Epigenetic and integrative cross-omics analyses of cerebral white matter hyperintensities on MRI.

Cerebral white matter hyperintensities on MRI are markers of cerebral small vessel disease, a major risk factor for dementia and stroke. Despite the successful identification of multiple genetic variants associated with this highly heritable condition, its genetic architecture remains incompletely understood. More specifically, the role of DNA methylation has received little attention. We investigated the association between white matter hyperintensity burden and DNA methylation in blood at ∼450 000 cytosine-phosphate-guanine (CpG) sites in 9732 middle-aged to older adults from 14 community-based studies. Single CpG and region-based association analyses were carried out. Functional annotation and integrative cross-omics analyses were performed to identify novel genes underlying the relationship between DNA methylation and white matter hyperintensities. We identified 12 single CpG and 46 region-based DNA methylation associations with white matter hyperintensity burden. Our top discovery single CpG, cg24202936 (P = 7.6 × 10-8), was associated with F2 expression in blood (P = 6.4 × 10-5) and co-localized with FOLH1 expression in brain (posterior probability = 0.75). Our top differentially methylated regions were in PRMT1 and in CCDC144NL-AS1, which were also represented in single CpG associations (cg17417856 and cg06809326, respectively). Through Mendelian randomization analyses cg06809326 was putatively associated with white matter hyperintensity burden (P = 0.03) and expression of CCDC144NL-AS1 possibly mediated this association. Differentially methylated region analysis, joint epigenetic association analysis and multi-omics co-localization analysis consistently identified a role of DNA methylation near SH3PXD2A, a locus previously identified in genome-wide association studies of white matter hyperintensities. Gene set enrichment analyses revealed functions of the identified DNA methylation loci in the blood-brain barrier and in the immune response. Integrative cross-omics analysis identified 19 key regulatory genes in two networks related to extracellular matrix organization, and lipid and lipoprotein metabolism. A drug-repositioning analysis indicated antihyperlipidaemic agents, more specifically peroxisome proliferator-activated receptor-alpha, as possible target drugs for white matter hyperintensities. Our epigenome-wide association study and integrative cross-omics analyses implicate novel genes influencing white matter hyperintensity burden, which converged on pathways related to the immune response and to a compromised blood-brain barrier possibly due to disrupted cell-cell and cell-extracellular matrix interactions. The results also suggest that antihyperlipidaemic therapy may contribute to lowering risk for white matter hyperintensities possibly through protection against blood-brain barrier disruption.

The Link Between Metabolic Syndrome and the Brain.

BACKGROUND: Metabolic syndrome (MetS) is a cluster of cardiometabolic conditions that has been linked to high risk for cardiovascular disease, liver complications and several malignancies. More recently MetS has been associated with cognitive dysfunction. SUMMARY: Studies have shown an association with minimal cognitive impairment (MCI), progression to vascular dementia (VaD) and even Alzheimer's disease (AD). MetS components have been individually explored and glucose intolerance has the strongest association with impairment in several cognitive domains. Several hypotheses have been proposed regarding the pathophysiology underlying the MetS-cognitive dysfunction association and even though insulin resistance plays a major role, more studies are needed to elucidate this topic. Moreover, several other factors contributing to this association have been identified. Liver disease and more specifically Metabolic dysfunction Associated Liver Disease (MASLD) can on its own contribute to cognitive decline through systemic inflammation and higher ammonia levels. Gut dysbiosis that has also been identified in MetS can also lead to cognitive impairment through several mechanisms that result in neurotoxicity. Finally, there are several other factors that may modify the MetS-cognitive dysfunction relationship, such as lifestyle, diet, education status and age. More recently circadian syndrome (CircS) was explored and was found to be even more strongly associated with cognitive impairment. KEY MESSAGE: MetS is associated with cognitive decline. Certain cardiometabolic risk factors have a stronger association with cognitive impairment and there are several factors that may modify this relationship. The aim of this review is to assess and summarize the existing body of evidence on the association between MetS and cognitive impairment and identify areas that necessitate further investigation.

Genome-wide identification, and gene expression analysis of NBS-LRR domain containing R genes in Chenopodium quinoa for unveiling the dynamic contribution in plant immunity against Cercospora cf. chenopodii.

