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Human immunodeficiency virus type 1 mutants resistant to nonnucleoside inhibitors of reverse transcriptase arise in tissue culture
We have recently described a nonnucleoside compound that specifically inhibits the reverse transcriptase of human immunodeficiency virus type 1 (HIV-1), the causative agent of AIDS. This compound, nevirapine (BI-RG-587), interacts with highly conserved tyrosine residues at positions 181 and 188 in the reverse transcriptase to inhibit the recombinant enzyme and virus replication in cell culture with 50% inhibitory concentrations in the 40 nM range. HIV-1 variants resistant to nevirapine emerged with passage in cell culture in the presence of drug. This resistant phenotype was stable with continued passage in the absence of drug. These mutants had a substitution of cysteine for the tyrosine at position 181. Introduction of this mutation into the recombinant enzyme increased the inhibitory concentration of nevirapine 100-fold. Substitution of cysteine for tyrosine at residue 181 into the wild-type viral genome conferred a similar reduction in susceptibility to nevirapine. Mutants were also resistant to a tetrahydroimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-one and -thione derivative and two 6-phenylthiouracil derivatives but retained their sensitivity to the other reverse transcriptase inhibitors, 3'-azido-3'-deoxythymidine and foscarnet
N-Terminal Pro-B-Type Natriuretic Peptide and Microsize Myocardial Infarction Risk in the Reasons for Geographic and Racial Differences in Stroke Study
Background: N-terminal pro B-type peptide (NT-proBNP) has been associated with risk of myocardial infarction (MI), but less is known about the relationship between NT-proBNP and very small non ST-elevation MI, also known as microsize MI. These events are now routinely detectable with modern troponin assays and are emerging as a large proportion of all MI. Here, we sought to compare the association of NT-proBNP with risk of incident typical MI and microsize MI in the REasons for Geographic and Racial Differences in Stroke (REGARDS) Study.
Methods: The REGARDS Study is a national cohort of 30,239 US community-dwelling black and white adults aged ≥ 45 years recruited from 2003 to 2007. Expert-adjudicated outcomes included incident typical MI (definite/probable MI with peak troponin ≥ 0.5 μg/L), incident microsize MI (definite/probable MI with peak troponin \u3c 0.5 μg/L), and incident fatal CHD. Using a case-cohort design, we estimated the hazard ratio of the outcomes as a function of baseline NT-proBNP. Competing risk analyses tested whether the associations of NT-proBNP differed between the risk of incident microsize MI and incident typical MI as well as if the association of NT-proBNP differed between incident non-fatal microsize MI and incident non-fatal typical MI, while accounting for incident fatal coronary heart disease (CHD) as well as heart failure (HF).
Results: Over a median of 5 years of follow-up, there were 315 typical MI, 139 microsize MI, and 195 incident fatal CHD. NT-proBNP was independently and strongly associated with all CHD endpoints, with significantly greater risk observed for incident microsize MI, even after removing individuals with suspected HF prior to or coincident with their incident CHD event.
Conclusion: NT-proBNP is associated with all MIs, but is a more powerful risk factor for microsize than typical MI
Direct venous inoculation of Plasmodium falciparum sporozoites for controlled human malaria infection: a dose-finding trial in two centres
BACKGROUND: Controlled human malaria infection (CHMI)
accelerates development of anti-malarial interventions. So far,
CHMI is done by exposure of volunteers to bites of five
mosquitoes carrying Plasmodium falciparum sporozoites (PfSPZ), a
technique available in only a few centres worldwide.
Mosquito-mediated CHMI is logistically complex, exact PfSPZ
dosage is impossible and live mosquito-based interventions are
not suitable for further clinical development. METHODS: An
open-labelled, randomized, dose-finding study in 18-45 year old,
healthy, malaria-naive volunteers was performed to assess if
intravenous (IV) injection of 50 to 3,200 aseptic, purified,
cryopreserved PfSPZ is safe and achieves infection kinetics
comparable to published data of mosquito-mediated CHMI. An
independent study site verified the fully infectious dose using
direct venous inoculation of PfSPZ. Parasite kinetics were
assessed by thick blood smear microscopy and quantitative real
time PCR. RESULTS: IV inoculation with 50, 200, 800, or 3,200
PfSPZ led to parasitaemia in 1/3, 1/3, 7/9, and 9/9 volunteers,
respectively. The geometric mean pre-patent period (GMPPP) was
11.2 days (range 10.5-12.5) in the 3,200 PfSPZ IV group.
