Genetically Determined Research Articles

Genetic determinants of renal scarring in children with febrile UTI.

Febrile urinary tract infections (UTIs) are among the most severe bacterial infections in infants, in which a subset of patients develops complications. Identifying infants at risk of recurrent infections or kidney damage based on clinical signs is challenging. Previous observations suggest that genetic factors influence UTI outcomes and could serve as predictors of disease severity. In this study, we conducted a nationwide survey of infant genotypes to develop a strategy for infection management based on individual genetic risk. Our aims were to identify genetic susceptibility variants for renal scarring(RS) and genetic host factors predisposing to dilating vesicoureteral reflux (VUR) and recurrent UTIs. To assess genetic susceptibility, we collected and analyzed DNA from blood using exome genotyping. Disease-associated genetic variants were identified through bioinformatics analysis, including allelic frequency tests and odds ratio calculations. Kidney involvement was defined using dimercaptosuccinic acid (DMSA) scintigraphy. In this investigation, a cohort comprising 1087 infants presenting with their first episode of febrile UTI was included. Among this cohort, a subset of 137 infants who underwent DMSA scanning was subjected to gene association analysis. Remarkable genetic distinctions were observed between patients with RS and those exhibiting resolved kidney involvement. Notably, the genetic signature indicative of renal scarring prominently featured mitochondrial genes. In this nationwide study of genetic susceptibility to RS after febrile UTIs in infancy, we identified a profile dominated by mitochondrial polymorphisms. This profile can serve as a predictor of future complications, including RS and recurrent UTIs.

Epistasis facilitates functional evolution in an ancient transcription factor.

A protein's genetic architecture - the set of causal rules by which its sequence produces its functions - also determines its possible evolutionary trajectories. Prior research has proposed that the genetic architecture of proteins is very complex, with pervasive epistatic interactions that constrain evolution and make function difficult to predict from sequence. Most of this work has analyzed only the direct paths between two proteins of interest - excluding the vast majority of possible genotypes and evolutionary trajectories - and has considered only a single protein function, leaving unaddressed the genetic architecture of functional specificity and its impact on the evolution of new functions. Here, we develop a new method based on ordinal logistic regression to directly characterize the global genetic determinants of multiple protein functions from 20-state combinatorial deep mutational scanning (DMS) experiments. We use it to dissect the genetic architecture and evolution of a transcription factor's specificity for DNA, using data from a combinatorial DMS of an ancient steroid hormone receptor's capacity to activate transcription from two biologically relevant DNA elements. We show that the genetic architecture of DNA recognition consists of a dense set of main and pairwise effects that involve virtually every possible amino acid state in the protein-DNA interface, but higher-order epistasis plays only a tiny role. Pairwise interactions enlarge the set of functional sequences and are the primary determinants of specificity for different DNA elements. They also massively expand the number of opportunities for single-residue mutations to switch specificity from one DNA target to another. By bringing variants with different functions close together in sequence space, pairwise epistasis therefore facilitates rather than constrains the evolution of new functions.

Determination of molecular types and resistance to macrolides in <i>Treponema pallidum</i> isolates isolated in the Russian Federation

Background. The number of syphilis cases in the Russian Federation increased significantly in 2022. Control of heterogeneity of Treponema pallidum subtypes is important to monitor the emergence and spread of antibiotic-resistant strains Aims. To determine molecular subtypes and resistance to macrolides in T. pallidum isolates isolated in the Russian Federation in 2022. Methods. We analyzed DNA isolated from 49 samples of clinical material obtained from patients from dermatovenerological treatment and prevention facilities in three federal districts (CFD, SFD, SCFD) of the Russian Federation in 2022 with diagnoses of primary syphilis and secondary syphilis. T. pallidum DNA isolation and confirmation of the presence of genetic material were performed according to the existing algorithms. To search for genetic determinants of resistance to macrolides, a fragment of the 23S rRNA gene was analyzed. Primary decoding of nucleotide sequences was performed in Sequencing Analysis 5.3.1. Mega 11 program was used to align the analyzed fragments of target genes to T. pallidum reference sequences. Results. In 2022, three subtypes of T. pallidum were identified in the territory of the represented federal districts of the Russian Federation: 14d/f, 14d/g, 14d/d with continued dominance of subtype 14d/f. The macrolide-resistant subtype 14d/d was identified in two federal districts, which is new for the Russian Federation. Conclusions. The population of T. pallidum continues to expand in the Russian Federation, including the emergence of azithromycin-resistant strains. The data obtained confirm the need for continuous monitoring of circulating strains and may facilitate understanding of their geographic distribution.