The plant R genes encode the NLR proteins comprising nucleotide-binding sites (NBS) and variable-length C-terminal leucine-rich repeat domains. The proteins act as intracellular immune receptors and recognize effector proteins of phytopathogens, which convene virulence. Among stresses, diseases contribute majorly to yield loss in crop plants, and R genes confer disease resistance against phytopathogens. We investigated the NLRome of Chenopodium quinoa for intraspecific diversity, characterization, and contribution to immune response regulation against phytopathogens. One eighty-three NBS proteins were identified and grouped into four distinct classes. Exon-intron organization displayed discrimination in gene structure patterns among NLR proteins. Thirty-eight NBS proteins revealed ontology with defense response, ADP binding, and inter alia cellular components. These proteins had shown functional homology with disease-resistance proteins involved in the plant-pathogen interaction pathway. Likewise, expression analysis demonstrated that NLRs encoding genes showed differential expression patterns. However, most genes displayed high expression levels in plant defense response with varying magnitude compared to ADP binding and cellular components. Twenty-four NBS genes were selected based on Heatmap analysis for quantitative polymerase chain reaction under Cercospora disease stress, and their progressive expression pattern provides insights into their functional role under stress conditions. The protein-protein interaction analysis revealed functional enrichment of NLR proteins in regulating hypersensitive, immune, and stress responses. This study, the first to identify and characterize NBS genes in C. quinoa, reveals their contribution to disease response and divulges their dynamic involvement in inducing plant immunity against phytopathogens. Supplementary Information: The online version contains supplementary material available at 10.1007/s12298-024-01475-0.

Spatial prediction of soil erosion risk using knowledge-driven method in Malaysia's Steepland Agriculture Forested Valley.

Soil is a fundamental resource with its value vital to the world's ecosystem. Due to the fact that soil is one of the bases of all terrestrial life, humans cannot survive without it. However, soil erosion has jeopardized soil sustainability and affected the environmental quality, leaving a bad impact if these issues were not tackled at an earlier phase. Many research has been done to predict soil erosion susceptibility areas using different methods. This research aims to classify the contributing factors of soil erosion according to the risk and generate a soil erosion risk prediction map in Cameron Highlands. Thus, this research focuses on a knowledge-driven method that uses Analytical Hierarchy Process (AHP) technique to achieve the objectives. This technique consists of weighing the factors adopted by comparing pairs of factors that control erosion in this area through experts' opinions. 15 factors have been chosen to build the prediction map. Result shows that rainfall erosivity is the main factor contributing to soil erosion in Cameron Highlands which is 0.110, followed by land use (0.095), slope steepness (0.089), soil texture (0.079), NDVI (0.079), TWI (0.072), slope length (0.065), slope aspect (0.064), slope altitude (0.062), SPI (0.061), lithology (0.060), slope curvature (0.054), drainage density (0.049), distance to road (0.029) and distance to stream (0.025). The west part of the study area was exposed to a high risk of soil erosion. This research will give the decision-makers, policymakers and planners insight into minimizing the soil erosion problem and suggest better precautions and solutions to overcome this severe environmental problem in the more advanced phase.

Comparison of bacterial diversity, root exudates and soil enzymatic activities in the rhizosphere of AVP1-transgenic and nontransgenic wheat (Triticum aestivum L.).

AIMS: Soil microbial communities are among the most diverse communities that might be affected due to transgenic crops. Therefore, risk assessment studies on transgenes are essentially required as any adverse effects may depend not only on the specific gene and crop involved but also on soil conditions. METHODS AND RESULTS: The present study deals with the comparison of bacterial populations, root exudates and activities of soil enzymes in nontransgenic and AVP1-transgenic wheat rhizosphere, overexpressing vacuolar H + pyrophosphatase for salinity and drought stress tolerance. Amounts of organic acids and sugars produced as root exudates and activities of dehydrogenase, phosphatase and protease enzymes in soil solution showed no significant differences in AVP1-transgenic and nontransgenic wheat rhizosphere, except for urease and phenol oxidase activities. The higher copy number of nifH gene showed the abundance of nitrogen-fixing bacteria in the rhizosphere of AVP1-transgenic wheat compared with nontransgenic wheat. nifH gene sequence analysis indicated the common diazotrophic genera Azospirillum, Bradyrhizobium, Rhizobium and Pseudomonas in AVP1-transgenic and nontransgenic wheat except for Zoogloea detected only in nontransgenic wheat. Using 454-pyrosequencing of 16S rRNA gene from soil DNA, a total of 156, 282 sequences of 18 phyla were obtained, which represented bacterial (128,006), Archeal (7928) and unclassified (21,568) sequences. Proteobacteria, Crenarchaeota and Firmicutes were the most abundant phyla in the transgenic and nontransgenic wheat rhizosphere. Further comparison of different taxonomic units at the genus level showed similar distribution in transgenic and nontransgenic wheat rhizospheres. CONCLUSION: We conclude that the AVP1 gene in transgenic wheat has no apparent adverse effects on the soil environment and different bacterial communities. However, the bacterial community depends on several other factors, not only genetic composition of the host plants. SIGNIFICANCE OF THE STUDY: The present research supports introduction and cultivation of transgenic plants in agricultural systems without any adverse effects on indigenous bacterial communities and soil ecosystems.

