bluuebunny/crossref_metadata_2025 huggingface dataset:
Disc settling and dynamical heating: histories of Milky Way-mass stellar discs across cosmic time in the FIRE simulations
Authors: McCluskey Fiona , Wetzel Andrew , Loebman Sarah R , Moreno Jorge , Faucher-Giguère Claude-André , Hopkins Philip F
Published: December 2023

We study the kinematics of stars both at their formation and today within 14 Milky Way (MW)-mass galaxies from the FIRE-2 cosmological zoom-in simulations. We quantify the relative importance of cosmological disc settling and post-formation dynamical heating. We identify three eras: a Pre-Disc Era (typically ≳ 8 Gyr ago), when stars formed on dispersion-dominated orbits; an Early-Disc Era (≈8–4 Gyr ago), when stars started to form on rotation-dominated orbits but with high velocity dispersion, σform; and a Late-Disc Era (≲ 4 Gyr ago), when stars formed with low σform. σform increased with time during the Pre-Disc Era, peaking ≈8 Gyr ago, then decreased throughout the Early-Disc Era as the disc settled and remained low throughout the Late-Disc Era. By contrast, the dispersion measured today, σnow, increases monotonically with age because of stronger post-formation heating for Pre-Disc stars. Importantly, most of σnow was in place at formation, not added post-formation, for stars younger than ≈10 Gyr. We compare the evolution of the three velocity components: at all times, σR, form > σϕ, form > σZ, form. Post-formation heating primarily increased σR at ages ≲ 4 Gyr but acted nearly isotropically for older stars. The kinematics of young stars in FIRE-2 broadly agree with the range observed across the MW, M31, M33, and PHANGS-MUSE galaxies. The lookback time that the disc began to settle correlates with its dynamical state today: earlier-settling galaxies currently form colder discs. Including stellar cosmic-ray feedback does not significantly change disc rotational support at fixed stellar mass.
FLASH: Faint Lenses from Associated Selection with Herschel
Authors: Bakx Tom J L C , Gray Bethany S , González-Nuevo Joaquin , Bonavera Laura , Amvrosiadis Aristeidis , Eales Stephen , Hagimoto Masato , Serjeant Stephen
Published: December 2023

We report the ALMA Band 7 observations of 86 Herschel sources that likely contain gravitationally lensed galaxies. These sources are selected with relatively faint 500 μm flux densities between 15 and 85 mJy in an effort to characterize the effect of lensing across the entire million-source Herschel catalogue. These lensed candidates were identified by their close proximity to bright galaxies in the near-infrared VISTA Kilo-Degree Infrared Galaxy survey. Our high-resolution observations (0.15 arcsec) confirm 47 per cent of the initial candidates as gravitational lenses, while lensing cannot be excluded across the remaining sample. We find average lensing masses (log M/M⊙ = 12.9 ± 0.5) in line with previous experiments, although direct observations might struggle to identify the most massive foreground lenses across the remaining 53 per cent of the sample, particularly for lenses with larger Einstein radii. Our observations confirm previous indications that more lenses exist at low flux densities than expected from strong galaxy–galaxy lensing models alone, where the excess is likely due to additional contributions of cluster lenses and weak lensing. If we apply our method across the total 660 square degree H-ATLAS field, it would allow us to robustly identify 3000 gravitational lenses across the 660 square degree Herschel ATLAS fields.
Non-ideal magnetohydrodynamics on a moving mesh II: Hall effect
Authors: Zier Oliver , Mayer Alexander C , Springel Volker
Published: December 2023

In this work, we extend the non-ideal magnetohydrodynamics (MHD) solver in the moving-mesh code arepo to include the Hall effect. The core of our algorithm is based on an estimation of the magnetic field gradients by a least-squares reconstruction on the unstructured mesh, which we also used in the companion paper for Ohmic and ambipolar diffusion. In an extensive study of simulations of a magnetic shock, we show that without additional magnetic diffusion our algorithm for the Hall effect becomes unstable at high resolution. We can however stabilize it by artificially increasing the Ohmic resistivity, ηOR, so that it satisfies the condition ηOR ≥ ηH/5, where ηH is the Hall diffusion coefficient. Adopting this solution, we find second-order convergence for the C-shock and are also able to accurately reproduce the dispersion relation of the whistler waves. As a first application of the new scheme, we simulate the collapse of a magnetized cloud with constant Hall parameter ηH and show that, depending on the sign of ηH, the magnetic braking can either be weakened or strengthened by the Hall effect. The quasi-Lagrangian nature of the moving-mesh method used here automatically increases the resolution in the forming core, making it well suited for more realistic studies with non-constant magnetic diffusivities in the future.
The structure and dynamics of massive high-z cosmic-web filaments: three radial zones in filament cross-sections
Authors: Lu Yue Samuel , Mandelker Nir , Oh Siang Peng , Dekel Avishai , van den Bosch Frank C , Springel Volker , Nagai Daisuke , van de Voort Freeke
Published: December 2023

