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Supplementary Table 1. Crystallographic Data and Refinement statistics. Supplementary Table 2. Comparing Target Inhibition by Quizartinib and PLX3397 in Engineered Ba/F3 cells Expressing FLT3-ITD, FLT3-ITD/F691L and FLT3-ITD/D835Y. Supplementary Table 3. Inhibitory Concentration (IC50) for Proliferation of Human Leukemia Cell Lines in PLX3397. Supplementary Table 4. 48 Hour Inhibitory Concentration (IC50) for Proliferation of Ba/F3 Cells Expressing Quizartinib and PLX3397-Resistant FLT3-ITD Mutant Isoforms. Supplementary Table 5. Patient Characteristics. Supplementary Table 6. Low Frequency FLT3 Kinase Domain Mutations of Uncertain Significance Observed at the Time of Resistance in Patient 1.14. Supplementary Figure 1. Composite omit map contoured at 1sigma level for the bound quizartinib and a structural water molecule. Supplementary Figure 2. Comparing the actual and previously predicted binding modes of quizartinib. Supplementary Figure 3. Structural model showing that D835 induces the DFG-in conformation of the activation loop, resulting in an orientation of F830 that precludes quizartinib binding. Supplementary Figure 4. Structural superposition of quizartinib (green) and PLX3397 (orange) highlighting the key structural difference responsible for their different susceptibilities to L691. Supplementary Figure 5. PLX3397 Inhibits FLT3 Signaling In Vitro. Supplementary Figure 6. Molm14 F691L Cells Demonstrate Resistance to Quizartinib. Supplementary Figure 7. Activity of PLX3397Against Quizartinib Resistance-Causing FLT3-ITD Kinase Domain Mutations.

Biological age, distinct from an individual’s chronological age, has been studied extensively through predictive aging clocks. However, these clocks have limited accuracy in short time-scales. Here we trained deep learning models on fundus images from the EyePACS dataset to predict individuals’ chronological age. Our retinal aging clocking, ‘eyeAge’, predicted chronological age more accurately than other aging clocks (mean absolute error of 2.86 and 3.30 years on quality-filtered data from EyePACS and UK Biobank, respectively). Additionally, eyeAge was independent of blood marker-based measures of biological age, maintaining an all-cause mortality hazard ratio of 1.026 even when adjusted for phenotypic age. The individual-specific nature of eyeAge was reinforced via multiple GWAS hits in the UK Biobank cohort. The top GWAS locus was further validated via knockdown of the fly homolog, Alk, which slowed age-related decline in vision in flies. This study demonstrates the potential utility of a retinal aging clock for studying aging and age-related diseases and quantitatively measuring aging on very short time-scales, opening avenues for quick and actionable evaluation of gero-protective therapeutics.

Background: Uncomplicated type B aortic dissection (un-TBAD) has been managed conservatively with medical therapy in order to control the heart rate and blood pressure to limit disease progression, in addition to radiological follow-up. However, several trials and observational studies have investigated the use of thoracic endovascular aortic repair (TEVAR) in un-TBAD and suggested that TEVAR provides a survival benefit over medical therapy. Outcomes of TEVAR have also been linked with the timing of intervention. Aims: The scope of this review is to collate and summarise all the evidence in the literature on the mid- and long-term outcomes of TEVAR in un-TBAD, confirming its superiority. We also aimed to investigate the relationship between timing of TEVAR intervention and results. Methods: We carried out a comprehensive literature search on multiple electronic databases including PubMed, Scopus and EMBASE in order to collate and summarise all research evidence on the mid- and long-term outcomes of TEVAR in un-TBAD, as well as its relationship with intervention timing. Results: TEVAR has proven to be a safe and effective tool in un-TBAD, offering superior mid- and long-term outcomes including all-cause and aorta-related mortality, aortic-specific adverse events, aortic remodelling, and need for reintervention. Additionally, performing TEVAR during the subacute phase of dissection seems to yield optimal results. Conclusion: The evidence demonstrating a survival advantage in favour TEVAR over medical therapy in un-TBAD means that with further research, particular trials and observational studies, TEVAR could become the gold-standard treatment option for un-TBAD patients.

Background Event-based surveillance (EBS) is an essential component of Early Warning Alert and Response (EWAR) as per the International Health Regulations (IHR), 2005. EBS was established in Sudan in 2016 as a complementary system for Indicator-based surveillance (IBS). This review will provide an overview of the current EBS structure, functions and performance in Sudan and identify the gaps and ways forward. Methods The review followed the WHO/EMRO guidelines and tools. Structured discussions, observation and review of records and guidelines were done at national and state levels. Community volunteers were interviewed through phone calls. Directors of Health Emergency and Epidemic Control, surveillance officers and focal persons for EBS at the state level were also interviewed. SPSS software was used to perform descriptive statistical analysis for quantitative data, while qualitative data was analysed manually using thematic analysis, paying particular attention to the health system level allowing for an exploration of how and why experiences differ across levels. Written and verbal consents were obtained from all participants as appropriate. Results Sudan has a functioning EBS; however, there is an underestimation of its contribution and importance at the national and states levels. The link between the national level and states is ad hoc or is driven by the need for reports. While community event-based surveillance (CEBS) is functioning, EBS from health facilities and from non-health sectors is not currently active. The integration of EBS into overall surveillance was not addressed, and the pathway from detection to action is not clear. The use of electronic databases and platforms is generally limited. Factors that would improve performance include training, presence of a trained focal person at state level, and regular follow-up from the national level. Factors such as staff turnover, income in relation to expenses and not having a high academic qualification (Diploma or MSc) were noticed as inhibiting factors. Conclusion The review recommended revisiting the surveillance structure at national and state levels to put EBS as an essential component and to update guidelines and standard operation procedures SOPs to foster the integration between EBS components and the overall surveillance system. The need for strengthening the link with states, capacity building and re-addressing the training modalities was highlighted.