Thoracic endometriosis presenting as hemopneumothorax.

Thoracic endometriosis is very rare. Usually, the thorax is the most frequent affected site outside the pelvis. Common symptoms include chest pain, dyspnea, and hemoptysis. Common manifestations include pneumothorax, hemothorax, and pulmonary or pleural nodules. In addition, symptoms and manifestations can be "catamenial" happening a few days after menstruation onset. This disease can be debilitating, causing a significant impact on the quality of life of young women. We present a case of a young female who was referred to our hospital with recurrent right-sided pleural effusions and pneumothoraces. Pleural fluid drainage was consistent with hemothorax. Transvaginal ultrasound showed mild intraperitoneal fluid in the Cul-de-Sac. Due to concerns for thoracic endometriosis, video-assisted thoracoscopic surgery was performed confirming the diagnosis by pathology. Therapeutic pleurectomy with diaphragmatic repair and pleurodesis was performed. The patient was started on medroxyprogesterone acetate injections two weeks after with great clinical response.

Cerebral Blood Flow and Its Connectivity Deficits in Mild Traumatic Brain Injury at the Acute Stage.

Objective: The influence of cognitive impairment after mild traumatic brain injury (mTBI) on cerebral vascular perfusion has been widely concerned, yet the resting-state cerebral blood flow (CBF) connectivity alterations based on arterial spin labeling (ASL) in mild traumatic brain injury (mTBI) remain unclear. This study investigated region CBF and CBF connectivity features in acute mTBI patients, as well as the associations between CBF changes and cognitive impairment. Materials and Methods: Forty-five acute mTBI patients and 42 health controls underwent pseudocontinuous arterial spin labeling (pCASL) perfusion magnetic resonance imaging (MRI). The alterations in regional CBF and relationship between the CBF changes and cognitive impairment were detected. The ASL-CBF connectivity of the brain regions with regional CBF significant differences was also compared between two groups. Neuropsychological tests covered seven cognitive domains. Associations between the CBF changes and cognitive impairment were further investigated. Results: Compared with the healthy controls, the acute mTBI patients exhibited increased CBF in the bilateral inferior temporal gyrus (ITG) and decreased CBF in the right middle frontal gyrus (MFG), the bilateral superior frontal gyrus (SFG), and the right cerebellum posterior lobe (CPL). In the mTBI patients, significant correlations were identified between the CBF changes and cognitive impairment. Importantly, the acute mTBI patients exhibited CBF disconnections between the right CPL and right fusiform gyrus (FG) as well as bilateral ITG, between the left SFG and left middle occipital gyrus (MOG), and between the right SFG and right FG as well as right parahippocampal gyrus. Conclusion: Our results suggest that acute mTBI patients exhibit both regional CBF abnormalities and CBF connectivity deficits, which may underlie the cognitive impairment of the acute mTBI patients.

The Systemic-immune-inflammation Index Independently Predicts Survival and Recurrence in Resectable Pancreatic Cancer and its Prognostic Value Depends on Bilirubin Levels: A Retrospective Multicenter Cohort Study.

