Biology subjects

Feldman, M.

Publications and source records attributed to Feldman, M..

9 recordsLinked to original sources

bioRxiv2018

Multicenter validation of a machine learning algorithm for 48 hour all-cause mortality prediction

PurposeThis study evaluates a machine-learning-based mortality prediction tool.\n\nMaterials and MethodsWe conducted a retrospective study with data drawn from three academic health centers. Inpatients of at least 18 years of age and with at least one observation of each vital sign were included. Predictions were made at 12, 24, and 48 hours before death. Models fit to training data from each institution were evaluated on hold-out test data from the same institution and data from the remaining institutions. Predictions were compared to those of qSOFA and MEWS using area under the receiver operating characteristic curve (AUROC).\n\nResultsFor training and testing on data from a single institution, machine learning predictions averaged AUROCs of 0.97, 0.96, and 0.95 across institutional test sets for 12-, 24-, and 48-hour predictions, respectively. When trained and tested on data from different hospitals, the algorithm achieved AUROC up to 0.95, 0.93, and 0.91, for 12-, 24-, and 48-hour predictions, respectively. MEWS and qSOFA had average 48-hour AUROCs of 0.86 and 0.82, respectively.\n\nConclusionThis algorithm may help identify patients in need of increased levels of clinical care.

bioinformatics↗

bioRxiv2018

Late Pleistocene human genome suggests a local origin for the first farmers of central Anatolia

Anatolia was home to some of the earliest farming communities. It has been long debated whether a migration of farming groups introduced agriculture to central Anatolia. Here, we report the first genome-wide data from a 15,000-year-old Anatolian hunter-gatherer and from seven Anatolian and Levantine early farmers. We find high genetic continuity ([~]80-90%) between the hunter-gatherer and early farmers of Anatolia and detect two distinct incoming ancestries: an early Iranian/Caucasus related one and a later one linked to the ancient Levant. Finally, we observe a genetic link between southern Europe and the Near East predating 15,000 years ago that extends to central Europe during the post-last-glacial maximum period. Our results suggest a limited role of human migration in the emergence of agriculture in central Anatolia.

genetics↗

bioRxiv2018

Analysis of Polygenic Score Usage and Performance across Diverse Human Populations

Studies examining relationships between genotypic and phenotypic variation have historically been carried out on people of European ancestry. Efforts are underway to address this limitation, but until they succeed, the legacy of a Euro-centric bias will continue to hinder research, including the use of polygenic scores, which are individual-level metrics of genetic risk. Ongoing debate surrounds the generalizability of polygenic scores based on genome-wide association studies (GWAS) conducted in European ancestry samples, to non-European ancestry samples. We analyzed the first decade of polygenic scoring studies (2008-2017, inclusive), and found that 67% of studies included exclusively European ancestry participants and another 19% included only East Asian ancestry participants. Only 3.8% of studies were carried out on samples of African, Hispanic, or Indigenous peoples. We find that effect sizes for European ancestry-derived polygenic scores are only 36% as large in African ancestry samples, as in European ancestry samples (t=-10.056, df=22, p=5.5x10-10). Analyzing global populations, we show that relationships between height polygenic scores and height are highly dependent on methodological choices in polygenic score construction, highlighting the need for caution in interpreting population level differences in distributions of polygenic scores, as currently calculated. These findings bolster the rationale for large-scale GWAS in diverse human populations and highlight the need for better handling of linkage disequilibrium and variant frequencies when applying scores to non-European samples.

genetics↗

bioRxiv2018

A dual motif mediates outer-membrane translocation and packing of glycosidases into Bacteroides Outer Membrane Vesicles.