Subsequently, six volunteers received 3,200 PfSPZ by direct
venous inoculation at an independent investigational site. All
six developed parasitaemia (GMPPP: 11.4 days, range: 10.4-12.3).
Inoculation of PfSPZ was safe. Infection rate and pre-patent
period depended on dose, and injection of 3,200 PfSPZ led to a
GMPPP similar to CHMI with five PfSPZ-infected mosquitoes. The
infectious dose of PfSPZ predicted dosage of
radiation-attenuated PfSPZ required for successful vaccination.
CONCLUSIONS: IV inoculation of PfSPZ is safe, well tolerated and
highly reproducible. It shall further accelerate development of
anti-malarial interventions through standardization and
facilitation of CHMI. Beyond this, rational dose selection for
whole PfSPZ-based immunization and complex study designs are now
possible. TRIAL REGISTRATION: ClinicalTrials.gov NCT01624961 and
NCT01771848
Exploring Action Dynamics as an Index of Paired-Associate Learning
Much evidence exists supporting a richer interaction between cognition and action than commonly assumed. Such findings demonstrate that short-timescale processes, such as motor execution, may relate in systematic ways to longer-timescale cognitive processes, such as learning. We further substantiate one direction of this interaction: the flow of cognition into action systems. Two experiments explored match-to-sample paired-associate learning, in which participants learned randomized pairs of unfamiliar symbols. During the experiments, their hand movements were continuously tracked using the Nintendo Wiimote. Across learning, participant arm movements are initiated and completed more quickly, exhibit lower fluctuation, and exert more perturbation on the Wiimote during the button press. A second experiment demonstrated that action dynamics index novel learning scenarios, and not simply acclimatization to the Wiimote interface. Results support a graded and systematic covariation between cognition and action, and recommend ways in which this theoretical perspective may contribute to applied learning contexts
Fully transformer-based biomarker prediction from colorectal cancer histology: a large-scale multicentric study
Background: Deep learning (DL) can extract predictive and prognostic
biomarkers from routine pathology slides in colorectal cancer. For example, a
DL test for the diagnosis of microsatellite instability (MSI) in CRC has been
approved in 2022. Current approaches rely on convolutional neural networks
(CNNs). Transformer networks are outperforming CNNs and are replacing them in
many applications, but have not been used for biomarker prediction in cancer at
a large scale. In addition, most DL approaches have been trained on small
patient cohorts, which limits their clinical utility. Methods: In this study,
we developed a new fully transformer-based pipeline for end-to-end biomarker
prediction from pathology slides. We combine a pre-trained transformer encoder
and a transformer network for patch aggregation, capable of yielding single and
multi-target prediction at patient level. We train our pipeline on over 9,000
patients from 10 colorectal cancer cohorts. Results: A fully transformer-based
approach massively improves the performance, generalizability, data efficiency,
and interpretability as compared with current state-of-the-art algorithms.
After training on a large multicenter cohort, we achieve a sensitivity of 0.97
with a negative predictive value of 0.99 for MSI prediction on surgical
resection specimens. We demonstrate for the first time that resection
specimen-only training reaches clinical-grade performance on endoscopic biopsy
tissue, solving a long-standing diagnostic problem. Interpretation: A fully
transformer-based end-to-end pipeline trained on thousands of pathology slides
yields clinical-grade performance for biomarker prediction on surgical
resections and biopsies. Our new methods are freely available under an open
source license
In vivo emergence of HIV-1 highly sensitive to neutralizing antibodies.
