Miracle-dz/UniFAR-FTUs huggingface dataset:
Neuronal dysfunction and disconnection of cortical hubs in non-demented subjects with elevated amyloid burden

Disruption of functional connectivity between brain regions may represent an early functional consequence of β-amyloid pathology prior to clinical Alzheimer's disease. We aimed to investigate if non-demented older individuals with increased amyloid burden demonstrate disruptions of functional whole-brain connectivity in cortical hubs (brain regions typically highly connected to multiple other brain areas) and if these disruptions are associated with neuronal dysfunction as measured with fluorodeoxyglucose-positron emission tomography. In healthy subjects without cognitive symptoms and patients with mild cognitive impairment, we used positron emission tomography to assess amyloid burden and cerebral glucose metabolism, structural magnetic resonance imaging to quantify atrophy and novel resting state functional magnetic resonance imaging processing methods to calculate whole-brain connectivity. Significant disruptions of whole-brain connectivity were found in amyloid-positive patients with mild cognitive impairment in typical cortical hubs (posterior cingulate cortex/precuneus), strongly overlapping with regional hypometabolism. Subtle connectivity disruptions and hypometabolism were already present in amyloid-positive asymptomatic subjects. Voxel-based morphometry measures indicate that these findings were not solely a consequence of regional atrophy. Whole-brain connectivity values and metabolism showed a positive correlation with each other and a negative correlation with amyloid burden. These results indicate that disruption of functional connectivity and hypometabolism may represent early functional consequences of emerging molecular Alzheimer's disease pathology, evolving prior to clinical onset of dementia. The spatial overlap between hypometabolism and disruption of connectivity in cortical hubs points to a particular susceptibility of these regions to early Alzheimer's-type neurodegeneration and may reflect a link between synaptic dysfunction and functional disconnection.
Effects of Carrageenans on Biological Properties of Echinochrome

Sea urchin pigment echinochrome A (Ech), a water-insoluble compound, is the active substance in the cardioprotective and antioxidant drug Histochrome® (PIBOC FEB RAS, Moscow, Russia). It has been established that Ech dissolves in aqueous solutions of carrageenans (CRGs). Herein, we describe the effects of different types of CRGs on some properties of Ech. Our results showed that CRGs significantly decreased the spermotoxicity of Ech, against the sea urchin S. intermedius sperm. Ech, as well as its complex with CRG, did not affect the division and development of early embryos of the sea urchin. Ech reduced reactive oxygen species production (ROS) in neutrophils, caused by CRG. The obtained complexes of these substances with pro- and anti-activating ROS formation properties illustrate the possibility of modulating the ROS induction, using these compounds. The CRGs stimulate the induction of anti-inflammatory IL-10 synthesis, whereas Ech inhibits this synthesis and increases the production of the pro-inflammatory cytokines IL-6 and TNFα. The inclusion of Ech, in the complex with the CRGs, decreases Ech’s ability to induce the expression of pro-inflammatory cytokines, especially TNFα, and increases the induction of anti-inflammatory cytokine IL-10. Thus, CRGs modify the action of Ech, by decreasing its pro-inflammatory effect. Whereas, the Ech’s protective action towards human epithelial HT-29 cells remains to be unaltered in the complex, with κ/β-CRG, under stress conditions.
The Puerto Rico Alzheimer Disease Initiative (PRADI): A Multisource Ascertainment Approach

Introduction Puerto Ricans, the second largest Latino group in the continental US, are underrepresented in genomic studies of Alzheimer disease (AD). To increase representation of this group in genomic studies of AD, we developed a multisource ascertainment approach to enroll AD patients, and their family members living in Puerto Rico (PR) as part of the Alzheimer’s Disease Sequencing Project (ADSP), an international effort to advance broader personalized/precision medicine initiatives for AD across all populations. Methods The Puerto Rico Alzheimer Disease Initiative (PRADI) multisource ascertainment approach was developed to recruit and enroll Puerto Rican adults aged 50 years and older for a genetic research study of AD, including individuals with cognitive decline (AD, mild cognitive impairment), their similarly, aged family members, and cognitively healthy unrelated individuals age 50 and up. Emphasizing identification and relationship building with key stakeholders, we conducted ascertainment across the island. In addition to reporting on PRADI ascertainment, we detail admixture analysis for our cohort by region, group differences in age of onset, cognitive level by region, and ascertainment source. Results We report on 674 individuals who met standard eligibility criteria [282 AD-affected participants (42% of the sample), 115 individuals with mild cognitive impairment (MCI) (17% of the sample), and 277 cognitively healthy individuals (41% of the sample)]. There are 43 possible multiplex families (10 families with 4 or more AD-affected members and 3 families with 3 AD-affected members). Most individuals in our cohort were ascertained from the Metro, Bayamón, and Caguas health regions. Across health regions, we found differences in ancestral backgrounds, and select clinical traits. Discussion The multisource ascertainment approach used in the PRADI study highlights the importance of enlisting a broad range of community resources and providers. Preliminary results provide important information about our cohort that will be useful as we move forward with ascertainment. We expect that results from the PRADI study will lead to a better understanding of genetic risk for AD among this population.
Comparison of Mechanical Properties of Natural Gut and Synthetic Polymer Harp Strings

