gebhart/patrepeval huggingface dataset:
Longitudinal clinical and biomarker characteristics of non-manifesting LRRK2 G2019S carriers in the PPMI cohort (2022)

We examined 2-year longitudinal change in clinical features and biomarkers in LRRK2 non-manifesting carriers (NMCs) versus healthy controls (HCs) enrolled in the Parkinson's Progression Markers Initiative (PPMI). We analyzed 2-year longitudinal data from 176 LRRK2 G2019S NMCs and 185 HCs. All participants were assessed annually with comprehensive motor and non-motor scales, dopamine transporter (DAT) imaging, and biofluid biomarkers. The latter included cerebrospinal fluid (CSF) Abeta, total tau and phospho-tau; serum urate and neurofilament light chain (NfL); and urine bis(monoacylglycerol) phosphate (BMP). At baseline, LRRK2 G2019S NMCs had a mean (SD) age of 62 (7.7) years and were 56% female. 13% had DAT deficit (defined as <65% of age/sex-expected lowest putamen SBR) and 11% had hyposmia (defined as ≤15th percentile for age and sex). Only 5 of 176 LRRK2 NMCs developed PD during follow-up. Although NMCs scored significantly worse on numerous clinical scales at baseline than HCs, there was no longitudinal change in any clinical measures over 2 years or in DAT binding. There were no longitudinal differences in CSF and serum biomarkers between NMCs and HCs. Urinary BMP was significantly elevated in NMCs at all time points but did not change longitudinally. Neither baseline biofluid biomarkers nor the presence of DAT deficit correlated with 2-year change in clinical outcomes. We observed no significant 2-year longitudinal change in clinical or biomarker measures in LRRK2 G2019S NMCs in this large, well-characterized cohort even in the participants with baseline DAT deficit. These findings highlight the essential need for further enrichment biomarker discovery in addition to DAT deficit and longer follow-up to enable the selection of NMCs at the highest risk for conversion to enable future prevention clinical trials.
Antibody-Based Strategies to Prevent and Treat Influenza (2015)

Passive immunization using antibodies is a promising alternative to other antiviral treatment options. The potential for seasonal protection arising from a single injection of antibodies is appealing and has been pursued for a number of infectious agents. However, until recently, antibody-based strategies to combat infectious agents have been hampered due to the fact that most antibodies have been found to be strain specific, with the virus evolving resistance in many cases. The discovery of broadly neutralizing antibodies (bNAbs) in influenza, dengue virus, and HIV, which bind to multiple, structurally diverse strains, has provided renewed interest in this area. This review will focus on new technologies that enable the discovery of bNAbs, the challenges and opportunities of immunotherapies as an important addition to existing antiviral therapy, and the role of antibody discovery in informing rational vaccine discovery – with agents targeting influenza specifically addressed. Multiple candidates have entered the clinic and raise the possibility that a single antibody or small combination of antibodies can effectively neutralize a wide variety of strains. However, challenges remain – including combating escape variants, pharmacodynamics of antibody distribution, and development of efficacy biomarkers beyond virologic endpoints.
History-adjusted Marginal Structural Models for Estimating Time-varying Effect Modification (2007)

Much of epidemiology and clinical medicine is focused on estimating the effects of treatments or interventions administered over time. In such settings of longitudinal treatment, time-dependent confounding is often an important source of bias. Marginal structural models (MSMs) are a powerful tool for estimating the causal effect of a treatment using observational data, particularly when time-dependent confounding is present. In recent statistical work, van der Laan et al. presented a generalized form of MSMs called "history-adjusted" MSMs (Int J Biostat 2005;1:article 4). Unlike standard MSMs, history-adjusted MSMs can be used to estimate modification of treatment effects by time-varying covariates. Estimation of time-dependent causal effect modification is frequently of great practical relevance. For example, clinical researchers are often interested in how the prognostic significance of a biomarker for treatment response can change over time. This article provides a practical introduction to the implementation and interpretation of history-adjusted MSMs. The method is illustrated using a clinical question drawn from the treatment of human immunodeficiency virus infection. Observational cohort data from San Francisco, California, collected between 2000 and 2004, are used to estimate the effect of time until switching antiretroviral therapy regimens among patients receiving a non suppressive regimen and how this effect differs depending on CD4-positive T-lymphocyte count.
Circulating Myeloid-Derived Suppressor Cells Predict Differentiated Thyroid Cancer Diagnosis and Extent (2016)

