliar fungal diseases in groundnut, and their co‐occurrence leads to significant yield loss in addition to the deterioration of fodder quality. To identify candidate genomic regions controlling resistance to rust and LLS, whole‐genome resequencing (WGRS)‐based approach referred as ‘QTL‐seq’ was deployed. A total of 231.67 Gb raw and 192.10 Gb of clean sequence data were generated through WGRS of resistant parent and the resistant and susceptible bulks for rust and LLS. Sequence analysis of bulks for rust and LLS with reference‐guided resistant parent assembly identified 3136 single‐nucleotide polymorphisms (SNPs) for rust and 66 SNPs for LLS with the read depth of ≥7 in the identified genomic region on pseudomolecule A03. Detailed analysis identified 30 nonsynonymous SNPs affecting 25 candidate genes for rust resistance, while 14 intronic and three synonymous SNPs affecting nine candidate genes for LLS resistance. Subsequently, allele‐specific diagnostic markers were identified for three SNPs for rust resistance and one SNP for LLS resistance. Genotyping of one RIL population (TAG 24 × GPBD 4) with these four diagnostic markers revealed higher phenotypic variation for these two diseases. These results suggest usefulness of QTL‐seq approach in precise and rapid identification of candidate genomic regions and development of diagnostic markers for breeding applications.

This chapter will discuss the knee, the largest synovial joint in the body. It will cover the normal bony anatomy and geometry of the knee and how this gives rise to its complex biomechanics which go beyond a simple hinge. The factors stabilising the knee during its motion will be discussed and how these stabilisers have both primary and secondary restraint functions. It will also discuss our current understanding of pathophysiology of the most common degenerative disease affecting the knee, osteoarthritis as well as its clinical and radiological features, with a brief discussion of the various management options available.

Postamputation pain (PAP) is a neuropathic pain condition that occurs frequently after limb amputation. PAP is comprised of residual limb pain (RLP, also known as stump pain) and phantom limb pain (PLP). There are several proposed mechanisms for PLP. It is believed that PLP is due to a combination of morphologic, physiologic, and chemical changes in the peripheral and central nervous systems. These changes begin peripherally and move centrally in a compounding manner through peripheral, spinal, and supra-spinal mechanisms. Treatment of PAP typically needs to be multi-modal and includes pharmacotherapy, injections, complementary and alternative therapy, surgical therapy, and preventative interventions. To assist with the treatment of PAP, studies leading to a better understanding of the pathophysiology of PAP and influences on the development of PAP are needed.

A 70-year-old gentleman was referred to our department for atypical chest pains and night sweats. He had an unremarkable past medical history and denied any history of familial disease. There were no complaints of dyspnoea, dizziness or palpitations. A routine echocardiogram showed a suspicious right atrial mass, seemingly extra cardiac in origin. Clinical examination was entirely unremarkable and further investigations were arranged as a matter of urgency. Contrast echocardiography confirmed a lesion wrapping around the right atrium with possible myocardial infiltration. Trans-oesophageal echocardiography showed extension of the mass into the adjacent atrioventricular groove. The appearances were of a compressive, non-vascular lesion measuring 4.8cm x 5.6cm. Overall cardiac systolic function remained preserved with no significant intra-cardiac abnormalities. A CT Thorax with contrast was the next step in investigation. This demonstrated nodular soft tissue infiltration of the entire pericardium, mainly involving the right heart chambers with encasement of the aortic root and coronary arteries. Significant lymphadenopathy was also identified suggesting a malignant process. Cardiac MRI was then performed and this substantiated the findings on CT, raising concern for encasement and external compression of the right coronary artery. Urgent transfer to a tertiary cardiac centre was arranged and subsequent biopsy confirmed histological diagnosis of Stage 4 Lymphoma. After a multi-disciplinary meeting, a non-operative approach was decided. Treatment with steroids and chemotherapy was commenced without delay leading to a significant reduction in the size of the mass. Abstract P1325 Figure.

Language identification is the detection of the language of a text in which it is written. The problem becomes challenging when the writer does not use the indigenous script of a language. Generally, this kind of text is generated by social media which is a mixture of English with the native language(s) of the writer. The users of social media platforms that belong to India write in code-mixed Hindi–English language. In this work, we study the word-level language identification as a classification problem to identify the language of a word written in Roman script. We employ POS tags in a transliteration-based approach to prepare the Hindi–English code-mixed corpus. We evaluate the corpus over itself and observe that notable results are obtained.

