A survey of k-mer methods and applications in bioinformatics.

The rapid progression of genomics and proteomics has been driven by the advent of advanced sequencing technologies, large, diverse, and readily available omics datasets, and the evolution of computational data processing capabilities. The vast amount of data generated by these advancements necessitates efficient algorithms to extract meaningful information. K-mers serve as a valuable tool when working with large sequencing datasets, offering several advantages in computational speed and memory efficiency and carrying the potential for intrinsic biological functionality. This review provides an overview of the methods, applications, and significance of k-mers in genomic and proteomic data analyses, as well as the utility of absent sequences, including nullomers and nullpeptides, in disease detection, vaccine development, therapeutics, and forensic science. Therefore, the review highlights the pivotal role of k-mers in addressing current genomic and proteomic problems and underscores their potential for future breakthroughs in research.

Deciphering the functional specialization of whole-brain spatiomolecular gradients in the adult brain.

Cortical arealization arises during neurodevelopment from the confluence of molecular gradients representing patterned expression of morphogens and transcription factors. However, whether similar gradients are maintained in the adult brain remains unknown. Here, we uncover three axes of topographic variation in gene expression in the adult human brain that specifically capture previously identified rostral-caudal, dorsal-ventral, and medial-lateral axes of early developmental patterning. The interaction of these spatiomolecular gradients i) accurately reconstructs the position of brain tissue samples, ii) delineates known functional territories, and iii) can model the topographical variation of diverse cortical features. The spatiomolecular gradients are distinct from canonical cortical axes differentiating the primary sensory cortex from the association cortex, but radiate in parallel with the axes traversed by local field potentials along the cortex. We replicate all three molecular gradients in three independent human datasets as well as two nonhuman primate datasets and find that each gradient shows a distinct developmental trajectory across the lifespan. The gradients are composed of several well-known transcription factors (e.g., PAX6 and SIX3), and a small set of genes shared across gradients are strongly enriched for multiple diseases. Together, these results provide insight into the developmental sculpting of functionally distinct brain regions, governed by three robust transcriptomic axes embedded within brain parenchyma.

Improving the direct air capture capacity of grafted amines via thermal treatment.

This study investigates the effects of elevated temperature thermal treatments on the direct air capture of CO2 by aminosilane-grafted SBA-15 silica sorbents. Exposing samples to high temperatures (200-250 °C compared to 80-120 °C) in an inert environment resulted in improved CO2 capacity (5-21%) that was sustained over multiple adsorption/desorption cycles.

kmerDB: A database encompassing the set of genomic and proteomic sequence information for each species.

The decrease in sequencing expenses has facilitated the creation of reference genomes and proteomes for an expanding array of organisms. Nevertheless, no established repository that details organism-specific genomic and proteomic sequences of specific lengths, referred to as kmers, exists to our knowledge. In this article, we present kmerDB, a database accessible through an interactive web interface that provides kmer-based information from genomic and proteomic sequences in a systematic way. kmerDB currently contains 202,340,859,107 base pairs and 19,304,903,356 amino acids, spanning 54,039 and 21,865 reference genomes and proteomes, respectively, as well as 6,905,362 and 149,305,183 genomic and proteomic species-specific sequences, termed quasi-primes. Additionally, we provide access to 5,186,757 nucleic and 214,904,089 peptide sequences absent from every genome and proteome, termed primes. kmerDB features a user-friendly interface offering various search options and filters for easy parsing and searching. The service is available at: www.kmerdb.com.

FAST and Furious About Quality: Impact of Continuous Review and Feedback on Point-of-Care Ultrasound Examinations.

