Miracle-dz/UniFAR-FTUs huggingface dataset:
Strong, but Age-Dependent, Protection Elicited by a Deoxyribonucleic Acid/Modified Vaccinia Ankara Simian Immunodeficiency Virus Vaccine

Background. In this study, we analyzed the protective efficacy of a simian immunodeficiency virus (SIV) macaque 239 (SIVmac239) analogue of the clinically tested GOVX-B11 deoxyribonucleic acid (DNA)/modified vaccinia Ankara (MVA) human immunodeficiency virus vaccine. Methods. The tested vaccine used a DNA immunogen mutated to mimic the human vaccine and a regimen with DNA deliveries at weeks 0 and 8 and MVA deliveries at weeks 16 and 32. Twelve weekly rectal challenges with 0.3 animal infectious doses of SIV sootey mangabey E660 (SIVsmE660) were administered starting at 6 months after the last immunization. Results. Over the first 6 rectal exposures to SIVsmE660, <10-year-old tripartite motif-containing protein 5 (TRIM5)α-permissive rhesus macaques showed an 80% reduction in per-exposure risk of infection as opposed to a 46% reduction in animals over 10 years old; and, over the 12 challenges, they showed a 72% as opposed to a 10% reduction. Analyses of elicited immune responses suggested that higher antibody responses in the younger animals had played a role in protection. Conclusions. The simian analogue of the GOVX-B11 HIV provided strong protection against repeated rectal challenges in young adult macaques.
Escherichia coli single-strand binding protein forms multiple, distinct complexes with single-stranded DNA.

Four distinct binding modes for the interaction of Escherichia coli single-strand binding (SSB) protein with single-stranded (ss) DNA have been identified on the basis of quantitative titrations that monitor the quenching of the SSB protein fluorescence upon binding to the homopolynucleotide poly(dT) over a range of MgCl2 and NaCl concentrations at 25 and 37 degrees C. This is the first observation of multiple binding modes for a single protein binding to DNA. These results extend previous studies performed in NaCl (25 degrees C, pH 8.1), in which two distinct SSB-ss DNA binding modes possessing site sizes of 33 and 65 nucleotides per bound SSB tetramer were observed [Lohman, T.M. , & Overman, L. B. (1985) J. Biol. Chem. 260, 3594-3603]. Each of these binding modes differs in the number of nucleotides occluded upon interaction with ss DNA (i.e., site size). Along with the previously observed modes with site sizes of 35 +/- 2 and 65 +/- 3 nucleotides per tetramer, a third distinct binding mode, at 25 degrees C, has been identified, possessing a site size of 56 +/- 3 nucleotides per bound SSB tetramer, which is stable over a wide range of MgCl2 concentrations. At 37 degrees C, a fourth binding mode is observed, possessing a site size of 40 +/- 2 nucleotides per tetramer, although this mode is observable only over a small range of salt concentration. (ABSTRACT TRUNCATED AT 250 WORDS)
Outcomes of L 1 – L 2 posterior lumbar interbody fusion with the Lumbar I / F cage and the variable screw placement system : reporting unexpected poor fusion results at L 1 – L 2

BACKGROUND CONTEXT: Posterior lumbar interbody fusion (PLIF) was introduced 50 years ago. The Lumbar I/F cage (DePuy Spine, Raynham, MA) was designed to enhance PLIF results. PLIF with the Lumbar I/F cage and posterior Variable Screw Placement System (VSP) has increased the success of fusion to nearly 100% at the four lowest lumbar levels, L2–L3 through L5–S1. Less commonly, PLIF is indicated for the L1–L2 level. Clinical-results of Lumbar I/F cage fusion and VSP at L1–L2 have-not been reported. PURPOSE: The purpose of this study is to report the functional outcomes, fusion rate, and complications related to PLIF with Lumbar I/F cage and VSP of L1–L2 STUDY DESIGN/SETTING: The setting is a retrospective, single-arm cohort study of consecutive PLIF surgical patients at a single center. PATIENT SAMPLE: A review of 373 of 425 patients who underwent PLIF with Lumbar I/F cage and VSP from 1999 to 2002 identified 12 patients who had PLIF with Lumbar I/F cage and VSP at L1–L2. Mean follow-up was 31 months (range 12–65 months). OUTCOME MEASURES: Clinical success was determined with a modified Prolo score evaluating pain, function, medication usage and economic status. Fusion success, determined by evaluation of plain radiographs, was defined by continuous bone bridging the fusion area with no lucencies. METHODS: The 12 patients were evaluated for clinical success and/fusion success at last followup. These results were compared with the results of the 373 patients reviewed, and historical groups of the original Investigational Device Exemption study and the 10-year follow-up study. RESULTS: Previous surgery was reported by 10 of 12 patients, with an average symptom-free period of 3 years after previous fusion and before presentation with severe symptomatology necessitating further surgery at L1–L2. Seven patients had clinical success (59%), and five patients were clinically unsuccessful (41%). This included zero excellent, 2 of 12 (15%) good, 5 of 12 (42%) fair, and 5 of 12 (42%) poor results. Fusion was successful in seven (58%) and failed in five patients (42%). Three failed fusions were associated with L1–L2 subsidence. Two patients required further revision for non-union. CONCLUSIONS: In 12 patients with L1–L2 fusion, we report an unexpected high rate of failed fusion and poor clinical outcome. 2006 Elsevier Inc. All rights reserved.
Puerperium and Celiac Disease: How to Explain this Association