Outer membrane vesicles (OMV) are spherical structures derived from the outer membrane (OM) of Gram-negative bacteria. Bacteroides spp. are prominent components of the human gut microbiota, and OMV produced with these species are proposed to play key roles in gut homeostasis. OMV biogenesis in Bacteroides is a poorly understood process. Here, we revisited the protein composition of B. theta OMVs by mass spectrometry. We confirmed that OMVs produced by this organism contain large quantities of glycosidases and proteases, with most of them being lipoproteins. We found that most of these OMV-enriched lipoproteins are encoded by polysaccharide utilization loci (PULs), such as the sus operon. We examined the subcellular localization of the components of the Sus system, and found that the alpha-amylase SusG is highly enriched in OMVs while the oligosaccharide importer SusC remains mostly in the OM. We show that all OMV-enriched lipoproteins possess a lipoprotein export sequence (LES) that mediates translocation of SusG from the periplasmic face of the OM towards the extracellular milieu and is required for SusG to localize preferentially to OMVs. We also show that surface-exposed SusG in OMVs is active and can rescue growth of bacterial cells incapable of growing on starch as only carbon source. Our results support the role of OMVs as \"public goods\" that can be utilized by other organisms with different metabolic capabilities.\n\nIMPORTANCESpecies from the Bacteroides genus are predominant members of the human gut microbiota. OMVs in Bacteroides have been shown to be important for the homeostasis of complex host-commensal relationships, mainly involving immune tolerance and protection from disease. OMVs carry many enzymatic activities involved in the cleavage of complex polysaccharides and have been proposed as public goods that can provide growth to other bacterial species by release of polysaccharide breakdown products into the gut lumen. Nevertheless, the mechanistic nature of OMV biogenesis is unclear for Bacteroides spp. This works shows the presence of a negatively-charged rich amino acid dual motif that is required for efficient packing of the surface-exposed alpha-amylase SusG into OMVs. Discovery of this motif (LES) is the first step in the generation of tailor made probiotic interventions that can exploit LES-related sequences to generate Bacteroides strains displaying proteins of interest in OMVs.

microbiology↗

bioRxiv2018

An Advancing Front of Old Age Human Survival

Old age mortality decline has driven recent increases in lifespans, but there is no agreement about trends in the age-pattern of old deaths. Some hypotheses argue that old-age deaths should have become compressed at high ages, others that old-age deaths should have become more dispersed with age, and yet others are consistent with little change in dispersion. However, direct analyses of old-age deaths presents unusual challenges: death rates at the oldest ages are always noisy; published life tables must assume an asymptotic age pattern of deaths; and the definition of \"old age\" changes as lives lengthen. Here we use robust percentile-based methods to overcome these challenges and show, for 5 decades in 20 developed countries, that old-age survival follows an advancing front, like a traveling wave. The front lies between the 25th and 90th percentiles of old-age deaths, advancing with nearly constant long-term shape but annual fluctuations in speed. The existence of this front leads to several predictions that we verify, e.g., that advances in life expectancy at age 65 are highly correlated with the advance of the 25th percentile, but not with distances between higher percentiles. Our unexpected result has implications for biological hypotheses about human aging, and for future mortality change.

epidemiology↗

bioRxiv2018

A genetic link between whole-plant water use efficiency and leaf carbon isotope composition in the C4 grass Setaria

Increasing whole plant water use efficiency (yield per transpiration; WUEplant) through plant breeding can benefit the sustainability of agriculture and improve crop yield under drought. To select for WUEplant, an efficient phenotyping method that reports on the genetic contribution of component traits such as transpiration efficiency (TEi; rate of CO2 assimilation per stomatal conductance) must be developed. Leaf carbon stable isotope composition ({delta}13Cleaf) has been proposed as a high-throughput proxy for TEi, and a negative correlation between {delta}13Cleaf and both WUEplant and TEi has previously been demonstrated in several C4 grass species. Therefore, the aim of the research presented here was to determine if the same loci control {delta}13Cleaf, WUEplant, and TEi under well-watered and water-limited conditions in a recombinant inbred line (RIL) population of closely related C4 grasses Setaria viridis and S. italica. Three quantitative trait loci (QTL) for {delta}13Cleaf were co-localized with transpiration, biomass, and a linear model of WUE. When WUEplant was calculated for allele classes based on the three QTL for {delta}13Cleaf, {delta}13Cleaf was negatively correlated with WUEplant as theory predicts when WUEplant is in part driven by differences in TEi. In any population, multiple traits can influence WUEplant; however, the analysis of {delta}13Cleaf in this RIL population demonstrates that there is genetic control of TEi that significantly contributes to WUEplant. Furthermore, this research suggests that {delta}13Cleaf can be used in marker-assisted breeding to select for TEi and as a tool to better understand the physiology and genetic architecture of TEi and WUEplant in C4 species.\n\nSignificance StatementOverextended water resources and drought are major agricultural problems worldwide. Therefore, selection for increased plant water use efficiency (WUEplant) in food and biofuel crop species is an important trait in plant breeding programs. Leaf carbon isotopic composition ({delta}13Cleaf) has potential as a rapid and effective high throughput phenotyping method for intrinsic transpiration efficiency (TEi), an important leaf-level component trait of WUEplant. Our research shows that {delta}13Cleaf and WUEplant share a common genetic architecture through their shared relationship with TEi. This suggests that {delta}13Cleaf can be used as a screen for TEi in marker-assisted plant breeding programs to improve crop drought resistance and decrease agricultural water consumption.

