The divergence of mutation rates and spectra across the Tree of Life.

Owing to advances in genome sequencing, genome stability has become one of the most scrutinized cellular traits across the Tree of Life. Despite its centrality to all things biological, the mutation rate (per nucleotide site per generation) ranges over three orders of magnitude among species and several-fold within individual phylogenetic lineages. Within all major organismal groups, mutation rates scale negatively with the effective population size of a species and with the amount of functional DNA in the genome. This relationship is most parsimoniously explained by the drift-barrier hypothesis, which postulates that natural selection typically operates to reduce mutation rates until further improvement is thwarted by the power of random genetic drift. Despite this constraint, the molecular mechanisms underlying DNA replication fidelity and repair are free to wander, provided the performance of the entire system is maintained at the prevailing level. The evolutionary flexibility of the mutation rate bears on the resolution of several prior conundrums in phylogenetic and population-genetic analysis and raises challenges for future applications in these areas.

Comprehensive Analysis of Feature Extraction Methods for Emotion Recognition from Multichannel EEG Recordings.

Advances in signal processing and machine learning have expedited electroencephalogram (EEG)-based emotion recognition research, and numerous EEG signal features have been investigated to detect or characterize human emotions. However, most studies in this area have used relatively small monocentric data and focused on a limited range of EEG features, making it difficult to compare the utility of different sets of EEG features for emotion recognition. This study addressed that by comparing the classification accuracy (performance) of a comprehensive range of EEG feature sets for identifying emotional states, in terms of valence and arousal. The classification accuracy of five EEG feature sets were investigated, including statistical features, fractal dimension (FD), Hjorth parameters, higher order spectra (HOS), and those derived using wavelet analysis. Performance was evaluated using two classifier methods, support vector machine (SVM) and classification and regression tree (CART), across five independent and publicly available datasets linking EEG to emotional states: MAHNOB-HCI, DEAP, SEED, AMIGOS, and DREAMER. The FD-CART feature-classification method attained the best mean classification accuracy for valence (85.06%) and arousal (84.55%) across the five datasets. The stability of these findings across the five different datasets also indicate that FD features derived from EEG data are reliable for emotion recognition. The results may lead to the possible development of an online feature extraction framework, thereby enabling the development of an EEG-based emotion recognition system in real time.

Plasticity of root anatomy during domestication of a maize-teosinte derived population.

Maize (Zea mays L.) has undergone profound changes in root anatomy for environmental adaptation during domestication. However, the genetic mechanism of plasticity of maize root anatomy during the domestication process remains unclear. In this study, high-resolution mapping was performed for nine root anatomical traits using a maize-teosinte population (mexicana × Mo17) across three environments. Large genetic variations were detected for different root anatomical traits. The cortex, stele, aerenchyma areas, xylem vessel number, and cortical cell number had large variations across three environments, indicating high plasticity. Sixteen quantitative trait loci (QTL) were identified, including seven QTL with QTL × environment interaction (EIQTL) for high plasticity traits and nine QTL without QTL × environment interaction (SQTL). Most of the root loci were consistent with shoot QTL depicting domestication signals. Combining transcriptome and genome-wide association studies revealed that AUXIN EFFLUX CARRIER PIN-FORMED LIKE 4 (ZmPILS4) serves as a candidate gene underlying a major QTL of xylem traits. The near-isogenic lines (NILs) with lower expression of ZmPILS4 had 18-24% more auxin concentration in the root tips and 8-15% more xylem vessels. Nucleotide diversity values analysis in the promoter region suggested that ZmPILS4 was involved in maize domestication and adaptation. These results revealed the potential genetic basis of root anatomical plasticity during domestication.

Inhibitory regulation of calcium transients in prefrontal dendritic spines is compromised by a nonsense Shank3 mutation.

The SHANK3 gene encodes a postsynaptic scaffold protein in excitatory synapses, and its disruption is implicated in neurodevelopmental disorders such as Phelan-McDermid syndrome, autism spectrum disorder, and schizophrenia. Most studies of SHANK3 in the neocortex and hippocampus have focused on disturbances in pyramidal neurons. However, GABAergic interneurons likewise receive excitatory inputs and presumably would also be a target of constitutive SHANK3 perturbations. In this study, we characterize the prefrontal cortical microcircuit in awake mice using subcellular-resolution two-photon microscopy. We focused on a nonsense R1117X mutation, which leads to truncated SHANK3 and has been linked previously to cortical dysfunction. We find that R1117X mutants have abnormally elevated calcium transients in apical dendritic spines. The synaptic calcium dysregulation is due to a loss of dendritic inhibition via decreased NMDAR currents and reduced firing of dendrite-targeting somatostatin-expressing (SST) GABAergic interneurons. Notably, upregulation of the NMDAR subunit GluN2B in SST interneurons corrects the excessive synaptic calcium signals and ameliorates learning deficits in R1117X mutants. These findings reveal dendrite-targeting interneurons, and more broadly the inhibitory control of dendritic spines, as a key microcircuit mechanism compromised by the SHANK3 dysfunction.

