Miracle-dz/UniFAR-FTUs huggingface dataset:
Deletion of the K1L Gene Results in a Vaccinia Virus That Is Less Pathogenic Due to Muted Innate Immune Responses, yet Still Elicits Protective Immunity

ABSTRACT All viruses strategically alter the antiviral immune response to their benefit. The vaccinia virus (VACV) K1 protein has multiple immunomodulatory effects in tissue culture models of infection, including NF-κB antagonism. However, the effect of K1 during animal infection is poorly understood. We determined that a K1L-less vaccinia virus (vΔK1L) was less pathogenic than wild-type VACV in intranasal and intradermal models of infection. Decreased pathogenicity was correlated with diminished virus replication in intranasally infected mice. However, in intradermally inoculated ears, vΔK1L replicated to levels nearly identical to those of VACV, implying that the decreased immune response to vΔK1L infection, not virus replication, dictated lesion size. Several lines of evidence support this theory. First, vΔK1L induced slightly less edema than vK1L, as revealed by histopathology and noninvasive quantitative ultrasound technology (QUS). Second, infiltrating immune cell populations were decreased in vΔK1L-infected ears. Third, cytokine and chemokine gene expression was decreased in vΔK1L-infected ears. While these results identified the biological basis for smaller lesions, they remained puzzling; because K1 antagonizes NF-κB in vitro, antiviral gene expression was expected to be higher during vΔK1L infection. Despite these diminished innate immune responses, vΔK1L vaccination induced a protective VACV-specific CD8+ T cell response and protected against a lethal VACV challenge. Thus, vΔK1L is the first vaccinia virus construct reported that caused a muted innate immune gene expression profile and decreased immune cell infiltration in an intradermal model of infection yet still elicited protective immunity. IMPORTANCE The vaccinia virus (VACV) K1 protein inhibits NF-κB activation among its other antagonistic functions. A virus lacking K1 (vΔK1L) was predicted to be less pathogenic because it would trigger a more robust antiviral immune response than VACV. Indeed, vΔK1L was less pathogenic in intradermally infected mouse ear pinnae. However, vΔK1L infection unexpectedly elicited dramatically reduced infiltration of innate immune cells into ears. This was likely due to decreased expression of cytokine and chemokine genes in vΔK1L-infected ears. As such, our finding contradicted observations from cell culture systems. Interestingly, vΔK1L conferred protective immunity against lethal VACV challenge. This suggests that the muted immune response triggered during vΔK1L infection remained sufficient to mount an effective protective response. Our results highlight the complexity and unpredictable nature of virus-host interactions, a relationship that must be understood to better comprehend virus pathogenesis or to manipulate viruses for use as vaccines.
The B-Cell Follicle in HIV Infection: Barrier to a Cure

The majority of HIV replication occurs in secondary lymphoid organs (SLOs) such as the spleen, lymph nodes, and gut-associated lymphoid tissue. Within SLOs, HIV RNA+ cells are concentrated in the B-cell follicle during chronic untreated infection, and emerging data suggest that they are a major source of replication in treated disease as well. The concentration of HIV RNA+ cells in the B-cell follicle is mediated by several factors. Follicular CD4+ T-cell subsets including T-follicular helper cells and T-follicular regulatory cells are significantly more permissive to HIV than extrafollicular subsets. The B cell follicle also contains a large reservoir of extracellular HIV virions, which accumulate on the surface of follicular dendritic cells (FDCs) in germinal centers. FDC-bound HIV virions remain infectious even in the presence of neutralizing antibodies and can persist for months or even years. Moreover, the B-cell follicle is semi-immune privileged from CTL control. Frequencies of HIV- and SIV-specific CTL are lower in B-cell follicles compared to extrafollicular regions as the majority of CTL do not express the follicular homing receptor CXCR5. Additionally, CTL in the B-cell follicle may be less functional than extrafollicular CTL as many exhibit the recently described CD8 T follicular regulatory phenotype. Other factors may also contribute to the follicular concentration of HIV RNA+ cells. Notably, the contribution of NK cells and γδ T cells to control and/or persistence of HIV RNA+ cells in secondary lymphoid tissue remains poorly characterized. As HIV research moves increasingly toward the development of cure strategies, a greater understanding of the barriers to control of HIV infection in B-cell follicles is critical. Although no strategy has as of yet proven to be effective, a range of novel therapies to address these barriers are currently being investigated including genetically engineered CTL or chimeric antigen receptor T cells that express the follicular homing molecule CXCR5, treatment with IL-15 or an IL-15 superagonist, use of bispecific antibodies to harness the killing power of the follicular CD8+ T cell population, and disruption of the follicle through treatments such as rituximab.
A Novel GMPPA Mutation in Two Adult Sisters with Achalasia, Alacrima, Short Stature, Dysmorphism, and Intellectual Disability

