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At least 19 recordsLinked to original sources

Uncertainty Modeling Outperforms Machine Learning for Microbiome Data Analysis.

Microbiome sequencing measures relative rather than absolute abundances, providing no direct information about total microbial load. Normalization methods attempt to compensate, but rely on strong, often untestable assumptions that can bias inference. Experimental measurements of load (e.g., qPCR, flow cytometry) offer a solution, but remain costly and uncommon. A recent high-profile study proposed that machine learning could bypass this limitation by predicting microbial load from sequencing data alone. To evaluate this claim, we assembled mutt, the largest public database of paired sequencing and load measurements, spanning 35 studies and over 15,000 samples. Using mutt, we show that published machine learning models fail to generalize: on average they perform worse than a naive baseline that always predicted the training set mean. These failures stem from covariate shift-limited shared taxa between studies, differences in community composition, and differences in preprocessing pipelines-that silently derail model inputs. In contrast, Bayesian partially identified models do not attempt to impute microbial load, but instead propagate scale uncertainty through downstream analyses. Across 30 benchmark datasets, Bayesian partially identified models consistently outperformed normalization and machine learning approaches, providing a principled and reproducible foundation for microbiome inference.

16S rRNA-seq↗

Associating functional recovery with neurocognitive profiles identified using partially ordered classification models.

Neurocognitive deficits are a core feature of schizophrenia and a significant cause of functional disability. However, targeting these deficits with new treatment approaches will only yield functional improvements if those cognitive operations that are responsible for different dimensions of functional recovery can be identified. A major challenge is that conventional neuropsychological tests, the most practical tools for broadly sampling cognitive functions in treatment trials, are polyfactorial, so that task performance is influenced by multiple cognitive operations. Hence, it is difficult to pinpoint exactly for which cognitive operations a low scoring subject may have poor functionality. We have previously applied in a neuropsychological test battery administered to 220 patients having schizophrenia or schizoaffective disorder, Bayesian statistical methods (yielding partially ordered sets, or posets) designed to mimic the expert analysis of a neuropsychologist by classifying patients into discrete groupings or "states" each having a unique cognitive profile. Here, we report on the association of attributes describing these states (viz. working memory, capacity for divergent thinking, cognitive flexibility and psychomotor speed) with two domains of functional outcome (work/education and residential functioning) rated up to 18 months later. After multiplicity correction, only working memory was associated with work/education outcome. While working memory was not associated with residential outcome, the remaining three attributes were. These findings suggest that different neurocognitive operations may be responsible for different outcome domains. Findings support the use of the poset methodology for clarifying patterns of relationships between discrete neurocognitive attributes and domains of functional outcome.

Adolescent↗

A dynamic model of angiotensin II infusion experiments.

Applications of control theory in studies of biological system dynamics have come to be called compartmental modelling. A second order, nonlinear, compartmental model is developed which describes the dynamics of the hormone angiotensin II (AII) and arterial blood pressure (BP) during AII infusion experiments. The model is partially identified using dose response data for constant infusion rates between 0.01 and 0.10 microgram/kg/min over a period of several minutes. This study represents a first step in understanding the dynamics of regulation of arterial blood pressure by the renin-angiotensin system. AII is a vasoconstrictor and is known to participate in the natural regulation of BP. AII is also believed to be an agent in the development of hypertension and atherosclerosis. The model is used to identify causal mechanisms which are consistent both with the established correlation between plasma AII concentration and arterial BP and with current physiological knowledge. The study demonstrates how a simple state variable model can be used to provide guidance concerning the design of future infusion experiments.

Angiotensin II↗

Latent structure of DSM-III-R Axis II psychopathology in a normal sample.

The Personality Disorder Examination was administered to 302 normal controls in the New York High-Risk Project in order to elicit Axis II diagnoses (revised 3rd edition of the Diagnostic and Statistical Manual of Mental Disorders; American Psychiatric Association, 1987) and quantitative dimensions of psychopathology. LISREL confirmatory factor analysis was used to evaluate the Axis II hypothesis of 3 orthogonal factors. There was considerable overlap among personality disorders. The best fitting LISREL model was of 3 oblique factors that were different for male and female subjects. Given that our choice of variables to constrain in order to mathematically identify our models was partially based on analysis of intercorrelations in our data set, our methods were not purely confirmatory. We present our results not to confirm specific hypotheses but to generate explicit hypotheses that can be tested in independent samples.