OBJECTIVE: Our aim was to determine the prognostic significance of the systemic-immune-inflammation index (SIII) in patients with resectable pancreatic cancer, using cancer-specific survival as the primary outcome. BACKGROUND: Pancreatic cancer is associated with a dysfunctional immune system and poor prognosis. We examined the prognostic significance of the SIII in patients with resectable pancreatic ductal adenocarcinoma (PDAC) and the effects of bilirubin on this index. METHODS: We retrospectively assessed all pancreatic resections performed between 2004 and 2015 at 4 tertiary referral centers to identify pathologically confirmed PDAC patients. Baseline clinicopathologic characteristics, preoperative laboratory values such as absolute neutrophil, lymphocyte, and platelet counts, C-reactive protein, albumin, bilirubin, and CA19-9 levels, and also follow-up information, were collected. The associations of the calculated inflammatory indices with outcome were both internally and externally validated. RESULTS: In all, 590 patients with resectable PDAC were included. The discovery and validation cohort included 170 and 420 patients, respectively. SIII >900 [hazard ratio (HR) 2.32, 95% confidence interval (CI) 1.55-3.48], lymph node ratio (HR 3.75, 95% CI 2.08-6.76), and CA19.9 >200 kU/L (HR 1.62, 95% CI 1.07-2.46) were identified as independent predictors of cancer-specific survival. Separate model analysis confirmed that preoperative SIII contributed significantly to prognostication. However, SIII appeared to lose its prognostic significance in patients with bilirubin levels above 200 µmol/L. CONCLUSIONS: SIII is an independent predictor of cancer-specific survival and recurrence in patients with resectable PDAC. SIII may lose its prognostic significance in patients with high bilirubin levels. Properly designed prospective studies are needed to further confirm this hypothesis.

Management errors in adults with congenital heart disease: prevalence, sources, and consequences.

Aims: Improved survival has resulted in increasing numbers and complexity of adults with congenital heart disease (ACHD). International guidelines recommend specialized care but many patients are still not managed at dedicated ACHD centres. This study analysed referral sources and appropriateness of management for patients referred to our tertiary ACHD Centre over the past 3 years. Methods and results: We compared differences in care between patients referred from paediatric/ACHD-trained vs. general adult cardiologists, according to Adherence (A) or Non-Adherence (NA) with published guidelines. Non-Adherent cases were graded according to the severity of adverse outcome or risk of adverse outcome. Of 309 consecutively referred patients (28 ± 14 years, 51% male), 134 (43%) were from general cardiologists (19% highly complex CHD) and 115 (37%) were from paediatric cardiology or ACHD specialists (33% highly complex CHD). Sixty referrals (20%) were from other medical teams and of those, 31 had been lost to follow-up. Guideline deviations were more common in referrals from general compared to CHD-trained cardiologists (P < 0.001). Of general cardiology referrals, 49 (37%) were NA; 18 had catastrophic or major complications (n = 2, 16 respectively). In contrast, only 12 (10%) of the paediatric/ACHD referrals were NA, but none of these were catastrophic and only 3 were major. Simple, moderate, and highly complex CHD patients were at increased risk of adverse outcome when not under specialized CHD cardiology care (P = 0.04, 0.009, and 0.002, respectively). Conclusion: Non-adherence with guidelines was common in the ACHD population, and this frequently resulted in important adverse clinical consequences. These problems were more likely in patients who had not been receiving specialized CHD care. Configuring healthcare systems to optimize 'whole of life' care for this growing population is essential.

The eye in CHD.

In recent years, there has been a rise in the number patients with CHD surviving into adulthood. Many have complications related to their CHD or its treatments, outside the heart, including ocular abnormalities. The objective of this review is to highlight the ocular abnormalities that occur in adults with CHD, either from their condition or related to the common drugs prescribed to manage it. In particular, we reviewed the effects of cyanosis, coarctation of the aorta, endocarditis, and the side effects of Sildenafil and Amiodarone. A change in the retinal vasculature is a common observation with cyanosis or coarctation of the aorta. Occlusion of the retinal vessels may also be observed in cyanotic patients, as well as those with infectious endocarditis. Sildenafil has established ocular side effects; here they are explored in the context of therapy for pulmonary hypertension. Similarly, Amiodarone has established ocular risks, which are summarised. The high prevalence of ocular consequences in adult CHD patients reinforces the need for knowledge of the risks involved and for frequent ophthalmological screening where appropriate.

Laparoscopic Supracolic Pancreaticoduodenectomy: A Novel Technique For Complete Uncinate Process Resection.

