bluuebunny/crossref_metadata_2025 huggingface dataset:
The UTMOST pulsar timing programme – II. Timing noise across the pulsar population
Authors: Lower M E , Bailes M , Shannon R M , Johnston S , Flynn C , Osłowski S , Gupta V , Farah W , Bateman T , Green A J , Hunstead R , Jameson A , Jankowski F , Parthasarathy A , Price D C , Sutherland A , Temby D , Venkatraman Krishnan V
Published: March 2020

While pulsars possess exceptional rotational stability, large-scale timing studies have revealed at least two distinct types of irregularities in their rotation: red timing noise and glitches. Using modern Bayesian techniques, we investigated the timing noise properties of 300 bright southern-sky radio pulsars that have been observed over 1.0–4.8 yr by the upgraded Molonglo Observatory Synthesis Telescope (MOST). We reanalysed the spin and spin-down changes associated with nine previously reported pulsar glitches, report the discovery of three new glitches and four unusual glitch-like events in the rotational evolution of PSR J1825−0935. We develop a refined Bayesian framework for determining how red noise strength scales with pulsar spin frequency (ν) and spin-down frequency ($\dot{\nu }$), which we apply to a sample of 280 non-recycled pulsars. With this new method and a simple power-law scaling relation, we show that red noise strength scales across the non-recycled pulsar population as $\nu ^{a} |\dot{\nu }|^{b}$, where $a = -0.84^{+0.47}_{-0.49}$ and $b = 0.97^{+0.16}_{-0.19}$. This method can be easily adapted to utilize more complex, astrophysically motivated red noise models. Lastly, we highlight our timing of the double neutron star PSR J0737−3039, and the rediscovery of a bright radio pulsar originally found during the first Molonglo pulsar surveys with an incorrectly catalogued position.
Limits on absorption from a 332-MHz survey for fast radio bursts
Authors: Rajwade K M , Mickaliger M B , Stappers B W , Bassa C G , Breton R P , Karastergiou A , Keane E F
Published: March 2020

Fast radio bursts (FRBs) are bright, extragalactic radio pulses whose origins are still unknown. Until recently, most FRBs have been detected at frequencies greater than 1 GHz with a few exceptions at 800 MHz. The recent discoveries of FRBs at 400 MHz from the Canadian Hydrogen Intensity Mapping Experiment (CHIME) telescope have opened up possibilities for new insights about the progenitors while many other low-frequency surveys in the past have failed to find any FRBs. Here, we present results from an FRB survey recently conducted at the Jodrell Bank Observatory at 332 MHz with the 76-m Lovell telescope for a total of 58 d. We did not detect any FRBs in the survey and report a 90${{\ \rm per\ cent}}$ upper limit of 5500 FRBs per day per sky for a Euclidean Universe above a fluence threshold of 46 Jy ms. We discuss the possibility of absorption as the main cause of non-detections in low-frequency (<800 MHz) searches and invoke different absorption models to explain the same. We find that Induced Compton Scattering alone cannot account for absorption of radio emission and that our simulations favour a combination of Induced Compton Scattering and Free-Free Absorption to explain the non-detections. For a free–free absorption scenario, our constraints on the electron density are consistent with those expected in the post-shock region of the ionized ejecta in superluminous supernovae.
Let there be more variability in two γ Cas stars
Authors: Nazé Yaël , Pigulski Andrzej , Rauw Gregor , Smith Myron A
Published: March 2020

We investigate the short-term optical variability of two γ Cas analogues,  πAqr and BZ Cru, thanks to intensive ground-based spectroscopic and space-borne photometric monitorings. For both stars, low-amplitude (mmag) coherent photometric variability is detected. The associated signals display long-term amplitude variations, as in other Be stars. However, these signals appear at high frequencies, especially in  πAqr, indicating p modes with a high degree l, a quite unusual feature amongst Be stars. While BZ Cru presents only low-level spectral variability, without clear periodicity, this is not the case of πAqr. In this star, the dominant photometric frequencies, near ∼12 d−1, are confirmed spectroscopically in separate monitorings taken during very different disc activity levels; the spectroscopic analysis suggests a probable tesseral nature for the mode.
A multiwavelength view of the open cluster NGC 2527: discovery of active stars
Authors: Shah Nevil , Singh K P , Subramaniam Annapurni
Published: March 2020

Star clusters are ideal platforms for categorizing X-ray emitting stars and to study X-ray emission as a function of stellar age and activity. We present a comprehensive study of an open star cluster, NGC 2527, by combining data from XMM-UVOT-Gaia. Cluster membership of stars and their photometry are taken from Gaia and cross-matched with XMM and UVOT detections. We estimate the age of NGC 2527 as ∼630 Myr, reddening as E(B − V) = 0.13 mag, and a distance of 642 ± 30 pc using PARSEC isochrones. We detect five sub-subgiants and five bandgap stars, which defy single star evolution. We estimate the temperature, mass, radius, and luminosity of 53 single stars and 10 potential binary stars using a python code that fits single and composite Kurucz spectra to broad-band spectral energy distribution. Among the 12 X-ray emitting members, we find that five are potential RS CVn-type binaries, two are potential FK Comae type of red giant branch (RGB) stars, and five are main sequence (MS) stars with high coronal activity. Members with strong UV emission comprise one RGB star and several MS stars with UV excess suggestive of chromospheric activity. Based on comparison with other clusters, we tentatively suggest that X-ray luminosity of both RS CVn and contact binaries increases with age, suggesting that more active binaries are present in older clusters as compared to younger clusters. This study suggests possible presence of W UMa and FK Comae-type stars in younger (age ≃ 630 Myr) clusters.
How to quench a dwarf galaxy: The impact of inhomogeneous reionization on dwarf galaxies and cosmic filaments
Authors: Katz Harley , Ramsoy Marius , Rosdahl Joakim , Kimm Taysun , Blaizot Jérémy , Haehnelt Martin G , Michel-Dansac Léo , Garel Thibault , Laigle Clotilde , Devriendt Julien , Slyz Adrianne
Published: March 2020

