Miracle-dz/UniFAR-FTUs huggingface dataset:
Identification of Secreted Proteins Involved in Nonspecific dsRNA-Mediated Lutzomyia longipalpis LL5 Cell Antiviral Response

Hematophagous insects transmit infectious diseases. Sand flies are vectors of leishmaniasis, but can also transmit viruses. We have been studying immune responses of Lutzomyia longipalpis, the main vector of visceral leishmaniasis in the Americas. We identified a non-specific antiviral response in L. longipalpis LL5 embryonic cells when treated with non-specific double-stranded RNAs (dsRNAs). This response is reminiscent of interferon response in mammals. We are investigating putative effectors for this antiviral response. Secreted molecules have been implicated in immune responses, including interferon-related responses. We conducted a mass spectrometry analysis of conditioned medium from LL5 cells 24 and 48 h after dsRNA or mock treatment. We identified 304 proteins. At 24 h, 19 proteins had an abundance equal or greater than 2-fold change, while the levels of 17 proteins were reduced when compared to control cells. At the 48 h time point, these numbers were 33 and 71, respectively. The two most abundant secreted peptides at 24 h in the dsRNA-transfected group were phospholipid scramblase, an interferon-inducible protein that mediates antiviral activity, and forskolin-binding protein (FKBP), a member of the immunophilin family, which mediates the effect of immunosuppressive drugs. The transcription profile of most candidates did not follow the pattern of secreted protein abundance.
Ghrelin affects stopover decisions and food intake in a long-distance migrant

Significance Twice a year, billions of birds migrate across continents. Along their route, most species spend considerable time at stopover sites to replenish their fuel stores. What physiological signals tell them when they are ready to continue their journey? Ghrelin is a recently discovered hormone involved in appetite regulation. We found that ghrelin concentrations correlated positively with fat stores of wild garden warblers. Further, birds injected with ghrelin decreased their food intake and increased their drive to continue migration. Hence, our study shows that hormones regulating food intake and energy stores control migratory behavior. This is a previously unknown role for a hormonal system shared by birds and mammals, whose disruption causes eating disorders and obesity. Billions of birds migrate long distances to either reach breeding areas or to spend the winter at more benign places. On migration, most passerines frequently stop over to rest and replenish their fuel reserves. To date, we know little regarding how they decide that they are ready to continue their journey. What physiological signals tell a bird’s brain that its fuel reserves are sufficient to resume migration? A network of hormones regulates food intake and body mass in vertebrates, including the recently discovered peptide hormone, ghrelin. Here, we show that ghrelin reflects body condition and influences migratory behavior of wild birds. We measured ghrelin levels of wild garden warblers (Sylvia borin) captured at a stopover site. Further, we manipulated blood concentrations of ghrelin to test its effects on food intake and migratory restlessness. We found that acylated ghrelin concentrations of garden warblers with larger fat scores were higher than those of birds without fat stores. Further, injections of unacylated ghrelin decreased food intake and increased migratory restlessness. These results represent experimental evidence that appetite-regulating hormones control migratory behavior. Our study lays a milestone in migration physiology because it provides the missing link between ecologically dependent factors such as condition and timing of migration. In addition, it offers insights in the regulation of the hormonal system controlling food intake and energy stores in vertebrates, whose disruption causes eating disorders and obesity.
Longitudinal Trends in the Prevalence of Detectable HIV Viremia: Population-Based Evidence From Rural KwaZulu-Natal, South Africa