MDSC measurement using this flow cytometry-based assay represents a novel approach for preoperatively assessing malignancy risk and cancer extent in patients with thyroid nodules. While further validation is needed, these data suggest that MDSC assessment may serve as a useful adjunct when cytology is indeterminate, and predict tumor stage and recurrence risk in cases of thyroid cancer.
Investigation of triplet harvesting and outcoupling efficiency in highly efficient two-color hybrid white organic light-emitting diodes (Phys. Status Solidi A 8/2013) (2013)

Organic light-emitting diodes (OLEDs) are promising candidates to replace current light sources such as incandescent bulbs and fl uorescent tubes. In this issue, Hofmann et al. (pp. 1467–1475) report on highly efficient white OLEDs that harvest otherwise unused triplet excitons from a blue fl uorescent emitter by adding a yellow phosphorescent compound. The CIE coordinates of the OLEDs can be adjusted over a wide range by varying the distance between exciton generation and triplet harvesting zone. The team utilized spectrally and time-resolved electroluminescence measurements and optical modeling to guide the design of these white triplet harvesting OLEDs. For a device with CIE color coordinates of (0.42/0.40), close to the warm white color point A, the group obtained nearly perfect Lambertian emission characteristics. This OLED achieves an external quantum efficiency of 9.4% and a luminous efficacy of 27.1 lm/W (at 1000 cd/m2) which can be further increased to 46 lm/W using outcoupling enhancement techniques. The photograph on the cover shows operating yellow and white OLEDs as well as the layer structure used to achieve triplet harvesting.
Natural killer cell mediated immunosurveillance of pediatric neuroblastoma (2015)

Until recently, the pathophysiological impact of natural killer (NK) lymphocytes has been largely elusive. Capitalizing on our previous discovery that NK cells mediate immunosurveillance against gastrointestinal stromal tumors (GISTs), we have now investigated the potential influence of immunostimulatory and immunosuppressive isoforms of the NK receptor NKp30 on the fate of infants with neuroblastoma. In three independent cohorts of high-risk neuroblastoma, we observed a similar prognostic impact of the ratio of immunostimulatory vs. immunosuppressive NKp30 isoforms. Patients with high-risk neuroblastoma that are in remission after induction chemotherapy have a higher risk of relapse if their circulating and bone marrow NK cells express the preponderantly immunosuppressive NKp30 C isoform, as determined by a robust RT-PCR-based assay. We also found that neuroblastoma cells express the NKp30 ligand B7-H6, which can be shed from the tumor cells. Elevated soluble B7-H6 levels contained in patient sera inhibited NK functions <i>in vitro</i> and correlated with downregulation of NK-p30 on NK cells, as well as with bone marrow metastasis and chemoresistance. Altogether, these results support the contention that NK cells play a decisive role in the immunosurveillance of neuroblastoma. In light of these results, efforts should be undertaken to investigate NK cell functions in all major cancer types, with the obvious expectation of identifying additional NK cell-related prognostic or predictive biomarkers and improving NK cell based immunotherapeutic strategies against cancer.
NitroSynapsin therapy for a mouse MEF2C haploinsufficiency model of human autism (2017)

Transcription factor MEF2C regulates multiple genes linked to autism spectrum disorder (ASD), and human MEF2C haploinsufficiency results in ASD, intellectual disability, and epilepsy. However, molecular mechanisms underlying MEF2C haploinsufficiency syndrome remain poorly understood. Here we report that Mef2c <sup>+/-</sup>(Mef2c-het) mice exhibit behavioral deficits resembling those of human patients. Gene expression analyses on brains from these mice show changes in genes associated with neurogenesis, synapse formation, and neuronal cell death. Accordingly, Mef2c-het mice exhibit decreased neurogenesis, enhanced neuronal apoptosis, and an increased ratio of excitatory to inhibitory (E/I) neurotransmission. Importantly, neurobehavioral deficits, E/I imbalance, and histological damage are all ameliorated by treatment with NitroSynapsin, a new dual-action compound related to the FDA-approved drug memantine, representing an uncompetitive/fast off-rate antagonist of NMDA-type glutamate receptors. These results suggest that MEF2C haploinsufficiency leads to abnormal brain development, E/I imbalance, and neurobehavioral dysfunction, which may be mitigated by pharmacological intervention.
Supplementary Figure S11 from Tumor Cell–Autonomous SHP2 Contributes to Immune Suppression in Metastatic Breast Cancer (2023)