Among gastrointestinal complaints, the most common are chronic diarrhea, abdominal pain and distension, vomiting, malnutrition and weight loss [1]. The extra-intestinal manifestations are becoming increasingly common and include dermatitis herpetiformis, enamel hypoplasia, recurrent oral thrush, anemia, osteoporosis, arthritis, neurological disorders, unexplained elevated transaminase levels and female infertility [2]. This enteropathy may occur at any age and it affects children and adults. It has a prevalence of about 1% in the general population, thus representing the most common genetic-based food intolerance in the world [2].
SAHA‐sensitized prostate cancer cells to TNFα‐related apoptosis‐inducing ligand (TRAIL): Mechanisms leading to synergistic apoptosis

Treatment of cancer cells with histone deacetylase inhibitors (HDACi) such as suberolylanilide hydroxamic acid (SAHA) activates genes that promote apoptosis. To enhance proapoptotic efficiency, SAHA has been used in combination with radiation, kinase inhibitors and cytotoxic drugs. Although several prostate cells respond to TNFα‐Related Apoptosis‐Inducing Ligand (TRAIL), LNCaP are resistant. This model system was utilized to examine the advantages of combined treatment with SAHA and TRAIL. In LNCaP cells, TRAIL induced synergistic apoptosis when combined with even with the lowest dose SAHA. Treatment with caspase inhibitor confirmed that SAHA‐induced apoptosis was mediated through caspases. In addition to induction of apoptosis, SAHA and TRAIL decreased the levels of proapoptotic proteins IKKα, IKKβ and IKKγ, suggesting that SAHA treatment may reduce the activity of NFκB. However, assay for NFκB luciferase reporter activity showed highly significant increase in SAHA‐treated cells, supporting earlier suggestions that HDACi promotes NFκB transcriptional activity. Further analyses to determine the mechanisms by which the combination of SAHA and TRAIL led to synergistic apoptosis indicated that the apoptotic response of LNCaP is due to a complex regulation of death receptor pathway and alterations of NFκB activity at several regulatory steps. © 2006 Wiley‐Liss, Inc.
Still at the Choice‐Point

Abstract: Contrary to classic stimulus–response (S‐R) theory, recent evidence suggests that, in instrumental conditioning, rats encode the relationship between their actions and the specific consequences that these actions produce. It has remained unclear, however, how encoding this relationship acts to control instrumental performance. Although S‐R theories were able to give a clear account of how learning translates into performance, the argument that instrumental learning constitutes the acquisition of information of the form “response R leads to outcome O” does not directly imply a particular performance rule or policy; this information can be used both to perform R and to avoid performing R. Recognition of this problem has forced the development of accounts that allow the O and stimuli that predict the O (i.e., S‐O) to play a role in the initiation of specific Rs. In recent experiments, we have used a variety of behavioral procedures in an attempt to isolate the processes that contribute to instrumental performance, including outcome devaluation, reinstatement, and Pavlovian–instrumental transfer. Our results, particularly from experiments assessing outcome–selective reinstatement, suggest that both “feed‐forward” (O‐R) and “feed‐back” (R‐O) associations are critical and that although the former appear to be important to response selection, the latter—together with processes that determine outcome value—mediate response initiation. We discuss a conceptual model that integrates these processes and its neural implementation.
HIV/AIDS and disability in Southern Africa: a review of relevant literature