Background The prevalence of detectable viremia has previously been used to infer the potential for ongoing human immunodeficiency virus (HIV) transmission. To date, no study has evaluated the longitudinal change in the prevalence of detectable viremia within the HIV-positive community (PDV+) and the entire population (PDVP) using data from a sub-Saharan African setting. Methods In 2011, 2013, and 2014, we obtained 6752 HIV-positive and 15415 HIV-negative test results from a population-based surveillance system in the KwaZulu-Natal province of South Africa. We quantified the PDV+ as the proportion of the 6752 HIV-positive results with a viral load >1550 copies/mL and the PDVP as the proportion of the 6752 HIV-positive and 15415 HIV-negative results with a viral load >1550 copies/mL. Results Between 2011 and 2014, the PDV+ decreased by 16.5 percentage points (pp) for women (from 71.8% to 55.3%) and 10.6 pp for men (from 77.8% to 67.2%). However, a steady rise in the overall HIV prevalence, from 26.7% to 32.4%, offset the declines in the PDV+ for both sexes. For women, the PDVP decreased by only 2.1 pp, from 21.3% to 19.2%, but for men, the PDVP actually increased by 1.6 pp, from 14.6% to 16.2%, over the survey period. Conclusions The PDV+, which is currently being tracked under the UNAIDS 90-90-90 targets, may not be an accurate indicator of the potential for ongoing HIV transmission. There is a critical need for countries to monitor and report the prevalence of detectable viremia among all adults, irrespective of HIV status.
Control of DEMETER DNA demethylase gene transcription in male and female gamete companion cells in Arabidopsis thaliana

Significance The Arabidopsis DEMETER (DME) DNA demethylase is required for reproduction and endosperm gene imprinting. We investigated mechanisms that restrict DME transcription to the female and male companion cells, the central and vegetative cells, adjacent to egg and sperm cells, respectively. We delineated a region, surprisingly within the DME gene, sufficient for proper DME expression, which rescues seed abortion and aberrant endosperm DNA methylation associated with dme mutations. We discovered overlapping DNA enhancers promoting vegetative and central cell expression, which can be used to pinpoint candidate transcription factors that regulate DME in companion cells. These results show how reproductive DNA demethylation is restricted to companion cells, thereby protecting egg and sperm cells from deleterious DNA demethylation that would be transmitted to progeny. The DEMETER (DME) DNA glycosylase initiates active DNA demethylation via the base-excision repair pathway and is vital for reproduction in Arabidopsis thaliana. DME-mediated DNA demethylation is preferentially targeted to small, AT-rich, and nucleosome-depleted euchromatic transposable elements, influencing expression of adjacent genes and leading to imprinting in the endosperm. In the female gametophyte, DME expression and subsequent genome-wide DNA demethylation are confined to the companion cell of the egg, the central cell. Here, we show that, in the male gametophyte, DME expression is limited to the companion cell of sperm, the vegetative cell, and to a narrow window of time: immediately after separation of the companion cell lineage from the germline. We define transcriptional regulatory elements of DME using reporter genes, showing that a small region, which surprisingly lies within the DME gene, controls its expression in male and female companion cells. DME expression from this minimal promoter is sufficient to rescue seed abortion and the aberrant DNA methylome associated with the null dme-2 mutation. Within this minimal promoter, we found short, conserved enhancer sequences necessary for the transcriptional activities of DME and combined predicted binding motifs with published transcription factor binding coordinates to produce a list of candidate upstream pathway members in the genetic circuitry controlling DNA demethylation in gamete companion cells. These data show how DNA demethylation is regulated to facilitate endosperm gene imprinting and potential transgenerational epigenetic regulation, without subjecting the germline to potentially deleterious transposable element demethylation.
In Vitro-In Vivo Discordance with Humanized Piperacillin-Tazobactam Exposures against Piperacillin-Tazobactam-Resistant/Pan-β-Lactam-Susceptible Escherichia coli

ABSTRACT Recent findings have identified Escherichia coli strains that are pan-β-lactam susceptible (PBL-S) but piperacillin-tazobactam resistant (TZP-R) in vitro. We assessed the in vivo significance of this resistance profile in a neutropenic murine pneumonia model using humanized exposures of TZP with 18 clinical E. coli isolates, 8 TZP-S/PBL-S and 10 genotypically confirmed TZP-R/PBL-S. Despite phenotypically and genotypically defined resistance, TZP displayed efficacy against these isolates. Additional studies are required to define the clinical implications of these TZP-R/PBL-S strains.
Developmental toxicant exposure in a mouse model of Alzheimer’s disease induces differential sex-associated microglial activation and increased susceptibility to amyloid accumulation