The alacrima, achalasia, and mental retardation syndrome (AAMR) is a newly described autosomal recessive disorder characterized by the onset of these 3 main features at birth or in early infancy. At present, only 16 cases have been reported. Recently, it was shown that AAMR is due to mutations in the guanosine diphosphate (GDP)-mannose pyrophosphorylase A (GMPPA) gene. These mutations induce a significant GDP-mannose overload, which may affect protein glycosylation. Herein, for the first time, we describe 2 adult sisters with AAMR with a previously not reported deleterious homozygous missense mutation c.1118G>C (p.Arg373Pro) in the GMPPA gene, born to healthy consanguineous heterozygous parents from an ancient endogamous population. The main symptoms in both sisters started soon after birth with achalasia and feeding difficulties, requiring surgical treatment. Both sisters showed alacrima identified during the first months of life, delayed psychomotor development, speech delay, facial dysmorphism, limb defects, short stature, and moderate intellectual disability. Alacrima and feeding difficulties due to achalasia during the neonatal period or first months of life, in the absence of adrenal cortical insufficiency, should spur to investigate AAMR by sequencing the GMPPA gene.
Mcm10 promotes rapid isomerization of CMG-DNA for replisome bypass of lagging strand DNA blocks

Replicative helicases in all cell types are hexameric rings that unwind DNA by steric exclusion in which the helicase encircles the tracking strand only and excludes the other strand from the ring. This mode of translocation allows helicases to bypass blocks on the strand that is excluded from the central channel. Unlike other replicative helicases, eukaryotic CMG helicase partially encircles duplex DNA at a forked junction and is stopped by a block on the non-tracking (lagging) strand. This report demonstrates that Mcm10, an essential replication protein unique to eukaryotes, binds CMG and greatly stimulates its helicase activity in vitro. Most significantly, Mcm10 enables CMG and the replisome to bypass blocks on the non-tracking DNA strand. We demonstrate that bypass occurs without displacement of the blocks and therefore Mcm10 must isomerize the CMG-DNA complex to achieve the bypass function.
An analytical model to determine interseed attenuation effect in low‐dose‐rate brachytherapy

