bluuebunny/crossref_metadata_2025_split huggingface dataset:
TPR1, a novel rifampicin derivative, demonstrates efficacy alone and in combination with doxycycline against the NIAID Category A priority pathogen Francisella tularensis
Authors: Cummings Jason E , Slayden Keaton W , Slayden Richard A 
Published: March 2021

Abstract

Background
Francisella tularensis is a highly virulent and contagious Gram-negative intracellular bacterium that causes the disease tularaemia in mammals and is classified as a Category A priority pathogen.

Methods
We utilized a systematic analysis of antibacterial potency, extent of dissemination by analysis of bacterial burden in a secondary vital organ, and survival rates to assess the efficacy of a novel rifampicin derivative, TPR1. The efficacy of TPR1 was evaluated alone and in combination with the standard of care drug, doxycycline, against type A F. tularensis Schu S4 using a lethal pulmonary model of infection in mice.

Results
TPR1 has an MIC value range of 0.125–4 mg/L against reference laboratory strain Schu S4 and a panel of clinical strains. TPR1 alone reduced the bacterial burden in the lungs and spleen at 40 mg/kg and 80 mg/kg, and no antagonism was observed when co-administered with doxycycline. Dosing at 40 mg/kg doxycycline reduced the bacterial burden by 1 log10 cfu in the lungs and 4 log10 cfu in the spleen in comparison to untreated controls. Co-administration of TPR1 and doxycycline demonstrated efficacy upon treatment withdrawal after 4 days of treatment, and 100% survival.

Conclusions
Significantly, TPR1 demonstrated efficacy when delivered alone and in combination with doxycycline, which provides compelling evidence of a superior treatment strategy that would normally rely on a single chemotherapeutic for efficacy. In addition, this work substantiates the use of rifampicin derivatives as a platform for the development of novel treatments to other bacterial agents in addition to tularaemia.
Bidirectional imputation of spatial GPS trajectories with missingness using sparse online Gaussian Process
Authors: Liu Gang , Onnela Jukka-Pekka 
Published: March 2021

Abstract

Objective
We propose a bidirectional GPS imputation method that can recover real-world mobility trajectories even when a substantial proportion of the data are missing. The time complexity of our online method is linear in the sample size, and it provides accurate estimates on daily or hourly summary statistics such as time spent at home and distance traveled.

Materials and Methods
To preserve a smartphone’s battery, GPS may be sampled only for a small portion of time, frequently &lt;10%, which leads to a substantial missing data problem. We developed an algorithm that simulates an individual’s trajectory based on observed GPS location traces using sparse online Gaussian Process to addresses the high computational complexity of the existing method. The method also retains the spherical geometry of the problem, and imputes the missing trajectory in a bidirectional fashion with multiple condition checks to improve accuracy.

Results
We demonstrated that (1) the imputed trajectories mimic the real-world trajectories, (2) the confidence intervals of summary statistics cover the ground truth in most cases, and (3) our algorithm is much faster than existing methods if we have more than 3 months of observations; (4) we also provide guidelines on optimal sampling strategies.

Conclusions
Our approach outperformed existing methods and was significantly faster. It can be used in settings in which data need to be analyzed and acted on continuously, for example, to detect behavioral anomalies that might affect treatment adherence, or to learn about colocations of individuals during an epidemic.
Genetic Analysis of Formosan Subterranean Termite (Blattodea: Rhinotermitidae) Populations in California
Authors: Tseng Shu-Ping , Boone Jason , Boone Lowell , King Natalee , Taravati Siavash , Choe Dong-Hwan , Lee Chow-Yang 
Published: March 2021

AbstractA new infestation of the Formosan subterranean termite, Coptotermes formosanus Shiraki (Blattodea: Rhinotermitidae), was discovered in Canyon Lake, Riverside County, California. We used three mitochondrial DNA (COI, COII, and 16S) and seven polymorphic microsatellite markers to characterize the genetic relationship of the colony with two other colonies that were collected in 1992 and 2018 in La Mesa, San Diego County. Maximum likelihood phylogeny of C. formosanus based on concatenated COI and COII sequences revealed that the two La Mesa populations (CA01 and CA02) and the Canyon Lake population (CA03) were from different maternal lineages. Based on the 14 COII haplotypes of C. formosanus found world-wide, CA01 and CA02 belonged to a haplotype widely distributed across the United States, while CA03 was grouped under a haplotype predominantly found in Asia. Microsatellite allele frequencies across all loci for both La Mesa populations were relatively similar, but significant genetic differences were found between CA02 and CA03 colonies (FST = 0.24; Dest = 0.30; G″ ST = 0.55; P &lt; 0.01).
Sticking to One’s Guns: Mass Shootings and the Political Economy of Gun Control in the United States
Authors: Yousaf Hasin 
Published: March 2021