BACKGROUND: Laparoscopic pancreaticoduodenectomy represents one of the most advanced surgical approaches for periampullary and pancreatic head tumors. This article aims to describe the novel technique for complete resection of the uncinate process from supracolic compartment only and summarizes the results from our institute. METHODOLOGY: Retrospective review of prospectively maintained database was performed for patients who underwent laparoscopic pancreaticoduodenectomy from April 2008 to March 2012 at our institute. RESULTS: A total of 38 patients with a mean age of 56.5 years (range: 35-70) underwent laparoscopic pancreaticoduodenectomy with this novel approach. Complete resection of uncinate process was achieved in 33 (86.84%) patients. The mean total operative time and resection time was 231.70 mins (range: 210-450) and 116.50 mins (range: 80-250), respectively. The mean blood loss was 183 ml (range 60-340). Major perioperative morbidity included pancreatic anastomotic leak (n = 3), billiary leak (n = 1) and hemorrhage (n = 1). Mean hospital stay was 14 days (range: 12-25 days). CONCLUSION: This novel supracolic approach for laparoscopic pancreaticoduodenectomy is feasible, safe and less time consuming. This technique can help achieving oncological outcomes comparable to those of the other techniques; though with the minimum invasion. This procedure can be performed conveniently by surgeons with substantial knowledge, experience and skills.

Empirical phenotyping and genome-wide association study reveal the association of panicle architecture with yield in Chenopodium quinoa.

Chenopodium quinoa manifests adaptability to grow under varying agro-climatic scenarios. Assessing quinoa germplasm's phenotypic and genetic variability is a prerequisite for introducing it as a potential candidate in cropping systems. Adaptability is the basic outcome of ecological genomics of crop plants. Adaptive variation predicted with a genome-wide association study provides a valuable basis for marker-assisted breeding. Hence, a panel of 72 quinoa plants was phenotyped for agro morphological attributes and association-mapping for distinct imperative agronomic traits. Inter simple sequence repeat (ISSR) markers were employed to assess genetic relatedness and population structure. Heatmap analysis showed three genotypes were early maturing, and six genotypes were attributed for highest yield. The SD-121-07 exhibited highest yield per plant possessing green, glomerulate shaped, compact density panicle with less leaves. However, SJrecm-03 yielded less exhibiting pink, intermediate shape, intermediate density panicles with less leaves. The phenotyping revealed strong correlation of panicle architecture with yield in quinoa. A genome-wide association study unraveled the associations between ISSR makers and agro-morphological traits. Mixed linear modes analysis yielded nine markers associated with eight traits at p ≤ 0.01. Moreover, ISSR markers significantly associated with panicle shape and leafiness were also associated with yield per plant. These findings contribute to the provision of authenticity for marker-assisted selection that ultimately would support quinoa breeding programs.

Theoretical study on the ring-opening reactions of cyclopropenes mediated by a AuI complex.

DFT calculations have been carried out in order to rationalize and predict the ring-opening regioselectivity of substituted cyclopropenes in the presence of gold(I) catalysts. It has been shown that the regioselectivity of these ring-opening processes is driven by the relative π-donor ability of the substituents on the cyclopropene double bond (C1 and C2). A stronger π-donor substituent at C2 favors Au(I)-induced polarization of the double bond toward C1, resulting in preferential breaking of the C1-C3 bond. An excellent correlation between ΔE(++) and the difference in the C1-C2 p(π) orbital population was observed for a broad range of substituents, providing a useful predictive model for gold-induced cyclopropene ring-opening. Furthermore, it was found that the stability of the resulting gold-stabilized allyl-cation intermediates do not follow the same trend as the ring-opening reaction energies. Generally, the more facile ring-opening process led to the less thermodynamically stable intermediate, which lacked stabilization of the carbocation by a π-donor in the α-position.

Physiological responses induced by phospholipase C isoform 5 upon heat stress in Arabidopsis thaliana.