The long-term mechanical behaviour of a number of fluorocarbon and gut harp strings has been examined, and the results compared with a previous study of rectified nylon strings. The stretching behaviour of the three materials was studied via different measures of the Young’s modulus; with test time scales on the order of weeks, minutes, and milliseconds. The strings were subjected to cyclic variations in temperature, enabling various aspects of their thermal behaviour to be investigated. The effects of humidity changes on gut strings were also examined. The behaviour of the fluorocarbon strings was found to be similar in many ways to that of the nylon strings, despite their different chemical formulation and significantly higher density. In particular, the faster measures of Young’s modulus were found to show an almost identical strong variation with the applied stress; while the thermal behaviour of both materials was largely determined by the balance between opposing effects associated with thermal contraction and thermal variations in the Young’s modulus. The gut strings showed some similarities of behaviour to the synthetic materials, but also major differences. All three measures of the Young’s modulus remained constant as the applied stress was increased. The gut strings were far more sensitive to changes in humidity than the synthetic materials, although some of the results, especially the thermal tuning sensitivity of the strings when held at constant length, displayed remarkable stability under changing humidity. The observed behaviour suggests very strongly that there is significant coupling between humidity-related changes in the linear density of a gut string and complementary changes in its tension.
Evolution of drug resistance in an antifungal-naive chronic Candida lusitaniae infection

Significance Drug-resistant subpopulations of microbes or tumor cells are difficult to detect but can confound disease treatment. In this deep characterization of a chronic fungal infection, we report unprecedented heterogeneity in the drug resistance-related gene MRR1 among Clavispora (Candida) lusitaniae isolates from a single individual. Cells expressing Mrr1 variants that led to drug resistance, by elevated expression of the MDR1-encoded efflux protein, were present at low levels in each sample and thus were undetected in standard assays. We provide evidence that these drug-resistant fungi may arise indirectly in response to other factors present in the infection. Our work suggests that alternative methods may be able to identify drug-resistant subpopulations and thus positively impact patient care. Management of the limited number of antimicrobials currently available requires the identification of infections that contain drug-resistant isolates and the discovery of factors that promote the evolution of drug resistance. Here, we report a single fungal infection in which we have identified numerous subpopulations that differ in their alleles of a single gene that impacts drug resistance. The diversity at this locus was markedly greater than the reported heterogeneity of alleles conferring antibiotic resistance in bacterial infections. Analysis of genomes from hundreds of Clavispora (Candida) lusitaniae isolates, through individual and pooled isolate sequencing, from a single individual with cystic fibrosis revealed at least 25 nonsynonymous mutations in MRR1, which encodes a transcription factor capable of inducing fluconazole (FLZ) resistance in Candida species. Isolates with high-activity Mrr1 variants were resistant to FLZ due to elevated expression of the MDR1-encoded efflux pump. We found that high Mrr1-regulated Mdr1 activity protected against host and bacterial factors, suggesting drug resistance can be selected for indirectly and perhaps explaining the Mrr1 heterogeneity in this individual who had no prior azole exposure. Regional analysis of C. lusitaniae populations from the upper and lower lobes of the right lung suggested intermingling of subpopulations throughout. Our retrospective characterization of sputum and lung populations by pooled sequencing found that alleles that confer FLZ resistance were a minority in each pool, possibly explaining why they were undetected before unsuccessful FLZ therapy. New susceptibility testing regimes may detect problematical drug-resistant subpopulations in heterogeneous single-species infections.
Psychosexual Aspects, Effects of Prenatal Androgen Exposure, and Gender Change in 46,XY Disorders of Sex Development