BACKGROUND: The rapid and continual viral escape from neutralizing antibodies is well documented in HIV-1 infection. Here we report in vivo emergence of viruses with heightened sensitivity to neutralizing antibodies, sometimes paralleling the development of neutralization escape. METHODOLOGY/PRINCIPAL FINDINGS: Sequential viral envs were amplified from seven HIV-1 infected men monitored from seroconversion up to 5 years after infection. Env-recombinant infectious molecular clones were generated and tested for coreceptor use, macrophage tropism and neutralization sensitivity to homologous and heterologous serum, soluble CD4 and monoclonal antibodies IgG1b12, 2G12 and 17b. We found that HIV-1 evolves sensitivity to contemporaneous neutralizing antibodies during infection. Neutralization sensitive viruses grow out even when potent autologous neutralizing antibodies are present in patient serum. Increased sensitivity to neutralization was associated with susceptibility of the CD4 binding site or epitopes induced after CD4 binding, and mediated by complex envelope determinants including V3 and V4 residues. The development of neutralization sensitive viruses occurred without clinical progression, coreceptor switch or change in tropism for primary macrophages. CONCLUSIONS: We propose that an interplay of selective forces for greater virus replication efficiency without the need to resist neutralizing antibodies in a compartment protected from immune surveillance may explain the temporal course described here for the in vivo emergence of HIV-1 isolates with high sensitivity to neutralizing antibodies
Generation of neutralizing antibodies and divergence of SIVmac239 in cynomolgus macaques following short-term early antiretroviral therapy.
Neutralizing antibodies (NAb) able to react to heterologous viruses are generated during natural HIV-1 infection in some individuals. Further knowledge is required in order to understand the factors contributing to induction of cross-reactive NAb responses. Here a well-established model of experimental pathogenic infection in cynomolgus macaques, which reproduces long-lasting HIV-1 infection, was used to study the NAb response as well as the viral evolution of the highly neutralization-resistant SIVmac239. Twelve animals were infected intravenously with SIVmac239. Antiretroviral therapy (ART) was initiated ten days post-inoculation and administered daily for four months. Viral load, CD4(+) T-cell counts, total IgG levels, and breadth as well as strength of NAb in plasma were compared simultaneously over 14 months. In addition, envs from plasma samples were sequenced at three time points in all animals in order to assess viral evolution. We report here that seven of the 12 animals controlled viremia to below 10(4) copies/ml of plasma after discontinuation of ART and that this control was associated with a low level of evolutionary divergence. Macaques that controlled viral load developed broader NAb responses early on. Furthermore, escape mutations, such as V67M and R751G, were identified in virus sequenced from all animals with uncontrolled viremia. Bayesian estimation of ancestral population genetic diversity (PGD) showed an increase in this value in non-controlling or transient-controlling animals during the first 5.5 months of infection, in contrast to virus-controlling animals. Similarly, non- or transient controllers displayed more positively-selected amino-acid substitutions. An early increase in PGD, resulting in the generation of positively-selected amino-acid substitutions, greater divergence and relative high viral load after ART withdrawal, may have contributed to the generation of potent NAb in several animals after SIVmac239 infection. However, early broad NAb responses correlated with relatively preserved CD4(+) T-cell numbers, low viral load and limited viral divergence
A Search for Neutrino Sources with Cascade Events in IceCube
IceCube has discovered a flux of astrophysical neutrinos, and more recently has used muon-neutrino datasets to present evidence for one source; a flaring blazar known as TXS 0506+056. However, the sources responsible for the majority of the astrophysical neutrino flux remain elusive. Opening up new channels for detection can improve sensitivity and increase the discovery potential. In this work we present a new neutrino dataset relying heavily on Deep-Neural-Networks (DNN) to select cascade events produced from neutral-current interactions of all flavors and charged-current interactions with flavors other than muon-neutrino. The speed of DNN processing makes it possible to select events in near realtime with a single GPU. Cascade events have reduced angular resolution when compared to muon-neutrino events, however the resulting dataset has a lower energy threshold in the Southern Sky and a lower background rate. These benefits lead to an factor of 2-3 improvement in sensitivity to sources in the Southern Sky when compared to muon-neutrino datasets. This dataset is particularly promising for identifying transient neutrino sources in the Southern Sky and neutrino production from the galactic plane
Penilaian Kinerja Keuangan Koperasi di Kabupaten Pelalawan
This paper describe development and financial performance of cooperative in District Pelalawan among 2007 - 2008. Studies on primary and secondary cooperative in 12 sub-districts. Method in this stady use performance measuring of productivity, efficiency, growth, liquidity, and solvability of cooperative. Productivity of cooperative in Pelalawan was highly but efficiency still low. Profit and income were highly, even liquidity of cooperative very high, and solvability was good
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