Purpose. HIV/AIDS has grown to become the biggest epidemic in modern history. Southern Africa is at the epicentre of the global epidemic, with just of a third of the world's HIV-positive population living here. It is known that HIV/AIDS affect vulnerable population groups. It is surprising then, that persons with disabilities, one of the world's most vulnerable population groups, particularly in southern Africa, have been largely overlooked with regards to HIV/AIDS. This review sought to establish the state of the knowledge at present. Method. This article reports on findings of a literature review conducted as an initial step in a research project currently underway in South Africa. This article focuses on HIV/AIDS as it affects persons with disabilities in southern Africa, as it is in this region that the majority of people living with HIV live. However, as fewer studies exist that have as its focus southern Africa (particularly looking at HIV/AIDS and persons with disabilities), relevant articles from the international literature were used as indications of what we may find through future research also in the southern African countries. Given the paucity of published literature dealing with HIV/AIDS and persons with disabilities, the review looked at various risk factors associated with HIV infection, and how it affects persons with disabilities. Results. Findings from the literature review suggest that persons with disabilities, particularly in southern Africa, are at significant risk for HIV infection. Conclusions. There is an urgent need for more research on HIV/AIDs and sexuality among persons with disabilities in Africa.
Optimal Vaccine Allocation for the Early Mitigation of Pandemic Influenza

With new cases of avian influenza H5N1 (H5N1AV) arising frequently, the threat of a new influenza pandemic remains a challenge for public health. Several vaccines have been developed specifically targeting H5N1AV, but their production is limited and only a few million doses are readily available. Because there is an important time lag between the emergence of new pandemic strain and the development and distribution of a vaccine, shortage of vaccine is very likely at the beginning of a pandemic. We coupled a mathematical model with a genetic algorithm to optimally and dynamically distribute vaccine in a network of cities, connected by the airline transportation network. By minimizing the illness attack rate (i.e., the percentage of people in the population who become infected and ill), we focus on optimizing vaccine allocation in a network of 16 cities in Southeast Asia when only a few million doses are available. In our base case, we assume the vaccine is well-matched and vaccination occurs 5 to 10 days after the beginning of the epidemic. The effectiveness of all the vaccination strategies drops off as the timing is delayed or the vaccine is less well-matched. Under the best assumptions, optimal vaccination strategies substantially reduced the illness attack rate, with a maximal reduction in the attack rate of 85%. Furthermore, our results suggest that cooperative strategies where the resources are optimally distributed among the cities perform much better than the strategies where the vaccine is equally distributed among the network, yielding an illness attack rate 17% lower. We show that it is possible to significantly mitigate a more global epidemic with limited quantities of vaccine, provided that the vaccination campaign is extremely fast and it occurs within the first weeks of transmission.
MIMO-NOMA Design for Small Packet Transmission in the Internet of Things

A feature of the Internet of Things (IoT) is that some users in the system need to be served quickly for small packet transmission. To address this requirement, a new multiple-input multiple-output non-orthogonal multiple access (MIMO-NOMA) scheme is designed in this paper, where one user is served with its quality of service requirement strictly met, and the other user is served opportunistically by using the NOMA concept. The novelty of this new scheme is that it confronts the challenge that the existing MIMO-NOMA schemes rely on the assumption that users' channel conditions are different, a strong assumption which may not be valid in practice. The developed precoding and detection strategies can effectively create a significant difference between the users' effective channel gains, and therefore, the potential of NOMA can be realized even if the users' original channel conditions are similar. Analytical and numerical results are provided to demonstrate the performance of the proposed MIMO-NOMA scheme.
Effects of once‐weekly dulaglutide on kidney function in patients with type 2 diabetes in phase II and III clinical trials