Early-onset severe retinal dystrophy (EOSRD) is a genetically heterogeneous group of diseases resulting in serious visual disability in children. A significant number of EOSRD cases, often diagnosed as Leber congenital amaurosis (LCA13), are associated with mutations in the gene encoding retinol dehydrogenase 12 (RDH12). RDH12 is a member of the enzyme family of short-chain dehydrogenases/reductases. In the retina, RDH12 plays a critical role in reducing toxic retinaldehydes generated by visual cycle activity that is required for the light response of the photoreceptor cells. Individuals with RDH12 deficiency exhibit widespread retinal degeneration impacting both rods and cones. Although Rdh12-deficient (Rdh12(−)(/−)) mice do not exhibit retinal degeneration, functional deficits relevant to visual cycle function can be demonstrated. In the present study, we describe the development and preclinical testing of a recombinant adeno-associated viral (rAAV) vector that has the potential for use in treating EOSRD due to RDH12 mutations. Wild-type and Rdh12(−)(/−) mice that received a subretinal injection of rAAV2/5 carrying a human RDH12 cDNA driven by a human rhodopsin-kinase promoter exhibited transgene expression that was stable, correctly localized, and did not cause retinal toxicity. In addition, administration of the vector reconstituted retinal reductase activity in the retinas of Rdh12(−/−) mice and decreased susceptibility to light damage associated with Rdh12 deficiency, thus demonstrating potential therapeutic efficacy in an animal model that does not exhibit a retinal degeneration phenotype. These findings support further efforts to develop gene replacement therapy for individuals with RDH12 mutations.

We report on the fabrication and transport properties of single-walled carbon nanotubes (SWCNT) blended with P3HT (poly 3-hexyl thiophene-2, 5-diyl). The composite is used as a hybrid organic active channel transistor. The performances of the fabricated devices were investigated as a function of the SWCNTs' loads in the composite, and their response evaluated under white light illumination. Our results show that for SWCNT loads ≤1.5 wt%, all the devices behave as p-type transistors, exhibiting excellent performance, with an I on /I off ratio of 104 and a maximum on-state current (I on) exceeding 80 μA. Moreover, compared with pristine transistors with a P3HT channel, the Hall mobility of these hybrid TFTs was found to increase by more than one order of magnitude, i.e. increasing from 0.062 to 1.54 cm2 V-1 s-1. Finally, under light illumination, the transfer characteristics (i.e. I DS as a function of V GS) were found to systematically undergo a typical shift together with a fully-reversible memory behavior. A fundamental understanding of this work can assist in providing new routes for the development of reliable efficient hybrid organic-based optoelectronic devices.

Organ regeneration requires precise coordination of new cell differentiation and remodeling of uninjured tissue to faithfully re-establish organ morphology and function. An atlas of gene expression and cell types in the uninjured state is therefore an essential pre-requisite for understanding how damage is repaired. Here, we use laser-capture microdissection (LCM) and RNA-Seq to define the transcriptome of the intestine ofSchmidtea mediterranea,a planarian flatworm with exceptional regenerative capacity. Bioinformatic analysis of 1,844 intestine-enriched transcripts suggests extensive conservation of digestive physiology with other animals, including humans. Comparison of the intestinal transcriptome to purified absorptive intestinal cell (phagocyte) and published single-cell expression profiles confirms the identities of known intestinal cell types, and also identifies hundreds of additional transcripts with previously undetected intestinal enrichment. Furthermore, by assessing the expression patterns of 143 transcriptsin situ, we discover unappreciated mediolateral regionalization of gene expression and cell-type diversity, especially among goblet cells. Demonstrating the utility of the intestinal transcriptome, we identify 22 intestine-enriched transcription factors, and find that several have distinct functional roles in the regeneration and maintenance of goblet cells. Furthermore, depletion of goblet cells inhibits planarian feeding and reduces viability. Altogether, our results show that LCM is a viable approach for assessing tissue-specific gene expression in planarians, and provide a new resource for further investigation of digestive tract regeneration, the physiological roles of intestinal cell types, and axial polarity.