As the resident macrophage of the central nervous system, microglia are thought to contribute to Alzheimer’s disease (AD) pathology through lack of neuroprotection. The role of immune dysfunction in AD may be due to disruption of regulatory signals for the activation of microglia that may occur early in development. We hypothesized that early toxicant exposure would systematically activate microglia, possibly reversing the pathological severity of AD. Offspring of a triple transgenic murine model for AD (3×TgAD) were exposed to a model neurotoxicant, lead acetate, from postnatal days (PND) 5–10. Our results indicated that female mice exposed to Pb had a greater and earlier incidence of amyloid burden within the hippocampus, coinciding with decreased markers of microglial activation at PND 50. Pb-exposed males had increased microglial activation at PND 50, as evidence by CD11b expression and microglial abundance, with no significant increase in amyloid burden at that time. There was greater amyloid burden at PND 90 and 180 in both male and female mice exposed to Pb compared with control. Together, these data suggest that activated microglia are neuroprotective against amyloid accumulation early in AD pathology, and that early exposure to Pb could increase susceptibility to later-life neurodegeneration. Likewise, females may be more susceptible to early-life microglial damage, and, subsequently, AD. Further investigation into the sex biased mechanisms by which microglial activation is altered by an early-life immune insult will provide critical insight into the temporal susceptibility of the developing neuroimmune system and its potential role in AD etiopathology.
Advanced Composite Materials for Heat Sink Applications

Novel heat sink materials reinforced with diamonds have been produced via powder metallurgy. As matrix, several copper alloys containing boron have been chosen. Prepared composites have been investigated regarding microstructure and the various properties such as thermal conductivity, thermal expansion, etc. Light and scanning electron microscopy have been used for observation of particle distribution in the matrix and for investigation of possible carbide formation at the matrix-diamond interfaces. The produced composites exhibit thermal conductivities up to 600 W/mK. The copper composites with good interfacial bonding show only small decrease in thermal conductivity and a relatively stable CTE after the thermal cycling test.
Inhibition effects of total flavonoids from Scutellaria barbata D. Don on human breast carcinoma bone metastasis via downregulating PTHrP pathway

It is abundantly clear that tumor-derived parathyroid hormone-related protein (PTHrP), receptor activator of nuclear factor-κB ligand (RANKL) and osteoprotegerin (OPG) are central contributors in promoting osteolytic process of breast carcinoma bone metastasis. Forcusing on this molecular basis, the study was undertaken to explore the inhibition effects of total flavonoids from Scutellaria barbata D. Don (TF-SB) on human breast carcinoma bone metastasis. MDA-MB-231 cells and nude mouse models of breast cancer bone metastasis were given TF-SB in different concentrations. The proliferation, migration and invasion potentials of MDA-MB-231 cells were respectively tested. The effects of TF-SB on tumor weights and bone destruction were investigated. The mRNA and protein expression of PTHrP, OPG and RANKL were assessed by qPCR and western blot analysis. In vitro, TF-SB inhibited the proliferation, migration and invasion of MDA-MB-231 cells in a dose-dependent manner. In vivo, TF-SB prevented bone metastasis of breast cancer by decreasing the number of osteoclast cells per field in a dose-dependent manner, but not affecting tumor growth or mouse survival. Molecular analysis revealed that TF-SB controled the secretion of osteolysis-related factors PTHrP and its downstream RANKL/OPG. Together, by controlling the expression of PTHrP and its downstream OPG/RANKL, TF-SB has significant inhibition effects on breast cancer bone metastasis, which indicates a new therapeutic method.
Isotope exchange reactions involving HCO+ with CO: A theoretical approach