Dulaglutide is a once‐weekly glucagon‐like peptide‐1 receptor agonist approved for the treatment of type 2 diabetes (T2D). Integrated data from 9 phase II and III trials in people with T2D (N = 6005) were used to evaluate the effects of dulaglutide on estimated glomerular filtration rate (eGFR [Chronic Kidney Disease Epidemiology Collaboration]), urine albumin‐to‐creatinine ratio (UACR) and kidney adverse events (AEs). No significant differences in eGFR were observed during treatment for dulaglutide vs placebo, active comparators or insulin glargine (mean ± standard deviation values: dulaglutide vs placebo: 87.8 ± 17.7 vs 88.2 ± 17.9 mL/min/1.73 m2, P = .075; dulaglutide vs active comparators: 89.9 ± 16.7 vs 88.8 ± 16.3 mL/min/1.73 m2, P = .223; and dulaglutide vs insulin glargine: 85.9 ± 18.2 vs 83.9 ± 18.6 mL/min/1.73 m2, P = .423). Lower UACR values were observed for dulaglutide vs placebo, active comparators and insulin glargine (at 26 weeks, median [Q1‐Q3] values were: dulaglutide vs placebo: 8.0 [4.4‐20.4] vs 8.0 [4.4‐23.9] mg/g, P = .023; dulaglutide vs active comparators: 8.0 [4.4‐21.2] vs 8.9 [4.4‐27.4] mg/g, P = .013; and dulaglutide vs insulin glargine: 8.9 [4.4‐29.2] vs 12.4 [5.3‐50.5] mg/g, P = .029). AEs reflecting potential acute renal failure were 3.4, 1.7 and 7.0 events/1000 patient‐years for dulaglutide, active comparators and placebo, respectively. In conclusion, dulaglutide treatment of clinical trial participants with T2D did not affect eGFR and slightly decreased albuminuria.
Caloric Restriction Shortens Lifespan through an Increase in Lipid Peroxidation, Inflammation and Apoptosis in the G93A Mouse, an Animal Model of ALS

Caloric restriction (CR) extends lifespan through a reduction in oxidative stress, delays the onset of morbidity and prolongs lifespan. We previously reported that long-term CR hastened clinical onset, disease progression and shortened lifespan, while transiently improving motor performance in G93A mice, a model of amyotrophic lateral sclerosis (ALS) that shows increased free radical production. To investigate the long-term CR-induced pathology in G93A mice, we assessed the mitochondrial bioenergetic efficiency and oxidative capacity (CS – citrate synthase content and activity, cytochrome c oxidase - COX activity and protein content of COX subunit- I and IV and UCP3- uncoupling protein 3), oxidative damage (MDA – malondialdehyde and PC – protein carbonyls), antioxidant enzyme capacity (Mn-SOD, Cu/Zn-SOD and catalase), inflammation (TNF-α), stress response (Hsp70) and markers of apoptosis (Bax, Bcl-2, caspase 9, cleaved caspase 9) in their skeletal muscle. At age 40 days, G93A mice were divided into two groups: Ad libitum (AL; n = 14; 7 females) or CR (n = 13; 6 females), with a diet equal to 60% of AL. COX/CS enzyme activity was lower in CR vs. AL male quadriceps (35%), despite a 2.3-fold higher COX-IV/CS protein content. UCP3 was higher in CR vs. AL females only. MnSOD and Cu/Zn-SOD were higher in CR vs. AL mice and CR vs. AL females. MDA was higher (83%) in CR vs. AL red gastrocnemius. Conversely, PC was lower in CR vs. AL red (62%) and white (30%) gastrocnemius. TNF-α was higher (52%) in CR vs. AL mice and Hsp70 was lower (62%) in CR vs. AL quadriceps. Bax was higher in CR vs. AL mice (41%) and CR vs. AL females (52%). Catalase, Bcl-2 and caspases did not differ. We conclude that CR increases lipid peroxidation, inflammation and apoptosis, while decreasing mitochondrial bioenergetic efficiency, protein oxidation and stress response in G93A mice.
Digital LDO with Time-Interleaved Comparators for Fast Response and Low Ripple

On-chip voltage regulation using distributed Digital Low Drop Out (LDO) voltage regulators has been identified as a promising technique for efficient power-management for emerging multi-core processors. Digital LDOs (DLDO) can offer low voltage operation, faster transient response, and higher current efficiency. Response time as well as output voltage ripple can be reduced by increasing the speed of the dynamic comparators. However, the comparator offset steeply increases for high clock frequencies, thereby leading to enhanced variations in output voltage. In this work we explore the design of digital LDOs with multiple dynamic comparators that can overcome this bottleneck. In the proposed topology, we apply time-interleaved comparators with the same voltage threshold and uniform current step in order to accomplish the aforementioned features. For a load step of 50mA, a DLDO with 8 time-interleaved comparators could achieve an output ripple of less than 5mV, while achieving a settling time of less than 0.5us. Load current dependant dynamic adjustment of clock frequency is proposed to maintain high current efficiency of ~97%.
Evaluation of cloud‐resolving model simulations of midlatitude cirrus with ARM and A‐train observations