Epistasis facilitates functional evolution in an ancient transcription factor

A protein’s genetic architecture – the set of causal rules by which its sequence produces its functions – also determines its possible evolutionary trajectories. Prior research has proposed that the genetic architecture of proteins is very complex, with pervasive epistatic interactions that constrain evolution and make function difficult to predict from sequence. Most of this work has analyzed only the direct paths between two proteins of interest – excluding the vast majority of possible genotypes and evolutionary trajectories – and has considered only a single protein function, leaving unaddressed the genetic architecture of functional specificity and its impact on the evolution of new functions. Here, we develop a new method based on ordinal logistic regression to directly characterize the global genetic determinants of multiple protein functions from 20-state combinatorial deep mutational scanning (DMS) experiments. We use it to dissect the genetic architecture and evolution of a transcription factor’s specificity for DNA, using data from a combinatorial DMS of an ancient steroid hormone receptor’s capacity to activate transcription from two biologically relevant DNA elements. We show that the genetic architecture of DNA recognition consists of a dense set of main and pairwise effects that involve virtually every possible amino acid state in the protein-DNA interface, but higher-order epistasis plays only a tiny role. Pairwise interactions enlarge the set of functional sequences and are the primary determinants of specificity for different DNA elements. They also massively expand the number of opportunities for single-residue mutations to switch specificity from one DNA target to another. By bringing variants with different functions close together in sequence space, pairwise epistasis therefore facilitates rather than constrains the evolution of new functions.

Local sorghum (Sorghum bicolor (L.) Moench) on‐farm genetic diversity status and possible determinants from Wollo lowland areas, northeastern Ethiopia

AbstractVarious agricultural crops are the world's sources of food, fodder, and energy. However, conservation management and diversification constraints remain a challenge. Therefore, the present study aimed to assess the status of local agricultural sorghum genetic diversity and potential determinants of the Wollo lowlands in northeastern Ethiopia. The greatest extent of local sorghum abundance was demonstrated in the study areas with the highest value being 4.25 DMg and 2.89 DMn in Werebabo district. However, 2.97 DMg and 2.04 DMn were recorded as the relatively lowest indices in Tehuledere province. In fact, the extent and type of diversity, measured by the number of varieties per farm, varied from region to region. Farmer perceived constraints such as late maturity, blending fluency, distance to nearest market (km), small land ownership, end‐use quality, and plume size attributed to these deviations. The priority of the constraints was first determined by ranking the constraints based on the answers received from the respondents and then calculating the rank‐based quotient. Several categorical variables of these constraints also showed a significant association with the status of local farm sorghum genetic diversity at p < 0.05 and p < 0.001. In general, the status of genetic diversity of local sorghum farms was low in all the provinces studied. Therefore, the seed exchange network between local farmers should be encouraged to use and conserve diversity on a daily basis. Community seed banks should also be established to enhance the conservation of beneficial local sorghum germplasm and maximize locally adapted sorghum landrace profiles.

Rice Transcriptomics Reveal the Genetic Determinants of An In Planta Photorespiratory Bypass: a Novel Way to Increase Biomass in C3 Plants

Rice Transcriptomics Reveal the Genetic Determinants of An In Planta Photorespiratory Bypass: a Novel Way to Increase Biomass in C3 Plants

Genetic determinants of serum bilirubin using inferred native American gene variants in Chilean adolescents