We use the SPHINX suite of high-resolution cosmological radiation hydrodynamics simulations to study how spatially and temporally inhomogeneous reionization impacts the baryonic content of dwarf galaxies and cosmic filaments. We compare simulations with and without stellar radiation to isolate the effects of radiation feedback from that of supernova, cosmic expansion, and numerical resolution. We find that the gas content of cosmic filaments can be reduced by more than 80 per cent following reionization. The gas inflow rates into haloes with ${M_{\rm vir}\lesssim 10^8\, \mathrm{M}_{\odot }}$ are strongly affected and are reduced by more than an order of magnitude compared to the simulation without reionization. A significant increase in gas outflow rates is found for halo masses ${M_{\rm vir}\lesssim 7\times 10^7\, \mathrm{M}_{\odot }}$. Our simulations show that inflow suppression (i.e. starvation), rather than photoevaporation, is the dominant mechanism by which the baryonic content of high-redshift dwarf galaxies is regulated. At fixed redshift and halo mass, there is a large scatter in the halo baryon fractions that is entirely dictated by the timing of reionization in the local region surrounding a halo which can change by Δz ≳ 3 at fixed mass. Finally, although the gas content of high-redshift dwarf galaxies is significantly impacted by reionization, we find that most haloes with ${M_{\rm vir}\lesssim 10^8\, \mathrm{M}_{\odot }}$ can remain self-shielded and form stars long after reionization, until their local gas reservoir is depleted, suggesting that Local Group dwarf galaxies do not necessarily exhibit star formation histories that peak prior to z = 6. Significantly larger simulation boxes will be required to capture the full process of reionization and understand how our results translate to environments not probed by our current work.
Estimated glomerular filtration rate at dialysis initiation and subsequent decline in residual kidney function among incident hemodialysis patients
Authors: Lertdumrongluk Paungpaga , Tantisattamo Ekamol , Obi Yoshitsugu , Nguyen Hoang Anh , Kovesdy Csaba P , Rhee Connie M , Kalantar-Zadeh Kamyar , Streja Elani
Published: March 2020

Background

Higher estimated glomerular filtration rate (eGFR) at dialysis initiation, known as earlier start of dialysis, is often a surrogate of poor outcomes including higher mortality. We hypothesized that earlier dialysis initiation is associated with a faster decline in residual kidney function (RKF), which is also associated with higher mortality among incident hemodialysis (HD) patients.

Methods

In a cohort of 4911 incident HD patients who initiated HD over a 5-year period (July 2001 to June 2006), we examined the trajectories of RKF, ascertained by renal urea clearance (KRU), over 2 years after HD initiation across strata of eGFR at HD initiation using case-mix adjusted linear mixed-effect models. We then investigated the association between annual change in RKF and mortality using Cox proportional hazard models.

Results

The median (interquartile range) baseline KRU was 2.20 (1.13–3.63)  mL/min/1.73 m2. The decline of KRU was faster in patients who initiated HD at higher eGFR. The relative changes with 95% confidence intervals (CIs) in KRU at 1 year after HD initiation were −1.29 (−1.28 to −1.30), −1.17 (−1.16 to −1.18), −1.11 (−1.10 to −1.12) and −0.78 (−0.78 to −0.79)  mL/min/1.73 m2 in the eGFR categories of ≥10, 8–<10, 6–<8 and <6 mL/min/1.73 m2, respectively. The faster decline of KRU at 1 year was associated with higher all-cause mortality (reference: ≥0 mL/min/1.73 m2): hazard ratios (95% CIs) for change in KRU of −1.5 to <0, −3 to less than −1.5 and less than −3 mL/min/1.73 m2 were 1.20 (1.03–1.40), 1.42 (1.17–1.72) and 1.88 (1.47–2.40), respectively.

Conclusions

The faster decline of RKF happens with earlier dialysis initiation and is associated with higher all-cause mortality.
Young adults have worse kidney transplant outcomes than other age groups
Authors: Pankhurst Tanya , Evison Felicity , Mytton Jemma , Williamson Samantha , Kerecuk Larissa , Lipkin Graham
Published: March 2020

Background

The objective of this study was to establish if renal transplant outcomes (graft and patient survival) for young adults in England were worse than for other age groups.

Methods

Outcomes for all renal transplant recipients in England (n = 26 874) were collected from Hospital Episode Statistics and the Office for National Statistics databases over 12 years. Graft and patient outcomes, follow-up and admissions were studied for all patients, stratified by age bands.