Background: Vitamin A supplementation is one of the robust interventions for vitamin A deficiency in developing and middle-income countries. However, despite the rollout of VAS over the last three decades, the uptake of vitamin A supplements in some countries including Somalia is still significantly low. There is therefore a need to understand the deterrent of the VAS program. Materials and Methods: The study employed a cross-sectional study design which aided in understanding the factors influencing VAS. Data were collected by research assistants using a semi-structured questionnaire from 324 caregivers. Data were analyzed using SPSS version 20 at a 95% confidence interval. The data were subjected to descriptive and regression analysis. All ethical considerations were adhered to in the study. Results: The rate of VAS among children aged 6 to 59 months in Yaqsgid district was significantly low as compared to the WHO recommendation. Socio-demographic factors that were found to significantly influence VAS were the caregiver's marital status, level of education and employment status. Conclusion: The community in Yaqshid district should be sensitized to the importance of educating girls as well as giving women the opportunity to work to improve the VAS rates. Additionally, the Somali government and partners in health should periodic health education for women and amplify the door-to-door supplementation program

Immunoglobulins (IGs), crucial components of the adaptive immune system, are encoded by three genomic loci. However, the complexity of the IG loci severely limits the effective use of short read sequencing, limiting our knowledge of population diversity in these loci. We leveraged existing long read whole-genome sequencing (WGS) data, fosmid technology, and IG targeted single-molecule, real-time (SMRT) long-read sequencing (IG-Cap) to create haplotype-resolved assemblies of the IG Lambda (IGL) locus from 6 ethnically diverse individuals. In addition, we generated 10 diploid assemblies of IGL from a diverse cohort of individuals utilizing IG-cap. From these 16 individuals, we identified significant allelic diversity, including 36 novel IGLV alleles. In addition, we observed highly elevated single nucleotide variation (SNV) in IGLV genes relative to IGL intergenic and genomic background SNV density. By comparing SNV calls between our high quality assemblies and existing short read datasets from the same individuals, we show a high propensity for false-positives in the short read datasets. Finally, for the first time, we nucleotide-resolved common 5–10 Kb duplications in the IGLC region that contain functional IGLJ and IGLC genes. Together these data represent a significant advancement in our understanding of genetic variation and population diversity in the IGL locus.

Biological age, distinct from an individual’s chronological age, has been studied extensively through predictive aging clocks. However, these clocks have limited accuracy in short time-scales. Deep learning approaches on imaging datasets of the eye have proven powerful for a variety of quantitative phenotype inference tasks and provide an opportunity to explore organismal aging and tissue health.Here we trained deep learning models on fundus images from the EyePACS dataset to predict individuals’ chronological age. These predictions led to the concept of a retinal aging clock, “eyeAge”, which we employed for a series of downstream longitudinal analyses. eyeAge was used to predict chronological age on timescales under a year using longitudinal fundus imaging data from a subset of patients. To further validate the model, it was applied to a separate cohort from the UK Biobank. The difference between individuals’ eyeAge and their chronological age, hereafter “eyeAgeAccel”, was computed and used for genome-wide association analysis (GWAS).EyeAge predicted chronological age more accurately than other aging clocks (mean absolute error of 2.86 and 3.30 years on quality-filtered data from EyePACS and UKBiobank, respectively). Additionally, eyeAgeAccel was highly independent of blood marker-based measures of biological age (e.g. “phenotypic age”), maintaining an all-cause mortality hazard ratio of 1.026 even in the presence of phenotypic age. Longitudinal studies showed that the resulting models were able to predict individuals’ aging, in time-scales less than a year, with 71% accuracy. The individual-specific component to this prediction was confirmed with the identification of multiple GWAS hits in the independent UK Biobank cohort. The knockdown of the fly homolog to the top hit, ALKAL2, which was previously shown to extend lifespan in flies, also slowed age-related decline in vision in flies.In conclusion, predicted age from retinal images can be used as a biomarker of biological aging that is independent from assessment based on blood markers. This study demonstrates the potential utility of a retinal aging clock for studying aging and age-related diseases and quantitatively measuring aging on very short time-scales, opening avenues for quick and actionable evaluation of gero-protective therapeutics.

Immunoglobulins (IGs), crucial components of the adaptive immune system, are encoded by three genomic loci. However, the complexity of the IG loci severely limits the effective use of short read sequencing, limiting our knowledge of population diversity in these loci. We leveraged existing long read whole-genome sequencing (WGS) data, fosmid technology, and IG targeted single-molecule, real-time (SMRT) long-read sequencing (IG-Cap) to create haplotype-resolved assemblies of the IG Lambda (IGL) locus from 6 ethnically diverse individuals. In addition, we generated 10 diploid assemblies of IGL from a diverse cohort of individuals utilizing IG-cap. From these 16 individuals, we identified significant allelic diversity, including 37 novel IGLV alleles. In addition, we observed highly elevated single nucleotide variation (SNV) in IGLV genes relative to IGL intergenic and genomic background SNV density. By comparing SNV calls between our high quality assemblies and existing short read datasets from the same individuals, we show a high propensity for false-positives in the short read datasets. Finally, for the first time, we nucleotide-resolved common 5-10 Kb duplications in the IGLC region that contain functional IGLJ and IGLC genes. Together these data represent a significant advancement in our understanding of genetic variation and population diversity in the IGL locus.

Modern experimental technologies can assay large numbers of biological sequences, but engineered protein libraries rarely exceed the sequence diversity of natural protein families. Machine learning (ML) models trained directly on experimental data without biophysical modeling provide one route to accessing the full potential diversity of engineered proteins. Here we apply deep learning to design highly diverse adeno-associated virus 2 (AAV2) capsid protein variants that remain viable for packaging of a DNA payload. Focusing on a 28-amino acid segment, we generated 201,426 variants of the AAV2 wild-type (WT) sequence yielding 110,689 viable engineered capsids, 57,348 of which surpass the average diversity of natural AAV serotype sequences, with 12–29 mutations across this region. Even when trained on limited data, deep neural network models accurately predict capsid viability across diverse variants. This approach unlocks vast areas of functional but previously unreachable sequence space, with many potential applications for the generation of improved viral vectors and protein therapeutics. Viable AAV capsids are designed with a machine learning approach.