Gene variants in the UGT1A1 gene are strongly associated with circulating bilirubin levels in several populations, as well as other variants of modest effect across the genome. However, the effects of such variants are unknown regarding the Native American ancestry of the admixed Latino population. Our objective was to assess the Native American genetic determinants of serum bilirubin in Chilean admixed adolescents using the local ancestry deconvolution approach. We measured total serum bilirubin levels in 707 adolescents of the Chilean Growth and Obesity Cohort Study (GOCS) and performed high-density genotyping using the Illumina-MEGA array (>1.7 million genotypes). We constructed a local ancestry reference panel with participants from the 1000 Genomes Project, the Human Genome Diversity Project, and our GOCS cohort. Then, we inferred and isolated haplotype tracts of Native American, European, or African origin to perform genome-wide association studies. In the whole cohort, the rs887829 variant and others near UGT1A1 were the unique signals achieving genome-wide statistical significance (b = 0.30; p = 3.34 × 10−57). After applying deconvolution methods, we found that significance is also maintained in Native American (b = 0.35; p = 3.29 × 10−17) and European (b = 0.28; p = 1.14 × 10−23) ancestry components. The rs887829 variant explained a higher percentage of the variance of bilirubin in the Native American (37.6%) compared to European ancestry (28.4%). In Native American ancestry, carriers of the TT genotype of this variant averaged 4-fold higher bilirubinemia compared to the CC genotype (p = 2.82 × 10−12). We showed for the first time that UGT1A1 variants are the primary determinant of bilirubin levels in Native American ancestry, confirming its pan-ethnic relevance. Our study illustrates the general value of the local ancestry deconvolution approach to assessing isolated ancestry effects in admixed populations.

Parkinson's Disease Associated with G2019S LRRK2 Mutations without Lewy Body Pathology.

The G2019S leucine-rich repeat kinase 2 (LRRK2) gene mutation is an important and commonly found genetic determinant of Parkinson's disease (PD). The neuropathological findings associated with this mutation have thus far been varied but are most often associated with Lewy body (LB) pathology. Describe a case of clinical Parkinson's disease with levodopa responsiveness found to have LRRK2 mutations and the absence of Lewy bodies. We present an 89-year-old man with a 10-year history of slowly progressive parkinsonism suspected to be secondary to Parkinson's disease. Neuropathological evaluation revealed nigral degeneration without Lewy bodies or Lewy neurites, but there were frequent tau-immunopositive neurites and astrocytes in the putamen and substantia nigra, neocortical glial tau positive astrocytes associated with aging-related tau astrogliopathy (ARTAG), as well as neurofibrillary tangles, beta amyloid plaques, and amyloid angiopathy typical of advanced Alzheimer's disease. G2019S LRRK2 homozygous mutations were found. This case illustrates that levodopa-responsive clinical PD caused by G2019S LRRK2 mutations can occur without Lewy bodies.

Genome‑wide association study and polygenic risk scores predict psoriasis and its shared phenotypes in Taiwan.

Psoriasis is a chronic inflammatory dermatological disease, and there is a lack of understanding of the genetic factors involved in psoriasis in Taiwan. To establish associations between genetic variations and psoriasis, a genome‑wide association study was performed in a cohort of 2,248 individuals with psoriasis and 67,440 individuals without psoriasis. Using the ingenuity pathway analysis software, biological networks were constructed. Human leukocyte antigen (HLA) diplotypes and haplotypes were analyzed using Attribute Bagging (HIBAG)‑R software and chi‑square analysis. The present study aimed to assess the potential risks associated with psoriasis using a polygenic risk score (PRS) analysis. The genetic association between single nucleotide polymorphisms (SNPs) in psoriasis and various human diseases was assessed by phenome‑wide association study. METAL software was used to analyze datasets from China Medical University Hospital (CMUH) and BioBank Japan (BBJ). The results of the present study revealed 8,585 SNPs with a significance threshold of P<5x10‑8, located within 153 genes strongly associated with the psoriasis phenotype, particularly on chromosomes 5 and 6. This specific genomic region has been identified by analyzing the biological networks associated with numerous pathways, including immune responses and inflammatory signaling. HLA genotype analysis indicated a strong association between HLA‑A*02:07 and HLA‑C*06:02 in a Taiwanese population. Based on our PRS analysis, the risk of psoriasis associated with the SNPs identified in the present study was quantified. These SNPs are associated with various dermatological, circulatory, endocrine, metabolic, musculoskeletal, hematopoietic and infectious diseases. The meta‑analysis results indicated successful replication of a study conducted on psoriasis in the BBJ. Several genetic loci are significantly associated with susceptibility to psoriasis in Taiwanese individuals. The present study contributes to our understanding of the genetic determinants that play a role in susceptibility to psoriasis. Furthermore, it provides valuable insights into the underlying etiology of psoriasis in the Taiwanese community.