We analyse the internal structure and dynamics of cosmic-web filaments connecting massive high-z haloes. Our analysis is based on a high-resolution arepo cosmological simulation zooming-in on three Mpc-scale filaments feeding three massive haloes of $\sim 10^{12}\, \text{M}_\odot$ at z ∼ 4, embedded in a large-scale sheet. Each filament is surrounded by a cylindrical accretion shock of radius $r_{\rm shock} \sim 50 \, {\rm kpc}$. The post-shock gas is in virial equilibrium within the potential well set by an isothermal dark-matter filament. The filament line-mass is $\sim 9\times 10^8\, \text{M}_\odot \, {\rm kpc}^{-1}$, the gas fraction within rshock is the universal baryon fraction, and the virial temperature is ∼7 × 105 K. These all match expectations from analytical models for filament properties as a function of halo mass and redshift. The filament cross-section has three radial zones. In the outer ‘thermal’ (T) zone, $r \ge 0.65 \, r_{\rm shock}$, inward gravity, and ram-pressure forces are overbalanced by outward thermal pressure forces, decelerating the inflowing gas and expanding the shock outwards. In the intermediate ‘vortex’ (V) zone, 0.25 ≤ r/rshock ≤ 0.65, the velocity field is dominated by a quadrupolar vortex structure due to offset inflow along the sheet through the post-shock gas. The outward force is dominated by centrifugal forces associated with these vortices, with additional contributions from global rotation and thermal pressure. Shear and turbulent forces associated with the vortices act inwards. The inner ‘stream’ (S) zone, $r \lt 0.25 \, r_{\rm shock}$, is a dense isothermal core, $T\sim 3 \times 10^4 \, {\rm K}$ and $n_{\rm H}\sim 0.01 \, {\rm cm^{-3}}$, defining the cold streams that feed galaxies. The core is formed by an isobaric cooling flow and is associated with a decrease in outward forces, though exhibiting both inflows and outflows.
Value chain microfinance
Authors: Casaburi Lorenzo , Willis Jack
Published: December 2023

We study the provision of financial services to small firms, consumers, and workers in developing countries as part of value chain relationships: value chain microfinance (VCMF). We first explore how VCMF can both overcome barriers to financial access—including asymmetric information, enforcement, and behavioural biases—and strengthen value chains, but also how it can introduce new challenges. We then review a recent empirical literature at the intersection of value chains and microfinance, studying the demand for and effects of VCMF in credit, insurance, and savings markets. We conclude by highlighting promising directions for future work.
Genetic dissection of cis-regulatory control of ZmWUSCHEL1 expression by type B RESPONSE REGULATORS
Authors: Chen Zongliang , Cortes Liz , Gallavotti Andrea
Published: December 2023

Mutations in cis-regulatory regions play an important role in the domestication and improvement of crops by altering gene expression. However, assessing the in vivo impact of cis-regulatory elements (CREs) on transcriptional regulation and phenotypic outcomes remains challenging. Previously, we showed that the dominant Barren inflorescence3 (Bif3) mutant of maize (Zea mays) contains a duplicated copy of the homeobox transcription factor gene ZmWUSCHEL1 (ZmWUS1), named ZmWUS1-B. ZmWUS1-B is controlled by a spontaneously generated novel promoter region that dramatically increases its expression and alters patterning and development of young ears. Overexpression of ZmWUS1-B is caused by a unique enhancer region containing multimerized binding sites for type B RESPONSE REGULATORs (RRs), key transcription factors in cytokinin signaling. To better understand how the enhancer increases the expression of ZmWUS1 in vivo, we specifically targeted the ZmWUS1-B enhancer region by CRISPR-Cas9-mediated editing. A series of deletion events with different numbers of type B RR DNA binding motifs (AGATAT) enabled us to determine how the number of AGATAT motifs impacts in vivo expression of ZmWUS1-B and consequently ear development. In combination with dual-luciferase assays in maize protoplasts, our analysis reveals that AGATAT motifs have an additive effect on ZmWUS1-B expression, while the distance separating AGATAT motifs does not appear to have a meaningful impact, indicating that the enhancer activity derives from the sum of individual CREs. These results also suggest that in maize inflorescence development, there is a threshold of buffering capacity for ZmWUS1 overexpression.
Diagnosis and management of Alagille and progressive familial intrahepatic cholestasis
Authors: Cheng Katherine , Rosenthal Philip
Published: December 2023

Alagille syndrome and progressive familial intrahepatic cholestasis are conditions that can affect multiple organs. Advancements in molecular testing have aided in the diagnosis of both. The impairment of normal bile flow and secretion leads to the various hepatic manifestations of these diseases. Medical management of Alagille syndrome and progressive familial intrahepatic cholestasis remains mostly targeted on supportive care focusing on quality of life, cholestasis, and fat-soluble vitamin deficiency. The most difficult therapeutic issue is typically related to pruritus, which can be managed by various medications such as ursodeoxycholic acid, rifampin, cholestyramine, and antihistamines. Surgical operations were previously used to disrupt enterohepatic recirculation, but recent medical advancements in the use of ileal bile acid transport inhibitors have shown great efficacy for the treatment of pruritus in both Alagille syndrome and progressive familial intrahepatic cholestasis.
Auditory Aversive Generalization Learning Prompts Threat-Specific Changes in Alpha-Band Activity
Authors: Farkas Andrew H. , Ward Richard T. , Gilbert Faith E. , Pouliot Jourdan , Chiasson Payton , McIlvanie Skylar , Traiser Caitlin , Riels Kierstin , Mears Ryan , Keil Andreas
Published: December 2023