Brachytherapy treatment planning systems (BTPS) are employing the American Association of Physicists in Medicine (AAPM) Task Group 43 (TG‐43)‐recommended dosimetric parameters of sources, which are measured in water. The majority of brachytherapy implant volumes are not homogeneous media. Particularly, an implant with multiple seeds significantly changes homogeneity of the implant volume. Heterogeneities, such as attenuation by adjacent seeds or interseed attenuation (ISA), are neglected to this day in all BTPS. The goal of this project is to determine a novel analytical method to evaluate the impact of the dose perturbations (P‐value) and/or interseed attenuation effect (ISA‐value). This method will be validated for low‐ and high‐energy brachytherapy seeds such as 125I and 192Ir using Monte Carlo (MC) simulation techniques. In this analytical model, determination of dose perturbation and interseed attenuation in a multisource brachytherapy implant is based on MC‐simulated 3D kernels of P‐values and ISA data for single active and single dummy configurations, arranged at different distances and orientations relative to each other. The accuracy of the final model in multisource implant configurations has been examined by a comparison of the calculated P‐values and ISA‐values with full Monte Carlo water simulations (FMCWS). This model enabled us to determine the total perturbation and ISA values for any multisource implant, and the results are in excellent agreement with the FMCWS data. The advantage of this model to FMCWS for daily clinical application is the speed of the calculations and ease of the implementation. The new perturbation and ISA formulism have shown a better accuracy for 192Ir than 125I due to Compton scattering and its independence of the atomic number of the chemical composition of the phantom materials. The maximum difference between the ISA model and FMCWS for all cases was less than 5%. This new model can provide inputs for brachytherapy planning software to consider the ISA effect in dose calculations based on TG‐43U1 algorithm. This approach is applicable for energy range of 125I to 192Ir sources. PACS number: 87.53. Jw
Self-Control Depletion and Nicotine Deprivation as Precipitants of Smoking Cessation Failure: A Human Laboratory Model

Objective: The need to understand potential precipitants of smoking relapse is exemplified by relapse rates as high as 95%. The Self-Control Strength model, which proposes that self-control is dependent upon limited resources and susceptible to fatigue, may offer insight into relapse processes. The current study tested the hypothesis that self-control depletion (SCD), produced from engagement in emotional suppression, would serve as a novel antecedent for cessation failure, as indexed by a validated laboratory analogue of smoking lapse and relapse. We also examined whether SCD effects interacted with those of a well-established relapse precipitant (i.e., nicotine deprivation). Craving and behavioral economic indices (delay discounting and demand) were tested as hypothesized mechanisms for increased cessation failure. Ultimately, a moderated mediation model was used to test nicotine deprivation as a hypothesized moderator of SCD effects. Method: We used a 2 × 2 (12-hr deprivation vs. no deprivation; SCD vs. no SCD) factorial between-subjects design (N = 128 smokers). Results: The primary hypothesis of the study was supported, as SCD increased lapse behavior (p = .04). Nicotine deprivation significantly increased craving, cigarette demand, delay discounting, and lapse behavior. No main effects were found for SCD on putative mediators (i.e., craving, demand, and discounting), but the SCD and deprivation manipulations interacted upon craving (p = .04). The moderated mediation model was significant. SCD was found to increase craving among nicotine deprived smokers, which mediated effects on lapse behavior. Conclusions: SCD appears to play an important role in smoking relapse and may be a viable target for intervention.
Maternal and perinatal outcomes in pregnancies with multiple sclerosis: a case-control study

Abstract Objective: To assess whether maternal multiple sclerosis (MS) is associated with adverse pregnancy outcomes by determining the clinical course of disease during pregnancy and postpartum throughout a 10-year-period in a single tertiary center. Methods: We conducted a case-control study that included pregnancies with a definitive diagnosis of MS (n=43), matched with 100 healthy pregnant women with similar characteristics. Maternal and perinatal data were retrieved from hospital files. Groups were compared with the Mann-Whitney and χ2 tests. Logistic regression models were constructed to determine independent effects. Results: Maternal demographic and baseline laboratory data were similar across the groups. Rates of preterm delivery, fetal growth restriction, preeclampsia, gestational diabetes, stillbirth, cesarean delivery, congenital malformation, and 5-min Apgar score were comparable (P>0.05 for all). General anesthesia during cesarean delivery (96% vs. 39%, P=0.002), urinary tract infection (UTI) (12% vs. 3%, P=0.04), low 1-min Apgar score (21% vs. 9%, P=0.04), and nonbreastfeeding (33% vs. 2%, P=0.001) were more frequent in women with MS. The low 1-min Apgar score and breastfeeding rates were independent of general anesthesia and UTI in regression models. Conclusion: MS during pregnancy was not associated with adverse maternal and perinatal outcomes except UTI, low 1-min Apgar scores, and decreased breastfeeding rates.
Endothelin-1 Overexpression Exaggerates Diabetes-Induced Endothelial Dysfunction by Altering Oxidative Stress.