Background: Focused Assessment with Sonography in Trauma (FAST) examination is a point-of-care ultrasound study used to evaluate for abdominal hemorrhage, pneumothorax, or pericardial blood in trauma patients as an adjunct to their initial assessment. The quality of the image can be limited, and its diagnostic value is heavily dependent on operator skill. Our objective was to determine whether a standardized review process improved image quality and reduced incidence of nondiagnostic or insufficient imaging by 10% over a 6-month period. Study Design: Between July 1, 2021, and March 31, 2022, we evaluated 1106 trauma activations at our level II trauma center. Two exams per practitioner per month were reviewed by an emergency medicine trained traumatologist with specialized training in point-of-care ultrasound and board certification in echocardiography. Priority was given to exams on patients with known injuries identified on other studies. If there were no exams that matched these criteria, random exams were selected. Images were reviewed for image quality, diagnostic accuracy, and labeling with counseling given to the provider if indicated. Categorical variables were compared using chi squared analysis, while continuous non-normally distributed variables were compared using the Mann-Whitney U test. Results: A total of 305 FAST exams were reviewed (186 pre-intervention and 119 during intervention). Image quality improved from 46.3% (n = 31/65) to 79.0% (n = 94/119) (P < .01) with need for counseling falling from 63.1% (n = 41/65) pre-QI to 42.0% (n = 50/119) post-QI (P < .01). Incidence of detectable injury, BMI, ISS, and AIS body regions were consistent across the study period. This was seen in both the geriatric and non-geriatric cohorts despite a significant increase in ISS in the post-intervention geriatric patients.Discussion: A FAST review program is associated with improvement in image quality and decreased need for counseling of trauma providers.

The determinants of the rarity of nucleic and peptide short sequences in nature.

The prevalence of nucleic and peptide short sequences across organismal genomes and proteomes has not been thoroughly investigated. We examined 45 785 reference genomes and 21 871 reference proteomes, spanning archaea, bacteria, eukaryotes and viruses to calculate the rarity of short sequences in them. To capture this, we developed a metric of the rarity of each sequence in nature, the rarity index. We find that the frequency of certain dipeptides in rare oligopeptide sequences is hundreds of times lower than expected, which is not the case for any dinucleotides. We also generate predictive regression models that infer the rarity of nucleic and proteomic sequences across nature or within each domain of life and viruses separately. When examining each of the three domains of life and viruses separately, the R² performance of the model predicting rarity for 5-mer peptides from mono- and dipeptides ranged between 0.814 and 0.932. A separate model predicting rarity for 10-mer oligonucleotides from mono- and dinucleotides achieved R² performance between 0.408 and 0.606. Our results indicate that the mono- and dinucleotide composition of nucleic sequences and the mono- and dipeptide composition of peptide sequences can explain a significant proportion of the variance in their frequencies in nature.

Protein-altering variants at copy number-variable regions influence diverse human phenotypes.

Copy number variants (CNVs) are among the largest genetic variants, yet CNVs have not been effectively ascertained in most genetic association studies. Here we ascertained protein-altering CNVs from UK Biobank whole-exome sequencing data (n = 468,570) using haplotype-informed methods capable of detecting subexonic CNVs and variation within segmental duplications. Incorporating CNVs into analyses of rare variants predicted to cause gene loss of function (LOF) identified 100 associations of predicted LOF variants with 41 quantitative traits. A low-frequency partial deletion of RGL3 exon 6 conferred one of the strongest protective effects of gene LOF on hypertension risk (odds ratio = 0.86 (0.82-0.90)). Protein-coding variation in rapidly evolving gene families within segmental duplications-previously invisible to most analysis methods-generated some of the human genome's largest contributions to variation in type 2 diabetes risk, chronotype and blood cell traits. These results illustrate the potential for new genetic insights from genomic variation that has escaped large-scale analysis to date.

Pregnane X receptor knockout mitigates weight gain and hepatic metabolic dysregulation in female C57BL/6 J mice on a long-term high-fat diet.

Obesity is a significant risk factor for several chronic diseases. However, pre-menopausal females are protected against high-fat diet (HFD)-induced obesity and its adverse effects. The pregnane X receptor (PXR, NR1I2), a xenobiotic-sensing nuclear receptor, promotes short-term obesity-associated liver disease only in male mice but not in females. Therefore, the current study investigated the metabolic and pathophysiological effects of a long-term 52-week HFD in female wild-type (WT) and PXR-KO mice and characterized the PXR-dependent molecular pathways involved. After 52 weeks of HFD ingestion, the body and liver weights and several markers of hepatotoxicity were significantly higher in WT mice than in their PXR-KO counterparts. The HFD-induced liver injury in WT female mice was also associated with upregulation of the hepatic mRNA levels of peroxisome proliferator-activated receptor gamma (Pparg), its target genes, fat-specific protein 27 (Fsp27), and the liver-specific Fsp27b involved in lipid accumulation, apoptosis, and inflammation. Notably, PXR-KO mice displayed elevated hepatic Cyp2a5 (anti-obesity gene), aldo-keto reductase 1b7 (Akr1b7), glutathione-S-transferase M3 (Gstm3) (antioxidant gene), and AMP-activated protein kinase (AMPK) levels, contributing to protection against long-term HFD-induced obesity and inflammation. RNA sequencing analysis revealed a general blunting of the transcriptomic response to HFD in PXR-KO compared to WT mice. Pathway enrichment analysis demonstrated enrichment by HFD for several pathways, including oxidative stress and redox pathway, cholesterol biosynthesis, and glycolysis/gluconeogenesis in WT but not PXR-KO mice. In conclusion, this study provides new insights into the molecular mechanisms by which PXR deficiency protects against long-term HFD-induced severe obesity and its adverse effects in female mice.