Pairing a neutral stimulus with aversive outcomes prompts neurophysiological and autonomic changes in response to the conditioned stimulus (CS+), compared to cues that signal safety (CS-). One of these changes—selective amplitude reduction of parietal alpha-band oscillations— has been reliably linked to processing of visual CS+. It is however unclear to what extent auditory conditioned cues prompt similar changes, how these changes evolve as learning progresses, and how alpha reduction in the auditory domain generalizes to similar stimuli. To address these questions, fifty-five participants listened to three sine wave tones, with either the highest or lowest pitch (CS+) being associated with a noxious white noise burst. A threat specific (CS+) reduction in occipital-parietal alpha-band power was observed similar to changes expected for visual stimuli. No evidence for aversive generalization to the tone most similar to the CS+ was observed in terms of alpha-band power changes, aversiveness ratings, or pupil dilation. By-trial analyses found that selective alpha-band changes continued to increase as aversive conditioning continued, beyond when participants reported awareness of the contingencies. The results support a theoretical model in which selective alpha power represents a cross-modal index of continuous aversive learning, accompanied by sustained sensory discrimination of conditioned threat from safety cues.
Investigation of genomic and transcriptomic risk factors in clopidogrel response in African Americans
Authors: Yang Guang , Alarcon Cristina , Chanfreau Catherine , Lee Norman H. , Friedman Paula , Nutescu Edith , Tuck Matthew , O’Brien Travis , Gong Li , Klein Teri E. , Chang Kyong-Mi , Tsao Philip S. , Meltzer David O. ,   Million Veteran Program, Tuteja Sony , Perera Minoli A
Published: December 2023

Clopidogrel, an anti-platelet drug, used to prevent thrombosis after percutaneous coronary intervention. Clopidogrel resistance results in recurring ischemic episodes, with African Americans suffering disproportionately. The aim of this study was to identify biomarkers of clopidogrel resistance in African American patients.

We conducted a genome-wide association study, including local ancestry adjustment, in 141 African Americans on clopidogrel to identify associations with high on-treatment platelet reactivity (HTPR). We validated genome-wide and suggestive hits in an independent cohort of African American clopidogrel patients (N = 823) from the Million Veteran’s Program (MVP) along within vitrofunctional follow up. We performed differential gene expression (DGE) analysis in whole blood with functional follow-up in MEG-01 cells.

We identified rs7807369, within thrombospondin 7A (THSD7A),as significantly associated with increasing risk of HTPR (p = 4.56 x 10−9). HigherTHSD7Aexpression was associated with HTPR in an independent gene expression cohort of clopidogrel treated patients (p = 0.004) and supported by increased gene expression onTHSD7Ain primary human endothelial cells carrying the risk haplotype. Two SNPs (rs1149515 and rs191786) were validated in the MVP cohort. DGE analysis identified an association with decreasedLAIR1expression to HTPR.LAIR1knockdown in a MEG-01 cells resulted in increased expression of SYK and AKT1, suggesting an inhibitory role ofLAIR1in the Glycoprotein VI pathway. Notably, theCYP2C19variants showed no association with clopidogrel response in the discovery or MVP cohorts.

In summary, these finding suggest that other variants outside ofCYP2C19star alleles play an important role in clopidogrel response in African Americans.

Key Points

SNPs withinTHSD7Awere associated to clopidogrel resistance in African Americans.

THSD7Agene expression is higher in patients with clopidogrel resistance and in endothelial cells carrying the risk variants.

No association to high on therapy platelet reactivity or major adverse cardiac events was seen withCYP2C19star alleles in either the African American cohort investigated.

DecreasedLAIR1gene expression in blood was associated to risk of HTPR and showed downstream effect on SKY and AKT.
Association between Stevens-Johnson syndrome and toxic epidermal necrolysis with ibuprofen: A pharmacovigilance study in the UK Yellow Card scheme and systematic review of case reports
Authors: Fletcher Guy , Ryan David K. , Bunker C B.
Published: December 2023

Introduction

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are a group of severe acute muco-cutaneous blistering disorders with a significant burden of morbidity and mortality. Drugs are commonly identified as potential precipitants of SJS/TEN, although it can be difficult to firmly identify causative agents. Ibuprofen has been proposed as a rare trigger for SJS/TEN and given the widespread use of this non-steroidal anti-inflammatory and significance of reaction, further pharmacovigilance analysis is warranted.

Methods

Serious or fatal adverse drug reaction (ADR) data from 1998 – October 2023 were downloaded from the UK MHRA Yellow Card Scheme website. Proportional reporting ratios (PRR) and 95% confidence intervals were calculated for SJS and TEN associated with ibuprofen using standard pharmacovigilance methods. Secondly, a systematic review of literature was conducted to explore reported cases where ibuprofen was the suspected trigger for a case of SJS/TEN. Eligible cases were assessed for the likelihood of ibuprofen being the causative agent by two reviewers using the Naranjo adverse drug reaction probability scale and the ALDEN algorithm for the assessment of drug causality in SJS/TEN.

Results

In total, 1, 994, 967 ARDs, relating to 1,811 SJS reports and 1,299 TEN reports. There was an increased signal for reports of SJS-TEN associated with ibuprofen use. The PRR for SJS with ibuprofen was 3.73 (95% confidence interval 2.68 – 5.18) and 4.49 (95% confidence interval 3.15 – 6.41). In our literature review, 23 individual case reports were deemed eligible for inclusion and the majority of these cases were determined as being doubtful in causality assessment. Difficulty in attributing causality was related to poorly defined temporal relationships between ibuprofen and SJS-TEN or poor reporting standards of case reports.