BACKGROUND Increased endothelin (ET)-1 expression causes endothelial dysfunction and oxidative stress. Plasma ET-1 is increased in patients with diabetes mellitus. Since endothelial dysfunction often precedes vascular complications in diabetes, we hypothesized that overexpression of ET-1 in the endothelium would exaggerate diabetes-induced endothelial dysfunction. METHODS Diabetes was induced by streptozotocin treatment (55mg/kg/day, i.p.) for 5 days in 6-week-old male wild type (WT) mice and in mice overexpressing human ET-1 restricted to the endothelium (eET-1). Mice were studied 14 weeks later. Small mesenteric artery (MA) endothelial function and vascular remodeling by pressurized myography, reactive oxygen species (ROS) production by dihydroethidium staining and mRNA expression by reverse transcription/quantitative PCR were determined. RESULTS Endothelium-dependent vasodilatory responses to acetylcholine of MA were reduced 24% by diabetes in WT ( P < 0.05), and further decreased by 12% in eET-1 ( P < 0.05). Diabetes decreased MA media/lumen in WT and eET-1 ( P < 0.05), whereas ET-1 overexpression increased MA media/lumen similarly in diabetic and nondiabetic WT mice ( P < 0.05). Vascular ROS production was increased 2-fold by diabetes in WT ( P < 0.05) and further augmented 1.7-fold in eET-1 ( P < 0.05). Diabetes reduced endothelial nitric oxide synthase (eNOS, Nos3 ) expression in eET-1 by 31% ( P < 0.05) but not in WT. Induction of diabetes caused a 52% ( P < 0.05) increase in superoxide dismutase 1 ( Sod1 ) and a 32% ( P < 0.05) increase in Sod2 expression in WT but not in eET-1. CONCLUSIONS Increased expression of ET-1 exaggerates diabetes-induced endothelial dysfunction. This may be caused by decrease in eNOS expression, increase in vascular oxidative stress, and decrease in antioxidant capacity.
Spectral model selection in the electronic measurement of the Boltzmann constant by Johnson noise thermometry

In the electronic measurement of the Boltzmann constant based on Johnson noise thermometry, the ratio of the power spectral densities of thermal noise across a resistor at the triple point of water, and pseudo-random noise synthetically generated by a quantum-accurate voltage-noise source is constant to within 1 part in a billion for frequencies up to 1 GHz. Given knowledge of this ratio, and the values of other parameters that are known or measured, one can determine the Boltzmann constant. Due, in part, to mismatch between transmission lines, the experimental ratio spectrum varies with frequency. We model this spectrum as an even polynomial function of frequency where the constant term in the polynomial determines the Boltzmann constant. When determining this constant (offset) from experimental data, the assumed complexity of the ratio spectrum model and the maximum frequency analyzed (fitting bandwidth) dramatically affects results. Here, we select the complexity of the model by cross-validation—a data-driven statistical learning method. For each of many fitting bandwidths, we determine the component of uncertainty of the offset term that accounts for random and systematic effects associated with imperfect knowledge of model complexity. We select the fitting bandwidth that minimizes this uncertainty. In the most recent measurement of the Boltzmann constant, results were determined, in part, by application of an earlier version of the method described here. Here, we extend the earlier analysis by considering a broader range of fitting bandwidths and quantify an additional component of uncertainty that accounts for imperfect performance of our fitting bandwidth selection method. For idealized simulated data with additive noise similar to experimental data, our method correctly selects the true complexity of the ratio spectrum model for all cases considered. A new analysis of data from the recent experiment yields evidence for a temporal trend in the offset parameters.
The First Letter Position Effect in Visual Word Recognition: The Role of Spatial Attention