CONTEXT In 46,XY disorders of sexual development (DSD) patients, several factors may affect psychosexual development, leading to gender identity discrepancy and gender change later in life. Prenatal sexual steroid exposure and external genital virilization are considered to influence human psychosexual development, but their roles not completely understood yet. DESIGN A total of 144 individuals (18 to 60 years of age) with a clinical/molecular diagnosis of 46,XY DSD from a single tertiary center were enrolled. Psychosexual outcomes (gender role, gender identity, and sexual orientation) were assessed using questionnaires and psychological test. The Sinnecker score was used for genital virilization measurement. Prenatal androgen exposure was estimated according to 46,XY DSD etiology. RESULTS We found a positive association between prenatal androgen exposure and male psychosexual outcomes. Alternatively, prenatal estrogen exposure, age of gonadectomy, and the degree of external genital virilization did not influence any psychosexual outcome. There were 19% (n = 27) with gender change, which was associated with prenatal androgen exposure (P < 0.001) but not with the external genital virilization. The median age of gender change was 15 years, but most of the patients reported the desire for gender change earlier. CONCLUSIONS Prenatal androgen exposure influenced psychosexual development in 46,XY DSD favoring male psychosexuality in all psychosexual outcomes, whereas the degree of external genital virilization did not influence these outcomes. The organizational effect of sexual steroids on psychosexuality at puberty appears to be weak in comparison with the prenatal effects. Prenatal androgen exposure also influenced female-to-male gender change frequency. All 46,XY DSD conditions with prenatal androgen exposure must be followed for gender issues in their management.
Why is double clutching rare in the Majorcan midwife toad?

In species with male parental care, multiple clutching is the provisioning of care to the eggs or offspring of two or more females simultaneously. Multiple clutching represents a strategy by which males reduce the reproductive costs associated with male parental care relative to the reproductive gains. Although multiple clutching is common in two species of midwife toads (Alytes obstetricansandA. cisternasii), double clutching in the Majorcan midwife toad,A. muletensis, is rare and triple clutching has never been observed. In this paper, the reasons for the low frequency of double clutching inA. muletensisrelative to the other species are examined. Two hypotheses were experimentally disproved: double clutching is not limited to particularly large males, and females do not prefer to mate with non-brooding than brooding males. The low incidence of double clutching inA. muletensisappears to result from a time constraint on males. Males only advertise for second clutches within 3 days of the first. This time limit may have evolved as a result of energetic constraints on either the duration of the brooding period of males, or the developmental plasticity of larvae. A model was constructed which illustrates that if females mate randomly with respect to the brooding status of males, the time limit for obtaining a second clutch partially explains the differences in frequencies of double clutching observed betweenA. muletensisand the other species of midwife toads. The female inter-clutch interval and the male brooding period are also likely to contribute significantly to the rate of double clutching in a population.
High Fat Mixed Meal Tolerance Test Leads to Suppression of Osteocalcin Decrease in Obese Insulin Resistant Subjects Compared to Healthy Adults

Nutrients influence bone turnover. Carboxylated osteocalcin (Gla-OC) participates in bone formation whereas its undercarboxylated form (Glu-OC) acts as a hormone in glucose metabolism. The aim of the study was to determine the responses of Gla-OC, Glu-OC, and total-OC (calculated as the sum of Gla-OC and Glu-OC) to a high fat mixed meal tolerance test (HFMTT) in non-obese (body mass index (BMI) < 30 kg/m2, n = 24) and obese subjects (30 < BMI < 40 kg/m2, n = 70) (both sexes, aged 25–65 years). Serum Gla-OC and Glu-OC were measured at baseline as well as at 2 and 6 h during a HFMTT by enzyme-linked immunosorbent assay (ELISA). Baseline Gla-OC, Glu-OC, and total-OC levels were lower in obese individuals compared to non-obese participants (p = 0.037, p = 0.016 and p = 0.005, respectively). The decrease in Gla-OC and total-OC, but not in Glu-OC, concentrations during the HFMTT was suppressed in obese, but not in non-obese controls (p < 0.05, p < 0.01, p = 0.08, respectively). Subjects with the highest homeostatic model assessment for insulin resistance (HOMA-IR) index values had a less pronounced decrease in total-OC compared to patients with values of HOMA-IR index in the 1st quartile (p < 0.05). Net incremental area under Gla-OC inversely correlated with adiponectin (rho = −0.35, p = 0.001). Increase in insulin sensitivity and adiponectin level in obese subjects could beneficially influence postprandial bone turnover expressed by osteocalcin concentration.
Tumor regression after combination of radiation and PD-1 antibody nivolumab treatment in a patient with metastatic mediastinal leiomyosarcoma: a case report

ABSTRACT The PD-1/PD-L1 axis is characterized as an important checkpoint of immune activation, particularly through negatively regulating T cell function. Although accumulated evidence has demonstrated the patients with some types of tumor benefit from blockade of PD-1/PD-L1 signaling pathway, the possible synergistic effect of combination of radiotherapy and anti-PD-1/PD-L1 antibody still need to be explored. Here, we report a case of patient who was diagnosed with metastatic mediastinal leiomyosarcoma and treated by combination of local radiotherapy and anti-PD-1 antibody nivolumab. Remarkable tumor regression was observed at both the irradiated focus and distant metastatic sites 2 months later after combined treatment. The patient has tumor mutational burden (8.7 somatic mutations/Mb) and positive PD-L1 expression. The increased circulating lymphocytes suggest induced activation of immune response after combination treatment. Free disease progression has reached one and a half years as far.
Household Accessibility and Residential Relocation in Older Adults.