Adolescent↗

Discrimination of spatiotemporal patterns: the role of sustained and transient mechanisms.

The role of sustained and transient mechanisms in pattern and flicker perception has been examined in two discrimination experiments. In the first, observers were required to analyze the temporal or spatial properties of a stimulus that highly stimulated either sustained or transient mechanisms. The results were only partially consistent with a model identifying sustained mechanisms with pattern perception and transient mechanisms with flicker perception. In the second experiment a subthreshold summation paradigm was used to explore interactions among those mechanisms that encode the temporal and spatial properties of a stimulus. The effect of a subthreshold temporal-frequency change on discrimination performance could not be explained by models in which temporal-frequency and spatial-frequency changes are evaluated separately and then combined.

Discrimination Learning↗

Supported education programming for adults with psychiatric disabilities: results from a national survey.

Over the last 10 years, supported education (SEd) programs have been the topic of many journal publications and conference presentations, but little is known about their numbers and types across the U.S. This article reports the results of a national survey of all known SEd programs, numbering over 100. The largest number was associated with clubhouses, where full and partial SEd models could be identified. On-site supported education programs were located in community colleges and universities. A dozen "free-standing" programs were also identified. Analyses documented differences across program types in services provided, budget amounts and sources, and coordination with mental health and higher educational institutions. If supported education is to move beyond a specialty program in mental health, providers need to do more to market these services and to work collaboratively with stakeholder groups to expand supported education programming.

Adult↗

Murine metabolic HFpEF is associated with altered mitochondrial substrate handling and S-nitrosylation remodeling.

Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous condition with incompletely defined myocardial mechanisms. Here, using a two-hit murine model of cardiometabolic HFpEF induced by high-fat diet and endothelial nitric oxide synthase inhibition, we define a mitochondrial metabolic phenotype characterized by altered substrate handling, redox stress, and S-nitrosylation remodeling. While global proteomic changes were modest, metabolomic profiling revealed selective remodeling of tricarboxylic acid cycle intermediates, increased dicarboxylic acids, and altered redox-associated metabolites, consistent with mitochondrial metabolic and redox imbalance in this experimental setting. S-nitrosylation proteomics demonstrated a highly organized and bidirectional remodeling pattern affecting proteins involved in fatty acid/lipid metabolism, carbohydrate metabolism, mitochondrial energy metabolism, amino acid and organic acid metabolism, nucleotide/co-factor metabolism, and redox defense. Stable isotope tracing showed reduced glucose-derived and increased palmitate-derived acetyl-CoA in HFpEF, whereas Na-βHB reduced palmitate contribution and increased βHB-derived acetyl-CoA without restoring glucose contribution, indicating substrate redistribution and preserved ketone oxidation. Na-βHB supplementation increased oligomycin-sensitive respiration in freshly prepared left ventricular tissue, partially normalized selected TCA-cycle intermediates, reduced mitochondrial ROS and the NADH/NAD+ ratio, restored the GSH/GSSG ratio, and improved diastolic function without altering ejection fraction. Together, these findings define a redox-sensitive mitochondrial metabolic state in the HFD/l-NAME model and identify ketone supplementation as a partial metabolic rescue strategy in this context. At the same time, these findings highlight an important limitation of the murine HFD/l-NAME model, which should be interpreted as an experimental system for studying high-fat-induced cardiometabolic stress rather than as a metabolic equivalent of human HFpEF.

Animals↗

Action of antiepileptic drugs against kainic acid-induced seizures and automatisms during ontogenesis in rats.