Purpose To compare retinal function by using fundus-guided microperimetry (MP) and multifocal electroretinography (mfERG) for detecting hydroxychloroquine (HCQ) maculopathy. Methods Forty-six eyes of 25 patients referred to our clinical practice for HCQ maculopathy assessment and 3 groups of normal control subjects were evaluated by mfERG and MP. Macular structure was assessed using spectral-domain optical coherence tomography (SD-OCT). Ring ratios from the three innermost mERG rings were compared with average sensitivity of each MP ring at approximately equivalent distances from the fovea. HCQ toxicity was defined as an mfERG ring ratio or mean MP ring sensitivity >2 standard deviations below the normal mean. The sensitivity and specificity of MP to detect HCQ toxicity relative to mfERG were evaluated. Results MP rings MR2 and MR3 were positively correlated with corresponding mfERG ring ratios (r = 0.52, P = 0.002 and r = 0.56, P < 0.001 respectively). Ring 2 and ring 3 measures of MP and mfERG were significantly worse in HCQ eyes than controls (P < 0.001). The sensitivity of MP to detect toxicity for MR1 through MR3 ranged from 33% to 88%, whereas specificity ranged from 72% to 85%. Through rings 1 to 3, the frequency of abnormal function ranged from 20% to 48% for MP, 11% to 35% for mfERG, and 41% to 45% for SD-OCT. Conclusions The frequency of detection of HCQ toxicity with MP was greater than with mfERG. MP showed an overall good sensitivity and moderate specificity in detecting HCQ-induced functional deficits. Translational Relevance Results from this study may allow clinicians to improve screening accuracy for HCQ toxicity by using the alternative modality of MP.

A complex, chronic mood disorder involving repeated episodes of depression and mania/hypomania is referred as Bipolar disorder [1]. The two most common bipolar disorders are bipolar I disorder and bipolar II disorder. The lifetime prevalence of MDD Is around 12.2% to 16.2% [2,3] while as the prevalence of bipolar disorder are significantly lower, ranging from 0.9% to 4.4%

The clinical presentation and optical coherence tomography findings in a patient with maternally inherited diabetes and deafness (MIDD) are presented to highlight the presence of macular cystoid spaces in some patients with this disease. Typically, patients with MIDD demonstrate progression of a pigmentary maculopathy into areas of geographic macular atrophy. At the time of initial visit, the 30-year-old patient had large macular cystoid changes in addition to retinal pigmentary changes in both eyes. The cystoid changes responded to treatment with systemic immunosuppression and a topical carbonic anhydrase inhibitor (CAI), recurred when treated with topical CAI monotherapy, and finally resolved after an intravitreal triamcinolone acetonide injection. Over time, the retinal atrophy continued to progress, but the macular cysts did not recur. The patient received systemic immunosuppression for renal transplantation due to renal failure resulting from focal glomerulosclerosis. There was no evidence of diabetic retinopathy at any time during the five-and-a-half-year follow-up, and the patient retained good visual acuity in both eyes.

This research paper presents the assimilation of ocean surface precipitable water (TPW) and wind speed obtained from Microwave Analysis and Detection of Rain and Atmospheric Structures (MADRAS) onboard Megha-Tropics satellite retrievals into the Weather Research and Forecasting Model (WRF) model to assess their impact on short-range precipitation forecasts. Two parallel experiments are performed daily with and without assimilation of the MADRAS geophysical parameters during the entire month of the July 2012. Initially, MADRAS retrieved TPW and wind speed are compared with the Tropical Rainfall Measuring Mission (TRMM) Microwave Imager (TMI) retrieved geophysical parameters and European Centre for Medium-Range Weather Forecasts (ECMWF) global model analyses. This comparison shows a root mean square difference (RMSD) of ∼1.8 ms−1 and ∼0.3 gcm−2, and mean difference (BIAS) of ∼−1.0 ms−1 and ∼0.15 gcm−2 in wind speed and TPW, respectively. Results show that the assimilation of MADRAS retrieved geophysical parameters improved the TPW and wind speed by about 20% and 10% reduction in RMSD, respectively. Six-hourly WRF model forecasts are also improved with the assimilation of MADRAS retrievals. The Forecast Impact (FI) parameter shows larger than 10 mm improvement in 24 h rainfall forecasts over the Indian Ocean.

Autophagy is a lysosomal degradation pathway critical to preventing the accumulation of cytotoxic proteins. Deletion of the essential autophagy gene Atg5 from the rod photoreceptors of the retina (atg5Δrod mouse) results in the accumulation of the phototransduction protein transducin and the degeneration of these neurons. The purpose of this study is to test the hypothesis that autophagic degradation of visual transduction proteins prevents retinal degeneration. Targeted deletion of both Gnat1 (a gene encoding the α subunit of the heterotrimeric G-protein transducin) and Atg5 in the rod photoreceptors resulted in a significantly decreased rate of rod cell degeneration as compared to the atg5Δrod mouse retina, and considerable preservation of photoreceptors. Supporting this we used a novel technique to immunoprecipitate green fluorescent protein (GFP)-tagged autophagosomes from the retinas of the GFP-LC3 mice and demonstrated that the visual transduction proteins transducin and ARR/arrestin are associated with autophagosome-specific proteins. Altogether, this study shows that degradation of phototransduction proteins by autophagy is necessary to prevent retinal degeneration. In addition, we demonstrate a simple and easily reproducible immunoisolation technique for enrichment of autophagosomes from the GFP-LC3 mouse retina, providing a novel application to the study of autophagosome contents across different organs and specific cell types in vivo.