This paper presents the design and implementation of unmanned ground vehicle (UGV) using a simple approach. An unmanned ground vehicle is an automobile without any onboard human presence. It is remotely controlled by an operator. It can be used in scenarios where the presence of human operator is inconvenient and dangerous. It is an Arduino and Android application based controlled vehicle. Bluetooth module (HC-06) provides the communication between the vehicle components and Android application. The motion of the vehicle is based on two DC gear motors that are connected to the rear wheels of the vehicle. The vehicle is equipped with the video camera (V380S) and a gun to provide live video stream to the operator and to fire in lethal situations respectively. The developed vehicle shows the possible usage of such prototype in security and military applications.

Background: Acne is a common, irritating chronic skin disease among adolescent age group worldwide. Despite good number of studies discussing and debating his skin condition, still there are serious psychosocial concerns, gap in knowledge and lack of awareness among acne patients. Methods: This is observational, cross sectional, institutional-based study to find out prevalence, awareness and psychological impact of acne among students in Majmaah University, conducted between January-April 2018. Results: The study showed that 56% of the university students had some form of acne. More than three quarter of the participants were less aware and had poor level of knowledge of the disease’s etiology and aggravating factors. 61% of the students had belief that folk medicine contributes positively in acne management. 84.6% of both male and female students responded that acne had obvious negative effects on the life of the affected and there is a social stigma associated with it. Conclusion: Acne is a well-known and prevalent irritating skin disease among Majmaah university students, affecting both sexes. Our study found out very poor level of awareness and knowledge about etiology and associated aggravating factors of acne. Furthermore, strong association of acne with severe psychological impact is also evident among (85.6%) of participants. More comprehensive health education about acne needed to be spread among University students and community, addressing the gap in knowledge, required for proper management of acne and to reduce the negative psychosocial impact of the disease among this age group.

Additional file 1. Appendix 1: Hospitals Covered by Hamad Medical Corporation (HMC) in Qatar. Appendix 2: Antibiotic Susceptibility and D Tests for 196 invasive GBS bacteraemia isolates.

Fossil fuel-based energy systems are mostly used for supplying energy that creates negative impacts on the environment, so in this study, the development of a 100% renewable energy system is evaluated for Pakistan for sustainable climate change. This study modeled three scenarios, namely, ongoing (ONG), energy saving policy (ESP), and green energy policy (GEP) scenarios using low emission analysis platform (LEAP) software for the study period 2022 to 2050 for Pakistan. The results revealed that a 100% renewable energy supply could be achieved through the GEP scenario. Model results show that the share of renewable sources in the total energy mix is 1117.08 TWh and non-renewable sources contribute only 18.12 TWh to meet the energy demand of 966.05 TWh until 2050. Non-renewable production leads to the generation of 8.85 million metric tons of carbon emissions, which is too low compared with the 135.47 million metric tons under the ONG scenario. The USD 1482.46 billion investment cost required for adding renewable energy capacity until 2050 is too high as compared with the USD 46.80 billion under the ONG scenario. Energy demand and production requirements are reduced by 34.18% under the ESP scenario until 2050. This approach can also be applicable to the majority of nations worldwide.

In the present study, cylindrical ABS P400 polymer parts (diameter 6.5 mm) to be used as die-sinking EDM (electric discharge machining) novel electrodes were fabricated using a fused deposition modeling (FDM) process. To meet the conductivity requirement in EDM, ABS parts were metallized using an innovative method that comprised putting aluminum–charcoal (Al–C) on them followed by their copper electroplating. Real-time EDM of the mild steel workpiece was performed using novel electrodes, and machining performance of the electrodes, measured in terms of dimensional accuracy, i.e., change in diameter (ΔD) and change in depth (ΔH) of the cavity, under varying levels of three EDM factors, i.e., current (I), pulse on time (Ton), and pulse off time (Toff), was investigated. Machining results were analyzed using analysis of variance (ANOVA), perturbation graphs, and 3D surface plots. The optimal setting of the EDM parameters for minimizing ΔD and ΔH was determined using the desirability function approach. The suitability of the novel electrodes for EDM was ascertained by comparing their machining results with those of solid copper (SC) electrodes and electrodes fabricated by FDM and metallized using the electro-deposition method (FDM-EM), already reported in the literature, under similar machining conditions. From the results, it was found that ΔD and ΔH were less when EDM was performed using novel electrodes.

Penetrating atherosclerotic ulcers present with an insidious onset with a reported mortality of 9%, varying across populations. With vast arrays of risk factors and potentially ominous complications, it is vital to efficiently provide optimum strategies for management. There exists controversy in the literature regarding management, especially for Type B penetrating atherosclerotic ulcers; the decision-making framework encompasses numerous factors in considerations for medical management versus invasive intervention and choice of endovascular versus open repair in the latter. The concomitant presence of intramural haematoma adds further complexity to the already intricate decision-making for management. We performed searches through PubMed and SCOPUS analysing studies reporting outcomes for management strategies for penetrating atherosclerotic ulcers treatment, focusing on Type B, further seeking to analyse studies reporting their experiences of PAU patients with concomitant intramural haematoma. Our review highlights the ambiguity and controversy existing in the literature, comprising studies burdened by their inherent hindering limitations of their single-centre retrospective experiences. Endovascular therapy has come to the forefront of penetrating atherosclerotic ulcers management, often considered first line therapy. In the case of penetrating atherosclerotic ulcers alongside intramural haematoma, there have been reports of potential hybrid surgical approaches to management. Studies further show misdiagnosis of penetrating atherosclerotic ulcers in earlier data sets further complicates management. However, it is clear we must progress on the journey towards precision medicine, allowing delivery of optimum care to our patients.

The share of wind-based electricity generation is gradually increasing in the world energy market. Wind energy can reduce dependency on fossil fuels, as the result being attributed to a decrease in global warming. This paper discusses and reviews the basic principle parameters that affect the performance of wind turbines. An overview presents the introduction and the background of energy consumption, following the order of the elaboration of wind turbines, including mathematical models, categories of wind turbines were critically discussed. Moreover, it also focuses on materials that are commonly considered for wind turbine manufacturing, and the process used to recycle them. The scale of recycling methods for fiberglass and thermoplastic is presented in the respective section. Various parameters that reduce the function of wind turbines are explained in depth. This review also discusses various environmental impacts of wind turbines. Future research studies are suggested in the conclusion section.