&lt;p&gt;Representative dot plots for data shown in figure 4G-H and additional myeloid composition analysis in mice bearing 4T1 metastases.&lt;/p&gt;
Implementation of Robotic Assistance in Pancreatic Surgery: Experiences from the First 101 Consecutive Cases (2021)

Robotic assisted minimally invasive surgery has been implemented to overcome typical limitations of conventional laparoscopy such as lack of angulation, especially during creation of biliary and pancreatic anastomoses. With this retrospective analysis, we provide our experience with the first 101 consecutive robotic pancreatic resection performed at our center. Distal pancreatectomies (RDP, N = 44), total pancreatectomies (RTP, N = 3) and pancreaticoduodenectomies (RPD, N = 54) were included. Malignancy was found in 45.5% (RDP), 66.7% (RTP) and 61% (RPD). Procedure times decreased from the first to the second half of the cohort for RDP (218 min vs. 128 min, p = 0.02) and RPD (378 min vs. 271 min, p &lt; 0.001). Overall complication rate was 63%, 33% and 66% for RPD, RPT and RDP, respectively. Reintervention and reoperation rates were 41% and 17% (RPD), 33% and 0% (RTP) and 50% and 11.4% (RPD), respectively. The thirty-day mortality rate was 5.6% for RPD and nil for RTP and RDP. Overall complication rate remained stable throughout the study period. In this series, implementation of robotic pancreas surgery was safe and feasible. Final evaluation of the anastomoses through the median retrieval incision compensated for the lack of haptic feedback during reconstruction and allowed for secure minimally invasive resection and reconstruction.
TCP over wireless with link level error control: analysis and design methodology (1999)

This paper considers the problem of supporting TCP, the Internet data transport protocol, over a lossy wireless link whose quality varies over time. In order to prevent throughput degradation, it is necessary to "hide" the losses and the time variations of the wireless link from TCP. A number of solutions to this problem have been proposed in previous studies, but their performance was studied on a purely experimental basis. This paper presents an approximate analysis, validated by computer simulations, for TCP performance over wireless links. The analysis provides the basis for a systematic approach to supporting TCP over wireless links. The specific case of a Rayleigh-faded wireless link and automatic repeat request-based link-layer recovery is considered for the purpose of illustration. The numerical results presented for this case show that a simple solution, that of using an appropriately designed link-layer error-recovery scheme, prevents excessive deterioration of TCP throughput on wireless links.
NIH Grant Application Testing the effects of genetic variations using MINIME technology (1999)

Earlier this year
 Science asked readers to imagine what life would be like in the year 2050. In Part III of a 4-part series we present the third installment of these fictional essays.
An Aptamer-siRNA Chimera Suppresses HIV-1 Viral Loads and Protects from Helper CD4 + T Cell Decline in Humanized Mice (2011)

Therapeutic strategies designed to treat HIV infection with combinations of antiviral drugs have proven to be the best approach for slowing the progression to AIDS. Despite this progress, there are problems with viral drug resistance and toxicity, necessitating new approaches to combating HIV-1 infection. We have therefore developed a different combination approach for the treatment of HIV infection in which an RNA aptamer, with high binding affinity to the HIV-1 envelope (gp120) protein and virus neutralization properties, is attached to and delivers a small interfering RNA (siRNA) that triggers sequence-specific degradation of HIV RNAs. We have tested the antiviral activities of these chimeric RNAs in a humanized Rag2(-/-)γc(-/-) (RAG-hu) mouse model with multilineage human hematopoiesis. In this animal model, HIV-1 replication and CD4(+) T cell depletion mimic the situation seen in human HIV-infected patients. Our results show that treatment with either the anti-gp120 aptamer or the aptamer-siRNA chimera suppressed HIV-1 replication by several orders of magnitude and prevented the viral-induced helper CD4(+) T cell decline. In comparison to the aptamer alone, the aptamer-siRNA combination provided more extensive inhibition, resulting in a significantly longer antiviral effect that extended several weeks beyond the last injected dose. The aptamer thus acts as a broad-spectrum HIV-neutralizing agent and an siRNA delivery vehicle. The combined aptamer-siRNA agent provides an attractive, nontoxic therapeutic approach for treatment of HIV infection.
Rational Design of Amperometric Gas Sensors with Ionic Liquid Electrolytes (2014)

