Miracle-dz/UniFAR-FTUs huggingface dataset:
Genetically Intact but Functionally Impaired HIV-1 Env Glycoproteins in the T-Cell Reservoir

ABSTRACT HIV-infected subjects under antiretroviral treatment (ART) harbor a persistent viral reservoir in resting CD4+ T cells, which accounts for the resurgence of HIV replication after ART interruption. A large majority of HIV reservoir genomes are genetically defective, but even among intact proviruses few seem able to generate infectious virus. To understand this phenomenon, we examined the function and expression of HIV envelope glycoproteins reactivated from the reservoir of four HIV-infected subjects under suppressive ART. We studied full-length genetically intact env sequences from both replicative viruses and cell-associated mRNAs. We found that these Env proteins varied extensively in fusogenicity and infectivity, with strongest functional defects found in Envs from cell-associated mRNAs. Env functional impairments were essentially explained by defects in Env protein expression. Our results support the idea that defects in HIV Env expression, preventing cytopathic or immune HIV clearance, contribute to the persistence of the HIV T-cell reservoir in vivo. IMPORTANCE In most individuals, evolution of HIV infection is efficiently controlled on the long-term by combination antiviral therapies. These treatments, however, fail to eradicate HIV from the infected subjects, a failure that results both in resurgence of virus replication and in resumption of HIV pathogenicity when the treatment is stopped. HIV resurgence, in these instances, is widely assumed to emerge from a reservoir of silent virus integrated in the genomes of a small number of T lymphocytes. The silent HIV reservoir is mostly composed of heavily deleted or mutated HIV DNA. Moreover, among the seemingly intact remaining HIV, only very few are actually able to efficiently propagate in tissue culture. In this study, we find that intact HIV in the reservoir often carry strong defects in their capacity to promote fusion to neighboring cells and infection of target cells, a defect related to the function and expression of the HIV envelope glycoprotein. Impaired envelope glycoprotein expression and function could explain why cells harboring these viruses tend to remain undetected and unharmed in the reservoir.
A novel GIS platform for UGV application in the unknown environment

Recently, the UGV (Unmanned Ground Vehicle) receives more and more attention from the public with the application in deep space exploration, national defense, and riot relief. Moreover, how to describe the driving environment of UGV with the sensor data objectively and share these data with other UGV efficiently becomes the focus of the research of the UGV. To solve the above problems, a novel GIS platform for UGV application in the unknown environment is proposed in this paper based on the features of UGV. First, the GIS database is redesigned and the properties such as road width, lane number, lane info, and if_traffic are proposed. The data structure of the database is redesigned to fit the need of UGV to describe the environment simply and explicitly. Then a two-line road model is proposed to model the feature of the road network clearly. This model can meet the driving need of UGV and represent the traffic rules of the urban environment. Moreover, the turning path in the intersection is designed to be an arc instead of a right angle path considering the dynamic features of UGV. Finally a cost map for navigating the UGV locally is generated with the road model and the environment information from the sensors. The GIS platform designed in this paper proves to be able to offer guidance and help to UGV for driving through the unknown environment wisely and quickly without human intervention. And it shows promising application of sharing data with other UGV efficiently by using cost map instead of the original sensor data.
Bit Error Rate Performance Bounds of SC-FDE under Arbitrary Multipath Mobile

This paper focuses on the bit error rate (BER) performance of intelligent transportation communication system under multipath mobile frequency-selective channels. After presenting the theoretical BER performance formula of single carrier frequency domain equalization (SC-FDE) in the form of double integral, a closed-form approximate upper bound of BER performance was derived,as well as specific analytical expressions for approximate BER performance bounds under typical modulations. Analysis and simulation show that the derived approximate BER bound highly approaches the theoretical one. The bound also indicates that the research about the preferable equalization methods is still necessary.
Children’s and Mothers’ Cardiovascular Reactivity to a Standardized Laboratory Stressor: Unique Relations With Maternal Anxiety and Overcontrol