Conclusions

There are pharmacovigilance signals suggesting increased reporting of SJS/TEN in patients exposed to ibuprofen within UK data. However, more detailed case reports describing this association in literature have low likelihood of supporting causality. It is possible that reverse causality or co-causality is mediating this association. Further studies and pharmacovigilance is required to clarify the association between SJS/TEN and ibuprofen.
Irritability in young people with copy number variants associated with neurodevelopmental disorders (ND-CNVs)
Authors: Hall Jessica H. , Chawner Samuel. J.R.A ,   IMAGINE-ID consortium, Wolstencroft Jeanne , Skuse David , Holmans Peter , Owen Michael J. , van den Bree Marianne B.M.
Published: December 2023

Background

A range of rare mutations involving micro-deletion or -duplication of genetic material (copy number variants (CNVs)) have been associated with high neurodevelopmental and psychiatric risk (ND-CNVs). Irritability is frequently observed in childhood neurodevelopmental conditions, yet its aetiology is largely unknown. Genetic variation may play a role, but there is a sparsity of studies investigating presentation of irritability in young people with ND-CNVs.

Aims

This study aimed to investigate whether there is a difference in irritability in young people with rare ND-CNVs compared to those without ND-CNVs, and to what extent irritability is associated with psychiatric diagnoses and cognitive ability (IQ).

Methods

Irritability and broader psychopathology was assessed in 485 young people with ND-CNVs and 164 sibling controls, using the child and adolescent psychiatric assessment (CAPA). Autism was assessed using the Social Communication Questionnaire (SCQ), and Intelligence Quotient (IQ) by the Wechsler Abbreviated Scale of Intelligence (WASI).

Results

54% of young people with ND-CNVs met the threshold for irritability; significantly more than controls (OR = 3.77, CI = 3.07-7.90, p= 5.31 x 10-11). When controlling for the presence of other psychiatric comorbidities, ND-CNV status was still associated with irritability. There was no evidence for a relationship between irritability and IQ.

Conclusions

Irritability is an important aspect of the clinical picture in young people with ND-CNVs. This work shows that genetic variation is associated with irritability in young people with ND-CNVs, independent of psychiatric comorbidities or IQ impairment. Clinicians should be aware of this increased risk to inform management and interventions.
Clinicopathological, surgical management and early postoperative outcome among obstructive jaundice inpatients at Kilimanjaro Christian Medical Centre from March 2020 to March 2023
Authors: Chambo Mkunde Ramadhani , Venant Elmes , Msuya David , Chugulu Samwel
Published: December 2023

Obstructive jaundice is a surgical condition that affects all age groups mostly to the above 18 individuals. This condition can lead to high morbidity and mortality if not early diagnosed and treated. It remains the common cause of surgical consultations globally accounting for 8-10/100,000 and 242/1000 annually in China and Saudi Arabia respectively. Clinicopathological and radiological investigations are the key to the disease diagnosis. Cholelithiasis and cancer head of pancreas are common causes of obstructive jaundice. Although the diagnosis and treatments of obstructive jaundice is advancing; some patients get poor treatment outcome such as SSI, peritonitis and long hospital stay with some of them dying.

To determine the clinicopathological, surgical management and early postoperative outcome among obstructive jaundice inpatients at KCMC from March 2020 to March 2023.

A hospital-based cross-sectional study was conducted using secondary data from hospital records, EHMS system, surgery admission and theater registry books. All files of patients aged 18 years and above from these registry books with a diagnosis of obstructive jaundice from March 2020 to March 2023 were included. The obtained data were collected using the questionnaire then entered and analyzed using SPSS version 26.

A total of 101 patients were studied, with the male to female ratio of 1.2:1. Cancer head of pancreas was the commonest malignant cause of obstructive jaundice where as choledocholithiasis was the commonest benign cause. Most of the clinical presentations were abdominal pain 47.6%, yellowish discoloration of the mucous membrane, eyes and skin by 43.6% and itching by 6.9%. Both laboratory investigations and radiological imaging were done which showed elevated liver enzymes 68.3%, low Hb 46.5%, histopathology 62.4%; benign and malignant obstructive jaundice cause by 33.7% and 46.5% respectively. Among all the patients who were surgically managed 29.7% had palliative triple bypass, 14.8% had laparoscopic cholecystectomy and 14.8% had CBD Exploration. The overall complication rate was 50.5%; Death 16.5% surgical site infections 13.9% and long hospital stay 9.9%.

Obstructive jaundice in our setting is more common in males where malignant causes being high in the list
The Role of Community Beliefs and Practices on the Spread of Ebola in Uganda, September 2022
Authors: Naiga Helen Nelly , Zalwango Jane Frances , Kizito Saudah N. , Agaba Brian , Simbwa Brenda N. , Zalwango Maria Goretti , Akunzirwe Rebecca , Kabami Zainah , Kawugenzi Peter Chris , Zavuga Robert , Ninsiima Mackline , King Patrick , Wanyana Mercy Wendy , Kiggundu Thomas , Migisha Richard , Gonahasa Doreen , Kyamwine Irene , Kwesiga Benon , Kadobera Daniel , Bulage Lilian , Riolexus Alex Ario , Paige Sarah B. , Harris Julie R.
Published: December 2023

Background

Traditional community beliefs and cultural practices can facilitate the spread of ebolaviruses during outbreaks. On September 20, 2022, Uganda declared a Sudan Virus Disease (SVD) outbreak after a case was confirmed in Mubende District. During September–November 2022, the outbreak spread to eight additional districts. We investigated the role of community beliefs and practices in the spread of SUDV in Uganda in 2022.