Assessment of spillover of antimicrobial resistance to untreated children 7 to 12 years old after mass drug administration of azithromycin for child survival in Niger: a secondary analysis of the MORDOR cluster-randomized trial.

The risk of antibiotic resistance is complicated by the potential for spillover effects from one treated population to another. Azithromycin mass drug administration programs report higher rates of antibiotic resistance among treatment arms in targeted groups. This study aims to understand the risk of spillover of antibiotic resistance to non-target groups in these programs. Data was used from a cluster-randomized trial comparing the effect of biannual azithromycin and placebo distribution to children 1-59 months on child mortality. Nasopharyngeal samples from untreated children 7-12 years old were tested for genetic determinants of macrolide resistance (primary outcome) and resistance to other antibiotic classes (secondary outcomes). Linear regression was used to compare the community-level mean difference in prevalence by arm at the 24-month timepoint adjusting for baseline prevalence. 1,103 children 7-12 years old in 30 communities were included in the analysis (15 azithromycin, 15 placebo). Adjusted mean differences in prevalence of resistance determinants for macrolides, beta-lactams and tetracyclines were 3.4% (95% CI -4.1% to 10.8%, P-value 0.37), -1.2% (95% CI -7.9% to 5.5%, P-value 0.72), and -3.3% (95% CI -9.5% to 2.8%, P-value 0.61), respectively. We were unable to demonstrate a statistically significant increase in macrolide resistance determinants in untreated groups in an azithromycin mass drug administration program. While the result might be consistent with a small spillover effect, this study was not powered to detect such a small difference. Larger studies are warranted to better understand the potential for spillover effects within these programs.

Cardiovascular Burden of the V142I Transthyretin Variant

Individual cohort studies concur that the amyloidogenic V142I variant of the transthyretin (TTR) gene, present in 3% to 4% of US Black individuals, increases heart failure (HF) and mortality risk. Precisely defining carrier risk across relevant clinical outcomes and estimating population burden of disease are important given established and emerging targeted treatments. To better define the natural history of disease in carriers across mid to late life, assess variant modifiers, and estimate cardiovascular burden to the US population. A total of 23 338 self-reported Black participants initially free from HF were included in 4 large observational studies across the US (mean [SD], 15.5 [8.2] years of follow-up). Data analysis was performed between May 2023 and February 2024. V142I carrier status (n = 754, 3.2%). Hospitalizations for HF (including subtypes of reduced and preserved ejection fraction) and all-cause mortality. Outcomes were analyzed by generating 10-year hazard ratios for each age between 50 and 90 years. Using actuarial methods, mean survival by carrier status was estimated and applied to the 2022 US population using US Census data. Among the 23 338 participants, the mean (SD) age at baseline was 62 (9) years and 76.7% were women. Ten-year carrier risk increased for HF hospitalization by age 63 years, predominantly driven by HF with reduced ejection fraction, and 10-year all-cause mortality risk increased by age 72 years. Only age (but not sex or other select variables) modified risk with the variant, with estimated reductions in longevity ranging from 1.9 years (95% CI, 0.6-3.1) at age 50 to 2.8 years (95% CI, 2.0-3.6) at age 81. Based on these data, 435 851 estimated US Black carriers between ages 50 and 95 years are projected to cumulatively lose 957 505 years of life (95% CI, 534 475-1 380 535) due to the variant. Among self-reported Black individuals, male and female V142I carriers faced similar and substantial risk for HF hospitalization, predominantly with reduced ejection fraction, and death, with steep age-dependent penetrance. Delineating the individual contributions of, and complex interplay among, the V142I variant, ancestry, the social construct of race, and biological or social determinants of health to cardiovascular disease merits further investigation.