Background: Sepsis is life-threatening and frequently a final common pathway to death for many infectious diseases worldwide and may lead to death if left untreated. The objective is to assess the scientific medical knowledge upon sepsis among House officers and Medical officers in terms of diagnosis and management.Method: An observational cross sectional Hospital-based study was conducted through self-administered retrospective questionnaires based on the objective of the study. We enrolled 155 participants through Convenience sampling. The questionnaire contains parts of validated Sepsis criteria in terms of diagnosis and management. Analysis was done by using SPSS version 20. Data are presenter as frequencies and percentages using figures and tables. P value less than 0.05 considered significant Mann Whitney U test use to compare level of knowledge adherence between trained participants and non-trained participants.Results: The mean knowledge score about sepsis diagnosis was 2.6 out of 10 (SD= 1.8), and about sepsis management was 2.8 out of 8 (SD=1.8) the mean overall score was 5.5 out of 18.No significant difference found between participants who were trained upon diagnosis and management of sepsis and those who were not.Conclusion: Study findings illustrated that the capacity to perceive and manage sepsis among House Officers and Medical Officers doctors is poor and there are dangerous gaps in their investigation and management of such septic patients.

In this article, cadmium oxide (CdO) was deposited using pulsed laser deposition approach on porous silicon (Si) wafer for visible light photodetector application, through which a series of devices were proposed as a function of the deposition energy. The microstructural as well as optical characteristics of the prepared film/s were demonstrated, respectively, using x-ray diffraction (XRD), field emission scanning electron microscopy (FE-SEM), and ultraviolet visible light spectroscopy (UV–Vis) analysis. In details, the UV–Vis analysis revealed the occurrence of optical band gaps within the range of 2.38–2.42eV, while an average nanoparticle diameter was found to be 45nmusing FE-SEM technique. This in turn demonstrated a sound relation with the photoresponsive behavior of the attained photodetectors. A photoresponsivity and specific detectivity of 1.9μAmW−1and1.21×109Jones were attained using 700mJlaser energy. In the meanwhile, the estimated response/recover time of the addressed laser energy was found to be 300sand 340s, respectively. The photo-responsive characteristics of the fabricated devices were found to be in positive linear correlation with the applied laser energy.

This paper focuses on the design and development of a reconfigurable three-degree-of-freedom articulated robot for conducting pick-and-place tasks. To implement the system, an Android platform for the manual control of an articulated robot using wireless Bluetooth technology was developed. This application allows the user to manually reconfigure the robot following the requirements of the integrated system via a user-friendly display. The articulated robot comprises four motors, three of which are used for positioning and orientation and finally used to carry out the pick-and-place task. An Arduino Un R3 board is used to control the movement of the links via a pulse width modulation method. We introduce a set of conveniently composed kinematic and dynamic mathematical models for positioning the robot’s arms and, in our results and discussion section, calculate and report the torque required to move each joint.

Background Structural variants (SVs) play a causal role in numerous diseases but are difficult to detect and accurately genotype (determine zygosity) in whole-genome next-generation sequencing data. SV genotypers that assume that the aligned sequencing data uniformly reflect the underlying SV or use existing SV call sets as training data can only partially account for variant and sample-specific biases. Results We introduce NPSV, a machine learning–based approach for genotyping previously discovered SVs that uses next-generation sequencing simulation to model the combined effects of the genomic region, sequencer, and alignment pipeline on the observed SV evidence. We evaluate NPSV alongside existing SV genotypers on multiple benchmark call sets. We show that NPSV consistently achieves or exceeds state-of-the-art genotyping accuracy across SV call sets, samples, and variant types. NPSV can specifically identify putative de novo SVs in a trio context and is robust to offset SV breakpoints. Conclusions Growing SV databases and the increasing availability of SV calls from long-read sequencing make stand-alone genotyping of previously identified SVs an increasingly important component of genome analyses. By treating potential biases as a “black box” that can be simulated, NPSV provides a framework for accurately genotyping a broad range of SVs in both targeted and genome-scale applications.

An incomplete ascertainment of genetic variation within the highly polymorphic immunoglobulin heavy chain locus (IGH) has hindered our ability to define genetic factors that influence antibody-mediated processes. Due to locus complexity, standard high-throughput approaches have failed to accurately and comprehensively capture IGH polymorphism. As a result, the locus has only been fully characterized two times, severely limiting our knowledge of human IGH diversity. Here, we combine targeted long-read sequencing with a novel bioinformatics tool, IGenotyper, to fully characterize IGH variation in a haplotype-specific manner. We apply this approach to eight human samples, including a haploid cell line and two mother-father-child trios, and demonstrate the ability to generate high-quality assemblies (>98% complete and >99% accurate), genotypes, and gene annotations, identifying 2 novel structural variants and 15 novel IGH alleles. We show multiplexing allows for scaling of the approach without impacting data quality, and that our genotype call sets are more accurate than short-read (>35% increase in true positives and >97% decrease in false-positives) and array/imputation-based datasets. This framework establishes a desperately needed foundation for leveraging IG genomic data to study population-level variation in antibody-mediated immunity, critical for bettering our understanding of disease risk, and responses to vaccines and therapeutics.

Modern experimental technologies can assay large numbers of biological sequences, but engineered protein libraries rarely exceed the sequence diversity of natural protein families. Machine learning (ML) models trained directly on experimental data without biophysical modeling provide one route to accessing the full potential diversity of engineered proteins. Here we apply deep learning to design highly diverse adeno-associated virus 2 (AAV2) capsid protein variants that remain viable for packaging of a DNA payload. Focusing on a 28-amino acid segment, we generated 201,426 variants of the AAV2 wild-type (WT) sequence yielding 110,689 viable engineered capsids, 57,348 of which surpass the average diversity of natural AAV serotype sequences, with 12-29 mutations across this region. Even when trained on limited data, deep neural network models accurately predict capsid viability across diverse variants. This approach unlocks vast areas of functional but previously unreachable sequence space, with many potential applications for the generation of improved viral vectors and protein therapeutics.

