Advancing fruiting season in Annona cv. Arka Sahan through pruning

Annona cultivar ‘Arka Sahan’, an inter-specific hybrid of Annona atemoya × A. squamosacomes to harvest during August-September under mild tropical climate, which coincides with monsoon rains resulting in poor fruit quality and high susceptibility to anthracnose and fruit fly. An attempt was made to advance the fruiting in this hybrid through pruning during 2016- 17 and 2017-18. The effect of three pruning levels (25, 50 and 75% of previous season’s growth) at five different times (60, 75, 90, 105 and 120 days after final harvest of previous crop) on flowering and fruiting were compared. Early sprouting, flowering and fruit harvest were recorded in trees pruned to 75% of the past season’s growth in both the years. Earliest fruits were harvested 271 (3rd week of June) and 268 (2nd week of June) days after pruning in trees pruned during first week of October in 2016-17 and 2017-18 respectively (P<0.05).Bigger fruits with lesser seeds per 100 g of pulp (P<0.05) were harvested from trees pruned to 75% and 25% levels in the first and second year, respectively, irrespective of pruning time. Tree canopy following pruning at 75%level recorded higher light interception and photosynthetic rate (P<0.05). Pruning time and levels significantly influenced the biochemical constituents of leaf and shoot. The fruiting in cultivar ‘Arka Sahan’ could be thus advanced by 8-9 weeks to June from the normal season of August-September with comparable or better fruit quality by pruning 75% of the last season’s growth during October

Glioma stem-like cells and metabolism:Potential for novel therapeutic strategies

Glioma stem-like cells (GSCs) were first described as a population which may in part be resistant to traditional chemotherapeutic therapies and responsible for tumour regrowth. Knowledge of the underlying metabolic complexity governing GSC growth and function may point to potential differences between GSCs and the tumour bulk which could be harnessed clinically. There is an increasing interest in the direct/indirect targeting or reprogramming of GSC metabolism as a potential novel therapeutic approach in the adjuvant or recurrent setting to help overcome resistance which may be mediated by GSCs. In this review we will discuss stem-like models, interaction between metabolism and GSCs, and potential current and future strategies for overcoming GSC resistance

Peripheral Blood Cell Gene Expression Diagnostic for Identifying Symptomatic Transthyretin Amyloidosis Patients: Male and Female Specific Signatures

BACKGROUND: Early diagnosis of familial transthyretin (TTR) amyloid diseases remains challenging because of variable disease penetrance. Currently, patients must have an amyloid positive tissue biopsy to be eligible for disease-modifying therapies. Endomyocardial biopsies are typically amyloid positive when cardiomyopathy is suspected, but this disease manifestation is generally diagnosed late. Early diagnosis is often difficult because patients exhibit apparent symptoms of polyneuropathy, but have a negative amyloid biopsy. Thus, there is a pressing need for an additional early diagnostic strategy for TTR-aggregation-associated polyneuropathy and cardiomyopathy. METHODS AND FINDINGS: Global peripheral blood cell mRNA expression profiles from 263 tafamidis-treated and untreated V30M Familiar Amyloid Neuropathy patients, asymptomatic V30M carriers, and healthy, age- and sex-matched controls without TTR mutations were used to differentiate symptomatic from asymptomatic patients. We demonstrate that blood cell gene expression patterns reveal sex-independent, as well as male- and female-specific inflammatory signatures in symptomatic FAP patients, but not in asymptomatic carriers. These signatures differentiated symptomatic patients from asymptomatic V30M carriers with >80% accuracy. There was a global downregulation of the eIF2 pathway and its associated genes in all symptomatic FAP patients. We also demonstrated that the molecular scores based on these signatures significantly trended toward normalized values in an independent cohort of 46 FAP patients after only 3 months of tafamidis treatment. CONCLUSIONS: This study identifies novel molecular signatures that differentiate symptomatic FAP patients from asymptomatic V30M carriers as well as affected males and females. We envision using this approach, initially in parallel with amyloid biopsies, to identify individuals who are asymptomatic gene carriers that may convert to FAP patients. Upon further validation, peripheral blood cell mRNA expression profiling could become an independent early diagnostic. This quantitative gene expression signature for symptomatic FAP could also become a biomarker to demonstrate significant disease-modifying effects of drugs and drug candidates. For example, when new disease modifiers are being evaluated in a FAP clinical trial, such surrogate biomarkers have the potential to provide an objective, quantitative and mechanistic molecular diagnostic of disease response to therapy.We acknowledge the following sources of research funding: NIH U19 A1063603 (DRS, SMK), NIH DK46335 (JWK) and NIH R01AG19259 (JNB)info:eu-repo/semantics/publishedVersio

Therapeutic Targeting of Histone Modifications in Adult and Pediatric High-Grade Glioma