Dynamics of genetic variation in transcription factors and its implications for the evolution of regulatory networks in Bacteria.

The evolution of regulatory networks in Bacteria has largely been explained at macroevolutionary scales through lateral gene transfer and gene duplication. Transcription factors (TF) have been found to be less conserved across species than their target genes (TG). This would be expected if TFs accumulate mutations faster than TGs. This hypothesis is supported by several lab evolution studies which found TFs, especially global regulators, to be frequently mutated. Despite these studies, the contribution of point mutations in TFs to the evolution of regulatory network is poorly understood. We tested if TFs show greater genetic variation than their TGs using whole-genome sequencing data from a large collection of Escherichia coli isolates. TFs were less diverse than their TGs across natural isolates, with TFs of large regulons being more conserved. In contrast, TFs showed higher mutation frequency in adaptive laboratory evolution experiments. However, over long-term laboratory evolution spanning 60 000 generations, mutation frequency in TFs gradually declined after a rapid initial burst. Extrapolating the dynamics of genetic variation from long-term laboratory evolution to natural populations, we propose that point mutations, conferring large-scale gene expression changes, may drive the early stages of adaptation but gene regulation is subjected to stronger purifying selection post adaptation.

The Baffle Length Effects on the Natural Convection in Nanofluid-Filled Square Enclosure with Sinusoidal Temperature.

The proper process of applying heat to many technological devices is a significant challenge. There are many nanofluids of different sizes used inside the system. The current study combines this potential to improve convection effects, considering numerical simulations of natural convection using Cu/water nanofluids in a square enclosure with bottom blocks embedded in baffles. The enclosure consists of two vertical walls with isothermal boundary conditions; the left wall is the sinusoidal heat source, whereas the right wall is cooled. The investigations dealt with the influences of nanoparticle concentration, Rayleigh number, baffle length, and thermal conductivity ratioon isotherms, stream functions, and average Nusselt number. The results present that, when the Rayleigh number rises, the fluid flow velocity increases, and the heat transfer improves. Furthermore, the baffle length case (Lb = 0.3) provides higher heat transfer characteristics than other baffle height cases.

Predicting How Well Adolescents Get Along with Peers and Teachers: A Machine Learning Approach.

How well adolescents get along with others such as peers and teachers is an important aspect of adolescent development. Current research on adolescent relationship with peers and teachers is limited by classical methods that lack explicit test of predictive performance and cannot efficiently discover complex associations with potential non-linearity and higher-order interactions among a large set of predictors. Here, a transparently reported machine learning approach is utilized to overcome these limitations in concurrently predicting how well adolescents perceive themselves to get along with peers and teachers. The predictors were 99 items from four instruments examining internalizing and externalizing psychopathology, sensation-seeking, peer pressure, and parent-child conflict. The sample consisted of 3232 adolescents (M = 14.0 years, SD = 1.0 year, 49% female). Nonlinear machine learning classifiers predicted with high performance adolescent relationship with peers and teachers unlike classical methods. Using model explainability analyses at the item level, results identified influential predictors related to somatic complaints and attention problems that interacted in nonlinear ways with internalizing behaviors. In many cases, these intrapersonal predictors outcompeted in predictive power many interpersonal predictors. Overall, the results suggest the need to cast a much wider net of variables for understanding and predicting adolescent relationships, and highlight the power of a data-driven machine learning approach with implications on a predictive science of adolescence research.

A misdiagnosis of choledochal cyst type IB and recommendation to use gold-standard imaging techniques: A case report.