Results

Young adults (14–23 years) had substantially greater likelihood [hazard ratio (HR) = 1.26, 95% confidence interval (CI) 1.10–1.19; P < 0.001] of kidney transplant failure than any other age band. They had a higher non-attendance rate for clinic appointments (1.6 versus 1.2/year; P < 0.001) and more emergency admissions post-transplantation (25% of young adults on average are admitted each year, compared with 15–20% of 34- to 43-year olds). Taking into account deprivation, ethnicity, transplant type and transplant centre, in the 14- to 23-year group, return to dialysis remained significantly worse than all other age bands (HR = 1.41, 95% CI 1.26–1.57). For the whole cohort, increasing deprivation related to poorer outcomes and black ethnicity was associated with poorer outcomes. However, neither ethnicity nor deprivation was over-represented in the young adult cohort.

Conclusions

Young adults who receive a kidney transplant have a significant increased likelihood of a return to dialysis in the first 10 years post-transplant when compared with those aged 34–43 years in multivariable analysis.
Assessing Hepatitis B Reactivation Risk With Rituximab and Recent Intravenous Immunoglobulin Therapy
Authors: Dysart Claire , Rozenberg-Ben-Dror Karine , Sales Mariscelle
Published: March 2020

Hepatitis B reactivation (HBR) is a complication of immunosuppression associated with significant morbidity and mortality. To further complicate interpretation of hepatitis B serologies, false positivity can occur in patients with recent intravenous immunoglobulin exposure. This scenario is not well recognized and may lead to inappropriate prescribing of HBR prophylaxis.
Quantum of the bare cosmological constant
Authors: Loran Farhang
Published: March 2020

We show that there exist scalar field theories with plausible one-particle states in general $D$-dimensional nonstationary curved spacetimes whose propagating modes are localized on $d\le D$ dimensional hypersurfaces, and the corresponding stress tensor resembles the bare cosmological constant $\lambda_{\rm B}$ in the $D$-dimensional bulk. We show that nontrivial $d=1$ dimensional solutions correspond to $\lambda_{\rm B}< 0$. Considering free scalar theories, we find that for $d=2$ the symmetry of the parameter space of classical solutions corresponding to $\lambda_{\rm B}\neq 0$ is $O(1,1)$, which enhances to $\mathbb{Z}_2\times{\rm Diff}(\mathbb{R}^1)$ at $\lambda_{\rm B}=0$. For $d>2$ we obtain $O(d-1,1)$, $O(d-1)\times {\rm Diff}(\mathbb{R}^1)$, and $O(d-1,1)\times O(d-2)\times {\rm Diff}(\mathbb{R}^1)$ corresponding to, respectively, $\lambda_{\rm B}<0$, $\lambda_{\rm B}=0$, and $\lambda_{\rm B}>0$.
Long-term outcomes and disease course of children with juvenile idiopathic arthritis in the ReACCh-Out cohort: a two-centre experience
Authors: Chhabra Amieleena , Robinson Cal , Houghton Kristin , Cabral David A , Morishita Kimberly , Tucker Lori B , Petty Ross E , Larché Maggie , Batthish Michelle , Guzman Jaime
Published: March 2020

Objective

To assess long-term outcomes of children with JIA diagnosed in the biologic era.

Methods

Chart review of patients prospectively enrolled in the Research in Arthritis in Canadian Children Emphasizing Outcomes inception cohort at two Canadian centres. Inactive disease and remission were defined according to Wallace criteria.

Results

We included 247 of 254 (97%) eligible patients diagnosed 2005–10. At the last follow-up visit at a median age of 16.9 years, 47% were in remission off medications, 25% in remission on medications and 27% had active disease; 51% were on at least one anti-rheumatic medication (22% on biologics). Patients with systemic JIA had the highest frequency of remission off medications (70%) and patients with RF-positive polyarthritis had the lowest (18%) (P <0.05 by Fisher’s exact test). Among 99 patients with oligoarthritis at enrolment, 14 (14%) had an oligoarthritis extended course. Forty-five patients (18%) had at least one erosion or joint space narrowing in X-rays or MRI, and two (0.8%) required joint replacement.

Conclusion

Relative to historical cohorts, this study suggests a reduction in JIA permanent damage, a more favourable prognosis for systemic JIA and a lower progression to oligoarthritis extended category. However, in an era of biologic therapy, one in four patients with JIA still enter adulthood with active disease and one in two still on treatment.
Segmented market economies in the Arab world: the political economy of insider–outsider divisions
Authors: Hertog Steffen
Published: March 2020

This article argues that the low dynamism of low- to mid-income Arab economies is explained with a set of interconnected factors that constitute a particular variety of capitalism which we call ‘segmented market economy’. These include an over-committed and interventionist state; deep insider–outsider divides in private sectors and labor markets that result from and reinforce lopsided state intervention; and an equilibrium of low skills and low productivity that results from and reinforces insider–outsider divides. These mutually reinforcing features undermine encompassing cooperation between state, business and labor. While some of these features are generic to developing countries, others are regionally specific, including the relative importance and historical ambition of the state in the economy and, closely related, the relative size and rigidity of the insider coalitions created through government intervention. Insiders and outsiders exist everywhere, but the divisions are particularly stark, immovable and consequential in the Arab world.
The Association of Acculturation with Overt and Covert Perceived Discrimination for Older Asian Americans
Authors: Chan Keith
Published: March 2020