Objectives It is unclear how home environmental factors influence relocation decisions. We examined whether indoor accessibility, entrance accessibility, bathroom safety features, housing type, and housing condition, were associated with relocations either within the community or to residential care facilities. Methods We used prospective data over four years from the nationally representative National Health and Aging Trends Study in the United States of Medicare beneficiaries 65 years and older living in the community (N = 7,197). We used multinomial regression analysis with survey weights. Results Over the four years, 8.2% of the population moved within the community, and 3.9% moved to residential care facilities. After adjusting for demographics and health factors, poor indoor accessibility was found to be associated with moves within the community but not to residential care facilities. No additional home environmental factors were associated with relocation. Discussion One-floor dwellings, access to a lift or having a kitchen, bedroom, and bathroom on the same floor may help older adults age in place. Understanding which modifiable home environmental factors trigger late life relocation, and to where, has practical implications for developing policies and programs to help older adults age in their place of choice.
Semiautomated Feature Extraction from RGB Images for Sorghum Panicle Architecture GWAS1[OPEN]

Image-based phenotyping facilitates the genetic dissection of uni- and multi-dimensional traits of sorghum panicles. Because structural variation in the inflorescence architecture of cereal crops can influence yield, it is of interest to identify the genes responsible for this variation. However, the manual collection of inflorescence phenotypes can be time consuming for the large populations needed to conduct genome-wide association studies (GWAS) and is difficult for multidimensional traits such as volume. A semiautomated phenotyping pipeline, TIM (Toolkit for Inflorescence Measurement), was developed and used to extract unidimensional and multidimensional features from images of 1,064 sorghum (Sorghum bicolor) panicles from 272 genotypes comprising a subset of the Sorghum Association Panel. GWAS detected 35 unique single-nucleotide polymorphisms associated with variation in inflorescence architecture. The accuracy of the TIM pipeline is supported by the fact that several of these trait-associated single-nucleotide polymorphisms (TASs) are located within chromosomal regions associated with similar traits in previously published quantitative trait locus and GWAS analyses of sorghum. Additionally, sorghum homologs of maize (Zea mays) and rice (Oryza sativa) genes known to affect inflorescence architecture are enriched in the vicinities of TASs. Finally, our TASs are enriched within genomic regions that exhibit high levels of divergence between converted tropical lines and cultivars, consistent with the hypothesis that these chromosomal intervals were targets of selection during modern breeding.
Hexokinase-2 Expression in 11C-Methionine–Positive, 18F-FDG–Negative Multiple Myeloma

PET with 18F-FDG is the standard modality in nuclear medicine for imaging multiple myeloma (MM). However, viable MM as detected by MRI or PET with other metabolic tracers, including 11C-methionine, may be missed—for example, because of low hexokinase 2 (HK2) expression of tumor cells. The aim of this study was to further investigate potential reasons for PET false negativity. Methods: A cohort of 15 mainly pretreated patients with relapsed or refractory biopsy-proven, serologically active MM who underwent both 18F-FDG and 11C-methionine PET/CT was retrospectively analyzed. Results: In 9 of the 15 patients, 18F-FDG PET was negative in the presence of viable disease. In the remaining 6 patients, both 18F-FDG and 11C-methionine PET/CT revealed the same number of MM lesions. At immunohistochemistry, 18F-FDG–negative myeloma did not exhibit significant differences in HK2 or glucose-6-phosphatase expression from 18F-FDG–positive disease (P = 0.57 and P = 0.44, respectively). Conclusion: Beyond HK2 expression, 18F-FDG negativity in (mainly pretreated) MM patients seems to be associated with additional causes not yet known.
From Water Source to Tap of Ceramic Filters—Factors That Influence Water Quality Between Collection and Consumption in Rural Households in Nepal

The study assessed changes in water quality between the water source and the tap of locally produced low cost ceramic water filters used by a community living in hygienically critical conditions in a remote mountainous area in Western Nepal. Data was collected from 42 rural households during two visits. The effectiveness of filter handling on its performance was assessed through microbiological analysis, structured household interviews and structured observations. Water quality decreased significantly when source water was filled into transport containers, while the use of the filters improved drinking water quality for about 40% of the households. Highly inadequate filter cleaning practices involving the use of contaminated raw water, hands (geo mean = 110 E. coli CFU/100 mL) and cleaning tools (geo mean = 80 E. coli CFU/100 mL) stained hygienic parts of the filter. The use of boiling water to disinfect the filters was significantly correlated with improved filter performance and should be further promoted. However, even disinfected filters achieved a very low average LRV for E. coli of 0.4 in the field and performed worse than during laboratory tests (LRV for E. coli of 1.5–2). Comprehensive training on adequate filter handling, as well as better filter products, are required to improve the impact of filter use.