Kainic acid (KA 4-14 mg/kg) administered intraperitoneally (i.p.) produces automatisms (scratching until third postnatal week, "wet dog" shakes thereafter), and clonic and tonic-clonic seizures in rats aged 7, 12, 18, 25, and 90 days. Administration of carbamazepine (CBZ) i.p. (25 or 50 mg/kg), phenobarbital (PB 20-80 mg/kg), clonazepam (CZP 0.2 or 1 mg/kg), or valproate (VPA 200 mg/kg) influenced neither incidence nor latency of automatisms. Clonic seizures that are regularly observed after the third postnatal week in controls were either abolished or substantially suppressed by any of the aforementioned antiepileptic drugs (AEDs). Tonic-clonic seizures observed in the first 3 postnatal weeks were suppressed only by solvent [including propyleneglycol (PEG), ethanol, and water]; the effect of AEDs on tonic-clonic seizures was proconvulsant instead. The automatisms were most resistant to AED therapy. These results induce some doubts about the adequacy of the KA model for identifying AEDs effective against complex partial seizures, but forthcoming AEDs that suppress automatisms in the KA rat model might also be active against human complex partial seizures.

Animals↗

Spatial and space-time correlations in systems of subpopulations with genetic drift and migration.

The geographic distribution of genetic variation is an important theoretical and experimental component of population genetics. Previous characterizations of genetic structure of populations have used measures of spatial variance and spatial correlations. Yet a full understanding of the causes and consequences of spatial structure requires complete characterization of the underlying space-time system. This paper examines important interactions between processes and spatial structure in systems of subpopulations with migration and drift, by analyzing correlations of gene frequencies over space and time. We develop methods for studying important features of the complete set of space-time correlations of gene frequencies for the first time in population genetics. These methods also provide a new alternative for studying the purely spatial correlations and the variance, for models with general spatial dimensionalities and migration patterns. These results are obtained by employing theorems, previously unused in population genetics, for space-time autoregressive (STAR) stochastic spatial time series. We include results on systems with subpopulation interactions that have time delay lags (temporal orders) greater than one. We use the space-time correlation structure to develop novel estimators for migration rates that are based on space-time data (samples collected over space and time) rather than on purely spatial data, for real systems. We examine the space-time and spatial correlations for some specific stepping stone migration models. One focus is on the effects of anisotropic migration rates. Partial space-time correlation coefficients can be used for identifying migration patterns. Using STAR models, the spatial, space-time, and partial space-time correlations together provide a framework with an unprecedented level of detail for characterizing, predicting and contrasting space-time theoretical distributions of gene frequencies, and for identifying features such as the pattern of migration and estimating migration rates in experimental studies of genetic variation over space and time.

Biometry↗

New ideas for solving identification and optimal control problems related to biomedical systems.

Many bio-medical models lead to differential systems where some parameters have to be identified from partial observation on the system's solution. For two- or three-compartment models parameters to be identified can be explicitly calculated (when uniqueness is ensured) from the algebraic relation obtained by using classical methods. However, when the number of compartments is greater than three, numerical techniques are necessary. In this work we propose new numerical methods based on Adomian's method for solving identification and optimal control problems associated to biomedical systems.

Algorithms↗

Injury initiation and progression in the anterior cruciate ligament.

OBJECTIVE: To develop a theoretical model to identify mechanisms by which total and partial tears of the anterior cruciate ligament could occur. DESIGN: A sagittal-plane knee model was used to investigate anterior cruciate ligament injury due to excessive anterior tibial translation. The ligament was modelled as an ordered array of fibres linking femur and tibia. BACKGROUND: Despite years of research, the detailed biomechanics of anterior cruciate ligament injury is not well understood. METHODS: A "critical strain criterion" was used to identify the onset and progression of model ligament fibre disruption. The associated forces were also calculated. RESULTS: At low flexion angles (<20 degrees ), the posterior fibre of the model ligament failed first, and the tear progressed anteriorly through the ligament. At higher flexion angles, the anterior fibre failed first, and the tear progressed posteriorly. Near the flexion angle at which the progression of injury changed direction, all fibres failed at approximately the same anterior tibial translation. At all but very high flexion angles, the force supported by the injured ligament was maximum when initial fibre failure occurred; the force then decreased with increasing anterior tibial translation. CONCLUSIONS: Near (20 degrees ) flexion, all model anterior cruciate ligament fibres fail at approximately the same anterior tibial translation, implying that a partial ligament tear may be impossible in this flexion region. Relevance. This study provides insight into possible mechanisms of initiation and progression of anterior cruciate ligament injury. It suggests that a partial tear of the posterior half of the ligament may be difficult to detect clinically.

Anterior Cruciate Ligament Injuries↗

Identification of genes specific to "oval cells" in the rat 2-acetylaminofluorene/partial hepatectomy model.