Asian older adults are a fast-growing population in the United States. Because Asian older adults are a largely immigrant population, acculturation has an impact on their perceived discrimination, which is negatively associated with health and mental health. Discrimination can be overt, characterized by distrust and direct messages that are hostile and exclusionary, or covert, characterized by unfair treatment and messages that are negative and degrading. This study investigates the association of acculturation with perceived overt and covert discrimination, measured by the Everyday Discrimination Scale, with a sample of 348 foreign-born older Asian Americans from the National Latino and Asian American Study. Acculturation was measured by English-speaking ability, immigration-related variables, and ethnic identity. Results indicated that perceived covert discrimination was more prevalent than overt discrimination among older Asians. Among acculturation variables, only citizenship was associated with higher perceived covert and overt discrimination. Identifying with the same race was associated with higher covert discrimination. Findings suggest that higher acculturation is associated with greater exposure to discrimination for Asian older adults. Efforts to increase access and utilization of social and health-related services should consider the context of older Asians’ experiences as a discriminated immigrant group in the United States.
Trauma and Gene Expression: Understanding the Connections
Authors: Pilkay Stefanie Renee , Combs-Orme Terri
Published: March 2020

Over 60% of trained social workers provide mental health services in their practices, and in all these settings clients are likely to have experienced trauma influencing their current circumstances, including childhood maltreatment and neglect. The 1998 Adverse Childhood Experiences Study has heightened interest in the long-term effects of trauma, especially early in life. Research has shown that our experiences influence our genes’ activity through biochemical changes in what is known as epigenetic marks. Yet social work practice has participated minimally in targeting the influences of genes on behavior for research or intervention, partially because of a lack of scientific knowledge. This systematic review examines published research that investigated the influences of early trauma experiences on changes in gene expression related to emotionality and stress response. Authors conducted a systematic literature review according to the steps outlined by Shuster in Google Scholar, PubMed, and PsycINFO. Collected literature was reduced to 76 peer-reviewed articles after applying exclusion criteria. A strong pattern of relationships emerged from the review. Trauma and early life stress were associated with epigenetic marks in offspring on genes linked to stress reactivity (22 studies) and emotionality (23 studies).
An ideal regime for the express trust—a comparative analysis: English, French, and Mexican law
Authors: Ibarra Garza Rafael
Published: March 2020

By comparing English, Mexican, and French trust law, it is possible to shed light on the successes and shortcomings of each jurisdiction and, by this, propose principles for an ideal regime of the express trust. The comparison starts by analyzing the personal elements of the express trust and continues with the study of its real elements. Proposing an ideal regime can be a theoretical basis for future reforms introducing or improving the trust in civil and common law jurisdictions.
Purification and characterization of nisin P produced by a strain of Streptococcus gallolyticus
Authors: Aldarhami Abdu , Felek Arif , Sharma Vikram , Upton Mathew
Published: March 2020

Introduction. Against the backdrop of increasing resistance to conventional antibiotics, bacteriocins represent an attractive alternative, given their potent activity, novel modes of action and perceived lack of issues with resistance.

Aim. In this study, the nature of the antibacterial activity of a clinical isolate of

Streptococcus gallolyticus

was investigated.

Methods. Optimization of the production of an inhibitor from strain AB39 was performed using different broth media and supplements. Purification was carried out using size exclusion, ion exchange and HPLC. Gel diffusion agar overlay, MS/MS, de novo peptide sequencing and genome mining were used in a proteogenomics approach to facilitate identification of the genetic basis for production of the inhibitor.

Results. Strain AB39 was identified as representing

Streptococcus gallolyticus

subsp.

pasteurianus

and the successful production and purification of the AB39 peptide, named nisin P, with a mass of 3133.78 Da, was achieved using BHI broth with 10 % serum. Nisin P showed antibacterial activity towards clinical isolates of drug-resistant bacteria, including methicillin-resistant

Staphylococcus aureus

, vancomycin-resistant

Enterococcus

and penicillin-resistant

Streptococcus pneumoniae

. In addition, the peptide exhibited significant stability towards high temperature, wide pH and certain proteolytic enzymes and displayed very low toxicity towards sheep red blood cells and Vero cells.

Conclusion. To the best of our knowledge, this study represents the first production, purification and characterization of nisin P. Further study of nisin P may reveal its potential for treating or preventing infections caused by antibiotic-resistant Gram-positive bacteria, or those evading vaccination regimens.
Mutations in the two component regulator systems PmrAB and PhoPQ give rise to increased colistin resistance in Citrobacter and Enterobacter spp.
Authors: Wand Matthew E. , Sutton J. Mark
Published: March 2020

Introduction. Colistin is a last resort antibiotic for treating infections caused by carbapenem-resistant isolates. Mechanisms of resistance to colistin have been widely described in

Klebsiella pneumoniae

and

Escherichia coli

but have yet to be characterized in

Citrobacter

and

Enterobacter

species.

Aim. To identify the causative mutations leading to generation of colistin resistance in

Citrobacter

and

Enterobacter

spp.

Methodology. Colistin resistance was generated by culturing in increasing concentrations of colistin or by direct culture in a lethal (above MIC) concentration. Whole-genome sequencing was used to identify mutations. Fitness of resistant strains was determined by changes in growth rate, and virulence in Galleria mellonella.