Plant's perception of heat stress involves several pathways and signaling molecules, such as phosphoinositide, which is derived from structural membrane lipids phosphatidylinositol. Phospholipase C (PLC) is a well-known signaling enzyme containing many isoforms in different organisms. In the present study, Phospholipase C Isoform 5 (PLC5) was investigated for its role in thermotolerance in Arabidopsis thaliana. Two over-expressing lines and one knock-down mutant of PLC5 were first treated at a moderate temperature (37 °C) and left for recovery. Then again exposed to a high temperature (45 °C) to check the seedling viability and chlorophyll contents. Root behavior and changes in 32Pi labeled phospholipids were investigated after their exposure to high temperatures. Over-expression of PLC5 (PLC5 OE) exhibited quick and better phenotypic recovery with bigger and greener leaves followed by chlorophyll contents as compared to wild-type (Col-0) and PLC5 knock-down mutant in which seedling recovery was compromised. PLC5 knock-down mutant illustrated well-developed root architecture under controlled conditions but stunted secondary roots under heat stress as compared to over-expressing PLC5 lines. Around 2.3-fold increase in phosphatidylinositol 4,5-bisphosphate level was observed in PLC5 OE lines upon heat stress compared to wild-type and PLC5 knock-down mutant lines. A significant increase in phosphatidylglycerol was also observed in PLC5 OE lines as compared to Col-0 and PLC5 knock-down mutant lines. The results of the present study demonstrated that PLC5 over-expression contributes to heat stress tolerance while maintaining its photosynthetic activity and is also observed to be associated with primary and secondary root growth in Arabidopsis thaliana.

Contribution of parasol-magnocellular pathway ganglion cells to foveal retina in macaque monkey.

Parasol-magnocellular pathway ganglion cells form an important output stream of the primate retina and make a major contribution to visual motion detection. They are known to comprise ON and OFF type response polarities but the relative numbers of ON and OFF parasol cells, and the overall contribution of parasol cells to high-acuity foveal vision are not well understood. Here we use antibodies against carbonic anhydrase 8 (CA8) and intracellular injections of the liphilic dye DiI to show that CA8 selectively labels OFF parasol cells in macaque retina. By combined labeling with CA8 antibodies and a previously-described marker for parasol cells (GABAA receptor antibodies), we show that ON and OFF parasol cells each comprise âˆ¼ 6% of all ganglion cells in central retina (each peak density âˆ¼ 3000 cells/mm2 at 5 deg.), and each population comprises âˆ¼ 10% of all ganglion cells in peripheral temporal retina. Thus, the spatial density of parasol cells in central retina is greater than reported by previous anatomical studies, and the central-peripheral gradient in parasol cell density is shallower than previously reported. The data nevertheless predict decline in spatial acuity with visual field eccentricity for both midget-parvocellular pathway and parasol-magnocellular pathway mediated visual functions. The spatial resolving power of the OFF parasol array (peak âˆ¼ 7 cpd) falls short of macaque behavioral grating acuity by at least a factor of three throughout the retina.

Physical activity is associated with slower epigenetic ageing-Findings from the Rhineland study.

Epigenetic ageing, i.e., age-associated changes in DNA methylation patterns, is a sensitive marker of biological ageing, a major determinant of morbidity and functional decline. We examined the association of physical activity with epigenetic ageing and the role of immune function and cardiovascular risk factors in mediating this relation. Moreover, we aimed to identify novel molecular processes underlying the association between physical activity and epigenetic ageing. We analysed cross-sectional data from 3567 eligible participants (mean age: 55.5 years, range: 30-94 years, 54.8% women) of the Rhineland Study, a community-based cohort study in Bonn, Germany. Physical activity components (metabolic equivalent (MET)-Hours, step counts, sedentary, light-intensity and moderate-to-vigorous intensity activities) were recorded with accelerometers. DNA methylation was measured with the Illumina HumanMethylationEPIC BeadChip. Epigenetic age acceleration (Hannum's age, Horvath's age, PhenoAge and GrimAge) was calculated based on published algorithms. The relation between physical activity and epigenetic ageing was examined with multivariable regression, while structural equation modeling was used for mediation analysis. Moreover, we conducted an epigenome-wide association study of physical activity across 850,000 CpG sites. After adjustment for age, sex, season, education, smoking, cell proportions and batch effects, physical activity (step counts, MET-Hours and %time spend in moderate-to-vigorous activities) was non-linearly associated with slower epigenetic ageing, in part through its beneficial effects on immune function and cardiovascular health. Additionally, we identified 12 and 7 CpGs associated with MET-Hours and %time spent in moderate-to-vigorous activities, respectively (p < 1 × 10-5 ). Our findings suggest that regular physical activity slows epigenetic ageing by counteracting immunosenescence and lowering cardiovascular risk.