Under certain conditions liver regeneration can be accomplished by hepatic progenitor cells ("oval cells"). So far, only few factors have been identified to be uniquely regulated by the "oval cell" compartment. Using macroarray analysis in a rat model of oval cell proliferation (treatment with 2-acetylaminofluorene and partial hepatectomy, AAF + PH), we identified 12 differentially expressed genes compared to appropriate control models (AAF treatment and sham operation or AAF treatment alone). Further analysis in models of normal liver regeneration (ordinary PH) and acute phase response (turpentine oil-treated rats) revealed that three out of 12 genes (thymidine kinase 1, Jun-D and ADP-ribosylation factor 4) were not affected by the hepatic acute phase reaction but similarly overexpressed in both "oval cell"-dependant and normal liver regeneration. We characterized Jun-D and ADP-ribosylation factors as novel factors upregulated in oval cells and in non-parenchymal liver cells of normally regenerating livers. However, two out of 12 differentially expressed genes were specifically expressed in oval cells: ras-related protein Rab-3b and Ear-2. On protein level, Rab-3b was increased in total liver homogenates and demonstrated only in clusters of oval cells. We postulate that Ear-2 and Rab-3b may represent novel regulatory factors specifically activated in "oval cells".

2-Acetylaminofluorene↗

Coupled computational analysis of arterial LDL transport -- effects of hypertension.

Hypertension, a risk factor for atherosclerosis, increases the uptake of low density lipoproteins (LDL) by the arterial wall. Our objective in this work was to use computational modeling to identify physical factors that could be partially responsible for this effect. Fluid flow and mass transfer patterns in the lumen and wall of an arterial model were computed in a coupled manner, replicating as closely as possible previous experimental studies in which LDL uptake into the artery wall was measured in straight, excised arterial segments. Under conditions of both flow and no-flow, simulations predicted an increase in concentration polarization of LDL at the artery wall when arterial pressure was increased from 120 to 160 mmHg. However, this led to only a slight increase in mean LDL concentration within the arterial wall. However, if the permeability of the endothelium to LDL was allowed to vary with intra-arterial pressure, then the simulations predicted that the uptake of LDL would be enhanced 1.9-2.6 fold at higher pressure. The magnitude of this increase was consistent with experimental data. We conclude that the concentration polarization effects, enhanced by elevated intra-arterial pressure, cannot explain the increase in LDL uptake seen under hypertensive conditions. Instead, the data are most consistent with a pressure-linked increase in endothelial permeability to LDL.

Arteries↗

Differential expression of proteins during healing of cutaneous wounds in experimental normal and chronic models.

Recent studies have demonstrated growth factors and other cellular proteins as being important in the healing process. In this study, we have investigated the differential expression of proteins in wound tissues of normal and chronic animal models. Proteins were identified by specific antibodies, partial N-terminal amino acid sequence, and molecular weight homology. In normal wound tissues de novo synthesis of a heat shock protein, platelet derived growth factor (PDGF), and fibroblast growth factor (FGF) was induced within 24 h of skin injury. Proteins resembling vascular endothelial growth factor, receptors for PGDF, FGF, and epidermal growth factor, were synthesized. The elevated synthesis declined to a basal level in 7 to 14 days after skin injury which coincided with healing of wounds. These changes occurred only in wound site tissues but not in distal tissues. In contrast, the chronic wounds presented a different picture. The expressions of these proteins were either delayed or inhibited. This suggested the role of these proteins during normal and chronic wound healing. The proteins which were down regulated in chronic wounds may be used in the management of wounds and exploited as targets for therapeutic development.

Animals↗

Cellular and molecular aspects of bladder hypertrophy.