A choledochal cyst (CC) is a rare congenital dilation of the biliary ductal system that can cause troublesome complications when left untreated. CC in children classically manifests as a rare triad of the right upper quadrant mass, jaundice, and abdominal pain. Here, we report the case of an eight-year-old boy seen in Paediatric Unit I of Dr Ruth K. M. Pfau Civil Hospital Karachi, Pakistan, on October 9, 2019, who was initially misdiagnosed for liver abscess due to the non-specific symptoms and managed appropriately with antibiotics, which failed to improve the symptoms. Moreover, a hydatid cyst was considered based on ultrasonography (USG) which was later ruled out by the negative serology. A definitive diagnosis of CC was established on magnetic resonance cholangiopancreatography (MRCP). In resource-limited countries, USG is always the first line screening tool for biliary duct abnormalities which in some cases is comprehensibly enough for the diagnosis of a rare entity like CC, thus requiring a highly specific imaging test like MRCP to be performed to devise an effective treatment and surgical plan.

Nanoscopic Visualization of Restricted Nonvolume Cholinergic and Monoaminergic Transmission with Genetically Encoded Sensors.

How neuromodulatory transmitters diffuse into the extracellular space remains an unsolved fundamental biological question, despite wide acceptance of the volume transmission model. Here, we report development of a method combining genetically encoded fluorescent sensors with high-resolution imaging and analysis algorithms which permits the first direct visualization of neuromodulatory transmitter diffusion at various neuronal and non-neuronal cells. Our analysis reveals that acetylcholine and monoamines diffuse at individual release sites with a spread length constant of ∼0.75 µm. These transmitters employ varied numbers of release sites, and when spatially close-packed release sites coactivate they can spillover into larger subcellular areas. Our data indicate spatially restricted (i.e., nonvolume) neuromodulatory transmission to be a prominent intercellular communication mode, reshaping current thinking of control and precision of neuromodulation crucial for understanding behaviors and diseases.

Case report of a female child with right nasal chondromyxoid fibroma.

Chondromyxoid fibroma is a rare tumour, representing <1% of all primary bone neoplasm. We report the case of a four-year-old female child with a one-year history of nasal obstruction and facial swelling. A large enhanced lesion with amorphous densities spreading into the right cribriform plate and floor of sphenoid sinus, laterally into the right lamina papyracea, inferolaterally into the medial wall of maxillary sinus, posteriorly into the nasopharynx and superior aspect of oropharynx was observed on CT scan. The mass was excised by Caldwell Luc's endoscopic medial maxillectomy via sublabial approach. CMF was confirmed histopathologically.

Paediatric Bickerstaff brainstem encephalitis: A rare case report.

Bickerstaff Brainstem Encephalitis, a rare variant of Guillain- Barre Syndrome has an estimated prevalence of eight per 100 million individuals. It presents with the classic triad of ataxia, ophthalmoplegia and altered consciousness. We report the case of a 10-year-old child who presented with low grade fever, hypersomnia and inability to walk. Central nervous system examination revealed ophthalmoplegia and multiple cranial nerve palsies. However, CSF examination showed lack of albuminocytological dissociation with no previous history of respiratory or gastrointestinal tract infection. Unavailability of Anti-GQ1b antibodies led to a diagnosis based on suggestive clinical features, abnormal MRI signals and prompt response to corticosteroid administration. Intravenous Methyl Prednisolone in a dose of 30mg/kg/day was administered for 10 days followed by oral Prednisolone 2 mg/kg/day. After complete recovery the patient was discharged, Prednisolone was tapered gradually and eventually discontinued after four months.

Genome wide association studies using a new nonparametric model reveal the genetic architecture of 17 agronomic traits in an enlarged maize association panel.

Association mapping is a powerful approach for dissecting the genetic architecture of complex quantitative traits using high-density SNP markers in maize. Here, we expanded our association panel size from 368 to 513 inbred lines with 0.5 million high quality SNPs using a two-step data-imputation method which combines identity by descent (IBD) based projection and k-nearest neighbor (KNN) algorithm. Genome-wide association studies (GWAS) were carried out for 17 agronomic traits with a panel of 513 inbred lines applying both mixed linear model (MLM) and a new method, the Anderson-Darling (A-D) test. Ten loci for five traits were identified using the MLM method at the Bonferroni-corrected threshold -log10 (P) >5.74 (α=1). Many loci ranging from one to 34 loci (107 loci for plant height) were identified for 17 traits using the A-D test at the Bonferroni-corrected threshold -log10 (P) >7.05 (α=0.05) using 556809 SNPs. Many known loci and new candidate loci were only observed by the A-D test, a few of which were also detected in independent linkage analysis. This study indicates that combining IBD based projection and KNN algorithm is an efficient imputation method for inferring large missing genotype segments. In addition, we showed that the A-D test is a useful complement for GWAS analysis of complex quantitative traits. Especially for traits with abnormal phenotype distribution, controlled by moderate effect loci or rare variations, the A-D test balances false positives and statistical power. The candidate SNPs and associated genes also provide a rich resource for maize genetics and breeding.