Results. We were able to generate colistin resistance upon exposure to sub-MIC levels of colistin, in several but not all strains of

Citrobacter

and

Enterobacter

resulting in a 16-fold increase in colistin MIC values for both species. The same individual strains also developed resistance to colistin after a single exposure at 10× MIC, with a similar increase in MIC. Genetic analysis revealed that this increased resistance was attributed to mutations in PmrB for

Citrobacter

and PhoP in

Enterobacter

, although we were not able to identify causative mutations in all strains. Colistin-resistant mutants showed little difference in growth rate, and virulence in G. mellonella, although there were strain-to-strain differences.

Conclusions. Stable colistin resistance may be acquired with no loss of fitness in these species. However, only select strains were able to adapt suggesting that acquisition of colistin resistance is dependent upon individual strain characteristics.
Vorpal: A novel RNA virus feature-extraction algorithm demonstrated through interpretable genotype-to-phenotype linear models
Authors: Davis Phillip , Bagnoli John , Yarmosh David , Shteyman Alan , Presser Lance , Altmann Sharon , Bradrick Shelton , Russell Joseph A.
Published: March 2020

In the analysis of genomic sequence data, so-called “alignment free” approaches are often selected for their relative speed compared to alignment-based approaches, especially in the application of distance comparisons and taxonomic classification1,2,3,4. These methods are typically reliant on excising K-length substrings of the input sequence, called K-mers5. In the context of machine learning, K-mer based feature vectors have been used in applications ranging from amplicon sequencing classification to predictive modeling for antimicrobial resistance genes6,7,8. This can be seen as an analogy of the “bag-of-words” model successfully employed in natural language processing and computer vision for document and image classification9,10. Feature extraction techniques from natural language processing have previously been analogized to genomics data11; however, the “bag-of-words” approach is brittle in the RNA virus space due to the high intersequence variance and the exact matching requirement of K-mers. To reconcile the simplicity of “bag-of-words” methods with the complications presented by the intrinsic variance of RNA virus space, a method to resolve the fragility of extracted K-mers in a way that faithfully reflects an underlying biological phenomenon was devised. Our algorithm,Vorpal, allows the construction of interpretable linear models with clustered, representative ‘degenerate’ K-mers as the input vector and, through regularization, sparse predictors of binary phenotypes as the output. Here, we demonstrate the utility ofVorpalby identifying nucleotide-level genomic motif predictors for binary phenotypes in three separate RNA virus clades; human pathogen vs. non-human pathogen inOrthocoronavirinae, hemorrhagic fever causing vs. non-hemorrhagic fever causing inEbolavirus, and human-host vs. non-human host in Influenza A. The capacity of this approach forin silicoidentification of hypotheses which can be validated by direct experimentation, as well as identification of genomic targets for preemptive biosurveillance of emerging viruses, is discussed. The code is available for download athttps://github.com/mriglobal/vorpal.
Non-canonical roles of caspase-4 and caspase-5 in heme driven- IL-1β release and cell death
Authors: Bolívar Beatriz E. , Brown Alexandra N. , Rohrman Brittany A. , Charendoff Chloé I. , Yazdani Vanda , Belcher John D. , Vercellotti Gregory M. , Flanagan Jonathan M. , Bouchier-Hayes Lisa
Published: March 2020

Excessive release of heme from red blood cells is a key pathophysiological feature of several disease states including bacterial sepsis, malaria, and sickle cell disease. This hemolysis results in an increased level of free heme that has been implicated in the inflammatory activation of monocytes, macrophages, and endothelium. Here, we show that extracellular heme engages the human inflammatory caspases, caspase-1, caspase-4, and caspase-5, resulting in the release of IL-1β. Heme-induced IL-1β release was further increased in macrophages from patients with sickle cell disease. In human primary macrophages, heme activated caspase-1 in an inflammasome-dependent manner, but heme-induced activation of caspase-4 and caspase-5 was independent of canonical inflammasomes. Furthermore, we show that both caspase-4, and caspase-5 are essential for heme-induced IL-1β release, while caspase-4 is the primary contributor to heme-induced cell death. Together, we have identified that extracellular heme acts as a damage associated molecular pattern (DAMP) that can engage canonical and non-canonical inflammasome activation as a key mediator of inflammation in macrophages.

Footnotes

Funding for the project includes NIH/NIDDK T32DK060445 (BEB, BAR), NIH/NIDDK F32DK121479 (BEB), NIH/NIGMS R01GM121389 (LBH), NIH/NHLBI R01HL114567 (JDB, GMV), NIH/NHLBI R01-HL136415 (JMF), and CPRIT-RP180672, NIHCA125123 and NIHRR024574 (Cytometry and Cell Sorting Core at Baylor College of Medicine)

Key Points

Heme induces oligomerization of caspase-1, caspase-4, and caspase-5.

Heme-induced IL-1β release requires both caspase-4 and caspase-5.