Genetic, virulence, and antimicrobial resistance characteristics associated with distinct morphotypes in ST11 carbapenem-resistant Klebsiella pneumoniae

ABSTRACT ST11 is the most common lineage among carbapenem-resistant Klebsiella pneumoniae (CRKP) infections in Asia. Diverse morphotypes resulting from genetic mutations are associated with significant differences in microbial characteristics among K. pneumoniae isolates. Here, we investigated the genetic determinants and critical characteristics associated with distinct morphotypes of ST11 CRKP. An ST11-KL47 CRKP isolate carrying a pLVPK-like virulence plasmid was isolated from a patient with a bloodstream infection; the isolate had the “mcsw” morphotype. Two distinct morphotypes (“ntrd” and “msdw”) were derived from this strain during in vitro passage. Whole genome sequencing was used to identify mutations that cause the distinct morphotypes of ST11 CRKP. Transmission electron microscopy, antimicrobial susceptibility tests, growth assays, biofilm formation, virulence assays, membrane permeability assays, and RNA-seq analysis were used to investigate the specific characteristics associated with different morphotypes of ST11 CRKP. Compared with the parental mcsw morphotype, the ntrd morphotype resulted from mutation of genes involved in capsular polysaccharide biosynthesis (wza, wzc, and wbaP), a result validated by gene knockout experiments. This morphotype showed capsule deficiency and lower virulence potential, but higher biofilm production. By contrast, the msdw morphotype displayed competition deficiency and increased susceptibility to chlorhexidine and polymyxin B. Further analyses indicated that these characteristics were caused by interruption of the sigma factor gene rpoN by insertion mutations and deletion of the rpoN gene, which attenuated membrane integrity presumably by downregulating the phage shock protein operon. These data expand current understanding of genetic, virulence, and antimicrobial resistance characteristics associated with distinct morphotypes in ST11 CRKP.

Negative Implications of Drug and Substance use on Mental Health

Mental health refers to a person's emotional, psychological, and social well-being, which encompasses aspects such as thoughts, feelings, behaviors, and the ability to cope with life's challenges. Several factors including drug abuse have been recognized to cause mental health disorders; hence, the urgent need to globally address these factors. Drug abuse emerges as a complex public health issue, involving the misuse of legal and illegal drugs, with consequences extending beyond individual health. The relationship between mental health and drug abuse intensifies challenges, as drug misuse contributes to the development or worsening of mental health disorders. This review examined biological, psychological, and social determinants, and advocate for a standardized approach to address the complex issue of drug abuse. Various electronic databases, such as PubMed, Scopus, Web of Science, Medline, and others, were used to access resources, in which thirty-three (33) literatures were reviewed. Results of the reviewed literatures revealed that the impact of drug abuse on mental health involves neurobiological alterations affecting neurotransmitter levels and structural changes in the brain. This does not only affect individuals, but also results in societal burdens, such as increased healthcare costs and criminal justice involvement, compounded by the stigma surrounding mental health and substance abuse. The classification of drugs into legal and illegal categories highlights the diversity of substances and emphasizes the need to understand their effects on mental well-being. Categories include legal drugs, prescription medications, socially accepted substances, and illegal drugs with varying dependency potentials. Addressing mental health disorders induced by drug abuse requires a comprehensive approach, involving strategies like Integrated Dual Diagnosis Treatment (IDDT), Medication-Assisted Treatment (MAT), Cognitive-Behavioral Therapy (CBT), Motivational Interviewing (MI), Dialectical Behavior Therapy (DBT), Peer Support, 12-Step Programs, and Recovery-Oriented Systems of Care (ROSC). These methods guarantee a care continuum that centers on the individual and emphasizes recovery, acknowledging the relationship between mental health and drug abuse disorders. Nevertheless, the review highlights a research gap in that, in-depth research is needed to evaluate the effectiveness of the aforementioned interventions. Additionally, exploring innovative strategies to address challenges such as stigma, limited treatment accessibility, and the cyclical nature of addiction would enhance intervention effectiveness.