plant biology↗

bioRxiv2017

Evolution Of Hierarchy In Bacterial Metabolic Networks

BackgroundIn self-organized systems, the concept of flow hierarchy is a useful way to characterize the movement of information throughout a network. Hierarchical network organizations are shown to arise when there is a cost of maintaining links in the network. A similar constraint exists in metabolic networks, where costs come from reduced efficiency of nonspecific enzymes or from producing unnecessary enzymes. Previous analyses of bacterial metabolic networks have been used to predict the minimal nutrients that a bacterium needs to grow, its mutualistic relationships with other bacteria, and its major ecological niche. Using flow hierarchy, we can also infer the tradeoffs between growth rate and metabolic efficiency that bacteria make given their environmental constraints.\n\nResultsUsing a comparative approach on 2,935 bacterial metabolic networks, we show that flow hierarchy in bacterial metabolic networks tracks a fundamental tradeoff between growth rate and biomass production, and reflects a bacteriums realized ecological strategy. Additionally, by inferring the ancestral metabolic networks, we find that hierarchy decreases with distance from the root of the tree, suggesting the important pressure of increased growth rate relative to efficiency in the face of competition.\n\nConclusionsJust as hierarchical character is an important structural property in efficiently engineered systems, it also evolves in self-organized bacterial metabolic networks, reflects the life-history strategies of those bacteria, and plays an important role in network organization and efficiency.

evolutionary biology↗

bioRxiv2017

The Genetic History of Northern Europe

Recent ancient DNA studies have revealed that the genetic history of modern Europeans was shaped by a series of migration and admixture events between deeply diverged groups. While these events are well described in Central and Southern Europe, genetic evidence from Northern Europe surrounding the Baltic Sea is still sparse. Here we report genome-wide DNA data from 24 ancient North Europeans ranging from [~]7,500 to 200 calBCE spanning the transition from a hunter-gatherer to an agricultural lifestyle, as well as the adoption of bronze metallurgy. We show that Scandinavia was settled after the retreat of the glacial ice sheets from a southern and a northern route, and that the first Scandinavian Neolithic farmers derive their ancestry from Anatolia 1000 years earlier than previously demonstrated. The range of Western European Mesolithic hunter-gatherers extended to the east of the Baltic Sea, where these populations persisted without gene-flow from Central European farmers until around 2,900 calBCE when the arrival of steppe pastoralists introduced a major shift in economy and established wide-reaching networks of contact within the Corded Ware Complex.

genetics↗

bioRxiv2016

The Stone Age Plague: 1000 years of Persistence in Eurasia

Molecular signatures of Yersinia pestis were recently identified in prehistoric Eurasian individuals, thus suggesting Y. pestis caused some form of disease in humans prior to the first historically documented pandemic. Here, we present six new Y. pestis genomes spanning from the European Late Neolithic to the Bronze Age (LNBA) dating from 4,800 to 3,700 BP. We show that all currently investigated LNBA strains form a single genetic clade in the Y. pestis phylogeny that appears to be extinct. Interpreting our data within the context of recent ancient human genomic evidence, which suggests an increase in human mobility during the LNBA, we propose a possible scenario for the spread of Y. pestis during the LNBA: Y. pestis may have entered Europe from Central Eurasia during an expansion of steppe people, persisted within Europe until the mid Bronze Age, and moved back towards Central Eurasia in parallel with subsequent human population movements.

evolutionary biology↗