Recent exciting work partly through The Cancer Genome Atlas has implicated epigenetic mechanisms including histone modifications in the development of both pediatric and adult high-grade glioma (HGG). Histone lysine methylation has emerged as an important player in regulating gene expression and chromatin function. Lysine (K) 27 (K27) is a critical residue in all seven histone 3 variants and the subject of posttranslational histone modifications, as it can be both methylated and acetylated. In pediatric HGG, two critical single-point mutations occur in the H3F3A gene encoding the regulatory histone variant H3.3. These mutations occur at lysine (K) 27 (K27M) and glycine (G) 34 (G34R/V), both of which are involved with key regulatory posttranscriptional modifications. Therefore, these mutations effect gene expression, cell differentiation, and telomere maintenance. In recent years, alterations in histone acetylation have provided novel opportunities to explore new pharmacological targeting, with histone deacetylase (HDAC) overexpression reported in high-grade, late-stage proliferative tumors. HDAC inhibitors have shown promising therapeutic potential in many malignancies. This review focuses on the epigenetic mechanisms propagating pediatric and adult HGGs, as well as summarizing the current advances in clinical trials using HDAC inhibitors

Locality-oblivious cache organization leveraging single-cycle multi-hop NoCs

Locality has always been a critical factor in on-chip data placement on CMPs as accessing further-away caches has in the past been more costly than accessing nearby ones. Substantial research on locality-aware designs have thus focused on keeping a copy of the data private. However, this complicatesthe problem of data tracking and search/invalidation; tracking the state of a line at all on-chip caches at a directory or performing full-chip broadcasts are both non-scalable and extremely expensive solutions. In this paper, we make the case for Locality-Oblivious Cache Organization (LOCO), a CMP cache organization that leverages the on-chip network to create virtual single-cycle paths between distant caches, thus redefining the notion of locality. LOCO is a clustered cache organization, supporting both homogeneous and heterogeneous cluster sizes, and provides near single-cycle accesses to data anywhere within the cluster, just like a private cache. Globally, LOCO dynamically creates a virtual mesh connecting all the clusters, and performs an efficient global data search and migration over this virtual mesh, without having to resort to full-chip broadcasts or perform expensive directory lookups. Trace-driven and full system simulations running SPLASH-2 and PARSEC benchmarks show that LOCO improves application run time by up to 44.5% over baseline private and shared cache.Semiconductor Research CorporationUnited States. Defense Advanced Research Projects Agency (Semiconductor Technology Advanced Research Network

Precision medicine for suicidality: from universality to subtypes and personalization

Suicide remains a clear, present and increasing public health problem, despite being a potentially preventable tragedy. Its incidence is particularly high in people with overt or un(der)diagnosed psychiatric disorders. Objective and precise identification of individuals at risk, ways of monitoring response to treatments and novel preventive therapeutics need to be discovered, employed and widely deployed. We sought to investigate whether blood gene expression biomarkers for suicide (that is, a ‘liquid biopsy’ approach) can be identified that are more universal in nature, working across psychiatric diagnoses and genders, using larger cohorts than in previous studies. Such markers may reflect and/or be a proxy for the core biology of suicide. We were successful in this endeavor, using a comprehensive stepwise approach, leading to a wealth of findings. Steps 1, 2 and 3 were discovery, prioritization and validation for tracking suicidality, resulting in a Top Dozen list of candidate biomarkers comprising the top biomarkers from each step, as well as a larger list of 148 candidate biomarkers that survived Bonferroni correction in the validation step. Step 4 was testing the Top Dozen list and Bonferroni biomarker list for predictive ability for suicidal ideation (SI) and for future hospitalizations for suicidality in independent cohorts, leading to the identification of completely novel predictive biomarkers (such as CLN5 and AK2), as well as reinforcement of ours and others previous findings in the field (such as SLC4A4 and SKA2). Additionally, we examined whether subtypes of suicidality can be identified based on mental state at the time of high SI and identified four potential subtypes: high anxiety, low mood, combined and non-affective (psychotic). Such subtypes may delineate groups of individuals that are more homogenous in terms of suicidality biology and behavior. We also studied a more personalized approach, by psychiatric diagnosis and gender, with a focus on bipolar males, the highest risk group. Such a personalized approach may be more sensitive to gender differences and to the impact of psychiatric co-morbidities and medications. We compared testing the universal biomarkers in everybody versus testing by subtypes versus personalized by gender and diagnosis, and show that the subtype and personalized approaches permit enhanced precision of predictions for different universal biomarkers. In particular, LHFP appears to be a strong predictor for suicidality in males with depression. We also directly examined whether biomarkers discovered using male bipolars only are better predictors in a male bipolar independent cohort than universal biomarkers and show evidence for a possible advantage of personalization. We identified completely novel biomarkers (such as SPTBN1 and C7orf73), and reinforced previously known biomarkers (such as PTEN and SAT1). For diagnostic ability testing purposes, we also examined as predictors phenotypic measures as apps (for suicide risk (CFI-S, Convergent Functional Information for Suicidality) and for anxiety and mood (SASS, Simplified Affective State Scale)) by themselves, as well as in combination with the top biomarkers (the combination being our a priori primary endpoint), to provide context and enhance precision of predictions. We obtained area under the curves of 90% for SI and 77% for future hospitalizations in independent cohorts. Step 5 was to look for mechanistic understanding, starting with examining evidence for the Top Dozen and Bonferroni biomarkers for involvement in other psychiatric and non-psychiatric disorders, as a mechanism for biological predisposition and vulnerability. The biomarkers we identified also provide a window towards understanding the biology of suicide, implicating biological pathways related to neurogenesis, programmed cell death and insulin signaling from the universal biomarkers, as well as mTOR signaling from the male bipolar biomarkers. In particular, HTR2A increase coupled with ARRB1 and GSK3B decreases in expression in suicidality may provide a synergistic mechanistical corrective target, as do SLC4A4 increase coupled with AHCYL1 and AHCYL2 decrease. Step 6 was to move beyond diagnostics and mechanistical risk assessment, towards providing a foundation for personalized therapeutics. Items scored positive in the CFI-S and subtypes identified by SASS in different individuals provide targets for personalized (psycho)therapy. Some individual biomarkers are targets of existing drugs used to treat mood disorders and suicidality (lithium, clozapine and omega-3 fatty acids), providing a means toward pharmacogenomics stratification of patients and monitoring of response to treatment. Such biomarkers merit evaluation in clinical trials. Bioinformatics drug repurposing analyses with the gene expression biosignatures of the Top Dozen and Bonferroni-validated universal biomarkers identified novel potential therapeutics for suicidality, such as ebselen (a lithium mimetic), piracetam (a nootropic), chlorogenic acid (a polyphenol) and metformin (an antidiabetic and possible longevity promoting drug). Finally, based on the totality of our data and of the evidence in the field to date, a convergent functional evidence score prioritizing biomarkers that have all around evidence (track suicidality, predict it, are reflective of biological predisposition and are potential drug targets) brought to the fore APOE and IL6 from among the universal biomarkers, suggesting an inflammatory/accelerated aging component that may be a targetable common denominator