Genetic determinants of obesity in adolescent girls

Significant progress in understanding the genetic contribution in obesity and its prevalence at all ages has been achieved since existing methods of treatment and preventive measures aimed at combating obesity are not effective enough.Purpose. To study the prevalence of pathologic single nucleotide polymorphisms rs6265 of the brain neutrophic factor gene BDNF; rs1137101 of the leptin receptor gene LEPR; rs9939609 of the gene, associated with fat mass, FTO; rs4762 and rs699 of angiotensinogen AGT gene; rs1799883 of fatty acid transporter gene FABP2; rs1801282 of PPARG2 gene in obese adolescent girls.Material and methods. 72 teenage girls aged 12–17 years were examined. Group 1 consisted of 36 obese children (standard deviation coefficient SDS BMI ≥ 2.0), group 2 — 36 non-obese children (SDS BMI &lt;1.0). Anthropometric, molecular genetic, and statistical methods were used.Results. In obese adolescent girls, an association was detected with only one gene — PPARG2, a polymorphic locus (Pro/Pro). The prevalence rate of the C allele in group 1 was 80%, in group 2 — 3% (p&lt;0.05). No statistically significant differences in the frequencies of genotypes and alleles of other genes in children with obesity and normal body weight were established.Conclusion. Further large-scale studies, including biochemical and hormonal parameters, are needed to establish the influence of specific polymorphic loci of various genes contributing in obesity and metabolic processes.

Molecular genetic determinants of virulence of Streptococcus agalactiae isolated from pregnant women and newborns in St. Petersburg and the Leningrad region in 2010–2023

Introduction. Colonization of the reproductive organs of pregnant women with group B streptococci (GBS; Streptococcus agalactiae) can lead to severe perinatal and neonatal pathology. In modern conditions, aside from the prevention of antenatal infection of the fetus during childbirth using antibacterial drugs, vaccination is also necessary. In this regard, surveillance of GBS genotypes is an important task. Objective. To determine the molecular genetic determinants of virulence of Streptococcus agalactiae isolated from pregnant women and newborns, and to monitor the distribution of capsular polysaccharides types and pili profiles in GBS clinical isolates. Materials and methods. The study used clinical isolates of GBS (n = 420) isolated from pregnant women and newborns in 2010–2023.The bacteriological method was used for isolation of S. agalactiae. PCR method was used to determine the types of capsular polysaccharides, pili, and whether the strains belonged to the hypervirulent sequence type ST-17. Results. During 13 years of observation, the predominance of Ia, III and V genotypes of GBS capsular polysaccharides was noted both in pregnant women and in newborns. The frequency of occurrence of genotype Ib increased from 0.7 to 6.7%, genotype V from 12.1 to 24.4%, and the prevalence of genotype III decreased significantly from 41.1 to 21.1%. Hypervirulent sequence type ST-17 was detected in 6 pregnant women and 2 newborns. However, there were no signs of neonatal infection in these children. More than half of all clinical isolates of S. agalactiae had pili genotypes PI-1 + PI-2a, as well as pili genotypes PI-2a and PI-1 + PI-2b. The distribution of pili types did not change over 13 years of the surveillance period. Conclusion. Surveillance of the GBS capsular polysaccharides and pili genotypes is necessary for the development of effective preventive vaccines.

Effect of light on dairy cattle in farm conditions – a review

Abstract Cattle are among the animals with diurnal activity, which is due to the specific animal– environment relationship and the natural role wild cattle play in the ecosystem. As humans began domesticating, breeding these animals, they became an integral part of this relationship. This review article addresses the most important current issues: 1) a characterisation of contemporary knowledge on the biological determinants of the vision abilities of dairy cattle, 2) a discussion of the relationship between these abilities and animal health and performance, and 3) a characterisation of the light–animal relationship under husbandry conditions. The intricate link between the anatomical and physiological aspects of visual function in cattle and their circadian rhythms was emphasised. This connection directly influences cattle growth and development, as well as the health and performance of dairy cows during the long/short day photoperiods. The article also considers the possibility of managing dairy cows’ photoperiod and light quality to enhance their performance and overall well-being.

Shedding light on bacteria–host interactions with the aid of TnSeq approaches

ABSTRACT Bacteria are highly adaptable and grow in diverse niches, where they often interact with eukaryotic organisms. These interactions with different hosts span the entire spectrum from symbiosis to pathogenicity and thus determine the lifestyle of the bacterium. Knowledge of the genetic determinants involved in animal and plant host colonization by pathogenic and mutualistic bacteria is not only crucial to discover new drug targets for disease management but also for developing novel biostimulant strategies. In the last decades, significant progress in genome-wide high-throughput technologies such as transposon insertion sequencing has led to the identification of pathways that enable efficient host colonization. However, the extent to which similar genes play a role in this process in different bacteria is yet unclear. This review highlights the commonalities and specificities of bacterial determinants important for bacteria–host interaction.

