Analysis of genomic downsizing on the basis of region-of-difference polymorphism profiling of Mycobacterium tuberculosis patient isolates reveals geographic partitioning

Mycobacterium tuberculosis, the etiological agent of tuberculosis, has lost many coding and noncoding regions in its genome during the course of evolution. We performed region-of-difference (RD) analysis using PCR-based genotyping of 131 M. tuberculosis clinical isolates obtained from four different countries, namely, India, Peru, Libya, and Angola. Our studies revealed that RD patterns are often distinct for strains circulating in specific geographical regions and can be used to trace the descent and spread of an isolate from its original reservoir. We describe our findings, which show that no single isolate from the four countries (n = 131) had all the 15 RDs either deleted or retained. Tuberculosis-specific deletion 1 (TbD1) was found to be conserved in 23% of the Indian isolates, indicating their possible ancient origin. RD9 was the most conserved region, RD11 was predominantly deleted, and RD6 was the most variable among the isolates in our collection irrespective of their geographic region. In contrast to earlier reports, our results demonstrate that the deletion of RD1 does not correlate with a decrease in the virulence potential of M. tuberculosis, as Indian isolates (n = 30) examined by us were from diseased individuals and yet had lost the RD1 region. Our results further illustrated that the intactness of the RD5 region may be associated with increased virulence of the organism. This study highlights that the RDs in M. tuberculosis genomes are geographically distributed and specific and may possibly be associated with virulence spectrum.     

Apolipoprotein(a) phenotypes are reliable biomarkers for familial aggregation of coronary heart disease

Lipoprotein(a) [Lp(a)] is an atherogenic and prothrombotic molecule formed by the covalent binding of the highly polymorphic apolipoprotein(a) [apo(a)] to apoprotein B-100 of LDL. High Lp(a) concentrations are a recognized genetic risk factor for coronary heart disease (CHD) and have been shown to be related with a familial clustering of ischemic cardiac events. Nevertheless, the association between apolipoprotein(a) isoforms and a positive familial history of CHD has received far less attention. In this report, we explored the distribution of apo(a) phenotypes in 127 CHD subjects with a family history of coronary events and in 92 CHD patients without such a history. Twenty-two apo(a) isoforms were detected by a high-resolution immunoblotting method. In univariate analysis, the percentage of subjects with at least one small sized apo(a) isoform was significantly higher in CHD patients with a positive family history than in those without (P<0.01). Multivariate analysis showed that apo(a) isoforms of low molecular weight were the best predictors of familial aggregation of cardiac ischemia. We conclude that apo(a) size polymorphism is strongly associated with a familial history of CHD and is more efficient than Lp(a) plasma concentrations in predicting the familial clustering of coronary disease. When detected by high-resolution techniques, apo(a) phenotypes are objective laboratory markers that can substitute for a knowledge of a positive family history of CHD and should be used, together with Lp(a) levels, to better assess the familial predisposition to coronary events.     

DC-SIGN mediates the binding of Aspergillus fumigatus and keratinophylic fungi by human dendritic cells

Human contact with fungi does not usually lead to pathological consequences, as the immune system manages to defeat the invader pathogens. Nevertheless, under immune suppression, fungi overcome immune defenses and cause diseases that range from nonserious colonizations of keratinizated tissue (Dermatophytosis) to life threatening disseminated infections (Aspergillosis). Host defenses against fungi rely on innate and adaptative responses, with dendritic cell (DC) and macrophage surface receptors having a major role in the recognition of fungal pathogens and in the orchestration of an effective immune response. DC-SIGN is a C-type lectin involved in the recognition of bacterial, viral and parasitic pathogens, as well as in interactions between cells of the immune system. Its expression is restricted to DCs and subsets of macrophages. Here we show that DC-SIGN mediates the binding and capture of Aspergillus fumigatus and keratinophylic fungi, including Chrysosporium tropicum, by human DCs, describe the requirements of these interactions and discuss their potential involvement in the onset and persistence of pulmonary fungal infections.     