Aims. We aim to investigate fractionation reactions involved in the 12 C/ 13 C, 16 O/ 18 O, and 17 O balance. Methods. Full-dimensional rovibrational calculations were used to compute numerically exact rovibrational energies and thermal equilibrium conditions to derive the reaction rate coefficients. A nonlinear least-squares method was employed to represent the rate coefficients by analytic functions. Results. New exothermicities are derived for 30 isotopic exchange reactions of HCO + with CO. For each of the reactions, we provide the analytic three-parameter Arrhenius-Kooij formula for both the forward reaction and backward reaction rate coefficients, that can further be used in astrochemical kinetic models. Rotational constants derived here for the 17 O containing forms of HCO + may assist detection of these cations in outer space.
Therapeutic Efficacy of AAV1.SERCA2a in Monocrotaline-Induced Pulmonary Arterial Hypertension

Background— Pulmonary arterial hypertension (PAH) is characterized by dysregulated proliferation of pulmonary artery smooth muscle cells leading to (mal)adaptive vascular remodeling. In the systemic circulation, vascular injury is associated with downregulation of sarcoplasmic reticulum Ca2+-ATPase 2a (SERCA2a) and alterations in Ca2+ homeostasis in vascular smooth muscle cells that stimulate proliferation. We, therefore, hypothesized that downregulation of SERCA2a is permissive for pulmonary vascular remodeling and the development of PAH. Methods and Results— SERCA2a expression was decreased significantly in remodeled pulmonary arteries from patients with PAH and the rat monocrotaline model of PAH in comparison with controls. In human pulmonary artery smooth muscle cells in vitro, SERCA2a overexpression by gene transfer decreased proliferation and migration significantly by inhibiting NFAT/STAT3. Overexpresion of SERCA2a in human pulmonary artery endothelial cells in vitro increased endothelial nitric oxide synthase expression and activation. In monocrotaline rats with established PAH, gene transfer of SERCA2a via intratracheal delivery of aerosolized adeno-associated virus serotype 1 (AAV1) carrying the human SERCA2a gene (AAV1.SERCA2a) decreased pulmonary artery pressure, vascular remodeling, right ventricular hypertrophy, and fibrosis in comparison with monocrotaline-PAH rats treated with a control AAV1 carrying &bgr;-galactosidase or saline. In a prevention protocol, aerosolized AAV1.SERCA2a delivered at the time of monocrotaline administration limited adverse hemodynamic profiles and indices of pulmonary and cardiac remodeling in comparison with rats administered AAV1 carrying &bgr;-galactosidase or saline. Conclusions— Downregulation of SERCA2a plays a critical role in modulating the vascular and right ventricular pathophenotype associated with PAH. Selective pulmonary SERCA2a gene transfer may offer benefit as a therapeutic intervention in PAH.
Explanation of the origin of quench distortion and residual stress in specimens using computer simulation

Measurements of distortion and internal residual stresses after quenching in specimens (e.g., cylinders, disks, rings) have been performed for many years. As a result, patterns of distortion and stress distribution have been identified in the typical shapes, steels and cooling conditions. These experimental data were examined by pioneers of the heat treatment simulation for verifying their computer programs in the 1970s and 1980s. However, early researchers did not fully explain the mechanism of distortion and residual stress generation based on their simulated results. A way to explain the generation mechanism using simulated results, especially distributions of all types of strains, has been recently developed and successfully applied to some experimental works by the authors of this paper. Its concept is described briefly, and its applications for some specimens are summarised.
Following Through on Good Intentions: The Power of Planning Prompts

We study whether prompts to form and recall a plan can increase individuals' responsiveness to reminders to make and attend beneficial appointments. At four companies, all employees due for a colonoscopy were randomly assigned to receive either a control mailing or a treatment mailing. The mailings were identical except that the control mailing included a blank sticky note while the treatment mailing included a sticky note that prompted the recipient to write down the appointment date for a colonoscopy and the name of the doctor who would conduct the procedure. During the seven-month follow-up period, 7.2% of treatment employees received a colonoscopy compared to 6.2% of control employees, a statistically significant difference that is roughly equal to the variation in compliance associated with a 10 percent increase in the fraction of the procedure's cost covered by insurance. The treatment effect was largest for demographic groups judged to be at the highest risk of failing to receive a colonoscopy due to forgetfulness.
Synergistic Apoptotic Effects of Tocotrienol Isomers and Acalypha wilkesiana on A549 and U87MG Cancer Cells