New technologies and analysis methods are enabling genomic structural variants (SVs) to be detected with ever-increasing accuracy, resolution and comprehensiveness. To help translate these methods to routine research and clinical practice, we developed a sequence-resolved benchmark set for identification of both false-negative and false-positive germline large insertions and deletions. To create this benchmark for a broadly consented son in a Personal Genome Project trio with broadly available cells and DNA, the Genome in a Bottle Consortium integrated 19 sequence-resolved variant calling methods from diverse technologies. The final benchmark set contains 12,745 isolated, sequence-resolved insertion (7,281) and deletion (5,464) calls ≥50 base pairs (bp). The Tier 1 benchmark regions, for which any extra calls are putative false positives, cover 2.51 Gbp and 5,262 insertions and 4,095 deletions supported by ≥1 diploid assembly. We demonstrate that the benchmark set reliably identifies false negatives and false positives in high-quality SV callsets from short-, linked- and long-read sequencing and optical mapping.

Summary We demonstrate early progress toward constructing a high-throughput, single-molecule protein sequencing technology utilizing barcoded DNA aptamers (binders) to recognize terminal amino acids of peptides (targets) tethered on a next-generation sequencing chip. DNA binders deposit unique, amino acid-identifying barcodes on the chip. The end goal is that, over multiple binding cycles, a sequential chain of DNA barcodes will identify the amino acid sequence of a peptide. Toward this, we demonstrate successful target identification with two sets of target-binder pairs: DNA-DNA and Peptide-Protein. For DNA-DNA binding, we show assembly and sequencing of DNA barcodes over six consecutive binding cycles. Intriguingly, our computational simulation predicts that a small set of semi-selective DNA binders offers significant coverage of the human proteome. Toward this end, we introduce a binder discovery pipeline that ultimately could merge with the chip assay into a technology called ProtSeq, for future high-throughput, single-molecule protein sequencing., Graphical abstract, Highlights • Designed ProtSeq protein sequencing method compatible with widely used NGS technology • Built Target-Switch SELEX to isolate aptamers specific to N-terminal amino acids (AAs) • Showed binding, ligation, cleavage, and NGS of six DNA binders in ordered barcode chain • Developed pipeline to deconvolve AAs from DNA barcodes to identify putative proteins, Biochemistry; Biochemistry applications; Sequence analysis; Proteomics; Transcriptomics

Whole-genome sequencing (WGS) of Staphylococcus aureus is increasingly used as part of infection prevention practices. In this study, we established a long-read technology-based WGS screening program of all first-episode methicillin-resistant Staphylococcus aureus (MRSA) blood infections at a major urban hospital., Whole-genome sequencing (WGS) of Staphylococcus aureus is increasingly used as part of infection prevention practices. In this study, we established a long-read technology-based WGS screening program of all first-episode methicillin-resistant Staphylococcus aureus (MRSA) blood infections at a major urban hospital. A survey of 132 MRSA genomes assembled from long reads enabled detailed characterization of an outbreak lasting several months of a CC5/ST105/USA100 clone among 18 infants in a neonatal intensive care unit (NICU). Available hospital-wide genome surveillance data traced the origins of the outbreak to three patients admitted to adult wards during a 4-month period preceding the NICU outbreak. The pattern of changes among complete outbreak genomes provided full spatiotemporal resolution of its progression, which was characterized by multiple subtransmissions and likely precipitated by equipment sharing between adults and infants. Compared to other hospital strains, the outbreak strain carried distinct mutations and accessory genetic elements that impacted genes with roles in metabolism, resistance, and persistence. This included a DNA recognition domain recombination in the hsdS gene of a type I restriction modification system that altered DNA methylation. Transcriptome sequencing (RNA-Seq) profiling showed that the (epi)genetic changes in the outbreak clone attenuated agr gene expression and upregulated genes involved in stress response and biofilm formation. Overall, our findings demonstrate the utility of long-read sequencing for hospital surveillance and for characterizing accessory genomic elements that may impact MRSA virulence and persistence.

The aim of the current study was to synthesize polyvinyl alcohol Cuprous Oxide composite films (PVA/Cu2O) for radiation detection depending on optical changes. The method adapted from solving of 5% PVA in hot (80 °C) stirred water and after cooling to ambient temperature a 0.5 g of Cu2O dissolved and stirred for 2 h. The films were made by casting in petri dishes contained 20 ml/each. The pealed films were enveloped after drying and receiving radiation doses of 1, 2, 4, 6 … 12 Gy. The analysis revealed a gradient change in color of films from light pink to dark brown with absorption peaks at 215 and 415 nm through entire doses which were increase as dose increment. The optical density of films increases linearly and significantly (R2 = 0.9) as the dose increases from 0.06 (arb. unit) at 1 Gy to 0.4 (a u) at 12 Gy with sensitivity at 0.06 mGy. The energy band gap of the film decreased as the radiation dose increases from 3 × 10−12 to 2 × 10−12 eV. Conclusively; the feasibility of utilizing PVA/Cu2O composite films as radiation detector and personal dosimeter would be applicable in rural sectors and low economic countries. Keywords: PVA, Films, Dosimeters, Cuprous, Radiation, Optical

Nanostructured Ni doped Bi2S3 (Bi2−xNixS3, 0 ≤ x ≤ 0.07) is explored as a candidate for telluride free thermoelectric material, through a combination process of mechanical alloying with subsequent consolidation by cold pressing followed with a sintering process. The cold pressing method was found to impact the thermoelectric properties in two ways: (1) introduction of the dopant atom in the interstitial sites of the crystal lattice which results in an increase in carrier concentration, and (2) introduction of a porous structure which reduces the thermal conductivity. The electrical resistivity of Bi2S3 was decreased by adding Ni atoms, which shows a minimum value of 2.35 × 10−3 Ω m at 300 °C for Bi1.99Ni0.01S3 sample. The presence of porous structures gives a significant effect on reduction of thermal conductivity, by a reduction of ~ 59.6% compared to a high density Bi2S3. The thermal conductivity of Bi2−xNixS3 ranges from 0.31 to 0.52 W/m K in the temperature range of 27 °C (RT) to 300 °C with the lowest κ values of Bi2S3 compared to the previous works. A maximum ZT value of 0.13 at 300 °C was achieved for Bi1.99Ni0.01S3 sample, which is about 2.6 times higher than (0.05) of Bi2S3 sample. This work show an optimization pathway to improve thermoelectric performance of Bi2S3 through Ni doping and introduction of porosity.