We discuss here further issues in the application of room temperature ionic liquid electrolytes to printed amperometric gas sensors. The main issue addressed is design of the amperometric gas sensor, relative to selection of optimal ionic liquid electrolytes for the realization of new gas sensors with superior properties of robustness, stability, sensitivity and limit of detection. Examples are provided in the context of ammonia monitoring.
Redox Sensitive Metastable DNA Junctions for Multivalent Delivery of Therapeutics (2018)

Delivery is one of the most challenging technical barriers for effective use of oligonucleotide therapeutics (OT) in vivo. Recent studies have demonstrated that simple nucleic acid nanostructures can act as molecularly uniform, multivalent carrier platforms for therapeutic cargos and cell targeting ligands. Although this approach has significant promise, much remains unknown regarding the effects of carrier nanostructures on the (I) in vivo distribution and pharmacokinetics, (II) cell entry and endosomal escape and (III) cytoplasmic processing of therapeutic cargos such as small interfering RNAs (siRNA).
Near-field thermophotovoltaics for efficient heat to electricity conversion at high power density (2021)

Thermophotovoltaic approaches that take advantage of near-field evanescent modes are being actively explored due to their potential for high-power density and high-efficiency energy conversion. However, progress towards functional near-field thermophotovoltaic devices has been limited by challenges in creating thermally robust planar emitters and photovoltaic cells designed for near-field thermal radiation. Here, we demonstrate record power densities of ~5 kW/m<sup>2</sup> at an efficiency of 6.8%, where the efficiency of the system is defined as the ratio of the electrical power output of the PV cell to the radiative heat transfer from the emitter to the PV cell. This was accomplished by developing novel emitter devices that can sustain temperatures as high as 1270 K and positioning them into the near-field (<100 nm) of custom-fabricated InGaAs-based thin film photovoltaic cells. In addition to demonstrating efficient heat-to-electricity conversion at high power density, we report the performance of thermophotovoltaic devices across a range of emitter temperatures (~800 K-1270 K) and gap sizes (70 nm-7 µm). The methods and insights achieved in this work represent a critical step towards understanding the fundamental principles of harvesting thermal energy in the near-field.
Activity of avian retroviral protease expressed in Escherichia coli (1988)

The 3' end of the avian sarcoma leukosis virus (ASLV) gag gene encodes a 124-amino-acid protease (PR) responsible for processing the gag and pol polyprotein precursors into the mature virion structural proteins and the reverse transcriptase. Here we report the synthesis of the mature ASLV PR and a nucleocapsid (NC)-PR gag precursor fragment in Escherichia coli. E. coli extracts containing mature PR correctly cleaved a synthetic decapeptide homologous to a known ASLV cleavage site. Also, the NC-PR precursor fragment appeared to be correctly processed to produce NC and PR in the bacterial cells. This cleavage was blocked by a mutation in the putative active site of PR. These results strongly support the hypothesis that PR is involved in cleaving itself from the gag precursor.
Faculty Opinions recommendation of A draft genome of Yersinia pestis from victims of the Black Death. (2011)