Efficacy of brow suspension with autogenous fascia lata in simple congenital ptosis.

OBJECTIVE: To assess the mean change in interpalpebral fissure height and marginal reflex distance after brow suspension with autogenous fascia lata sling in patients of ptosis. METHODS: This was a Quasi experimental study conducted at Department of Ophthalmology, Mayo Hospital, King Edwards Medical University Lahore, from Jan 2013 to June 2016. Included were the patients who had unilateral or bilateral ptosis with poor levator function (< 5 mm). Informed consent was obtained from all patients after explaining about the research project. Patients were admitted in ward and all of them underwent surgery by a single surgical team. The surgical procedure was performed in supine position under general anesthesia in children and uncooperative patients. Patients were followed at week 4, 8, 12 and 24 to observe vertical interpalpebral fissure height and marginal reflex distance. RESULTS: The mean age of the patients was 9.03 ± 5.26 years. The mean Inter palpebral fissure height (IPFH) was 4.40±0.91 mm and mean MRD was 0.50 ± 1.00 mm before surgery while after surgery it was 7.41±0.76 mm and 3.10 ± 1.50 mm respectively at 04 weeks. The mean IPFH and MRD at 24 weeks postoperatively were 8.43±0.98 mm and 3.60 + 1.50 mm respectively. The mean change in IPFH and MRD at 24th week, were 3.90 ± 0.34 mm and 3.50 ± 1.00 mm. CONCLUSION: Brow suspension with fascia lata sling is safe and effective technique for correction of ptosis with poor levator function.

Phenotypic variability in patients with osteogenesis imperfecta caused by BMP1 mutations.

Osteogenesis Imperfecta (OI) is an inherited bone fragility disorder most commonly associated with autosomal dominant mutations in the type I collagen genes. Autosomal recessive mutations in a number of genes have also been described, including the BMP1 gene that encodes the mammalian Tolloid (mTLD) and its shorter isoform bone morphogenic protein-1 (BMP1). To date, less than 20 individuals with OI have been identified with BMP1 mutations, with skeletal phenotypes ranging from mild to severe and progressively deforming. In the majority of patients, bone fragility was associated with increased bone mineral density (BMD); however, the full range of phenotypes associated with BMP1 remains unclear. Here, we describe three children with mutations in BMP1 associated with a highly variable phenotype: a sibship homozygous for the c.2188delC mutation that affects only the shorter BMP1 isoform and a further patient who is compound heterozygous for a c.1293C>G nonsense mutation and a c.1148G>A missense mutation in the CUB1 domain. These individuals had recurrent fractures from early childhood, are hypermobile and have no evidence of dentinogenesis imperfecta. The homozygous siblings with OI had normal areal BMD by dual energy X-ray absorptiometry whereas the third patient presented with a high bone mass phenotype. Intravenous bisphosphonate therapy was started in all patients, but discontinued in two patients and reduced in another due to concerns about increasing bone stiffness leading to chalk-stick fractures. Given the association of BMP1-related OI with very high bone material density, concerns remain whether anti-resorptive therapy is indicated in this ultra-rare form of OI.© 2016 Wiley Periodicals, Inc.

Genome-wide association mapping reveals novel sources of resistance to northern corn leaf blight in maize.

BACKGROUND: Northern corn leaf blight (NCLB) caused by Exserohilum turcicum is a destructive disease in maize. Using host resistance to minimize the detrimental effects of NCLB on maize productivity is the most cost-effective and appealing disease management strategy. However, this requires the identification and use of stable resistance genes that are effective across different environments. RESULTS: We evaluated a diverse maize population comprised of 999 inbred lines across different environments for resistance to NCLB. To identify genomic regions associated with NCLB resistance in maize, a genome-wide association analysis was conducted using 56,110 single-nucleotide polymorphism markers. Single-marker and haplotype-based associations, as well as Anderson-Darling tests, identified alleles significantly associated with NCLB resistance. The single-marker and haplotype-based association mappings identified twelve and ten loci (genes), respectively, that were significantly associated with resistance to NCLB. Additionally, by dividing the population into three subgroups and performing Anderson-Darling tests, eighty one genes were detected, and twelve of them were related to plant defense. Identical defense genes were identified using the three analyses. CONCLUSION: An association panel including 999 diverse lines was evaluated for resistance to NCLB in multiple environments, and a large number of resistant lines were identified and can be used as reliable resistance resource in maize breeding program. Genome-wide association study reveals that NCLB resistance is a complex trait which is under the control of many minor genes with relatively low effects. Pyramiding these genes in the same background is likely to result in stable resistance to NCLB.