Caspase-4 alone contributes to heme-induced cell death.
Conformation control of the histidine kinase BceS ofBacillus subtilisby its cognate ABC-transporter facilitates need-based activation of antibiotic resistance
Authors: Koh Alan , Gibbon Marjorie J. , Van der Kamp Marc W. , Pudney Christopher R. , Gebhard Susanne
Published: March 2020

Bacteria closely control gene expression to ensure optimal physiological responses to their environment. Such careful gene expression can minimize the fitness cost associated with antibiotic resistance. We previously described a novel regulatory logic inBacillus subtilisenabling the cell to directly monitor its need for detoxification. This cost-effective strategy is achieved via a two-component regulatory system (BceRS) working in a sensory complex with an ABC-transporter (BceAB), together acting as a flux-sensor where signaling is proportional to transport activity. How this is realized at the molecular level has remained unknown. Using experimentation and computation we here show that the histidine kinase is activated by piston-like displacements in the membrane, which are converted to helical rotations in the catalytic core via an intervening HAMP-like domain. Intriguingly, the transporter was not only required for kinase activation, but also to actively maintain the kinase in its inactive state in the absence of antibiotics. Such coupling of kinase activity to that of the transporter ensures the complete control required for transport flux-dependent signaling. Moreover, we show that the transporter likely conserves energy by signaling with sub-maximal sensitivity. These results provide the first mechanistic insights into transport flux-dependent signaling, a unique strategy for energy-efficient decision making.
Temporal learning among prefrontal and striatal ensembles
Authors: Emmons Eric , Tunes-Chiuffa Gabriela , Choi Jeeyu , Bruce R. Austin , Weber Matthew A. , Kim Youngcho , Narayanan Nandakumar S.
Published: March 2020

Behavioral flexibility requires the prefrontal cortex and striatum. Here, we investigate neuronal ensembles in the medial frontal cortex (MFC) and the dorsomedial striatum (DMS) during one form of behavioral flexibility: learning a new temporal interval. We studied corticostriatal neuronal activity as rodents trained to respond after a 12-second fixed interval (FI12) learned to respond at a shorter 3-second fixed interval (FI3). On FI12 trials, we discovered time-related ramping was reduced in the MFC but not in the DMS in two-interval vs. one-interval sessions. We also found that more DMS neurons than MFC neurons exhibited differential interval-related activity on the first day of two-interval performance. Finally, MFC and DMS ramping was similar with successive days of two-interval performance but DMS temporal decoding increased on FI3 trials. These data suggest that the MFC and DMS play distinct roles during temporal learning and provide insight into corticostriatal circuits.
Amygdala-cortical control of striatal plasticity drives the acquisition of goal-directed action
Authors: Fisher Simon D. , Ferguson Lachlan A. , Bertran-Gonzalez Jesus , Balleine Bernard W.
Published: March 2020

The acquisition of goal-directed action requires the encoding of specific action-outcome associations involving plasticity in the posterior dorsomedial striatum (pDMS). We first investigated the relative involvement of the major inputs to the pDMS argued to be involved in this learning-related plasticity, from prelimbic prefrontal cortex (PL) and from the basolateral amygdala (BLA). Using ex vivo optogenetic stimulation of PL or BLA terminals in pDMS, we found that goal-directed learning potentiated the PL input to direct pathway spiny projection neurons (dSPNs) bilaterally but not to indirect pathway neurons (iSPNs). In contrast, learning-related plasticity was not observed in the direct BLA-pDMS pathway. Using toxicogenetics, we ablated BLA projections to either pDMS or PL and found that only the latter was necessary for goal-directed learning. Importantly, transient inactivation of the BLA during goal-directed learning prevented the PL-pDMS potentiation of dSPNs, establishing that the BLA input to the PL is necessary for the corticostriatal plasticity underlying goal-directed learning.
A comprehensive survey on the nature of ring:ring nucleobase stacking interactions in RNA: occurrence, structural variability and classification of the associated contacts
Authors: Jhunjhunwala Ayush , Ali Zakir , Bhattacharya Sohini , Halder Antarip , Mitra Abhijit , Sharma Purshotam
Published: March 2020

The astonishing diversity in folding patterns of RNA 3D structures is crafted by myriads of noncovalent contacts, of which base pairing and stacking are the most prominent. Although the classification scheme proposed by Leontis and Westhof (RNA(2001), 7, 499) has been widely accepted for the annotation of RNA base pairs, the absence of an unambiguous classification system for base stacks appears to be a roadblock for exploring the stacking diversity in RNA. Here we provide an unambiguous and structurally-intuitive scheme for a geometry cum topology based classification of base stacking, where a stack is essentially classified in terms of the topology of the interacting nucleobase faces and the geometry described by the relative orientation of the glycosidic bonds. For heterodimeric stacks, this generates eight basic stacking geometric families, whereas for homodimeric stacks, this generates six of those. Further annotation in terms of the identity of the bases and the region of involvement of purines (5-membered, 6-membered or both rings), leads to the enumeration of 384 distinct RNA base stacks. Based on our classification scheme, we also present an algorithm for automated identification of stacks in RNA crystal structures. Overall, the work described here is expected to greatly facilitate structure-based RNA research.
Estimating weight in patients of all-ages: a prospective study in Rwanda
Authors: Cattermole Giles N , Manirafasha Appolinaire
Published: March 2020

Introduction

Weight estimation of both adult and paediatric patients is often necessary in emergency or low-resource settings when it is not possible to weigh the patient. There are many methods for paediatric weight estimation, but no standard methods for adults. PAWPER and Mercy tapes are used in children, but have not been assessed in adults. The primary aim of this study was to assess weight estimation methods in patients of all ages.