In this work, we investigate the effects of Ni doping on the thermoelectric (TE) properties of Yb0.25Co4Sb12 sample. Yb0.25Co4-xNixSb12 (0 ≤ x ≤ 0.5) samples were prepared by mechanical alloying and subsequently consolidated by spark plasma sintering. The morphology of consolidated samples were characterized by X-ray diffraction (XRD) and scanning electron microscopy and energy-dispersive X-ray spectroscopy (SEM-EDS). The thermoelectric properties of bulk samples were measured from room temperature to 800 K. The XRD analysis confirmed that, the successful formation of the Co4Sb12 skutterudite phase and Ni is substituted into Co site of the skutterudite crystal lattice. Moreover, the electrical resistivity decreased to 14.6 μΩm at 785 K for Yb0.25Co3.5Ni0.5Sb12 sample, due to increase of the electron concentration by Ni-addition. The absolute Seebeck coefficient reached the highest value of 223 μV/K at 592 K for Yb0.25Co3.7Ni0.3Sb12 sample, thus yielding a maximum value of power factor of 2.41 × 10-3 W/mK2 at 592 K. The highest dimensionless thermoelectric figure of merit value ZT of 0.49 at 692 K has been achieved for the Yb0.25Co3.7Ni0.3Sb12 sample, compared to ZT=0.06 for the Yb0.25Co4Sb12 sample at same temperature. This work indicates a strategy to improve the thermoelectric performance by Ni substitution of Co sites in the Yb0.25Co4Sb12 skutterudite through simultaneous improvement of its electrical conductivity, Seebeck coefficient and reduction of its thermal conductivity.

The contribution of In addition to the La0.5Co4Sb12 skutterudite structure to improve its thermoelectric properties has been demonstrated. In x La0.5Co4Sb12 (0 ≤ x ≤ 0.3) samples were prepared through mechanical alloying followed by spark plasma sintering. Characterization of the phase structure and morphology of the sintered In x La0.5Co4Sb12 bulk samples was carried out using x-ray diffraction (XRD) analysis, scanning electron microscopy, and energy-dispersive x-ray spectroscopy. Rietveld analysis of the XRD spectra indicated that double filling at the 2a (000) interstitial site with La and In was successfully achieved, significantly improving the thermoelectric performance of the La0.5Co4Sb12 compound through simultaneous increase in the electrical conductivity and Seebeck coefficient. A maximum power factor of 3.39 × 10−3 W/ m-K2 was recorded at 644 K for the In0.3La0.5Co4Sb12 sample, more than 96% of that of the La0.5Co4Sb12 sample. Double filling also effectively reduced the lattice thermal conductivity by about 46%, thus demonstrating that the overall improvement in ZT was primarily due to the reduced thermal conductivity. A maximum ZT value of 1.15 was achieved at 692 K for In0.3La0.5Co4Sb12.

Developments in the design of wind turbines with augmentation are advancing around the globe with the goal of generating electricity close to the user in built-up areas. This is certain to help lessen the power generation load as well as distribution and transmission network costs by reducing the distance between the user and the power source. The main objectives driving the development and advancement of vertical-axis wind turbines are increasing the power coefficient and the torque coefficient by optimizing the upstream wind striking on the rotor blades. Unlike horizontal-axis wind turbines, vertical axis turbines generate not only positive torque but also negative torque during operation. The negative torque generated by the returning blade is a key issue for vertical-axis wind turbines (VAWTs) that is counterproductive. Installation of wind deflectors for flow augmentation helps to reduce the negative torque generated by the returning blades as well as enhance the positive torque by creating a diversion in the upstream wind towards the forwarding blade during operation. This paper reviews various designs, experiments, and CFD simulations of wind deflectors reported to date. Optimization techniques for VAWTs incorporating wind deflectors are discussed in detail. The main focus of the review was on the installation position and orientation of the deflectors and their potential contribution to increasing the power coefficient. Topics for future study are suggested in the conclusion section of the paper.

ZnO/ZnAl2O4 nanocomposites (Z r A-MMO) with homogeneously distributed ZnAl2O4 nanoparticles in the interpenetrating network of ZnO were successfully prepared via two-step solution process, namely co-precipitation of Zn/Al–NO3 layered double hydroxide (Z r A-LDH) precursor and thermal treatment methods. The effect of cation molar ratio (r) between Zn2+ and Al3+ on the morphological, structural, thermal, optical as well as electrical properties of ZnO-based MMOs was investigated in detail. A mechanism study related to the surface modification, optical band edge alteration as well as improvement of electrical conductivity after phase transformation from LDH to MMO was also elucidated. The optimum Z5A-MMO sample presents the highest electrical conductivity of 8.23 × 10−3 S/cm as compared to 7.26 × 10−7 S/cm for the standard ZnO nanocrystal. It is believed that the bathochromic shift in optical band gap of Z5A-MMO plays a pivotal role in facilitating the photoemission process and leads to the increase in number of carrier concentration in the sample. This method could provide alternative pathways for fabricating a high electrical conductivity MMO-based material and benefit in future optoelectronic devices.

In this work, the effects of Te doping on the microstructure and thermoelectric properties of the partially filled skutterudite La0.5Co4Sb12 compounds have been examined. La0.5Co4Sb12−x Te x skutterudite compounds were synthesized by a combination of the mechanical alloying technique and spark plasma sintering processing, which resulted in partial substitution of Te atoms in Sb sites. The XRD results showed that all the Te-doped bulk samples were composed of a major phase of the Co4Sb12 skutterudite with a small amount of CoSb2 and Sb as the secondary phases. Thermoelectric measurements of the consolidated samples were examined in a temperature range of 300 K to 800 K (27 °C to 527 °C). With the La0.5Co4Sb11.7Te0.3 sample, the highest absolute Seebeck coefficient of 300 μV/K was obtained at 404 K (131 °C) and the lowest lattice thermal conductivity of 2 W/mK was achieved at 501 K (228 °C). Moreover, the minimum electrical resistivity of 19.7 μΩm was recorded at 501 K (228 °C) for La0.5Co4Sb11.5Te0.5 sample. The effect of the secondary phases was negligible for the electrical resistivity, and between 0.5 to 1.6 pct for the thermal conductivity. Thus, the highest figure of merit, ZT = 0.47, was obtained at 792 K (519 °C) for La0.5Co4Sb11.5Te0.5 sample due to a significant reduction in electrical resistivity and a moderate increase in the absolute Seebeck coefficient.