AbstractHow do events that highlight a policy issue impact political preferences? In this paper, I analyze the impact of mass shootings on voter behavior. I show that, conditional on population, mass shootings are largely random events. Using a difference-in-differences strategy, I find that mass shootings result in a 1.7 percentage point loss in Republican vote share in counties where they occur. Identification that relies on comparing successful and failed mass shootings yields similar results. Mass shootings lead to an increase in the salience of gun policy and increase the divide on gun policy among both voters and politicians. Democrats (Republicans) tend to demand even stricter (looser) gun control after mass shootings. These results suggest that increasing the salience of an issue may polarize the electorate.
Patterns of immune infiltration in gastric cancer and their clinical significance
Authors: Jin Yin , Tao Liping , Jin Shuqing , Cai Weiyang 
Published: March 2021

Abstract

Objective
The malignant phenotypes of cancer are defined not only by its intrinsic tumor cells but also by the tumor-infiltrating immune cells activated and recruited to the cancer microenvironment. However, a comprehensive introduction of gastric cancer immune cell infiltration has not been identified so far.

Methods
In this study, we comprehensively analyzed the tumor-infiltrating immune cells abundance in gastric cancer for the first time by CIBERSORT. The meta-analysis, single-sample gene set enrichment analysis and hierarchical agglomerative clustering were used to measure and evaluate the respective proportions of 22 cell types of immune infiltration using normalized gene expression data. The fraction of tumor-infiltrating immune cells subpopulations was also evaluated to determine the associations with clinical features and molecular subtypes.

Results
Tumor-infiltrating immune cells are extensively involved in the pathogenesis and development of the gastric cancer. We discovered Tfh and activated CD4+ memory T cells were associated with poorer overall survival and Progression-free survival (PFS), but that naïve B cells were opposite for PFS. Unsupervised clustering analysis revealed there existed three tumor-infiltrating immune cells subgroups with distinct survival patterns. Specially, cluster 1 showed significantly better clinical outcome than other two clusters.

Conclusions
Collectively, our data explored the differences of tumor-infiltrating immune cells in gastric cancer, and these variations were likely to be important clues for prognosis and management of its future clinical implementation.
Tumor Cellularity and Infiltrating Lymphocytes as a Survival Surrogate in HER2-Positive Breast Cancer
Authors: Chic Nuria , Luen Stephen J , Nuciforo Paolo , Salgado Roberto , Fumagalli Debora , Hilbers Florentine , Wang Yingbo , de Azambuja Evandro , Láng István , Di Cosimo Serena , Saura Cristina , Huober Jens , Prat Aleix , Loi Sherene 
Published: March 2021

Abstract
In early-stage HER2-positive breast cancer, biomarkers that guide deescalation and/or escalation of systemic therapy are needed. CelTIL score is a novel, combined biomarker based on stromal tumor-infiltrating lymphocytes and tumor cellularity and is determined in tumor biopsies at week 2 of anti-HER2 therapy only. We evaluated the prognostic value of CelTIL in 196 patients with early-stage HER2-positive disease treated with standard trastuzumab-based chemotherapy in the NeoALTTO phase III trial. Using a prespecified CelTIL cutoff, a better 5-year event-free survival and overall survival was observed between CelTIL-high and CelTIL-low score with a 76.4% (95% confidence interval [CI] = 68.0% to 85.0%) vs 59.7% (95% CI = 50.0% to 72.0%) (hazard ratio = 0.40, 95% CI = 0.17 to 0.94) and 86.4% (95% CI = 80.0% to 94.0%) vs 73.5% (95% CI = 64.0% to 84.0%) (hazard ratio = 0.43, 95% CI = 0.20 to 0.92), respectively. Statistical significance was maintained after adjusting for baseline tumor-infiltrating lymphocytes, hormone receptor status, pretreatment tumor size and nodal status, type of surgery, treatment arm, and pathological complete response. Further studies to support CelTIL as an early readout biomarker to help deescalate or escalate systemic therapy in HER2-positive breast cancer seem warranted.
Evaluation of a Multiethnic Polygenic Risk Score Model for Prostate Cancer
Authors: Plym Anna , Penney Kathryn L , Kalia Sarah , Kraft Peter , Conti David V , Haiman Christopher , Mucci Lorelei A , Kibel Adam S 
Published: March 2021