Methods

A qualitative study was conducted in Mubende, Kassanda, and Kyegegwa districts in February 2023. We conducted nine focus group discussions (FGDs) and six key informant interviews (KIIs). FGDs included SVD survivors, household members of SVD patients, traditional healers, religious leaders, and community leaders. Key informants included community, political, and religious leaders, traditional healers, and health workers. We asked about community beliefs and practices to understand if and how they contributed to the spread of SUDV. Interviews were recorded, translated, transcribed, and analyzed thematically.

Results

Frequently-reported themes included beliefs that the community deaths, later found to be due to SVD, were the result of witchcraft or poisoning. Key informants reported that SVD patients frequently consulted traditional healers or spiritual leaders before seeking formal healthcare or visited them after formal healthcare failed to improve their health conditions. They also noted that traditional healers treated patients with signs and symptoms of SVD without protective measures. Additional themes included religious leaders conducting laying-on-of-hands prayers for SVD patients and symptomatic contacts, SVD patients and their symptomatic contacts hiding in friends’ homes, and exhumation of SVD patients originally buried in safe and dignified burials, to enable traditional burials.

Conclusion

Varied community beliefs and cultural practices likely promoted SVD outbreak spread during the 2022 outbreak in Uganda. Controlling ebolavirus outbreaks in Uganda could be aided by the involvement of formal public health systems, traditional healers, and religious leaders. Community engagement during inter-epidemic periods could aid in the effective management of future outbreaks in Uganda by identifying socially acceptable and scientifically supported alternatives for infection control.
Comparison of electrophysiological left bundle branch pacing characteristics in different bilateral electrode pacing vector configurations
Authors: Wu Hao , Jiang Longfu , Shen Jiabo , Zhang Lu
Published: December 2023

Background

Left bundle branch pacing (LBBP) in bipolar pacing produces a more balanced ventricular activation than conventional unipolar pacing but need high pacing output. The present study aimed to compare the electrophysiological characteristics of LBBP in different bilateral electrode pacing vector configurations.

Methods

A total of 57 patients who met the criteria for left bundle branch (LBB) capture and underwent three bilateral electrode pacing vector configuration test were enrolled. The electrocardiogram (ECG) and electrogram (EGM) parameters were evaluated and other electrophysiological characteristics were analyzed using a three-electrode configuration test.

Results

Seven capture modes (right ventricular septal (RVS) + left ventricular septal (LVS) + LBB, RVS + LBB, LVS + LBB, RVS + LVS, RVS, LVS, and LBB) were utilized in the study. The thresholds of full fusion mode (RVS+LVS+LB) in Bilateral Cathodes and Ring Bipolar were all lower than that in Tip Bipolar (1.2 ± 0.5 V vs. 2.7 ± 1.0 V, P < 0.001; 1.6 ± 0.6 V vs. 2.7 ± 1.0 V, P < 0.001). Full fusion mode had the shortest P-QRS (116.9 ± 12.8 ms), V6 RWPT (64.9 ± 9.7 ms), and V1 RWPT (94.5 ± 12.3 ms).

Conclusion

Changing the bilateral electrode pacing vector configuration to Bilateral Cathodes and Ring Bipolar can reduce the full fusion mode capture threshold compared to conventional bipolar pacing.

What is Known?

Left bundle branch pacing in bipolar pacing can capture left bundle branch, left ventricular septal myocardial, and right ventricular septal myocardial at a higher pacing output, which was termed full fusion mode.

What the Study Adds?

This study indicates that the full fusion mode threshold can be reduced by changing the pacing vector configuration.

Seven capture modes were observed in Ring Bipolar and Bilateral Cathodes during threshold testing.

GRAPHICAL ABSTRACT

The characteristics of ECG and EGM of different types of capture in three bilateral electrode pacing vector configurations and the schematic representation.
Infection Control Program Among the Ysleta del Sur Pueblo Prevents Hospitalizations and Deaths During the Covid-19 Pandemic
Authors: Torres Cameron M. , Aparicio Victoria , Morales Gabriela , Mena Ascension , Spencer Charles T.
Published: December 2023

In response to the SARS-CoV-2 pandemic, the United States declared a state of emergency and implemented large scale shutdowns and public health initiatives to prevent overwhelming public resources. The success of these prevention methods remains unresolved as restrictions and implementation varied greatly from national, state, and local levels. Despite national and local regulations, individual adherence to preventative guidelines presented an additional layer of variability. Cases of Covid-19 continued to rise and fall over a two-year period on a national level despite masking recommendations, ease of testing, and availability of vaccines. The Ysleta del Sur Pueblo is a Native American tribal community and sovereign nation located in El Paso, Texas. Speaking Rock Entertainment Center is a major business operated by the tribe, employing a large number of tribal and non-tribal members from the El Paso community. Following nationwide re-openings of non-essential businesses, Speaking Rock implemented an infection control program with strict adherence to recommendations provided by the Center for Disease Control and Prevention (CDC). Herein, we examine the efficacy of these measures and report on the success of the program resulting in zero employee hospitalizations or deaths in a region heavily impacted by severe Covid-19 during the height of the pandemic.
Cost-effectiveness of sotagliflozin for the treatment of patients with diabetes and recent worsening heart failure
Authors: Kim Jaehong , Wang Shanshan , Sikirica Slaven , Shafrin Jason
Published: December 2023