Realized impact of COVID-19 related disruptions on the National Bowel Cancer Screening Program.

BACKGROUND: Colorectal cancer is the second most common cause of cancer mortality in Australia (1). The National Bowel Cancer Screening Program (NBCSP) aims to reduce mortality through early detection with a biennial faecal occult blood test for Australians aged 50-74 years (2). Modelling predicted COVID-19 would reduce participation and delay colonoscopies despite the NBCSP continuing during the pandemic (3). This study analyses the realized impact of COVID-19 related disruptions on the NBCSP and the effect on mortality. METHODS: NBCSP participation, time to colonoscopy and annualized mortality were compared before and during COVID-19. The effect on mortality was determined using a validated microsimulation model (4, 5). RESULTS: From 1 January 2018 to 31 December 2019, 2 497 317 people participated in the NBCSP and 168 390 received a colonoscopy, compared to 2 490 265 and 162 573 from 1 January 2020 to 31 December 2021. Relative participation decreased 6 % and the proportion of colonoscopies performed within the recommended 120 days increased 14.5%. A disproportionally greater impact was observed outside major cities and in lower socioeconomic areas. An estimated 98-111 additional colorectal cancer deaths resulted from 3 % fewer colonoscopies performed during the pandemic. CONCLUSION: This study presents the most comprehensive analysis of the realized impact of COVID-19 on the NBCSP. Catch-up screening would be best targeted at Australians from rural and lower socioeconomic areas where participation remains low. Streamlined referral pathways and additional colonoscopy provisioning is required as less than two thirds of screen positive patients receive a colonoscopy within the recommended 120 days.

Exploring infant and young child-feeding practices among mothers of well-nourished children in northern Ghana: An INPreP substudy.

This study investigated infant and young child-feeding (IYCF) practices among mothers of well-nourished children in northern Ghana. This was a qualitative study where in-depth individual interviews were conducted with participants. The interviews were audio recorded, transcribed, and QSR Nvivo software version 11 was used to organize the data before thematic analysis. It was observed that mothers of well-nourished children were likely to adhere to breastfeeding guidelines and also practice appropriate complementary feeding. Furthermore, these mothers mostly had some form of support from their husbands and mother-in-laws in feeding their infants. While adoption and adherence to appropriate IYCF practices contribute to improved nutrition outcomes in children, social support systems are needed to sustain the practice.

Eosinophils in psoriasis: A systematic review and meta-analysis introducing a study quality assessment tool for diagnostic pathology studies.

BACKGROUND: The histopathologic features of psoriasis are well-documented, but recent studies have highlighted atypical features, such as eosinophils, in clinically confirmed cases. METHODS: A systematic review exploring eosinophils in psoriasis was performed. A novel quality assessment tool (SQAT-Path) we designed for cross-sectional pathology studies was employed. RESULTS: Five studies (N = 218) were identified. The pooled prevalence of dermal eosinophils in psoriasis was 46% (95% confidence interval, 0.27-0.66). The prevalences of 1 to 5 lesional eosinophils (24%) compared to >5 eosinophils (26%) were similar. There was no association between eosinophils and prior treatment. There was also no association between eosinophils and spongiosis. In SQAT-Path, studies scored between 9 and 18 (out of a maximum of 27: "fair" to "good"), consistent with the ratings using other assessment tools. CONCLUSION: Eosinophils were found in approximately half of systematically studied and published cases of psoriasis. When present, their quantity is variable, with the likelihood of having greater than 5 eosinophils in a biopsy section comparable to having between 1 and 5. Greater than 5 eosinophils, as an isolated finding, would not be typical of psoriasis, but should not preclude its diagnosis without considering the overall histologic context.