A new point mutation in the HC-Pro of potato virus Y is involved in tobacco vein necrosis.

Tobacco vein necrosis (TVN) is a complex phenomenon regulated by different genetic determinants mapped in the HC-Pro protein (amino acids N330, K391 and E410) and in two regions of potato virus Y (PVY) genome, corresponding to the cytoplasmic inclusion (CI) protein and the nuclear inclusion protein a-protease (NIa-Pro), respectively. A new determinant of TVN was discovered in the MK isolate of PVY which, although carried the HC-Pro determinants associated to TVN, did not induce TVN. The HC-Pro open reading frame (ORF) of the necrotic infectious clone PVY N605 was replaced with that of the non-necrotic MK isolate, which differed only by one amino acid at position 392 (T392 instead of I392). The cDNA clone N605_MKHCPro inoculated in tobacco induced only weak mosaics at the systemic level, demostrating that the amino acid at position 392 is a new determinant for TVN. No significant difference in accumulation in tobacco was observed between N605 and N605_MKHCPro. Since phylogenetic analyses showed that the loss of necrosis in tobacco has occurred several times independently during PVY evolution, these repeated evolutions strongly suggest that tobacco necrosis is a costly trait in PVY.

FlourishCare Model of Integrated Care: The Validation of the Flourish Index-Revised (FI-R)

Abstract Background and Objectives This study validates the Flourish Index–Revised (FI-R), a tool evaluating integrated health care models. The original Flourish Index (FI) was developed in 2018 (Faul et al., 2018) and has been refined to align with the FlourishCare (FC)TM Model (Model) for geriatric primary care. Research Design and Methods The Model provides integrated biopsychosocial health care to older adults. The FI-R uses 25 quality-of-care indicators and 7 contextual community indicators. The FI-R was validated with Categorial Principal Components Analysis (CATPCA) using a sample of 949 patients 50+ who were mostly female (73%), Non-Hispanic White (70%), living in urban areas (90%), and married (29%), single (22%) or divorced (19%). The mean age was 73.46 (SD=10.86) and mean years of education was 14.30 (SD=2.14). Results CATPCA showed a four-dimensional structure of biological, psychological, and two social determinants of health (SDOH) subdomains: health behaviors and community. Final selection of indicators was based on total variance accounted for &amp;gt;0.30, absolute values of item loadings &amp;gt;0.45, and not having cross loadings &amp;gt;0.45 on two factors. Internal consistency (Cronbach Alpha) for the determinants were: biological=0.75, psychological=0.76, SDOH: community=0.70, SDOH: Health Behaviors=0.50 and total FI-R=0.95. Sensitivity to change was shown for the total FI-R, psychological determinants, and SDOH:health behaviors but not for biological determinants. Discussion and Implications The validation of the FI-R shows promise for its usability to evaluate integrated health care models using existing measures in electronic health systems. More work is needed to improve the incorporation of SDOH:sociodemographics into the FI-R.

Association between childhood obesity, trace elements, and heavy metals: Recent discoveries and future perspectives.

Trace elements and heavy metals play pivotal roles in health status by regulating a myriad of vital biological functions. Abnormal metal homeostasis has been linked to a constellation of pathogenic complications, including oxidative stress, inflammatory processes, dyslipidemia, and impaired insulin-mediated metabolism of carbohydrates, thereby increasing the odds of developing childhood obesity and related comorbidities. Herein, we provide a comprehensive revision of recent literature on the association between childhood obesity, trace elements, and heavy metals. Further, we emphasize on the crucial importance of addressing the influence that interindividual variability factors (e.g., sex, age, genetic determinants, concomitance of comorbidities, and environmental factors) may have in modulating the susceptibility to disease development. Altogether, this review article represents a concise guide to better understand the involvement of metals in childhood obesity pathogenesis and discusses future needs with the aim of establishing robust biomarkers in the context of precision medicine.