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Abstract Genetic variation accounts for much of the risk for developing a substance use disorder, but the underlying genetic factors and their genetic effector mechanisms are mostly unknown. Inbred mouse strains exhibit substantial and heritable differences in the extent of voluntary cocaine self-administration. Computational genetic analysis of cocaine self-administration data obtained from twenty-one inbred strains identified Nav1, a member of the neuron navigator family that regulates dendrite formation and axonal guidance, as a candidate gene. To test this genetic hypothesis, we generated and characterized Nav1 knockout mice. Consistent with the genetic prediction, Nav1 knockout mice exhibited increased voluntary cocaine intake and had increased motivation for cocaine consumption. Immunohistochemistry, electrophysiology, and transcriptomic studies were performed as a starting point for investigating the mechanism for the Nav1 knockout effect. Nav1 knockout mice had a reduced inhibitory synapse density in their cortex, increased excitatory synaptic transmission in their cortex and hippocampus, and increased excitatory neurons in a deep cortical layer. Collectively, our results indicate that Nav1 regulates the response to cocaine, and we identified Nav1 knockout induced changes in the excitatory and inhibitory synaptic balance in the cortex and hippocampus that could contribute to this effect.

Abstract Background ‘Long read’ sequencing methods have been used to identify previously uncharacterized structural variants that cause human genetic diseases. Therefore, we investigated whether long read sequencing could facilitate genetic analysis of murine models for human diseases. Results The genomes of six inbred strains (BTBR T + Itpr3tf/J, 129Sv1/J, C57BL/6/J, Balb/c/J, A/J, SJL/J) were analyzed using long read sequencing. Our results revealed that (i) Structural variants are very abundant within the genome of inbred strains (4.8 per gene) and (ii) that we cannot accurately infer whether structural variants are present using conventional short read genomic sequence data, even when nearby SNP alleles are known. The advantage of having a more complete map was demonstrated by analyzing the genomic sequence of BTBR mice. Based upon this analysis, knockin mice were generated and used to characterize a BTBR-unique 8-bp deletion within Draxin that contributes to the BTBR neuroanatomic abnormalities, which resemble human autism spectrum disorder. Conclusion A more complete map of the pattern of genetic variation among inbred strains, which is produced by long read genomic sequencing of the genomes of additional inbred strains, could facilitate genetic discovery when murine models of human diseases are analyzed.

Abstract Short tandem repeats (STRs) play a crucial role in genetic diseases. However, classic disease models such as inbred mice lack such genome wide data in public domain. The examination of STR alleles present in the protein coding regions (are known as protein tandem repeats or PTR) can provide additional functional layer of phenotype regulars. Motivated with this, we analysed the whole genome sequencing data from 71 different mouse strains and identified STR alleles present within the coding regions of 562 genes. Taking advantage of recently formulated protein models, we also showed that the presence of these alleles within protein 3-dimensional space, could impact the protein folding. Overall, we identified novel alleles from a large number of mouse strains and demonstrated that these alleles are of interest considering protein structure integrity and functionality within the mouse genomes. We conclude that PTR alleles have potential to influence protein functions through impacting protein structural folding and integrity.

COVID-19 related acute respiratory distress syndrome (ARDS) requires intensive care, which is highly expensive in lower-income countries. Outcomes of COVID-19 patients requiring invasive mechanical ventilation in Pakistan have not been widely reported. Identifying factors forecasting outcomes will help decide optimal care levels and prioritise resources.