Melanoma is an aggressive skin cancer, however it is immunogenic. The size of the primary tumor is associated with the nodal metastases. Our goals were to characterize melanoma-associated antigens (MAAs) and tumor-infiltrating T-lymphocytes (TILs) subsets in the few very large tumors (VLTs) developing in ret transgenic mice of melanoma. Tumors >700mg (VLTs) were investigated for MAAs and subsets of TILs. Immunohistochemistry and flow cytometry-based studies were performed to determine the infiltration patterns of T-lymphocytes in VLTs. It was observed that zinc fixative restores the antigenicity of the cell-surface markers of lymphocyte subpopulations without the need of antigen retrieval, whereas formalin-based fixative fails to restore the antigenicity in the presence of antigen retrieval in the immunohistochemistry. VLTs from ret mice express MAAs, such as Tyrosinase, TRP-1, TRP-2 and gp-100. The mean±standard deviation (S.D.) T-cell infiltration per 400 times-high power field in VLTs; CD4(+) (2.33±1.3), CD8(+) (2.00±1.0), and CD4(+) Foxp3(+) (2.5±0.5) regulatory T cells infiltration was exclusively restricted to the tumor stroma. Moreover, our flow cytometry-based data reveal that % mean±S.D. naive CD3(+) CD4(+) T cell infiltration (32.8±4.0%) was significantly larger than effector (25.8±2.8%, p

Peanut or groundnut (Arachis hypogaea L.), a legume of South American origin, has high seed oil content (45–56%) and is a staple crop in semiarid tropical and subtropical regions, partially because of drought tolerance conferred by its geocarpic reproductive strategy. We present a draft genome of the peanut A-genome progenitor, Arachis duranensis, and 50,324 protein-coding gene models. Patterns of gene duplication suggest the peanut lineage has been affected by at least three polyploidizations since the origin of eudicots. Resequencing of synthetic Arachis tetraploids reveals extensive gene conversion in only three seed-to-seed generations since their formation by human hands, indicating that this process begins virtually immediately following polyploid formation. Expansion of some specific gene families suggests roles in the unusual subterranean fructification of Arachis. For example, the S1Fa-like transcription factor family has 126 Arachis members, in contrast to no more than five members in other examined plant species, and is more highly expressed in roots and etiolated seedlings than green leaves. The A. duranensis genome provides a major source of candidate genes for fructification, oil biosynthesis, and allergens, expanding knowledge of understudied areas of plant biology and human health impacts of plants, informing peanut genetic improvement and aiding deeper sequencing of Arachis diversity.

Google Glass (Google, Mountain View, CA) is a wearable technology with a computer and camera mounted on an eyeglass frame. The camera captures wide-angle video and projects it onto a prism located in the right superior temporal quadrant of the wearer's visual field. The authors present a case of an individual who used Google Glass' video projection feature to expand his severely constricted right visual field. This patient reported improved ambulatory navigation. Using Google Glass, the patient's peripheral vision, measured using Goldmann kinetic perimetry, expanded impressively. Based on these preliminary results, the authors propose further characterization on the potential utility of such head-mount display technology as a tool to improve the lives of patients with severely constricted visual fields. [ Ophthalmic Surg Lasers Imaging Retina. 2016;47:486–489.]

Summary Terminal drought is a major constraint to chickpea productivity. Two component traits responsible for reduction in yield under drought stress include reduction in seeds size and root length/root density. QTL‐seq approach, therefore, was used to identify candidate genomic regions for 100‐seed weight (100SDW) and total dry root weight to total plant dry weight ratio (RTR) under rainfed conditions. Genomewide SNP profiling of extreme phenotypic bulks from the ICC 4958 × ICC 1882 population identified two significant genomic regions, one on CaLG01 (1.08 Mb) and another on CaLG04 (2.7 Mb) linkage groups for 100SDW. Similarly, one significant genomic region on CaLG04 (1.10 Mb) was identified for RTR. Comprehensive analysis revealed four and five putative candidate genes associated with 100SDW and RTR, respectively. Subsequently, two genes (Ca_04364 and Ca_04607) for 100SDW and one gene (Ca_04586) for RTR were validated using CAPS/dCAPS markers. Identified candidate genomic regions and genes may be useful for molecular breeding for chickpea improvement.