In this work, a skutterudite-based compound, Yb0.25Co4Sb12, added with Al x (x = 0, 0.1, 0.2, 0.3) was synthesized with a simple mechanical alloying technique followed by spark plasma sintering. The microstructural properties and thermoelectric properties of the as-sintered samples were investigated. The Al atoms formed AlSb nano-inclusions in the grain boundaries instead of entering the Sb-icosahedral voids, introducing point defects in the matrix lattice. By scattering low-energy electrons, the grain boundaries acted as a potential barrier in simultaneously attaining low electrical resistivity and high Seebeck coefficient. Therefore, Al0.1Yb0.25Co4Sb12 exhibited a high power factor of 4.8 × 10−3 W/m K2 at 377 °C. AlSb of nanometer length enhanced interfacial phonon scattering, thereby significantly reducing the lattice thermal conductivity of Al0.3Yb0.25Co4Sb12 to 0.6 W/m K at 500 K. The Al0.3Yb0.25Co4Sb12 composite exhibited the highest figure of merit, ZT = 1.36, at 850 K.

A third of the world’s population is latently infected with TB with an increased risk of developing active TB. Household contacts (HHCs) of pulmonary TB cases are at a greater risk of developing disease. Early identification and treatment of latent TB infected individuals may reduce progression to active TB. This study aimed to determine latent TB infections (LTBI) point prevalence among HHCs and community contacts (CCs) using Tuberculin Skin Test (TST) and whole blood IFN-γ release assay in an area of high TB prevalence. In a prospective, longitudinal and community-based study and following informed consent, 768 volunteers (HHCs n = 245; CCs n = 523) were enrolled. Tuberculin Skin Test (TST), whole blood stimulation with PPD and IFN-γ levels determination using ELISA were performed. Mean ages of HHCs and the CCs were not significantly different (HHCs 35.6 ± 15.7 and CCs 30.6 ± 11.7 years; p = 0.99), with a Male:Female ratio of 1:2. Mean recruitment TST indurations were 4.6 ± 5.5 mm and 2.8 ± 3 mm for HHCs and CCs respectively (p = 0.000). Follow-up (Day 614) mean TST indurations increased significantly to 9.1 ± 7.2 mm and 4.4 ± 3.2 mm for HHCs and CCs respectively (p = 0.001). Using TST indurations ≥ 10 mm, LTBI point prevalence for HHCs and CCs was significantly different (HHCs 461/1000 and 367/1000 individuals, p = 0.03). The mean IFN-γ levels for HHCs and CCs at recruitment day (Day 0) were 0.66 ± 0.17 IU/ml and 0.06 ± 0.04 respectively. The mean of IFN-γ production levels dropped significantly at Day 614 for HHCs and CCs to 0.66 ± 0.15 IU/ml and 0.02 ± 0.02 respectively (p = 0.03) (p = 0.00001). Recruitment LTBI point prevalence using IFN-γ level ≥ 0.35 IU/ml for HHCs and CCs was 440/1000 and 203/1000 respectively (p = 0.000000001). No correlations between TST indurations and IFN-γ levels were detected among HHCs or CCs (p > 0.05). TST is a simple, efficient and cheap technique for LTBI diagnosis and triaging individuals for treatment.

The objective of this dissertation is to explore the meanings of knowledge as understood\ud by senior medical staff in the UK’s National Health Service. It asks the question: 'What\ud does it mean to know something?' The assumption is that an exploration of these meanings\ud will help in designing systems to manage such knowledge. This is because the meaning\ud of knowledge in the literature is contested and the models for its management are\ud extremely variable, to the extent that it is proving challenging to establish knowledge\ud management as an academic discipline or credible business tool. Twelve in-depth\ud interviews were completed and analysed using a constructivist grounded theory approach.\ud Six main categories were constructed. These are: finding motivating factors to pursue\ud knowledge; interacting with knowledge sources; undergoing a process of knowledge\ud acquisition; practising skills; seeking peers’ views; and, finally, building confidence as\ud knowledge. Confidence was selected as the core category and the backbone of the\ud constructed theory. The constructed theory argues that confidence is an important, integral\ud aspect of our knowledge. One knows something if one thinks confidently that one knows\ud it. Someone who understands a subject very well but lacks confidence simply does not\ud know that subject. On the other hand, people can be overconfident or possess completely\ud unjustified, misplaced confidence in situations where they lack understanding or ability.\ud According to the emergent theory, these individuals are still knowledgeable, albeit in an\ud incorrect or negative way. The emergent theory provides a new understanding of the\ud concept of knowledge: knowledge as a type of emotion, i.e. confidence. This differs from\ud the current understanding of knowledge, which views it as either objective information that\ud requires cognitive processing or as human behaviour that influences practice. According\ud to the emergent theory, knowledge is not necessarily a logical mental process nor\ud purposeful human behaviour, but a fallible emotion, which can be harder to measure,\ud observe or control than the two former phenomena. Confidence is an essential feature of\ud knowledge and this thesis concludes by proposing a tool for confidence management\ud within the NHS.

New technologies and analysis methods are enabling genomic structural variants (SVs) to be detected with ever-increasing accuracy, resolution, and comprehensiveness. To help translate these methods to routine research and clinical practice, we developed the first sequence-resolved benchmark set for identification of both false negative and false positive germline large insertions and deletions. To create this benchmark for a broadly consented son in a Personal Genome Project trio with broadly available cells and DNA, the Genome in a Bottle (GIAB) Consortium integrated 19 sequence-resolved variant calling methods from diverse technologies. The final benchmark set contains 12745 isolated, sequence-resolved insertion (7281) and deletion (5464) calls ≥50 base pairs (bp). The Tier 1 benchmark regions, for which any extra calls are putative false positives, cover 2.51 Gbp and 5262 insertions and 4095 deletions supported by ≥1 diploid assembly. We demonstrate the benchmark set reliably identifies false negatives and false positives in high-quality SV callsets from short-, linked-, and long-read sequencing and optical mapping.