Methods

Patients were prospectively recruited from emergency and out-patient departments. Subjects (or guardians) were asked to estimate weight. Investigators collected weight, height, mid-arm circumference (MAC) and humeral-length data. In all subjects, estimates of weight were calculated from height and MAC (PAWPER tapes), MAC and humeral-length (Mercy tape). In children, Broselow tape and age-based formulae were also used. Primary outcome measures were proportions of estimates within 10%, 20% and 30% of actual weight (p10, p20, p30).

Results

947 subjects were recruited: 307 children, 309 adolescents and 331 adults. For p20, the best methods were: in children, guardian estimate (90.2%) and PAWPER XL-MAC (89.3%); in adolescents, PAWPER XL-MAC (91.3%) and guardian estimate (90.9%); in adults, subject estimate (98.5%) and PAWPER XL-MAC (83.7%).

Conclusion

This is the first prospective study of weight estimation methods in Rwanda, and the first adult study of PAWPER and Mercy tapes. In children, age-based rules performed poorly. In patients of all ages, the PAWPER XL-MAC and guardian/subject estimates of weight were the most reliable and we would recommend their use in this setting.
An epidemiological forecast model and software assessing interventions on COVID-19 epidemic in China
Authors: Wang Lili , Zhou Yiwang , He Jie , Zhu Bin , Wang Fei , Tang Lu , Eisenberg Marisa , Song Peter X.K.
Published: March 2020

We develop a health informatics toolbox that enables public health workers to timely analyze and evaluate the time-course dynamics of the novel coronavirus (COVID-19) infection using the public available data from the China CDC. This toolbox is built upon a hierarchical epidemiological model in which two observed time series of daily proportions of infected and removed cases are emitted from the underlying infection dynamics governed by a Markov SIR infectious disease process. We extend the SIR model to incorporate various types of time-varying quarantine protocols, including government-level macro isolation policies and community-level micro inspection measures. We develop a calibration procedure for under-reported infected cases. This toolbox provides forecast, in both online and offline forms, of turning points of interest, including the time when daily infected proportion becomes smaller than the previous ones and the time when daily infected proportions becomes smaller than that of daily removed proportion, as well as the ending time of the epidemic. An R software is made available for the public, and examples on the use of this software are illustrated. Some possible extensions of our novel epidemiological models are discussed.
smiFISH and embryo segmentation for single-cell multi-gene RNA quantification in arthropods
Authors: Calvo Llilians , Ronshaugen Matthew , Pettini Tom
Published: March 2020

Recently, advances in fluorescent in-situ hybridization techniques and in imaging technology have enabled visualisation and counting of individual RNA molecules in single cells. This has greatly enhanced the resolution in our understanding of transcriptional processes. Here, we adapt a recently published smiFISH protocol (single-molecule inexpensive fluorescent in-situ hybridization) to whole embryos across a range of arthropod model species, and also to non-embryonic tissues. Using multiple fluorophores with distinct spectra and white light laser confocal imaging, we simultaneously detect and separate single RNAs from up to eight different genes in a whole embryo. We also combine smiFISH with cell membrane immunofluorescence, and present an imaging and analysis pipeline for 3D cell segmentation and single-cell RNA counting in whole blastoderm embryos. Finally, using whole embryo single-cell RNA count data, we propose two alternative single-cell variability measures to the commonly used Fano factor, and compare the capacity of these three measures to address different aspects of single-cell expression variability.
Identification of PCNA interacting protein motifs in human DNA polymerase delta
Authors: Khandagale Prashant , Thakur Shweta , Acharya Narottam
Published: March 2020

DNA polymerase delta (Polδ) is a highly processive essential replicative DNA polymerase. In humans, Polδ holoenzyme consists of p125, p50, p68, and p12 subunits and recently, we have shown that p12 exists as a dimer. Extensive biochemical studies suggest that all the subunits of Polδ interact with the processivity factor proliferating cell nuclear antigen (PCNA) to carry out a pivotal role in genomic DNA replication. While PCNA interaction protein (PIP) motifs in p68, p50 and p12 have been mapped, the PIP in p125, the catalytic subunit of the holoenzyme, remains elusive. Therefore, in this study by using multiple approaches we have conclusively mapped a non-canonical PIP box from residues999VGGLLAFA1008in p125, which binds to inter domain-connecting loop of PCNA with high affinity. Collectively, including previous studies, we conclude that similar toS. cerevisiaePolδ, each of the human Polδ subunits possess motif to interact with PCNA and significantly contribute towards the processive nature of this replicative DNA polymerase.
E93-depleted adult insects preserve the prothoracic gland and molt again
Authors: Kamsoi Orathai , Belles Xavier
Published: March 2020

Insect metamorphosis originated around the middle Devonian, associated with the innovation of the final molt; this occurs after the histolysis of the prothoracic gland (PG; which produces the molting hormone) in the first days of adulthood. We previously hypothesized that transcription factor E93 was crucial in the emergence of metamorphosis, since it triggers metamorphosis in extant insects. This work on the cockroachBlattella germanicareveals that E93 also plays a crucial role in the histolysis of PG, which fits the above hypothesis. Previous studies have shown that the transcription factor FTZ-F1 is essential for PG histolysis. We have found that FTZ-F1 depletion, towards the end of the final nymphal instar, downregulates the expression ofE93, while E93-depleted nymphs molt to adults that retain a functional PG. Interestingly, these adults are able to molt again, which is exceptional in insects. The study of insects able to molt again in the adult stage may reveal clues as to how nymphal epidermal cells definitively become adult cells, and if it is possible to revert this process.