A prominent question in visual word recognition is whether letters within a word are processed in parallel or in a left to right sequence. Although most contemporary models posit parallel processing, this notion seems at odds with well-established serial position effects in word identification that indicate preferential processing for the initial letter. The present study reports 4 experiments designed to further probe the locus of the first position processing advantage. The paradigm involved masked target words presented for short durations and required participants to subsequently select from 2 alternatives, 1 which was identical to the target and 1 that differed by a single letter. Experiment 1 manipulated the case between the target and the alternatives to ensure that previous evidence for a first position effect was not due to simple perceptual matching. The results continued to yield a robust first position advantage. Experiment 2 attempted to eliminate postperceptual decision processes as the explanatory mechanism by presenting single letters as targets and requiring participants to select an entire word that contained the target letter at different positions. Here the first position advantage was eliminated, suggesting postperceptual decision processes do not underlie the effect. The final 2 experiments presented masked stimuli either all vertically (Experiment 3) or randomly intermixed vertical and horizontal orientation (Experiment 4). In both cases, a robust first position advantage was still obtained. The authors consider alternative interpretations of this effect and suggest that these results are consistent with a rapid deployment of spatial attention to the beginning of a target string which occurs poststimulus onset.
Prescribed Performance Consensus of Uncertain Nonlinear Strict-Feedback Systems With Unknown Control Directions

In this paper, a leader-following consensus scheme is presented for networked uncertain nonlinear strict-feedback systems with unknown control directions under directed graphs, which can achieve predefined synchronization error bounds. Fuzzy logic systems are employed to approximate system uncertainties. A specific Nussbaum-type function is introduced to solve the problem of unknown control directions. Using a dynamic surface control technique, distributed consensus controllers are developed to guarantee that the outputs of all followers synchronize with that of the leader with prescribed performance. Based on Lyapunov stability theory, it is proved that all signals in closed-loop systems are uniformly ultimately bounded and the outputs of all followers ultimately synchronize with that of the leader with bounded tracking errors. Simulation results are provided to demonstrate the effectiveness of the proposed consensus scheme.
Seasonally Relevant Cool Temperatures Interact with N Chemistry to Increase Microcystins Produced in Lab Cultures of Microcystis aeruginosa NIES-843.

Freshwater cyanobacterial blooms are regularly formed by Microcystis spp. , which are well-known producers of the hepatotoxin microcystin. The environmental factors that regulate microcystin synthesis remain unclear. We used reverse transcription-quantitative PCR (RT-qPCR), metabolomics, and toxin profiling (both by LC-MS) to measure the response of Microcystis aeruginosa NIES-843 to nitrogen (N) concentration, N chemistry (nitrate versus urea), and a range of seasonally relevant temperatures. Growth rates at lower temperatures were slower but resulted in increased cellular microcystin content (quota), and at these lower temperatures, N concentration had no effect on toxin production. In contrast, at warmer temperatures, reduction in N concentration increased toxin production, especially when urea was supplied as the nitrogen source. Our culture results demonstrate how temperature may lead to physiological responses ranging from slow growing yet very toxic cells at cool temperatures, to faster growing but less-toxic cells at warmer temperatures. This response represents a key interaction in bloom dynamics. Capturing this phenomenon as a temperature-driven toxin phenotype incorporated into models might improve the ability to predict microcystin biosynthesis during cyanobacterial blooms.
A Study on Power Side Channels on Mobile Devices

Power side channel is a very important category of side channels, which can be exploited to steal confidential information from a computing system by analyzing its power consumption. In this paper, we demonstrate the existence of various power side channels on popular mobile devices such as smartphones. Based on unprivileged power consumption traces, we present a list of real-world attacks that can be initiated to identify running apps, infer sensitive UIs, guess password lengths, and estimate geo-locations. These attack examples demonstrate that power consumption traces can be used as a practical side channel to gain various confidential information of mobile apps running on smartphones. Based on these power side channels, we discuss possible exploitations and present a general approach to exploit a power side channel on an Android smartphone, which demonstrates that power side channels pose imminent threats to the security and privacy of mobile users. We also discuss possible countermeasures to mitigate the threats of power side channels.