New technologies and analysis methods are enabling genomic structural variants (SVs) to be detected with ever-increasing accuracy, resolution, and comprehensiveness. Translating these methods to routine research and clinical practice requires robust benchmark sets. We developed the first benchmark set for identification of both false negative and false positive germline SVs, which complements recent efforts emphasizing increasingly comprehensive characterization of SVs. To create this benchmark for a broadly consented son in a Personal Genome Project trio with broadly available cells and DNA, the Genome in a Bottle (GIAB) Consortium integrated 19 sequence-resolved variant calling methods, both alignment- and de novo assembly-based, from short-, linked-, and long-read sequencing, as well as optical and electronic mapping. The final benchmark set contains 12745 isolated, sequence-resolved insertion and deletion calls ≥50 base pairs (bp) discovered by at least 2 technologies or 5 callsets, genotyped as heterozygous or homozygous variants by long reads. The Tier 1 benchmark regions, for which any extra calls are putative false positives, cover 2.66 Gbp and 9641 SVs supported by at least one diploid assembly. Support for SVs was assessed using svviz with short-, linked-, and long-read sequence data. In general, there was strong support from multiple technologies for the benchmark SVs, with 90% of the Tier 1 SVs having support in reads from more than one technology. The Mendelian genotype error rate was 0.3%, and genotype concordance with manual curation was >98.7%. We demonstrate the utility of the benchmark set by showing it reliably identifies both false negatives and false positives in high-quality SV callsets from short-, linked-, and long-read sequencing and optical mapping. GIAB is working towards a new version of the benchmark set that will use new technologies and methods such as PacBio Circular Consensus Sequencing and ultralong Oxford Nanopore sequencing to expand to more challenging genome regions and include more challenging SVs such as inversions. We are also developing a robust integration process to make calls on GRCh37 and GRCh38 for all seven GIAB samples.

The incomplete identification of structural variants (SVs) from whole-genome sequencing data limits studies of human genetic diversity and disease association. Here, we apply a suite of long-read, short-read, strand-specific sequencing technologies, optical mapping, and variant discovery algorithms to comprehensively analyze three trios to define the full spectrum of human genetic variation in a haplotype-resolved manner. We identify 818,054 indel variants (, Structural variants (SVs) in human genomes contribute diversity and diseases. Here, the authors use a multi-platform strategy to generate haplotype-resolved SVs for three human parent–child trios.

Summary While next-generation sequencing (NGS) has dramatically increased the availability of genomic data, phased genome assembly and structural variant (SV) analyses are limited by NGS read lengths. Long-read sequencing from Pacific Biosciences and NGS barcoding from 10x Genomics hold the potential for far more comprehensive views of individual genomes. Here, we present MsPAC, a tool that combines both technologies to partition reads, assemble haplotypes (via existing software) and convert assemblies into high-quality, phased SV predictions. MsPAC represents a framework for haplotype-resolved SV calls that moves one step closer to fully resolved, diploid genomes. Availability and implementation https://github.com/oscarlr/MsPAC. Supplementary information Supplementary data are available at Bioinformatics online.

Denote[n]=(1,2,..., n ) to be finite n -chain, where is a natural number. Let P n and T n denote the semigroups of partial and full transformations of [ n ], respectively. Let CP n =(α ∈ P n :|xα-yα|≤|x-y|∀x,y ∈ Dom α) and CT n = (α ∈ T n :|xα-yα|≤|x-y| ∀x,y ∈ [n], then CP n and CT n are known to be subsemigroup of Pn and Tn, respectively. The algebraic properties of these semigroup have been investigated, however the combinatorial properties are yet to be investigated. In this paper, combinatorial problems (or questions) of these subsemigroups where explored. Let DCP n =(α ∈ DP n : |xα - yα|≤|x-y|∀x,y ∈ Dom α) and DCTn = (α ∈ DT n : |xα - yα|≤|x-y|∀x,y ∈ [n]) (where DP n and DT n are the semigroup of order decreasing partial and full transformations, respectively. ) Then DCP n and DCT n are known to be the semigroup of order decreasing partial and full contractions, respectively. In this paper we give a necessary and sufficient conditions for an element to be regular for the semigroups DCP n and DCT n Keywords : Transformation semigroup, Contractions, Number of fixed point, equivalences

Whole-genome sequencing (WGS) of Staphylococcus aureus is increasingly used as part of infection prevention practices, but most applications are focused on conserved core genomic regions due to limitations of short-read technologies. In this study we established a long-read technology-based WGS screening program of all first-episode MRSA blood infections at a major urban hospital. A survey of 132 MRSA genomes assembled from long reads revealed widespread gain/loss of accessory mobile genetic elements among established hospital- and community-associated lineages impacting >10% of each genome, and frequent megabase-scale inversions between endogenous prophages. We also characterized an outbreak of a CC5/ST105/USA100 clone among 3 adults and 18 infants in a neonatal intensive care unit (NICU) lasting 7 months. The pattern of changes among complete outbreak genomes provided full spatiotemporal resolution of its origins and progression, which was characterized by multiple sub-transmissions and likely precipitated by equipment sharing. Compared to other hospital strains, the outbreak strain carried distinct mutations and accessory genetic elements that impacted genes with roles in metabolism, resistance and persistence. This included a DNA-recognition domain recombination in the hsdS gene of a Type-I restriction-modification system that altered DNA methylation. RNA-Seq profiling showed that the (epi)genetic changes in the outbreak clone attenuated agr gene expression and upregulated genes involved in stress response and biofilm formation. Overall our findings demonstrate that long-read sequencing substantially improves our ability to characterize accessory genomic elements that impact MRSA virulence and persistence, and provides valuable information for infection control efforts.