Cirrus clouds are ubiquitous in the upper troposphere and still constitute one of the largest uncertainties in climate predictions. This paper evaluates cloud‐resolving model (CRM) and cloud system‐resolving model (CSRM) simulations of a midlatitude cirrus case with comprehensive observations collected under the auspices of the Atmospheric Radiation Measurements (ARM) program and with spaceborne observations from the National Aeronautics and Space Administration A‐train satellites. The CRM simulations are driven with periodic boundary conditions and ARM forcing data, whereas the CSRM simulations are driven by the ERA‐Interim product. Vertical profiles of temperature, relative humidity, and wind speeds are reasonably well simulated by the CSRM and CRM, but there are remaining biases in the temperature, wind speeds, and relative humidity, which can be mitigated through nudging the model simulations toward the observed radiosonde profiles. Simulated vertical velocities are underestimated in all simulations except in the CRM simulations with grid spacings of 500 m or finer, which suggests that turbulent vertical air motions in cirrus clouds need to be parameterized in general circulation models and in CSRM simulations with horizontal grid spacings on the order of 1 km. The simulated ice water content and ice number concentrations agree with the observations in the CSRM but are underestimated in the CRM simulations. The underestimation of ice number concentrations is consistent with the overestimation of radar reflectivity in the CRM simulations and suggests that the model produces too many large ice particles especially toward the cloud base. Simulated cloud profiles are rather insensitive to perturbations in the initial conditions or the dimensionality of the model domain, but the treatment of the forcing data has a considerable effect on the outcome of the model simulations. Despite considerable progress in observations and microphysical parameterizations, simulating the microphysical, macrophysical, and radiative properties of cirrus remains challenging. Comparing model simulations with observations from multiple instruments and observational platforms is important for revealing model deficiencies and for providing rigorous benchmarks. However, there still is considerable need for reducing observational uncertainties and providing better observations especially for relative humidity and for the size distribution and chemical composition of aerosols in the upper troposphere.
Serotonin: Vital affects and psychotherapy

Including biological measures such as the serotonin function to the outcome variables of psychotherapy opens novel perspectives, which may enable better integration of diagnostic and neurobiological aspects with psychotherapy research. However, the problems of epistemology, ontology and the conceptual differences pertaining to such interdisciplinary efforts have to be adequately considered in order to avoid confusion between the different explanatory models used in neurobiological and clinical psychotherapy research. A number of studies have already shown that psychotherapy can be connected with significant changes in the function of brain networks. Recently, preliminary evidence has been gained that also changes in the synaptic transmission in serotonin pathways may take place during the psychotherapy of patients with depression. Although these findings have to be repeated and confirmed in future research with larger patient samples, it seems likely that in selected individuals, especially in those with atypical symptoms of depression, the reduced serotonin function can be normalized during psychotherapy.
Characterization of Neuropilin-1 Structural Features That Confer Binding to Semaphorin 3A and Vascular Endothelial Growth Factor 165*

Neuropilin-1 (Npn-1) is a receptor for both semaphorin 3A (Sema3A) and vascular endothelial growth factor 165 (VEGF165). To understand the role Npn-1 plays as a receptor for these structurally and functionally unrelated ligands, we set out to identify structural features of Npn-1 that confer binding to Sema3A or VEGF165. We constructed Npn-1 variants containing deletions within the “a” and “b” domains of Npn-1. More than 16 variants were expressed in COS-1 cells and tested for alkaline phosphatase-Sema3A as well as alkaline phosphatase-VEGF165binding. Our results indicate that each of the two Npn-1 CUB domains and the amino-terminal coagulation factor V/VIII domain (CF V/VIII) are essential for Sema3A binding, but only the amino-terminal Npn-1 CF V/VIII domain is required for binding to VEGF165. Guided by the structure of the bovine spermadhesin CUB domain, point mutants targeting defined surfaces of the Npn-1 a1 CUB domain were generated and tested for Sema3A and VEGF165 binding. One Npn-1 variant, Npn-12ABC, exhibits complete loss of Sema3A binding while retaining normal VEGF165 binding. Moreover, co-immunoprecipitation experiments show that Npn-12ABC can form a signaling complex with the VEGF165 signaling receptor KDR/VEGFR-2. These results establish the identity of contact sites between Npn-1 and its semaphorin ligands, and they provide a foundation for understanding how Npn-1 functions as a receptor for distinct classes of ligands in vivo.