Research documents bidirectional associations between parental overcontrol (OC) and children’s anxiety; OC may place children at risk for anxiety and also may occur in response to children’s requests for help. However, to date no studies have examined children’s or parents’ in-the-moment emotional responses to OC. Using a community sample of mothers and school-age children, we examine the individual and interactive influences of maternal OC, maternal anxiety, children’s help-seeking, and children’s anxiety in predicting physiological reactivity in response to a stressor faced by children and observed by mothers, predicting that for children of higher anxiety mothers, higher OC will be associated with increases in reactivity (decreases in respiratory sinus arrhythmia [RSA]), whereas for higher anxiety mothers themselves, engaging in OC will be associated with reductions in physiological reactivity (decreases in heart rate). Multilevel modeling suggested that for children of higher anxiety mothers, greater peak OC is associated with greater reductions in RSA (increases in reactivity) after the onset of OC. In contrast, for higher anxiety mothers themselves, greater peak OC was linked with attenuations in heart rate. Effects held when controlling for children’s anxiety and help-seeking, and no pattern of effects was observed with analyses in which children’s help-seeking was the predictor or children’s anxiety was the moderator, suggesting that in this case, physiological reactivity is uniquely associated with the interaction between maternal OC and anxiety. Among mothers with higher anxiety, OC may serve a regulatory function, reducing physiological reactivity, while exacerbating children’s reactivity.
Biomarkers and surrogate outcomes in neurodegenerative disease: Lessons from multiple sclerosis

SummaryMultiple sclerosis (MS) is a chronic disease of the CNS that most commonly affects young adults. It is usually characterized in the early years by acute relapses followed by partial or complete remission; in later years progressive and irreversible disability develops. Because of the protracted and unpredictable clinical course, biological surrogate markers are much needed to make clinical trials of potential disease-modifying treatments more efficient. Magnetic resonance (MR) outcome measures are now widely used to monitor treatment outcome in MS trials. Areas of multifocal inflammation are detected with a high sensitivity as new areas of gadolinium enhancement and T2 abnormality, and these may be considered as surrogate markers for clinical relapses. However, progressive disability is not clearly related to inflammatory lesions but rather to a progressive and diffuse process with increasing neuroaxonal loss. MR surrogate measures for neuroaxonal loss include atrophy (tissue loss in brain and spinal cord), N-acetyl aspartate, and T1 hypointense lesions. Diffuse abnormality in normal appearing brain tissue may also be monitored using magnetization transfer ratio and other quantitative MR measures. For treatment trials of new agents aimed at preventing disability, measures of neuroaxonal damage should be acquired, especially atrophy, which occurs at all stages of MS and which can be quantified in a sensitive and reproducible manner. Because the MR surrogates for neuroaxonal loss are not yet validated as predicting future disability, definitive trials should continue to monitor an appropriate disability endpoint.
Specific activation of the TLR1-TLR2 heterodimer by small-molecule agonists

A small-molecule agonist of the Toll-like receptor 1/2 signaling pathway does it by stabilizing heterodimeric associations. Toll-like receptor (TLR) agonists activate both the innate and the adaptive immune systems. These TLR agonists have been exploited as potent vaccine adjuvants and antitumor agents. We describe the identification and characterization of a small molecule, N-methyl-4-nitro-2-(4-(4-(trifluoromethyl)phenyl)-1H-imidazol-1-yl)aniline (CU-T12-9), that directly targets TLR1/2 to initiate downstream signaling. CU-T12-9 specifically induces TLR1/2 activation, which can be blocked by either the anti-hTLR1 or the anti-hTLR2 antibody, but not the anti-hTLR6 antibody. Using a variety of different biophysical assays, we have demonstrated the binding mode of CU-T12-9. By binding to both TLR1 and TLR2, CU-T12-9 facilitates the TLR1/2 heterodimeric complex formation, which in turn activates the downstream signaling. Fluorescence anisotropy assays revealed competitive binding to the TLR1/2 complex between CU-T12-9 and Pam3CSK4 with a half-maximal inhibitory concentration (IC50) of 54.4 nM. Finally, we showed that CU-T12-9 signals through nuclear factor κB (NF-κB) and invokes an elevation of the downstream effectors tumor necrosis factor–α (TNF-α), interleukin-10 (IL-10), and inducible nitric oxide synthase (iNOS). Thus, our studies not only provide compelling new insights into the regulation of TLR1/2 signaling transduction but also may facilitate future therapeutic developments.
Cranial irradiation increases tumor growth in experimental breast cancer brain metastasis