Ocular measurements in fetal alcohol spectrum disorders

Fetal alcohol spectrum disorders (FASD) describe a range of physical, behavioral, and neurologic deficits in individuals exposed to alcohol prenatally. Reduced palpebral fissure length is one of the cardinal facial features of FASD. However, other ocular measurements have not been studied extensively in FASD. Using the Fetal Alcohol Syndrome Epidemiologic Research (FASER) database, we investigated how inner canthal distance (ICD), interpupillary distance (IPD), and outer canthal distance (OCD) centiles differed between FASD and non‐FASD individuals. We compared ocular measurement centiles in children with FASD to non‐FASD individuals and observed reductions in all three centiles for ICD, IPD, and OCD. However, when our non‐FASD children who had various forms of growth deficiency (microcephaly, short‐stature, or underweight) were compared to controls, we did not observe a similar reduction in ocular measurements. This suggests that reductions in ocular measurements are a direct effect of alcohol on ocular development independent of its effect on growth parameters, which is consistent with animal models showing a negative effect of alcohol on developing neural crest cells. Interpupillary distance centile appeared to be the most significantly reduced ocular measure we evaluated, suggesting it may be a useful measure to be considered in the diagnosis of FASD.     

Differentiating molecular etiologies of Angelman syndrome through facial phenotyping using deep learning

Angelman syndrome (AS) is caused by several genetic mechanisms that impair the expression of maternally‐inherited UBE3A through deletions, paternal uniparental disomy (UPD), UBE3A pathogenic variants, or imprinting defects. Current methods of differentiating the etiology require molecular testing, which is sometimes difficult to obtain. Recently, computer‐based facial analysis systems have been used to assist in identifying genetic conditions based on facial phenotypes. We sought to understand if the facial‐recognition system DeepGestalt could find differences in phenotype between molecular subtypes of AS. Images and molecular data on 261 individuals with AS ranging from 10 months through 32 years were analyzed by DeepGestalt in a cross‐validation model with receiver operating characteristic (ROC) curves generated. The area under the curve (AUC) of the ROC for each molecular subtype was compared and ranked from least to greatest differentiable phenotype. We determined that DeepGestalt demonstrated a high degree of discrimination between the deletion subtype and UPD or imprinting defects, and a lower degree of discrimination with the UBE3A pathogenic variants subtype. Our findings suggest that DeepGestalt can recognize subclinical differences in phenotype based on etiology and may provide decision support for testing.     

Time course for strength and muscle thickness changes following upper and lower body resistance training in men and women

 The purpose of this study was to investigate the time course of skeletal muscle adaptations resulting from high-intensity, upper and lower body dynamic resistance training (WT). A group of 17 men and 20 women were recruited for WT, and 6 men and 7 women served as a control group. The WT group performed six dynamic resistance exercises to fatigue using 8–12 repetition maximum (RM). The subjects trained 3 days a week for 12 weeks. One-RM knee extension (KE) and chest press (CP) exercises were measured at baseline and at weeks 2, 4, 6, 8, and 12 for the WT group. Muscle thickness (MTH) was measured by ultrasound at eight anatomical sites. One-RM CP and KE strength had increased significantly at week 4 for the female WT group. For the men in the WT group, 1 RM had increased significantly at week 2 for KE and at week 6 for CP. The mean relative increases in KE and CP strength were 19% and 19% for the men and 19% and 27% for the women, respectively, after 12 weeks of WT. Resistance training elicited a significant increase in MTH of the chest and triceps muscles at week 6 in both sexes. There were non-significant trends for increases in quadriceps MTH for the WT groups. The relative increases in upper and lower body MTH were 12%–21% and 7%–9% in the men and 10%–31% and 7%–8% in the women respectively, after 12 weeks of WT. These results would suggest that increases in MTH in the upper body are greater and occur earlier compared to the lower extremity, during the first 12 weeks of a total body WT programme. The time-course and proportions of the increase in strength and MTH were similar for both the men and the women. Accepted: 6 September 1999     

Absence of TREM2 polymorphisms in patients with Alzheimer's disease and Frontotemporal Lobar Degeneration

Triggering Receptor Expressed on Myeloid cells (TREM)2 deficiency originates a genetic syndrome characterized by bone cysts and presenile dementia, named Nasu-Hakola disease (NHD). Early onset dementia and marked involvement of frontal regions are features characterizing both NHD and other kinds of neurodegenerative disorders, such as Frontotemporal Lobar Degeneration (FTLD), and, in some cases, Alzheimer's disease (AD). Three Single Nucleotide Polymorphisms (SNPs) in TREM2 coding region were screened by allelic discrimination in a population of probable AD patients as well as FTLD patients as compared with age-matched controls. In addition, mutation scanning of the coding region of TREM2 gene was carried out in 7 patients with early onset AD (EOAD), 16 FTLD, and 20 controls. None of the SNPs analyzed was present, either in patients or controls. Moreover, mutation scanning of the five exons of TREM2 failed to detect the presence of novel polymorphisms. These data demonstrate that TREM2 coding region is highly conserved, implying a crucial role of this receptor. Further studies, including a functional analysis, are certainly required to clarify the role of TREM2 in neurodegenerative processes.