Recent studies suggested that combined treatment approaches can be used to improve anticancer potency and circumvent the limitations of high-dose tocotrienols administration. Acalypha wilkesiana is a medicinal plant that has been used as an adjunct treatment for cancers in traditional medicine. Herein, the effects of single and combined treatments of β-, γ- and δ-tocotrienols and ethyl acetate extract (9EA) of Acalypha wilkesiana on lung (A549) and brain (U87MG) cancer cells were investigated. γ- and δ-tocotrienols exhibited higher potent antiproliferative effects against A549 (12.1 μg/ml and 13.6 μg/ml) and U87MG cells (3.3 μg/ml and 5.2 μg/ml) compared to β-tocotrienols (9.4 μg/ml and 92.4 μg/ml), respectively. Whereas, 9EA induced potent antiproliferative effects against U87MG cells only (2.0 μg/ml). Combined treatments of tocotrienols and 9EA induced a synergistic growth inhibition with up to 8.4-fold reduction in potent doses of β-, γ- and δ-tocotrienols on A549 cells. Apoptotic features were also evidenced on A549 cells receiving single and combined treatments. The synergism may greatly improve the therapeutic outcome for lung cancer.
Death of family members as an overlooked source of racial disadvantage in the United States

Significance Due to historical racial inequalities in the United States, including poverty, inadequate health care, and criminal victimization, black Americans die at much higher rates than white Americans. How the consequences of these elevated rates reverberate across family networks warrants attention. If blacks die at higher rates and earlier in the life course than whites, then blacks lose more loved ones from childhood through adulthood. Through the damaging effects of grief and other mechanisms, such losses are likely to undermine multiple life course outcomes. By analyzing nationally representative datasets to compare black and white Americans on the likelihood of losing family members over the life course, this study documents an intergenerational process with corrosive effects on black families and communities. Long-standing racial differences in US life expectancy suggest that black Americans would be exposed to significantly more family member deaths than white Americans from childhood through adulthood, which, given the health risks posed by grief and bereavement, would add to the disadvantages that they face. We analyze nationally representative US data from the National Longitudinal Study of Youth (n = 7,617) and the Health and Retirement Study (n = 34,757) to estimate racial differences in exposure to the death of family members at different ages, beginning in childhood. Results indicate that blacks are significantly more likely than whites to have experienced the death of a mother, a father, and a sibling from childhood through midlife. From young adulthood through later life, blacks are also more likely than whites to have experienced the death of a child and of a spouse. These results reveal an underappreciated layer of racial inequality in the United States, one that could contribute to the intergenerational transmission of health disadvantage. By calling attention to this heightened vulnerability of black Americans, our findings underscore the need to address the potential impact of more frequent and earlier exposure to family member deaths in the process of cumulative disadvantage.
The solitary wave of asexual evolution

Using a previously undescribed approach, we develop an analytic model that predicts whether an asexual population accumulates advantageous or deleterious mutations over time and the rate at which either process occurs. The model considers a large number of linked identical loci, or nucleotide sites; assumes that the selection coefficient per site is much less than the mutation rate per genome; and includes back and compensating mutations. Using analysis and Monte Carlo simulations, we demonstrate the accuracy of our results over almost the entire range of population sizes. Two limiting cases of our results, when either deleterious or advantageous mutations can be neglected, correspond to the Fisher–Muller effect and Muller's ratchet, respectively. By comparing predictions of our model (no recombination) to those of simple single-locus models (strong recombination), we show that the accumulation of advantageous mutations is slowed by linkage over a broad, finite range of population size. This supports the view of Fisher and Muller, who argued in the 1930s that progressive evolution of organisms is slowed because loci at which beneficial mutations can occur are often linked together on the same chromosome. These results follow from our main finding, that distribution of sequences over the mutation number evolves as a traveling wave whose speed and width depend on population size and other parameters. The model explains a logarithmic dependence of steady-state fitness on the population size reported recently for an RNA virus.