Technological advances in DNA recovery and sequencing have drastically expanded the scope of genetic analyses of ancient specimens to the extent that full genomic investigations are now feasible and are quickly becoming standard. This trend has important implications for infectious disease research because genomic data from ancient microbes may help to elucidate mechanisms of pathogen evolution and adaptation for emerging and re-emerging infections. Here we report a reconstructed ancient genome of Yersinia pestis at 30-fold average coverage from Black Death victims securely dated to episodes of pestilence-associated mortality in London, England, 1348-1350. Genetic architecture and phylogenetic analysis indicate that the ancient organism is ancestral to most extant strains and sits very close to the ancestral node of all Y. pestis commonly associated with human infection. Temporal estimates suggest that the Black Death of 1347-1351 was the main historical event responsible for the introduction and widespread dissemination of the ancestor to all currently circulating Y. pestis strains pathogenic to humans, and further indicates that contemporary Y. pestis epidemics have their origins in the medieval era. Comparisons against modern genomes reveal no unique derived positions in the medieval organism, indicating that the perceived increased virulence of the disease during the Black Death may not have been due to bacterial phenotype. These findings support the notion that factors other than microbial genetics, such as environment, vector dynamics and host susceptibility, should be at the forefront of epidemiological discussions regarding emerging Y. pestis infections. PMID: 21993626 Funding information This work was supported by: Canadian Institutes of Health Research, Canada NICHD NIH HHS, United States Grant ID: R24 HD044943
Modeling and Estimation of Cardiorespiratory Function, with Application to Mechanical Ventilation (2018)

Evidence-based medicine is at the heart of current medical practice where clinical decisions are driven by research data. However, most current therapy recommendations follow generalized protocols and guidelines that are based on epidemiological (population) studies and thus not suited for the individual patient's demands. Patient-tailored therapies are considered, hence, an unmet clinical need. We believe that mathematical models of the physiology can attend to such a clinical need, because they can be tuned to the individual patient. Such models provide a sound mathematical framework for personalized clinical decisions. In particular, physiological models in medicine can serve the following two purposes: 1) They can be an efficient tool to quantify cardiopulmonary dynamics, conduct virtual clinical/physiological experiments, and investigate the effects of specific treatments. 2) Model-based estimation techniques can assess physiological parameters or variables, which are otherwise impractical or dangerous to measure; they can effectively tune a generic model to become patient-specific, able to mimic the behavior of a particular patient. In this thesis, we propose a series of modifications to a previously developed cardiopulmonary model (CP Model) in order to better replicate heart-lung interaction phenomena that are typically observed under mechanical ventilation, hence allowing for a more accurate analysis of ventilation-induced changes in cardiac function. The response of this modified model is validated with experimental data collected during mechanical ventilation conditions. Further, as an industrial application of mathematical models, we present a patient emulator system that comprises the modified CP Model, a physical ventilator, and a piston-cylinder arrangement that serves as an electrical-to-hydraulic transducer. The modified CP Model then serves as the virtual patient that is being ventilated, where disease conditions can be instilled. Such a system is designed to offer a well-controlled experimental environment for ventilator manufacturers to efficaciously test and compare ventilation modalities and therapies, thereby enhancing their verification and validation manufacturing processes. Finally, we develop a model-based approach to estimate (noninvasively) the function of the cardiovascular system, in terms of cardiac performance (i.e., cardiac output) and the dynamics of the systemic arterial tree (i.e., time constant). With this technique, we envision to provide continuous and real-time bedside monitoring of changes in cardiovascular function, such as those induced by changes in ventilator settings.
Identification of amastigote-specific antigens of Leishmania donovani using kala-azar patient sera. (2001)

Antigenic characterization of the soluble fraction of axenic amastigotes of Leishmania donovani ( strain Dd8, causative agent of Indian kala-azar) and their comparison with promastigotes is reported. The axenic amastigotes were assessed for their immunological status employing anti-A2 monoclonal antibody which is extremely specific for L. donovani amastigotes. SDS-PAGE of 35[S] methionine labeled proteins of the two parasite stages exhibited few stage specific and some conserved antigens in both the stages. An increased synthesis of heat shock proteins was observed in axenic amastigotes. Western blot experiments employing sera of kala azar positive patients identified immunodominent antigens of 116,83,26 and 12 kDa in axenic amastigotes which were not present in promastigotes. These amastigote stage specific antigens may have immense potential in immunodiagnosis and prophylaxis of kala-azar.
Cardiac Energetics in Congestive Heart Failure (2002)

failure rats were undoubtedly in decompensated failure because, as a consequence of reduced velocity of shortening of the left ventricle and high end diastolic pressure, they had severe lung congestion. However, it remains to be seen whether MCT1 upregulation is a general feature of end stage heart failure irrespective of cause.