Abstract
Polygenic risk scores (PRSs) of common genetic variants have shown promise in prostate cancer risk stratification, but their validity across populations has yet to be confirmed. We evaluated a multiethnic PRS model based on 269 germline genetic risk variants (261 were available for analysis) using an independent population of 13 628 US men. The PRS was strongly associated with prostate cancer but not with any other disease. Comparing men in the top PRS decile with those at average risk (40%-60%), the odds ratio of prostate cancer was 3.89 (95% confidence interval = 3.24 to 4.68) for men of European ancestry and 3.81 (95% confidence interval = 1.48 to 10.19) for men of African ancestry. By age 85 years, the cumulative incidence of prostate cancer for European American men was 7.1% in the bottom decile and 54.1% in the top decile. This suggests that the PRS can be used to identify a substantial proportion of men at high risk for prostate cancer.
Therapy-Induced Senescence: Opportunities to Improve Anticancer Therapy
Authors: Prasanna Pataje G , Citrin Deborah E , Hildesheim Jeffrey , Ahmed Mansoor M , Venkatachalam Sundar , Riscuta Gabriela , Xi Dan , Zheng Guangrong , Deursen Jan van , Goronzy Jorg , Kron Stephen J , Anscher Mitchell S , Sharpless Norman E , Campisi Judith , Brown Stephen L , Niedernhofer Laura J , O’Loghlen Ana , Georgakilas Alexandros G , Paris Francois , Gius David , Gewirtz David A , Schmitt Clemens A , Abazeed Mohamed E , Kirkland James L , Richmond Ann , Romesser Paul B , Lowe Scott W , Gil Jesus , Mendonca Marc S , Burma Sandeep , Zhou Daohong , Coleman C Norman 
Published: March 2021

Abstract
Cellular senescence is an essential tumor suppressive mechanism that prevents the propagation of oncogenically activated, genetically unstable, and/or damaged cells. Induction of tumor cell senescence is also one of the underlying mechanisms by which cancer therapies exert antitumor activity. However, an increasing body of evidence from preclinical studies demonstrates that radiation and chemotherapy cause accumulation of senescent cells (SnCs) both in tumor and normal tissue. SnCs in tumors can, paradoxically, promote tumor relapse, metastasis, and resistance to therapy, in part, through expression of the senescence-associated secretory phenotype. In addition, SnCs in normal tissue can contribute to certain radiation- and chemotherapy-induced side effects. Because of its multiple roles, cellular senescence could serve as an important target in the fight against cancer. This commentary provides a summary of the discussion at the National Cancer Institute Workshop on Radiation, Senescence, and Cancer (August 10-11, 2020, National Cancer Institute, Bethesda, MD) regarding the current status of senescence research, heterogeneity of therapy-induced senescence, current status of senotherapeutics and molecular biomarkers, a concept of “one-two punch” cancer therapy (consisting of therapeutics to induce tumor cell senescence followed by selective clearance of SnCs), and its integration with personalized adaptive tumor therapy. It also identifies key knowledge gaps and outlines future directions in this emerging field to improve treatment outcomes for cancer patients.
Intensive Parent–Child Interaction Therapy for Children with Traumatic Brain Injury: Feasibility Study
Authors: Garcia Dainelys , Rodríguez Gabriela M , Lorenzo Nicole E , Coto Jennifer , Blizzard Angela , Farias Alina , Smith Nicholas David W , Kuluz John , Bagner Daniel M 
Published: March 2021

AbstractObjectiveThis study examined the feasibility and initial outcome of a time-limited and intensive format of Parent–Child Interaction Therapy (PCIT) for families of young children who have sustained a traumatic brain injury (TBI).MethodsThe nonrandomized open trial included 15 families with a child aged 2–5 years who had sustained a TBI and displayed clinically elevated levels of externalizing behavior problems. Families received clinic-based PCIT twice per week over an average of 6 weeks, with the exception of two families that received the same intensity and format of PCIT in the home.ResultsTen of the 14 families who completed the baseline assessment (71%) completed the intervention and post and follow-up assessments. On average, caregivers completed homework practice on 52% of the days in between sessions. Caregivers reported high acceptability and satisfaction following the intervention, as well as decreases in child externalizing and internalizing behavior problems at the post-assessment and 2-month follow-up.ConclusionsResults of this open trial provide preliminary support for the feasibility of a time-limited and intensive format of PCIT for families of young children who have sustained a TBI and have elevated levels of behavior problems. This study highlights a promising intervention approach for improving domains commonly affected by early childhood TBI and preventing the development of more severe and persistent problems.
Reflections on the Mentor-Mentee Relationship
Authors: Manthiram Kalpana , Edwards Kathryn M 
Published: March 2021