A survey of low titer O whole blood use within the trauma quality improvement program registry.

INTRODUCTION: The use of low titer O whole blood (LTOWB) has expanded although it remains unclear how many civilian trauma centers are using LTOWB. METHODS: We analyzed data on civilian LTOWB recipients in the American College of Surgeons Trauma Quality Improvement Program (TQIP) database 2020-2021. Unique facility keys were used to determine the number of centers that used LTOWB in that period. RESULTS: A total of 16,603 patients received LTOWB in the TQIP database between 2020 and 2021; 6600 in 2020, and 10,003 in 2021. The total number of facilities that reported LTOWB use went from 287/779 (37%) in 2020 to 302/795 (38%) in 2021. Between 2020 and 2021, among all level 1-3 designated trauma facilities that report to TQIP LTOWB use increased at level-1 centers (118 to 129), and level-2 centers (81 to 86), but decreased in level-3 facilities (9 to 4). Among pediatric and dual pediatric-adult designated hospitals there was a decrease in the number of pediatric level-1 centers (29 to 28) capable of administering LTOWB. Among centers with either single or dual level-1 trauma center designation with adult centers, the number that administered LTOWB to injured pediatric patients also decreased from 17 to 10, respectively. CONCLUSIONS: There was an increase in the number of facilities transfusing LTOWB between 2020 and 2021. The use of LTOWB is underutilized in children at centers that have it available. These findings inform the expansion of LTOWB use in trauma.

Comparison of S100A8 and PRAME as biomarkers for distinguishing melanoma from melanocytic naevus: a case-control analysis.

BACKGROUND: S100A8 is a melanoma biomarker expressed in the melanoma-associated epidermal keratinocytes, but its diagnostic utility has not been compared with other biomarkers, including PRAME. OBJECTIVES: To compare the utility of S100A8 and PRAME immunohistochemistry (IHC) in the differential diagnosis of melanoma and naevi in a case-control study. METHODS: A previously described cohort of 209 melanomas (case samples) and naevi (control samples) dual-immunostained for S100A8 and PRAME were included. For S100A8, previously reported scores indicating the proportion of tumour-associated epidermis stained (0 = indeterminate; 1 = 0-4%; 2 = 5-25%; 3 = 26-50%; 4 = 51-75%; 5 = > 75%) were utilized. PRAME IHC was reviewed by at least two reviewers and a consensus score assigned, with score indicating the proportion of tumour stained (0 = indeterminate; 1 = 0%; 2 = 1-50%; 3 = > 50%). A positive test was defined as > 50% staining. RESULTS: The area under the receiver operating characteristic curves for S100A8 (0.833) and PRAME (0.874) were not significantly different from each other (P = 0.22). The diagnostic sensitivity and specificity were 42.4% [95% confidence interval (CI) 32.6-52.8%] and 98.2% (95% CI 93.6-99.8%) for S100A8, and 79.8% (95% CI 70.5-87.2%) and 87.3% (95% CI 79.6-92.9%) for PRAME, respectively. A combined test requiring both S100A8 and PRAME IHC positivity had a sensitivity of 39.4% (95% CI 29.7-49.7%) and specificity of 99.1% (95% CI 95.0-100.0%). CONCLUSIONS: S100A8 and PRAME have utility in the diagnostic workup of melanoma, with S100A8 being more specific and PRAME being more sensitive when using this threshold. Our findings suggest that these two immunohistochemical markers may favourably complement one another to improve the detection of melanoma.

Therapeutic efficacy of a potent anti-Venezuelan equine encephalitis virus antibody is contingent on Fc effector function.