Rapid detection of BRCA1/2 recurrent mutations in Chinese breast and ovarian cancer patients with multiplex SNaPshot genotyping panels.

BRCA1/2 mutations are significant risk factors for hereditary breast and ovarian cancer (HBOC), its mutation frequency in HBOC of Chinese ethnicity is around 9%, in which nearly half are recurrent mutations. In Hong Kong and China, genetic testing and counseling are not as common as in the West. To reduce the barrier of testing, a multiplex SNaPshot genotyping panel that targeted 25 Chinese BRCA1/2 mutation hotspots was developed, and its feasibility was evaluated in a local cohort of 441 breast and 155 ovarian cancer patients. For those who tested negative, they were then subjected to full-gene testing with next-generation sequencing (NGS). BRCA mutation prevalence in this cohort was 8.05% and the yield of the recurrent panel was 3.52%, identifying over 40% of the mutation carriers. Moreover, from 79 Chinese breast cancer cases recruited overseas, 2 recurrent mutations and one novel BRCA2 mutation were detected by the panel and NGS respectively. The developed genotyping panel showed to be an easy-to-perform and more affordable testing tool that can provide important contributions to improve the healthcare of Chinese women with cancer as well as family members that harbor high risk mutations for HBOC

Functional outcome following conservative management of acetabular fractures

Background: Acetabular fractures are complex injuries caused due to high velocity injury and constitutes about 18 % of Pelvic fractures. To obtain articular congruency and anatomical reduction is the gold standard in treating these fractures. In this study we have studied about the functional outcome in acetabular fractures managed conservatively with the long-term follow.Methods: A retrospective study with prospective analysis done between 2011-2020 involved 39 patients with acetabular fractures who were treated conservatively at St John’s Medical college Hospital. Patients were followed up at 6 months, 1 year, 2 years and at the end of 5 years for functional evaluation and assessment with the clinical outcome scores with Merle d’Aubigne and Postel score & Harris Hip Score.Results: Study included 39 patients with the average age of 41.3 years with 31 male and 8 female patients. Functional outcome score showed good to excellent results in 80%, fair to satisfactory results in 18%, 0.5 to 2% had poor result in the patient analyzed with both Merle d’Aubigne and Postel score and Harris Hip Score. 80 % of the patients were able to sit cross legged, 90% had returned to regular work and 10% of the patients changed their occupation to desk jobs.Conclusions: Conservative management of acetabular fractures gives a good long-term result following congruent reduction of the fracture, good early rehabilitation and gradual weight bearing. Return to activity of daily living was good even in congruently reduced acetabular dome fractures with good to excellent functional outcome scores