Background

The efficacy and safety of sotagliflozin, a novel therapy for the treatment of patients with heart failure, was demonstrated in SOLOIST-WHF, but its economic value is yet to be determined. This study assesses the cost-effectiveness of sotagliflozin for the treatment of patients hospitalized with heart failure and comorbid diabetes.

Methods

An economic model with a Markov structure was created for patients hospitalized for heart failure with comorbid diabetes. Outcomes of interest included hospital readmissions, emergency department visits, and all-cause mortality measured over a 30-year time horizon. Baseline event frequencies were derived from published real-world data studies; sotagliflozin’s efficacy was estimated from SOLOIST-WHF. Health benefits were synthesized using quality-adjusted life years. Costs included pharmaceutical costs, rehospitalization, emergency room visits and adverse events. Economic value was measured using the incremental cost effectiveness ratio.

Results

Sotagliflozin use decreased annualized rehospitalization rates by 34.5% (0.228 vs. 0.348, difference: -0.120), annualized emergency department visits by 40.0% (0.091 vs. 0.153, difference: -0.061), and annualized mortality by 18.0% (0.298 vs. 0.363, difference: -0.065) relative to standard of care, resulting in a net gain in quality adjusted life-years of 0.425 for sotagliflozin vs. standard of care. Incremental costs using sotagliflozin increased by $19,374 over the lifetime of the patient, driven largely by increased pharmaceutical cost. Estimated incremental cost effectiveness ratio was $45,596 per quality adjusted life-year.

Conclusions

Sotagliflozin is a cost-effective addition to standard of care for patients hospitalized with heart failure and comorbid diabetes.
Three-dimensional histology reveals dissociable human hippocampal long axis gradients of Alzheimer’s pathology
Authors: Ortega-Cruz Diana , Bress Kimberly S. , Gazula Harshvardhan , Rabano Alberto , Iglesias Juan Eugenio , Strange Bryan A.
Published: December 2023

INTRODUCTION

Three-dimensional (3D) histology analyses are essential to overcome sampling variability and understand pathological differences beyond the dissection axis. We present Path2MR, the first pipeline allowing 3D reconstruction of sparse human histology without an MRI reference. We implemented Path2MR with post-mortem hippocampal sections to explore pathology gradients in Alzheimer’s Disease.

METHODS

Blockface photographs of brain hemisphere slices are used for 3D reconstruction, from which an MRI-like image is generated using machine learning. Histology sections are aligned to the reconstructed hemisphere and subsequently to an atlas in standard space.

RESULTS

Path2MR successfully registered histological sections to their anatomical position along the hippocampal longitudinal axis. Combined with histopathology quantification, we found an expected peak of tau pathology at the anterior end of the hippocampus, while amyloid-β displayed a quadratic anterior-posterior distribution.

CONCLUSION

Path2MR, which enables 3D histology using any brain bank dataset, revealed significant differences along the hippocampus between tau and amyloid-β.
Chronic exposure to predator cues fails to elicit plastic responses or transgenerational effects in banded crickets
Authors: Dalos Jeremy , Dochtermann Ned A.
Published: December 2023

Plasticity is a major feature of behavior and particularly important for how animals respond to predators. While animals frequently show plastic responses when directly exposed to predators, with these exposures even leading to permanent behavioral changes and transgenerational effects, whether indirect cues of predator presence can elicit similarly severe responses is unclear. We exposed banded crickets (Gryllodes siglattus) to cues of predator presence throughout development and compared their behavior—as well as the behavior of their offspring—to individuals who had not been reared in the presence of predator cues. Contrary to findings in bothG. sigilattusand related species, we did not detect either developmental plasticity in the form of differences between adult behavior or differences in offspring behavior. These findings suggest that chronic exposure to cues of predator presence have a substantially different affect on behaviors than does direct exposure to predators. How habituation might interact with developmental plasticity and transgenerational effects requires further investigation.

Significance Statement

Previous research has established that exposure to predators elicits behavioral plasticity, including life-long effects, as well as transgenerational effects. Here we show that chronic exposure to cues of predator presence throughout development, with a resulting potential for habituation, results in neither differences in adult behavior or transgenerational effects. This suggests an important role for habituation in how plasticity manifests within and between generations
G1 length dictates H3K27me3 landscapes
Authors: Trouth Abby , Ravichandran Kamesh , Gafken Philip R , Martire Sara , Boyle Gabriel E. , Veronezi Giovana M. B. , La Van , Namciu Stephanie J. , Banaszynski Laura A. , Sarthy Jay F. , Ramachandran Srinivas
Published: December 2023