Snowfall and ice formation on road surface significantly impact the safety of driving conditions. To resolve this, every year salt and de-icing chemicals are sprinkled on roads. However, use of salts and snow ploughing have environmental as well as economical disadvantages. To resolve these problems, hydronic road heating systems are valid alternatives. Heat transfer fluid, i.e. mixture of ethanol and water, is pumped into a tubular circulation system under the asphalt. By this technology, the road and pavements shall stay ice-free even in times of snowfall and temperatures below the freezing point. The system can also be used to cool the asphalt in case of extreme heat, which – besides the heating effect – could also prevent road from damages in extreme summers. This study aims to compare the environmental impact of use of salts and road-heating system in terms of GHG emissions. To assess the environmental impact, an operational road heating system for a ramp in Ingolstadt, Germany, is considered. A cradle-to-grave analysis technique is used to determine the environmental effects based on a life-cycle assessment (LCA) framework. The analysis includes nine components solemnly responsible for hydronic heating of asphalt surface such as local heating pipe, insulation, pumps, and heat meters. Comparison is performed in terms of relative and total impact over 50-year lifetime of three heated ramps having 1989 m2 surface area in total. The results show that the asphalt and heating-circuit causes the major fraction (65 %) of overall GHG emissions, with total life-time emissions of 28.10 kg CO2 eq./m2 of heated surface. During an operational life of 50 years, road heating systems emit 18 % less CO2 eq./m2 as compared to the use of salts.

Objective The aim of this article was to study the impact of early versus late tracheostomy on clinical outcomes of moderate-to-severe traumatic brain injury (TBI). Materials and Methods A retrospective cross-sectional study was conducted in the Neurosurgery Department, Mayo Hospital, Lahore, in which a sample size of 50 cases was calculated over a period of 6 months from January 1, 2022, to June 30, 2022. The included cases were patients who suffered from moderate-to-severe TBI, isolated TBI, needed elective ventilation, required intensive care unit (ICU) admission during their hospital stay, and were between the ages of 18 and 65 years. All the rest were excluded. A structured proforma was used by the physician to collect data after the informed consent of the patient. The results were computed and analyzed statistically using Statistical Package for Social Sciences , version 26. Results The median age of patients was 40 (interquartile [IQ] range 34) years and were predominantly male (72%). The most common mode of injury was road traffic accidents (58%). The median Glasgow Coma Scale (GCS) score at arrival was 8 (IQ range 6) and the most common pupillary light reflex at presentation was bilaterally equally responsive to light (68%). Neurologic deficits were mostly absent or cannot be assessed on presentation (86%) and in 38% of the cases multiple findings were noted on computed tomography (CT) scan while among single findings seen on CT scan, subdural hematoma was the most common (22%). Multiple regression analysis was done through two separate models using age, gender, mode of injury, presenting GCS score, number of CT-scan findings, number of days after endotracheal intubation after which tracheostomy was done, and the timing of tracheostomy (early vs. late) as predictors, and a significant relationship was noted between the timing of tracheostomy (early vs. late) and GCS at discharge (p = 0.001) as well as extended Glasgow Outcome Score (GOS) at discharge (p = 0.013). Conclusion This study suggests that moderate-to-severe TBIs are most common in middle-aged males and mostly involve road traffic accidents. In most cases, multiple CT-scan findings are seen as compared with a single predominant finding. In such patients, early tracheostomy is superior to late tracheostomy as it results in significantly better GCS and GOS scores at discharge as well as a decreased duration of mechanical ventilation and ICU stay. [ABSTRACT FROM AUTHOR]

In this article, the modified Kudryashov and extended simple equation methods are employed to obtain analytical solutions for the Zhiber–Shabat problem. The outcomes of this study clearly indicate that the provided methodologies are appropriate techniques for generating some new exact solutions for nonlinear evolution equations. Furthermore, the nature of the solutions would be presented in three dimensions for various parameters applying the most advanced scientific instruments. The physical behavior of the solutions are graphically displayed, and it is established that the acquired solutions are newly constructed in the form of bright, dark, optical, singular, and bell-shaped periodic soliton wave structures. The properties of the nonlinear model have been illustrated using 3D, 2D, and contour plots by selecting an appropriate set of parameters, which is demonstrated to visualize the physical structures more productively. Finally, it is concluded that similar strategies can also be implemented to study many contemporary models. To the best of our knowledge, the current work presents a novel case study that has not been previously studied in order to generate several new solutions to the governing model appearing in diverse disciplines. The results show that the strategies that have been employed are more effective and capable than the traditional methods found in previous research. [ABSTRACT FROM AUTHOR]