Whole‐brain radiotherapy is the standard of care for patients with breast cancer with multiple brain metastases and, although this treatment has been essential in the management of existing brain tumors, there are many known negative consequences associated with the irradiation of normal brain tissue. In our study, we used in vivo magnetic resonance imaging analysis to investigate the influence of radiotherapy‐induced damage of healthy brain on the arrest and growth of metastatic breast cancer cells in a mouse model of breast cancer brain metastasis. We observed that irradiated, but otherwise healthy, neural tissue had an increased propensity to support metastatic growth compared with never‐irradiated controls. The elucidation of the impact of irradiation on normal neural tissue could have implications in clinical patient management, particularly in patients with residual systemic disease or with residual radio‐resistant brain cancer.
Itsy Bitsy Spider…: Infants React with Increased Arousal to Spiders and Snakes

Attention biases have been reported for ancestral threats like spiders and snakes in infants, children, and adults. However, it is currently unclear whether these stimuli induce increased physiological arousal in infants. Here, 6-month-old infants were presented with pictures of spiders and flowers (Study 1, within-subjects), or snakes and fish (Study 1, within-subjects; Study 2, between-subjects). Infants’ pupillary responses linked to activation of the noradrenergic system were measured. Infants reacted with increased pupillary dilation indicating arousal to spiders and snakes compared with flowers and fish. Results support the notion of an evolved preparedness for developing fear of these ancestral threats.
Label‐free quantitative chemical imaging and classification analysis of adipogenesis using mouse embryonic stem cells

Stem cells have received much attention recently for their potential utility in regenerative medicine. The identification of their differentiated progeny often requires complex staining procedures, and is challenging for intermediary stages which are a priori unknown. In this work, the ability of label‐free quantitative coherent anti‐Stokes Raman scattering (CARS) micro‐spectroscopy to identify populations of intermediate cell states during the differentiation of murine embryonic stem cells into adipocytes is assessed. Cells were imaged at different days of differentiation by hyperspectral CARS, and images were analysed with an unsupervised factorization algorithm providing Raman‐like spectra and spatially resolved maps of chemical components. Chemical decomposition combined with a statistical analysis of their spatial distributions provided a set of parameters that were used for classification analysis. The first 2 principal components of these parameters indicated 3 main groups, attributed to undifferentiated cells, cells differentiated into committed white pre‐adipocytes, and differentiating cells exhibiting a distinct protein globular structure with adjacent lipid droplets. An unsupervised classification methodology was developed, separating undifferentiated cell from cells in other stages, using a novel method to estimate the optimal number of clusters. The proposed unsupervised classification pipeline of hyperspectral CARS data offers a promising new tool for automated cell sorting in lineage analysis.
Surgical treatment strategy for diabetic forefoot osteomyelitis

The aim of this study was to propose an appropriate surgical treatment for diabetic forefoot osteomyelitis (DFO) involving ischemia or moderate to severe soft tissue infection. The records of 28 patients with osteomyelitis from 2009 to 2015 were retrospectively studied. All patients had undergone surgery based on preoperative magnetic resonance imaging examinations and histopathological or culture analyses confirming the surgical bone margin. The appropriate surgical margin, crucial factors for early healing, and prognosis after complete resection of osteomyelitis were examined. After healing, patients were followed up to assess prognosis (range 32–1,910 days, median 546 days). The healing rate of nonischemic cases of DFO with negative surgical margins was 100% and that of ischemic cases was 84.6%; the ambulatory rates for both types of cases were 100%. No wound (and/or osteomyelitis) recurrence was observed. Nine new cases of DFO developed in six patients (21.4%; eight were due to vascular stenosis, and one was due to biomechanical changes in the foot. After complete resection of osteomyelitis, preoperative and postoperative C‐reactive protein levels and the size of the ulcer were significant predictors of early healing (p < 0.05, 0.01, and 0.05, respectively). The appropriate surgical margin should be set in the area of bone marrow edema, based on magnetic resonance imaging examinations after revascularization. In cases with high preoperative or postoperative C‐reactive protein levels, long‐term antibiotic therapy is recommended, and surgery should be planned after the C‐reactive protein levels decrease, except in emergencies.
Measures and markers in Amyotrophic Lateral Sclerosis

SummaryAmyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder characterized by loss of spinal and cortical motor neurons, leading to progressive weakness and ultimately, death. Clinically, there appears to be an anatomic focus at disease onset, from which the disease then spreads. Because the focus of initial symptoms and the subsequent direction of spread can vary from patient to patient, disease monitoring is difficult, especially in a clinical trial, in which outcome measures must be identical and able to capture progression of all types. Thus, the search for markers of disease progression is especially important in ALS. Many approaches have been taken, from voluntary strength assessment and functional rating scales to physiological and pathological sampling of affected portions of nervous system. No proposed marker has been demonstrated to meet the desired criteria of biological meaning, sensitivity to disease progression, clear relationship to overall prognosis and survival, and ease of measurement. However, progress is being made in all of these regards.
Differential abundance of CK1α provides selectivity for pharmacological CK1α activators to target WNT-dependent tumors

A small-molecule CK1α activator inhibits the growth of WNT-driven intestinal tumors without toxicity to normal epithelium. Treating WNT-driven tumors The WNT signaling pathway powers the growth of various tumors, particularly colorectal cancer (CRC). However, WNT-targeted inhibitors are very toxic to normal gastrointestinal tissue, precluding their approval for clinical use. Li et al. show that WNT could be targeted by activating a kinase that inhibits the pathway. A small-molecule activator of the kinase CK1α called SSTC3 suppressed WNT activity in CRC cell lines, prevented tumor growth, and increased survival in mouse models of primary and metastatic CRC. Because the effects of SSTC3 were selective to cells with high WNT activity and low CK1α abundance, SSTC3 was minimally toxic to normal gastrointestinal epithelium. Thus, SSTC3 and its future derivatives may be a promising therapeutic for CRC patients. Constitutive WNT activity drives the growth of various human tumors, including nearly all colorectal cancers (CRCs). Despite this prominence in cancer, no WNT inhibitor is currently approved for use in the clinic largely due to the small number of druggable signaling components in the WNT pathway and the substantial toxicity to normal gastrointestinal tissue. We have shown that pyrvinium, which activates casein kinase 1α (CK1α), is a potent inhibitor of WNT signaling. However, its poor bioavailability limited the ability to test this first-in-class WNT inhibitor in vivo. We characterized a novel small-molecule CK1α activator called SSTC3, which has better pharmacokinetic properties than pyrvinium, and found that it inhibited the growth of CRC xenografts in mice. SSTC3 also attenuated the growth of a patient-derived metastatic CRC xenograft, for which few therapies exist. SSTC3 exhibited minimal gastrointestinal toxicity compared to other classes of WNT inhibitors. Consistent with this observation, we showed that the abundance of the SSTC3 target, CK1α, was decreased in WNT-driven tumors relative to normal gastrointestinal tissue, and knocking down CK1α increased cellular sensitivity to SSTC3. Thus, we propose that distinct CK1α abundance provides an enhanced therapeutic index for pharmacological CK1α activators to target WNT-driven tumors.
Blood-brain barrier genomics, proteomics, and new transporter discovery