Stem cells have lower facultative heterochromatin as defined by trimethylation of histone H3 lysine 27 (H3K27me3) compared to differentiated cells. However, the mechanisms underlying these differential H3K27me3 levels remain elusive. Because H3K27me3 levels are diluted two-fold in every round of replication and then restored through the rest of the cell cycle, we reasoned that the cell cycle length could be a key regulator of total H3K27me3 levels. Here, we propose that a fast cell cycle restricts H3K27me3 levels in stem cells. To test this model, we determined changes to H3K27me3 levels in mESCs globally and at specific loci upon G1 phase lengthening – accomplished by thymidine block or growth in the absence of serum (with the “2i medium”). H3K27me3 levels in mESC increase with G1 arrest when grown in serum and in 2i medium. Additionally, we observed via CUT&RUN and ChIP-seq that regions that gain H3K27me3 in G1 arrest and 2i media overlap, supporting our model of cell cycle length as a critical regulator of the stem cell epigenome and cellular identity. Furthermore, we demonstrate the inverse effect – that G1 shortening in differentiated cells results in a loss of H3K27me3 levels. Finally, in tumor cells with extreme H3K27me3 loss, lengthening of the G1 phase leads to H3K27me3 recovery despite the presence of the dominant negative, sub-stoichiometric H3.1K27M mutation. Our results indicate that G1 length is an essential determinant of H3K27me3 landscapes across diverse cell types.
The small iron-deficiency-induced protein OLIVIA and its relation to the bHLH transcription factor POPEYE
Authors: Lichtblau Daniela M. , Baby Dibin , Khan Mather , Trofimov Ksenia , Ari Yunus , Schwarz Birte , Bauer Petra
Published: December 2023

Iron (Fe) is a crucial micronutrient needed in many metabolic processes. To balance needs and potential toxicity, plants control the amount of Fe they take up and allocate to leaves and seeds during their development. One important regulator of this process is POPEYE (PYE). PYE is a Fe deficiency-induced key bHLH transcription factor (TF) for allocation of internal Fe in plants. In the absence of PYE, there is altered Fe translocation and plants develop a leaf chlorosis.NICOTIANAMINE SYNTHASE4(NAS4),FERRIC-REDUCTION OXIDASE3(FRO3), andZINC-INDUCED FACILITATOR1(ZIF1) genes are expressed at higher level inpye-1indicating that PYE represses these genes. PYE activity is controlled in a yet unknown manner. Here, we show that a small Fe deficiency-induced protein OLIVIA (OLV) can interact with PYE. OLV has a conserved C-terminal motif, that we named TGIYY. Through deletion mapping, we pinpointed that OLV TGIYY and several regions of PYE can be involved in the protein interaction. AnOLVoverexpressing (OX) mutant line exhibited an enhancedNAS4gene expression. This was a mild Fe deficiency response phenotype that was related to PYE function. Leaf rosettes ofolvmutants remained smaller than those of wild type, indicating that OLV promotes plant growth. Taken together, our study identified a small protein OLV as a candidate that may connect aspects of Fe homeostasis with regulation of leaf growth.

Highlights

OLIVIA (OLV), a small protein, can interact with the bHLH transcription factor POPEYE (PYE)

OLV has a conserved motif, named TGIYY, that can be involved in protein interaction with PYE

OLV mutant plants have mild phenotypes related with PYE andNAS4regulation.

OLV promotes rosette growth.
Evolutionary repurposing of trypanosomal Pam18 and Pam16 reveals a new regulatory circuit for mitochondrial genome replication
Authors: von Känel Corinne , Oeljeklaus Silke , Calderaro Salvatore , Durante Ignacio M. , Rašková Vendula , Warscheid Bettina , Schneider André
Published: December 2023

Protein import and genome replication are essential processes for mitochondrial biogenesis and propagation. The J-domain proteins Pam16 and Pam18 regulate the presequence translocase of the mitochondrial inner membrane. In the protozoanTrypanosoma brucei, their counterparts are TbPam16 and TbPam18, which are essential for the procyclic form of the parasite, though not involved in mitochondrial protein import. Here, we show that during evolution, the two proteins have been repurposed to regulate the replication of maxicircles within the intricate kDNA network, the most complex mitochondrial genome known. TbPam18 and TbPam16 have inactive J-domains suggesting a function independent of heat shock proteins. However, their single transmembrane domain is essential for function. Pulldown of TbPam16 identifies a putative client protein, termed MaRF11, the depletion of which causes the selective loss of maxicircles, akin to the effects observed for TbPam18 and TbPam16. Moreover depletion of the mitochondrial proteasome results in increased levels of MaRF11. Thus, we propose a model for a membrane-bound regulatory circuit that controls maxicircle replication in response to an unknown nuclear signal. This model posits that MaRF11 directly mediates maxicircle replication, that its level is controlled by proteasomal digestion, and that it is protected from degradation by binding to the TbPam18/TbPam16 dimer.
Post-GWAS Prioritization of Genome-Phenome Association in Sorghum
Authors: Pal Debasmita , Schaper Kevin , Thompson Addie , Guo Jessica , Jaiswal Pankaj , Lisle Curtis , Cooper Laurel , LeBauer David , Thessen Anne , Ross Arun
Published: December 2023