Abstract
A successful mentoring relationship can bring significant benefits to the mentee in terms of academic research productivity and career satisfaction. Through their mentees, mentors can also traverse new and fulfilling research directions. Here, we reflect on our own mentor-mentee relationship from both of our vantage points. We offer advice on how to choose a mentee/mentor, what each person needs to bring to the relationship, and how the relationship changes with time.
Summary: We reflect on how mentors and mentees can make their relationship fulfilling and successful for both.
Seed dormancy and weed emergence: from simulating environmental change to understanding trait plasticity, adaptive evolution, and population fitness
Authors: Nakabayashi Kazumi , Leubner-Metzger Gerhard 
Published: March 2021

This article comments on:
Fernández Farnocchia RB, Benech-Arnold RL, Mantese A, Batlla D. 2021. Optimization of timing of next-generation emergence in Amaranthus hybridus is determined via modulation of seed dormancy by the maternal environment. Journal of Experimental Botany 72, 4283–4297.
Measuring ultralarge scale effects in the presence of 21 cm intensity mapping foregrounds
Authors: Fonseca José , Liguori Michele 
Published: March 2021

ABSTRACT
H i intensity mapping will provide maps of the large-scale distribution of neutral hydrogen (H i) in the universe. These are prime candidates to be used to constrain primordial non-Gaussianity using the large-scale structure of the Universe as well as to provide further tests of Einstein’s theory of Gravity (GR). But H i maps are contaminated by foregrounds, which can be several orders of magnitude above the cosmological signal. Here we quantify how degenerated are the large-scale effects (fNL and GR effects) with the residual foregrounds. We conclude that a joint analysis does not provide a catastrophic degradation of constraints and provides a framework to determine the marginal errors of large scale-effects in the presence of foregrounds. Similarly, we conclude that the macroscopical properties of the foregrounds can be measured with high precision. Notwithstanding, such results are highly dependent on accurate forward modelling of the foregrounds, which incorrectly done catastrophically bias the best-fitting values of cosmological parameters, foreground parametrizations, and large-scale effects.
Metals and a search for molecules in the distant Universe: Magellan mike observations of sub-DLAs at 2 &lt; z &lt; 3
Authors: Poudel Suraj , Kulkarni Varsha P , Som Debopam , Péroux Céline 
Published: March 2021

ABSTRACT
We present abundance measurements of the elements Zn, S, O, C, Si, and Fe for four sub-DLAs at redshifts ranging from z = 2.173 to 2.635 using observations from the MIKE spectrograph on the Magellan telescope to constrain the chemical enrichment and star formation of gas-rich galaxies. Using weakly depleted elements O, S, and or Zn, we find the metallicities after the photoionization corrections to be [S/H] = −0.50 ± 0.11, [O/H] &gt; −0.84, [O/H] = −1.27 ± 0.12, and [Zn/H] = +0.40 ± 0.12 for the absorbers at z = 2.173, 2.236, 2.539, and 2.635, respectively. Moreover, we are able to put constraints on the electron densities using the fine structure lines of C ii⋆ and Si ii⋆ for two of the sub-DLAs. We find that these values are much higher than the median values found in DLAs in the literature. Furthermore, we estimate the cooling rate lc = 1.20 × 10−26 erg s−1 per H atom for an absorber at z = 2.173, suggesting higher star formation rate density in this sub-DLA than the typical star formation rate density for DLAs at similar redshifts. We also study the metallicity versus velocity dispersion relation for our absorbers. Most of the absorbers follow the trend one can expect from the mass versus metallicity relation for sub-DLAs in the literature. Finally, we are able to put limits on the molecular column density from the non-detections of various strong lines of CO molecules. We estimate 3σ upper limits of logN(CO, J = 0) &lt; 13.87, logN(CO, J = 0) &lt; 13.17, and logN(CO, J = 0) &lt; 13.08, respectively, from the non-detections of absorption from the J = 0 level in the CO AX 0–0, 1–0, and 2–0 bands near 1544, 1510, and 1478 Å.
Using Pantheon and DES supernova, baryon acoustic oscillation, and Hubble parameter data to constrain the Hubble constant, dark energy dynamics, and spatial curvature
Authors: Cao Shulei , Ryan Joseph , Ratra Bharat 
Published: March 2021