SummaryThe blood-brain barrier (BBB) is an impermeable cellular interface that physically separates the blood from the interstices of the brain. The endothelial cells lining the brain blood vessels form the principle barrier, and their unique phenotype is a consequence of dynamic interactions with several perivascular cell types present in the brain parenchyma. In addition, BBB dysfunction has been observed in the large majority of neurological diseases, but the causes of aberrant vascular behavior are generally unknown. Because of its barrier phenotype, drug delivery to the brain has also proven to be a very difficult task. Global genomics and proteomics analyses are currently being used to examine BBB function in healthy and diseased brain to better characterize this dynamic interface. It is becoming increasingly evident that these approaches have the potential to clarify the unique attributes of a healthy BBB, to identify therapeutic targets in diseased brain, and to identify novel conduits for noninvasive delivery of drugs against these targets. This review will discuss the application of genomics and proteomics to blood-brain barrier research and will offer views on the prospects of such approaches.
Setting the Threshold for Surgical Prevention in Women at Increased Risk of Ovarian Cancer

Abstract The number of ovarian cancer cases is predicted to rise by 14% in Europe and 55% worldwide over the next 2 decades. The current absence of a screening program, rising drug/treatment costs, and only marginal improvements in survival seen over the past 30 years suggest the need for maximizing primary surgical prevention to reduce the burden of ovarian cancer. Primary surgical prevention through risk-reducing salpingo-oophorectomy (RRSO) is well established as the most effective method for preventing ovarian cancer. In the UK, it has traditionally been offered to high-risk women (>10% lifetime risk of ovarian cancer) who have completed their family. The cost-effectiveness of RRSO in BRCA1/BRCA2 carriers older than 35 years is well established. Recently, RRSO has been shown to be cost-effective in postmenopausal women at lifetime ovarian cancer risks of 5% or greater and in premenopausal women at lifetime risks greater than 4%. The acceptability, uptake, and satisfaction with RRSO at these intermediate-risk levels remain to be established. Prospective outcome data on risk-reducing salpingectomy and delayed-oophorectomy for preventing ovarian cancer is lacking, and hence, this is best offered for primary prevention within the context and safe environment of a clinical trial. An estimated 63% of ovarian cancers occur in women with greater than 4% lifetime risk and 53% in those with 5% or greater lifetime-risk. Risk-reducing salpingo-oophorectomy can be offered for primary surgical prevention to women at intermediate risk levels (4%–5% to 10%). This includes unaffected women who have completed their family and have RAD51C, RAD51D, or BRIP1 gene mutations; first-degree relatives of women with invasive epithelial ovarian cancer; BRCA mutation–negative women from high-risk breast-and-ovarian cancer or ovarian-cancer-only families. In those with BRCA1, RAD51C/RAD51D/MMR mutations and the occasional families with a history of ovarian cancer in their 40s, surgery needs to be considered at younger than 45. In other moderate-risk gene mutation carriers and those with polygenic risk, RRSO needs be considered at 50. There is need for establishment/expansion of well-defined pathways to increase clinical access to RRSO. It is time to lower the risk threshold for RRSO to enable introduction of a targeted primary prevention approach, which could significantly impact the future burden of ovarian cancer.
Location-Aware Worker Selection for Mobile Opportunistic Crowdsensing in VANETs

Worker selection for location-based crowdsensing can be described as the strategy of choosing the proper cooperative participants to complete the allocated tasks in specified regions. Due to the mobility pattern of vehicles and regular road networks, the Vehicular Ad-hoc Networks (VANETs) are expected to provide many opportunities for task execution in opportunistic crowdsensing, enabling some emerging applications. To fulfill tasks with the least execution time under the spatial-temporal restrictions, we propose a Location-Aware Worker Selection scheme (LAWS) for mobile opportunistic crowdsensing in urban areas. Different from the traditional worker selection schemes assigning a task to one designated worker, LAWS exploits the vehicles contacts provided by taxicabs and buses and makes full advantage of prior knowledge of vehicles to promote the performance of task execution. Real-world vehicle traces are introduced to construct the extensive simulations. The simulation results show that our scheme outperforms the well-known algorithms, e.g., Epidemic, Prophet, in terms of the task execution success ratio, the execution time and the network load.