Theoretical investigation into the mechanism of Au(I)-catalyzed reaction of alcohols with 1,5 enynes.

Density functional theory has been used to investigate the reactions of 1,5 enynes with alcohols in the presence of a gold catalyst. We have compared the mechanism of the alcohol addition reaction for the enyne with that of the enyne where the carbon at position 3 is replaced with silicon. We find that different intermediates are present in both cases, and in the case of the silicon analogue, the intermediate that we find from the calculations is different from any that have previously been proposed in the literature. For the silicon analogue we have been able to rationalize the observed effects of alcohol concentration and nucleophilicity on the product distribution. For the carbon-based enyne we have shown why different products are observed depending on the substitution at position 3 of the enyne. Overall, we have provided for the first time a consistent explanation and rationalization of several different experiments that have been previously published in the literature. Our mechanism will assist in predicting the outcome of experimental reactions involving different alcohols, reagent concentrations, and substitution patterns of the 1,5 enynes.

Positive Margins Following Excision of Primary Bone & Soft Tissue Tumours in a Tertiary Centre and the Impact on Patient Outcomes.

Background Primary bone and soft tissue sarcoma treatment includes surgical resection, with or without peri-operative chemoradiotherapy. The aim of surgery is to achieve complete excision, to prevent localised recurrence and achieve cure. For various reasons, excision with adequate margins is not always possible. Our aim is to assess the occurrence of unexpected positive margins following primary excision within a tertiary centre and the impact on patient outcomes. Methods A retrospective analysis of 567 patients discussed at the Royal National Orthopaedic Hospital Multi-disciplinary team (MDT) meeting with positive margins between 1999-2020 was performed. Exclusion criteria included: excisions performed externally and lesions treated with curettage. Information gathering from electronic records highlighted 23 cases with unexpected positive margins following primary excision. Results All patients pre-operatively expected to achieve complete primary resection. The median age was 60 years (8-92), 10M:13F. Tumour location included lower limb (12), upper limb (six), pelvis (two) and trunk (three); eight bone tumours and 15 soft tissue. The overall recurrence rate was 30.4% (7/23). In those recommended for re-excision (n=16), the recurrence rate was 31.25% (5/16). Of the patients not initially recommended for re-excision (n=7), four proceeded to surveillance alone with 50% recurrence (2/4), both with metastatic disease not surviving to follow-up. A further three patients underwent post-operative radiotherapy alone with no recurrences at follow-up, one patient not surviving for further treatment due to stroke. The mean follow-up for patients was 3.1 years. Conclusion When positive margins do occur unexpectedly, the impact due to the need for further treatment and ultimately increased risk of recurrence can be significant. Results can be compared to those for unplanned excisions. Therefore, surgeons should be aware of the different circumstances in which positive margins occur to help guide treatment planning and managing patient expectations.

Dehydrin responsive HVA1 driven inducible gene expression enhanced salt and drought tolerance in wheat.

Heterologous expression of plant genes is becoming an important strategy for the improvement of specific traits in existing cultivars. This study presents the response of a salt-sensitive high-yielding wheat variety under stress-inducible expression of barley HVA1 gene belonging to the Late embryogenesis abundance (LEA) gene family. Six homozygous transgenic wheat plants were developed and advanced for testing under various water regimes and salt stress conditions. Putative transgenic plants showed better germination and root shoot development at the early developmental stages under drought stress conditions. Moreover, transgenic plants illustrated higher values of physiological features as compared to non-transgenic plants under both drought and salinity stresses that indicate improved physiological processes in transgenic plants. Higher membrane stability index (MSI) and lower electrolyte leakage (EL) after exposure to abiotic stresses reveal improved cellular membrane stability (CMS) and reduced injury to chloroplast membrane. Interestingly, under salinity stress, transgenic wheat plants showed preference towards higher K+ accumulation in the shoot, which is not a well-understood HVA1 mediated Na + avoidance mechanism under excessive subsurface salts. The predisposition of K+/Na + under salt stress conditions on heterologous expression of the HVA1 gene in wheat needs to be studied in detail in further studies.