Summary statement

The prothoracic gland disintegrates after insect metamorphosis. It was believed that the factor FTZ-F1 determines this disintegration. This work reveals that FTZ-F1 action is mediated by the factor E93.
Gene-environment interactions in Multiple Sclerosis: a UK Biobank study
Authors: Jacobs Benjamin Meir , Noyce Alastair , Bestwick Jonathan , Belete Daniel , Giovannoni Gavin , Dobson Ruth
Published: March 2020

Importance

Multiple Sclerosis (MS) is a neuro-inflammatory disorder caused by a combination of environmental exposures and genetic risk factors. We sought to determine whether genetic risk modifies the effect of environmental MS risk factors.

Methods

People with MS were identified within UK Biobank using ICD10-coded MS or self-report. Associations between environmental risk factors and MS risk were quantified with a case-control design using multivariable logistic regression. Polygenic risk scores (PRS) were derived using the clumping-and-thresholding approach with external weights from the largest genome-wide association study of MS. Separate scores were created including (PRSMHC) and excluding (PRSNon-MHC) the MHC locus. The best performing PRS were identified in 30% of the cohort and validated in the remaining 70%. Interaction between environmental and genetic risk factors was quantified using the Attributable Proportion due to interaction (AP) and multiplicative interaction.

Results

Data were available for 2250 people with MS and 486,000 controls. Childhood obesity, earlier age at menarche, and smoking were associated with MS. The optimal PRS were strongly associated with MS in the validation cohort (PRSMHC: Nagelkerke’s Pseudo-R20.033, p=3.92×10−111; PRSNon-MHC: Nagelkerke’s Pseudo-R20.013, p=3.73×10−43). There was strong evidence of interaction between polygenic risk for MS and childhood obesity (PRSMHC: AP=0.17, 95% CI 0.06 - 0.25, p=0.004; PRSNon-MHC: AP=0.17, 95% CI 0.06 - 0.27, p=0.006).

Conclusions and Relevance

This study provides novel evidence for an interaction between childhood obesity and a high burden of autosomal genetic risk. These findings may have significant implications for our understanding of MS biology and inform targeted prevention strategies.
Somatic cell-derived BMPs induce male germ cell meiosis initiation during embryonic stage via regulatingDazlexpression
Authors: Zhang Lianjun , Li Yaqiong , Hu Yuqiong , Lin Limei , Zhou Jingjing , Chen Min , Qin Yan , Zhou Yang , Chen Min , Cui Xiuhong , Tang Fuchou , Gao Fei
Published: March 2020

Germ cell fate is believed to be determined by the signaling from sexually differentiated somatic cell. However, the molecular mechanism remains elusive. In this study, ectopic initiation of meiosis in male germ cells was observed during embryonic stage by over-activating CTNNB1 in Sertoli cells. Somatic cell transcriptome and single germ cell RNA-seq analysis indicated that TGF-β signaling was activated after CTNNB1 over-activation.In vitroandin vivoexperiments confirmed somatic cell-derived BMPs played crucial roles in germ cell meiosis initiation. Further studies revealed thatDazlwas significantly increased in germ cells of CTNNB1 over-activated testes and induced by BMP signaling. DNMT3a and DNA methylation was also reduced in germ cells of CTNNB1 over-activated testes and increased by BMP signaling inhibitor treatment. Taken together, this study demonstrates that germ cell fate could be reprogrammed after sex determination. BMP signaling pathway is involved in germ cell meiosis initiation via up-regulatingDazlexpression.
Estimation of local novel coronavirus (COVID-19) cases in Wuhan, China from off-site reported cases and population flow data from different sources
Authors: Zhuang Zian , Cao Peihua , Zhao Shi , Lou Yijun , Yang Shu , Wang Weiming , Yang Lin , He Daihai
Published: March 2020

Backgrounds

In December 2019, a novel coronavirus (COVID-19) pneumonia hit Wuhan, Hubei Province, China and spread to the rest of China and overseas. The emergence of this virus coincided with the Spring Festival Travel Rush in China. It is possible to estimate total number of cases of COVID-19 in Wuhan, by 23 January 2020, given the cases reported in other cities and population flow data between cities.

Methods

We built a model to estimate the total number of cases in Wuhan by 23 January 2020, based on the number of cases detected outside Wuhan city in China, with the assumption that if the same screening effort used in other cities applied in Wuhan. We employed population flow data from different sources between Wuhan and other cities/regions by 23 January 2020. The number of total cases was determined by the maximum log likelihood estimation.

Findings

From overall cities/regions data, we predicted 1326 (95% CI: 1177, 1484), 1151 (95% CI: 1018, 1292) and 5277 (95% CI: 4732, 5859) as total cases in Wuhan by 23 January 2020, based on different source of data from Changjiang Daily newspaper, Tencent, and Baidu. From separate cities/regions data, we estimated 1059 (95% CI: 918, 1209), 5214 (95% CI: 4659, 5808) as total cases in Wuhan in Wuhan by 23 January 2020, based on different sources of population flow data from Tencent and Baidu.

Conclusion

Sources of population follow data and methods impact the estimates of local cases in Wuhan before city lock down.