ABSTRACT
We use Pantheon Type Ia supernova (SN Ia) apparent magnitude, DES-3 yr binned SN Ia apparent magnitude, Hubble parameter, and baryon acoustic oscillation measurements to constrain six spatially flat and non-flat cosmological models. These sets of data provide mutually consistent cosmological constraints in the six cosmological models we study. A joint analysis of these data sets provides model-independent estimates of the Hubble constant, $H_0=68.8\pm 1.8\ \rm {km \, s^{-1} \ Mpc^{-1}}$, and the non-relativistic matter density parameter, $\Omega _{\rm m_0}=0.294\pm 0.020$. Although the joint constraints prefer mild dark energy dynamics and a little spatial curvature, they do not rule out dark energy being a cosmological constant and flat spatial hypersurfaces. We also add quasar angular size and H ii starburst galaxy measurements to the combined data set and find more restrictive constraints.
Impact of high fat diet on the sterol regulatory element-binding protein 2 cholesterol pathway in the testicle
Authors: Funes Abi K , Simón Layla , Colombo Regina , Avena María Virginia , Monclús María , Crescitelli Julieta , Cabrillana María E , Conte María Inés , Cayado Niubys , Boarelli Paola , Fornés Miguel W , Saez Lancellotti Tania E 
Published: March 2021

Abstract
Male fertility has been shown to be dependent on cholesterol homeostasis. This lipid is essential for testosterone synthesis and spermatogenesis, but its levels must be maintained in an optimal range for proper testicular function. In particular, sperm cells’ development is very sensitive to high cholesterol levels, noticeably during acrosomal formation. The aim of this work was to study whether the molecular pathway that regulates intracellular cholesterol, the sterol regulatory element-binding protein (SREBP) pathway, is affected in the testicles of animals under a fat diet. To investigate this, we took advantage of the non-obese hypercholesterolemia (HC) model in New Zealand rabbits that displays poor sperm and seminal quality. The testicular expression of SREBP isoform 2 (SREBP2) and its target molecules 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) and low-density lipoprotein receptor (LDLR) were studied under acute (6 months) and chronic (more than 12 months) fat intake by RT–PCR, western blot and immunofluorescence. Our findings showed that fat consumption promoted down-regulation of the SREBP2 pathway in the testicle at 6 months, but upregulation after a chronic period. This was consistent with load of testicular cholesterol, assessed by filipin staining. In conclusion, the intracellular pathway that regulates cholesterol levels in the testicle is sensitive to dietary fats, and behaves differently depending on the duration of consumption: it has a short-term protective effect, but became deregulated in the long term, ultimately leading to a detrimental situation. These results will contribute to the understanding of the basic mechanisms of the effect of fat consumption in humans with idiopathic infertility.
Water structure around a left-handed Z-DNA fragment analyzed by cryo neutron crystallography
Authors: Harp Joel M , Coates Leighton , Sullivan Brendan , Egli Martin 
Published: March 2021

Abstract
Even in high-quality X-ray crystal structures of oligonucleotides determined at a resolution of 1 Å or higher, the orientations of first-shell water molecules remain unclear. We used cryo neutron crystallography to gain insight into the H-bonding patterns of water molecules around the left-handed Z-DNA duplex [d(CGCGCG)]2. The neutron density visualized at 1.5 Å resolution for the first time allows us to pinpoint the orientations of most of the water molecules directly contacting the DNA and of many second-shell waters. In particular, H-bond acceptor and donor patterns for water participating in prominent hydration motifs inside the minor groove, on the convex surface or bridging nucleobase and phosphate oxygen atoms are finally revealed. Several water molecules display entirely unexpected orientations. For example, a water molecule located at H-bonding distance from O6 keto oxygen atoms of two adjacent guanines directs both its deuterium atoms away from the keto groups. Exocyclic amino groups of guanine (N2) and cytosine (N4) unexpectedly stabilize waters H-bonded to O2 keto oxygens from adjacent cytosines and O6 keto oxygens from adjacent guanines, respectively. Our structure offers the most detailed view to date of DNA solvation in the solid-state undistorted by metal ions or polyamines.