Patterns of Change in Nucleotide Diversity Over Gene Length.

Nucleotide diversity at a site is influenced by the relative strengths of neutral and selective population genetic processes. Therefore, attempts to estimate Effective population size based on the diversity of synonymous sites demand a better understanding of their selective constraints. The nucleotide diversity of a gene was previously found to correlate with its length. In this work, I measure nucleotide diversity at synonymous sites and uncover a pattern of low diversity towards the translation initiation site of a gene. The degree of reduction in diversity at the translation initiation site and the length of this region of reduced diversity can be quantified as "Effect Size" and "Effect Length" respectively, using parameters of an asymptotic regression model. Estimates of Effect Length across bacteria covaried with recombination rates as well as with a multitude of translation-associated traits such as the avoidance of mRNA secondary structure around translation initiation site, the number of rRNAs, and relative codon usage of ribosomal genes. Evolutionary simulations under purifying selection reproduce the observed patterns and diversity-length correlation and highlight that selective constraints on the 5'-region of a gene may be more extensive than previously believed. These results have implications for the estimation of effective population size, and relative mutation rates, and for genome scans of genes under positive selection based on "silent-site" diversity.

Gender Disparity in Academic Trauma Surgery: The Current State of Affairs.

INTRODUCTION: Despite the increasing number of female surgeons in general surgery programs, women are still inadequately represented in leadership positions. This study aims to investigate the magnitude of gender bias in university-based trauma surgery fellowship programs and leadership positions in the United States of America. MATERIAL AND METHODS: FRIEDA was used to identify trauma surgery programs. A thorough website review of each program obtained further information on faculty members, including their name, age, gender, and faculty rank. Trauma surgeons with an MD or DO qualification and a faculty rank of Professor, Associate Professor, or Assistant Professor were selected for inclusion in this study. SCOPUS was used to assess the H-index and the number of publications and citations of surgeons. RESULTS: The total number of programs included was 136, consisting of 715 faculty members. Less than a quarter (n = 166; 23.2%) comprised females and less than one-fifth (n = 30; 19%) of female surgeons were Professors. The difference in the research productivity of male and female trauma surgeons was statistically significant (P < .05), with the average H-index being 10 vs 7.5, respectively, amongst the top 50 surgeons of both genders. Based on a multiple regression analysis, academic rank was significantly associated (P < .05), and gender was not significantly associated (P > .05) with H-index. CONCLUSION: Gender disparity exists in the field of trauma surgery, as noted in senior faculty ranks and leadership positions. Female-inclusive state policies, appropriate mentorship, and supportive institutions can help to bridge this gap.

Socio-economic factors determine maternal and neonatal outcomes in women with peripartum cardiomyopathy: A study of the ESC EORP PPCM registry.

BACKGROUND: Peripartum cardiomyopathy (PPCM) is a global disease with substantial morbidity and mortality. The aim of this study was to analyze to what extent socioeconomic factors were associated with maternal and neonatal outcomes. METHODS: In 2011, >100 national and affiliated member cardiac societies of the European Society of Cardiology (ESC) were contacted to contribute to a global PPCM registry, under the auspices of the ESC EORP Programme. We investigated the characteristics and outcomes of women with PPCM and their babies according to individual and country-level sociodemographic factors (Gini index coefficient [GINI index], health expenditure [HE] and human developmental index [HDI]). RESULTS: 739 women from 49 countries (Europe [33%], Africa [29%], Asia-Pacific [15%], Middle East [22%]) were enrolled. Low HDI was associated with greater left ventricular (LV) dilatation at time of diagnosis. However, baseline LV ejection fraction did not differ according to sociodemographic factors. Countries with low HE prescribed guideline-directed heart failure therapy less frequently. Six-month mortality was higher in countries with low HE; and LV non-recovery in those with low HDI, low HE and lower levels of education. Maternal outcome (death, re-hospitalization, or persistent LV dysfunction) was independently associated with income. Neonatal death was significantly more common in countries with low HE and low HDI, but was not influenced by maternal income or education attainment. CONCLUSIONS: Maternal and neonatal outcomes depend on country-specific socioeconomic characteristics. Attempts should therefore be made to allocate adequate resources to health and education, to improve maternal and fetal outcomes in PPCM.