The mouse model for autism, BTBRT+ Itpr3tf/J (BTBR), has been intensively studied for various biological anomalies at genomic, transcriptomics and proteomics levels. However, complex genomic variations beyond linear differences (i.e., single base pair, or few pairs to several kilo-base pair alterations covering a chromosome) have been undetected, so far. This is largely due to limitations both in sequencing platforms and detection algorithms. However, recent advances have been encouraging in identifying complex genomic structures like tandem repeat variations, and complex inter-chromosomal rearrangements. To further uncover the distinct genetic architecture underlying autism-like phenotypes of this mouse model, we used long-read sequencing and advanced computational pipelines and identified tandem repeats, and rearrangements. We prioritised repeat alleles in 27 disease related genes and nine genomic rearrangements that are unique to the model. To assess impact on several phenotypes related to autism, we also predicted potential disrupting contributions of these alleles on the biological features, like protein structure integrity, genome 3D-folding, transcript splicing sites, enhancers of nearby other genes. Overall, we identified novel alleles that underpin the complex nature of genomic variations which could, together, govern autism related traits within BTBR.

Objective: This study aimed to investigate the status of antimicrobial‐resistant strains of Staphylococcus aureus in Pakistan, their association in terms of co‐occurrence with the biofilm‐forming genes, resistance profiling and associated discrepancies in diagnostic methods. Methodology: A total of 384 milk samples from bovine was collected by using convenient sampling technique and were initially screened for subclinical mastitis, further preceded by isolation and confirmation of S. aureus. The S. aureus isolates were subjected to evaluation of antimicrobial resistance by phenotypic identification using Kirby–Bauer disc diffusion method, while the genotypic estimation was done by polymerase chain reaction to declare isolates as methicillin, beta‐lactam, vancomycin, tetracycline, and aminoglycoside resistant S. aureus (MRSA, BRSA, VRSA, TRSA, and ARSA), respectively. Results: The current study revealed an overall prevalence of subclinical mastitis and S. aureus to be 59.11% and 46.69%, respectively. On a phenotypic basis, the prevalence of MRSA, BRSA, VRSA, TRSA, and ARSA was found to be 44.33%, 58.49%, 20.75%, 35.84%, and 30.18%, respectively. The results of PCR analysis showed that 46.80% of the tested isolates were declared as MRSA, 37.09% as BRSA, and 36.36% as VRSA, while the occurrence of TRSA and ARSA was observed in 26.31% and 18.75%, respectively. The current study also reported the existence of biofilm‐producing genes (icaA and icaD) in 49.06% and 40.57% isolates, respectively. Lastly, this study also reported a high incidence of discrepancies for both genotypic and phenotypic identification methods of resistance evaluation, with the highest discrepancy ratio for the accA‐aphD gene, followed by tetK, vanB, blaZ, and mecA genes. Conclusion: The study concluded that different antibiotic resistance strains of S. aureus are prevalent in study districts with high potential to transmit between human populations. The study also determined that there are multiple resistance determinants and mechanisms that are responsible for the silencing and expression of antibiotic resistance genes. [ABSTRACT FROM AUTHOR]

In October 2020, 62 scientists from nine nations worked together remotely in the Second Baylor College of Medicine & DNAnexus hackathon, focusing on different related topics on Structural Variation, Pan-genomes, and SARS-CoV-2 related research. The overarching focus was to assess the current status of the field and identify the remaining challenges. Furthermore, how to combine the strengths of the different interests to drive research and method development forward. Over the four days, eight groups each designed and developed new open-source methods to improve the identification and analysis of variations among species, including humans and SARS-CoV-2. These included improvements in SV calling, genotyping, annotations and filtering. Together with advancements in benchmarking existing methods. Furthermore, groups focused on the diversity of SARS-CoV-2. Daily discussion summary and methods are available publicly at https://github.com/collaborativebioinformatics provides valuable insights for both participants and the research community.