The development of specific, safe, and potent monoclonal antibodies (Abs) has led to novel therapeutic options for infectious disease. In addition to preventing viral infection through neutralization, Abs can clear infected cells and induce immunomodulatory functions through engagement of their crystallizable fragment (Fc) with complement proteins and Fc receptors on immune cells. Little is known about the role of Fc effector functions of neutralizing Abs in the context of encephalitic alphavirus infection. To determine the role of Fc effector function in therapeutic efficacy against Venezuelan equine encephalitis virus (VEEV), we compared the potently neutralizing anti-VEEV human IgG F5 (hF5) Ab with intact Fc function (hF5-WT) or containing the loss of function Fc mutations L234A and L235A (hF5-LALA) in the context of VEEV infection. We observed significantly reduced binding to complement and Fc receptors, as well as differential in vitro kinetics of Fc-mediated cytotoxicity for hF5-LALA compared to hF5-WT. The in vivo efficacy of hF5-LALA was comparable to hF5-WT at -24 and + 24 h post infection, with both Abs providing high levels of protection. However, when hF5-WT and hF5-LALA were administered + 48 h post infection, there was a significant decrease in the therapeutic efficacy of hF5-LALA. Together these results demonstrate that optimal therapeutic Ab treatment of VEEV, and possibly other encephalitic alphaviruses, requires neutralization paired with engagement of immune effectors via the Fc region.

Body Mass Index Does Not Predict Injury Pattern or Outcome After Motorcycle Crash.

INTRODUCTION: The obesity epidemic plagues the United States, affecting approximately 42% of the population. The relationship of obesity with injury severity and outcomes has been poorly studied among motorcycle collisions (MCC). This study aimed to compare injury severity, mortality, injury regions, and hospital and intensive care unit length of stay (LOS) between obese and normal-weight MCC patients. METHODS: Trauma registries from three Pennsylvania Level 1 trauma centers were queried for adult MCC patients (January 1, 2016, and December 31, 2020). Obesity was defined as adult patients with body mass index ≥ 30 kg/m2 and normal weight was defined as body mass index < 30 kg/m2 but > 18.5 kg/m2. Demographics and injury characteristics including injury severity score (ISS), abbreviated injury score, mortality, transfusions and LOS were compared. P ≤ 0.05 was considered significant. RESULTS: One thousand one hundred sixty-four patients met the inclusion criteria: 40% obese (n = 463) and 60% nonobese (n = 701). Comparison of ISS demonstrated no statistically significant difference between obese and normal-weight patients with median ISS (interquartile range) 9 (5-14) versus 9 (5-14), respectively (P = 0.29). Obese patients were older with median age 45 (32-55) y versus 38 (26-54) y, respectively (P < 0.01). Comorbidities were equally distributed among both groups except for the incidence of hypertension (30 versus 13.8%, P < 0.01) and diabetes (11 versus 4.4%, P < 0.01). There was no statistically significant difference in Trauma Injury Severity Score or abbreviated injury score. Hospital LOS, intensive care unit LOS, and 30-day mortality among both groups were similar. CONCLUSIONS: Obese patients experiencing MCC had no differences in distribution of injury, mortality, or injury severity, mortality, injury regions, and hospital compared to normal-weight adults. Our study differs from current data that obese motorcycle drivers may have different injury characteristics and increased LOS.

High-fat diet induced obesity promotes inflammation, oxidative stress, and hepatotoxicity in female FVB/N mice.

Although obesity and subsequent liver injury are increasingly prevalent in women, female mouse models have generally shown resistance to high-fat diet (HFD)-induced obesity. We evaluated control and HFD-fed male and female FVB/N mice, a strain well-suited to transgenic analyses, for phenotypic, histological, and molecular markers related to control of glucose, lipids, and inflammation in serum, liver, and perigonadal white adipose tissues. Unlike many mouse models, HFD-fed FVB/N females gained more perigonadal and mesenteric fat mass and overall body weight than their male counterparts, with increased hepatic expression of lipogenic PPARγ target genes (Cd36, Fsp27, and Fsp27ß), oxidative stress genes and protein (Nqo1 and CYP2E1), inflammatory gene (Mip-2), and the pro-fibrotic gene Pai-1, along with increases in malondialdehyde and serum ALT levels. Further, inherent to females (independently of HFD), hepatic antioxidant heme oxygenase-1 (HMOX1, HO-1) protein levels were reduced compared to their male counterparts. In contrast, males may have been relatively protected from HFD-induced oxidative stress and liver injury by elevated mRNA and protein levels of hepatic antioxidants BHMT and Gpx2, increased fatty acid oxidation genes in liver and adipocytes (Pparδ), despite disorganized and inflamed adipocytes. Thus, female FVB/N mice offer a valuable preclinical, genetically malleable model that recapitulates many of the features of diet-induced obesity and liver damage observed in human females.