Bladder dysfunction secondary to benign prostatic hyperplasia (BPH) is a major affliction associated with ageing. As the disease slowly progresses, the bladder changes from a state of compensation to decompensation, in which there are severe, irreversible alterations in bladder function. Using a rabbit model of partial outlet obstruction we have identified three major cellular changes in the bladder which result from such obstruction. These include progressive denervation, mitochondrial dysfunction and disturbances of calcium storage and release from the sarcoplasmic reticulum. Our hypothesis is that outlet obstruction results in bladder hypertrophy which induces ischaemia. This leads to a release of intracellular calcium, leading to activation of specific enzymes and generation of free radicals. These then attack the membranes of nerves, sarcoplasmic reticulum and mitochondria. We have demonstrated that pretreatment of rabbits with Pygeum africanum extract (Tadenan) significantly reduced the severity of both the contractile and metabolic dysfunctions induced by partial outlet obstruction. Our current hypothesis is that Tadenan may either prevent the activation of degradative enzymes (or generation of free radicals), or protect the intracellular membranes against the destructive effects of free radicals or degredative enzymes. In conclusion, identifying cellular mechanisms responsible for bladder dysfunction induced by partial outlet obstruction provides new possibilities for non-surgical treatment of BPH. Our studies on Tadenan support this concept that the bladder provides a novel target for therapeutic intervention.

Aging↗

Determinants of home health visit length: results of a multisite prospective study.

OBJECTIVES: The authors (1) compare visit length across four categories of skilled nursing home health visits which reflect recent changes in home health casemix-AIDS-related, hospice/terminal (HT), intravenous (IV) therapy, and maternal and child health (MCH)-with general adult medical/surgical (MS) visits and (2) identify factors influencing visit length. METHODS: The study sites were 12 nonproprietary Massachusetts home health agencies (HHAs). Staff nurses collected data concurrently on a sample of visits they provided between December 1, 1992 and November 30, 1993. The visits were stratified by agency, time of year, and visit category. The authors used analysis of variance to test for significant differences across visit categories in Home Length of Visit (the number of minutes between when the nurse entered and left the home) (HLOV). The authors used multivariate regression analysis to develop models identifying determinants of HLOV and adjusted R2 to measure the explanatory power of partial models. RESULTS: In univariate analysis, the categories differed significantly from each other in length (P < 0.0001). HT visits were the longest (median visit length = 60, 80, and 59 minutes for HT Only visits, visits in both the HT and AIDS categories (HT/AIDS), and HT/IV visits, respectively). MS visits were the shortest (median = 30 minutes). The remaining categories were intermediate in length (medians = 37 to 50 minutes). Almost half the variability in HLOV was explained by the full multivariate regression model, which includes all independent variables (adjusted R2 = .4486; P < 0.0001). Visit characteristics alone in a partial model explained 18% of the variability in HLOV. Three other variable sub-groups-agency, client characteristics, and nursing workload-each explained about 15% of the variability in HLOV. Nursing activities performed during the visit explained 11%; several of these related to teaching, education, or assessment. CONCLUSIONS: Accurate reimbursement reflecting casemix differences is important to protect the teaching, education, and assessment functions of nurses; measure nurse productivity and allocate caseloads; maintain access to services for clients with greater needs; and avoid creating economic disincentives to the agencies that serve them. Payers formulating prospective payment systems can adjust per visit reimbursement rates to reflect differences in visit length by category and incorporate functional limitations, clinical instability, and case coordination as classification variables. Developers of home health casemix systems can use factor analysis to improve the robustness of multivariate models and include nursing workload in predicting visit length. Home health agencies measuring productivity and caseload across complex client populations can classify visits into three groups-MS; HT; and AIDS, IV, and MCH-or use the regression results to develop more refined predictors of visit length and nursing caseload.

Adult↗

Transverse instability of avalanches in granular flows down an incline.

Avalanche experiments on an erodible substrate are analyzed using the "partial fluidization" model of dense granular flows. The model identifies a family of propagating solitonlike avalanches with shape and velocity controlled by the inclination angle and the depth of the substrate. At high inclination angles, the solitons display a transverse instability, followed by coarsening and fingering similar to recent experimental observation. A primary cause for the transverse instability is directly related to the dependence of the soliton velocity on the granular mass trapped in the avalanche.

Journal Article↗

Structural characterization of the lactoferrin receptor from Neisseria meningitidis.

The meningococcal lactoferrin receptor is composed of the integral outer membrane protein LbpA and the peripheral lipoprotein LbpB. Homooligomeric complexes of LbpA and heterooligomers consisting of LbpA and LbpB were identified. Furthermore, five cell surface-exposed loops of LbpA were identified, which partially confirms a previously proposed topology model.

Amino Acid Sequence↗