Genome-Wide Association Studies (GWAS) are widely used to infer the genetic basis of traits in organisms, yet selecting appropriate thresholds for analysis remains a significant challenge. In this study, we developed the Sequential SNP Prioritization Algorithm (SSPA) to elucidate the genetic underpinnings of two key phenotypes inSorghum bicolor: maximum canopy height and maximum growth rate. Utilizing a subset of the Sorghum Bioenergy Association Panel cultivated at the Maricopa Agricultural Center in Arizona, our objective was to employ GWAS with specific permissive-filtered thresholds to identify the genetic markers associated with these traits, allowing for a broader collection of explanatory candidate genes. Following this, our proposed method incorporates a feature engineering approach based on statistical correlation coefficient to reveal patterns between phenotypic similarity and genetic proximity across 274 accessions. This approach helps prioritize Single Nucleotide Polymorphisms (SNPs) likely to be associated with the studied phenotype. Additionally, we evaluated the impact of SSPA by considering all variants (SNPs) as inputs, without any GWAS filtering, as a complementary analysis. Empirical evidence including ontology- based gene function, spatial and temporal expression, and similarity to known homologs, demonstrated that SSPA effectively prioritizes SNPs and genes influencing the phenotype of interest, providing valuable insights for functional genetics research.
OOPS: Object-Oriented Polarization Software for analysis of fluorescence polarization microscopy images
Authors: Dean William F. , Nawara Tomasz J. , Albert Rose M. , Mattheyses Alexa L.
Published: December 2023

Most essential cellular functions are performed by proteins assembled into larger complexes. Fluorescence Polarization Microscopy (FPM) is a powerful technique that goes beyond traditional imaging methods by allowing researchers to measure not only the localization of proteins within cells, but also their orientation or alignment within complexes or cellular structures. FPM can be easily integrated into standard widefield microscopes with the addition of a polarization modulator. However, the extensive image processing and analysis required to interpret the data have limited its widespread adoption. To overcome these challenges and enhance accessibility, we introduce OOPS (Object-Oriented Polarization Software), a MATLAB-based analysis tool tailored for FPM data. This work highlights the distinctive features of our software, which empower researchers to efficiently manage large datasets; detect and analyze individual structures; conduct population assessments based on morphology, intensity, and polarization-specific parameters; and create publication-quality visualizations, all within a user-friendly graphical interface. Importantly, OOPS is adaptable to various sample types, labeling techniques, and imaging setups, facilitating in-depth analysis of diverse polarization-sensitive samples. Here, we demonstrate the power and versatility of our approach by applying OOPS to FPM images of both punctate and filamentous structures. OOPS is freely available under the GNU GPL 3.0 license and can be downloaded athttps://github.com/Mattheyses-Lab/OOPS.
Persistence of genetically engineered canola populations in the U.S. and the adventitious presence of transgenes in the environment
Authors: Travers Steven , Bishop D. Bryan , Sagers Cynthia
Published: December 2023

Feralization of genetically engineered (GE) crops increases the risk that transgenes will become integrated into natural and naturalizing plant populations. A key assumption of the management of GE crops is that populations of escaped plants are short-lived and that the risks they pose, therefore, are limited. However, few populations of escaped crop plants have been tracked over the long term so our understanding of their persistence in ruderal or natural landscapes is limited. In 2021, we repeated a large-scale road survey of feral GE canola populations in North Dakota, USA, initially conducted in 2010. Our objectives were to determine the current distribution of feral canola populations, and to establish the relative frequency of GE and non-GE phenotypes in populations of canola throughout North Dakota, where most of the canola in the USA is grown. Our results indicate that, although the incidence of feral canola was less in 2021 than 2010, escaped canola populations remain common throughout the state. The prevalence of alternate forms of GE herbicide resistance changed between surveys, and we found an overabundance of non-GE plants compared to the frequency of non-transgenic forms in cultivation. Indirect evidence that canola escaped from cultivation has established persistent populations outside of management includes finding plants with multiple transgenic traits, and locating populations far from transportation routes. We conclude that feral canola populations expressing transgenic herbicide resistance are established outside of cultivation, that they may be under selection for loss of the transgene, but that they nonetheless pose long-term risks by harboring transgenes in the unmanaged landscape.
Evolutionary analyses of IDRs reveal widespread signals of conservation
Authors: Singleton Marc , Eisen Michael
Published: December 2023

Intrinsically disordered regions (IDRs) are segments of proteins without stable three-dimensional structures. As this flexibility allows them to interact with diverse binding partners, IDRs play key roles in cell signaling and gene expression. Despite the prevalence and importance of IDRs in eukaryotic proteomes and various biological processes, associating them with specific molecular functions remains a significant challenge due to their high rates of sequence evolution. However, by comparing the observed values of various IDR-associated properties against those generated under a simulated model of evolution, a recent study found most IDRs across the entire yeast proteome contain conserved features. Furthermore, it showed clusters of IDRs with common “evolutionary signatures,”i.e.patterns of conserved features, were associated with specific biological functions. To determine if similar patterns of conservation are found in the IDRs of other systems, in this work we applied a series of phylogenetic models to over 8,500 orthologous IDRs identified in theDrosophilagenome to dissect the forces driving their evolution. By comparing models of constrained and unconstrained continuous trait evolution using the Brownian motion and Ornstein-Uhlenbeck models, respectively, we identified signals of widespread constraint, indicating conservation of distributed features is mechanism of IDR evolution common to multiple biological systems. In contrast to the previous study in yeast, however, we observed limited evidence of IDR clusters with specific biological functions, which suggests a more complex relationship between evolutionary constraints and function in the IDRs of multicellular organisms.