bluuebunny/crossref_metadata_2025 huggingface dataset:
Incidence and Determinants of loss to follow-up of HIV pre-exposure prophylaxis among key and priority population groups in Addis Ababa health centers, Ethiopia retrospective cohort study
Authors: Aragaw Addisu , Taddse Fentaw
Published: September 2023

Background

- ‘loss of follow-up’ is a significant public health concern globally. Retention in preventive care among at-risk key and priority population groups is critical for the successful prevention of HIV acquisition. Loss to follow-up of individuals has countless negative impacts on HIV prevention outcomes. There is, however, limited information about the incidence and predictors of loss to follow-up in the study area. Thus, this study aimed to determine the incidence rate and predictors of loss to follow-up among Prep users.

Method

- A retrospective cohort study was undertaken using 240 PrEP users between May 2020, and May 26, 2022, at Addis Ababa selected health centers. All eligible clients who fulfilled the inclusion criteria were included in study.

Results and discussion

A total of 240 participants with a median age of 32.0 years (interquartile range [IQR]: 27.0 to 40.0) had a median time since initiation of PrEP 21.2 months (IQR: 6.5 to 22.1). Almost half 122 (50.8%) were married, single 58 (24.2%), divorced 10 (4.2%), and widowed 50 (20.8%). One third were female sex workers (33.3%), and the rest (66.7%) were sero-discordant couples. Most of the users were from ART clinics (60.8%) and (39.2%) were from PMTCT clinics Being male is associated with 1.77 times in risk of getting lost than female (ARR=1.77, 95% CI =1.12-2.79). those who had no adherence counseling was associated with 1.86 times in the chance of LTFU as compared to those who had have adherence counseling (ARR=1.863, 95% CI =1.184, 2.930, P-value=0.003). 86 (35.8%) experienced loss to follow-up and the overall incidence rate of loss to follow-up was 7.3 (95% CI: 4.3-12.6) per 100 person-years of observation (PYs). PrEP adherence strategies should be developed and designed as a holistic approach, acknowledging the contextual factors of key population groups.

Conclusion

- About 35.8% clients became LTFU of PrEP with overall incidence of 7.3(4.3-12.6) per 100 pys observation. Research preparedness involving key and priority population groups should be strengthened for HIV prevention intervention evaluations in Ethiopia.
Is addressing violence against women prioritised in health policies? Findings from a WHO Policies Database
Authors: Burke Eva , Watson Katherine , Eva Gillian , Gold Judy , Garcia-Moreno Claudia , Amin Avni
Published: September 2023

Violence against women (VAW) affects almost 1 in 3 women and can lead to short and long-term adverse health outcomes. The health sector is an important entry point to respond to VAW. Globally, countries have committed to eliminating VAW through the SDGs and WHO Member States have endorsed a Global Plan of Action on Violence, which asks countries to provide comprehensive health services to VAW survivors. To track progress and establish a baseline for the Global Plan of Action on Violence, WHO developed a VAW Policies Database to assess how countries are addressing VAW in health and multisectoral policies. This paper presents findings from 15 select indicators related to the existence of VAW-related policies and the inclusion of health services for survivors in policies in line with WHO recommendations. Results show that while 80% of countries have multisectoral VAW policies in place, only 34% have national health policies that include VAW response and/or prevention as a strategic priority, and 48% have clinical guidelines for the health sector response. Policies were analysed to identify inclusion of WHO-recommended VAW health services: 75% of countries’ policies mention provision of first-line support; while 50% or fewer of countries mention clinical enquiry to identify intimate partner violence, post-rape care services, or mental health assessment, referral and treatment. The high-income countries group had the lowest proportion of countries that specified each of the above-mentioned health services in policies. Findings show that more efforts are needed to raise the awareness of ministries of health about the public health impact of VAW and the importance of including VAW in health policies. Where policies exist, many are not aligned with WHO-recommendations. Policy dialogues should be conducted with governments on how to better align their VAW policies with internationally-agreed, evidence-based standards, and to implement them through programmes and services.
CONTRAST MEDIA VOLUME CONTROL FOR LIMITING ACUTE KIDNEY IN ACUTE CORONARY SYNDROME: THE REMEDIAL IV RANDOMIZED CLINICAL TRIAL
Authors: Briguori Carlo , Quintavalle Cristina , Mariano Enrica , D’Agostino Alessandro , Scarpelli Mario , Focaccio Amelia , Zoccai Giuseppe Biondi , Evola Salvatore , Esposito Giovanni , Sangiorgi Giuseppe Massimo , Condorelli Gerolama
Published: September 2023

BACKGROUND

Acute kidney injury (AKI) is a common complication in patients suffering from acute coronary syndromes (ACS) and treated by percutaneous coronary intervention (PCI). Contrast media (CM) volume minimization has been advocated to prevent AKI. The DyeVert™ system (Osprey Medical Inc., Minnetonka, MN, USA) is a device designed to reduce CM volume during coronary procedures, while maintaining fluoroscopic image quality.

METHODS

In this is study a randomized, single-blind, investigator-driven clinical trial conducted in 4 italian interventional cardiology centers from February 4, 2020 to September 13, 2022, 550 ACS participants were randomly assigned in 1:1 ratio to 1)Control group(n = 274), in which a conventional manual or automatic injection syringe was used, and 2)Contrast Volume Reduction (CVR) group(n = 276), in which CM injection was handled by the DyeVertTMsystem. The primary endpoints were 1) CM volume, and 2) the rate of AKI, defined as a serum creatinine (sCr) increase ≥0.3 mg/dL within 48 hours after CM exposure.

RESULTS

There were 412/550 (74.5%) participants with ST-elevation myocardial infarction (201/274 [73.3%] in theControl groupand 211/276 [76.4%] in theCVR group). Mean glomerular filtration rate was 84±32 mL/min/1.73 m2in theControl groupand in 85±34 mL/min/1.73 m2in theCVR group(p = 0.78). CM volume was higher in theControl group(160 ± 23 mL versus 95 ± 30 mL; p < 0.001). Seven participants (6 in theControl groupand one in theCVR group) did not have post-procedural sCr values. AKI occurred in 65/268 (24.3%) participants in theControl groupand in 44/275 (16%) participants in theCVR group(RR = 0.66; 95% confidence interval 0.47-0.93; p = 0.018).

CONCLUSIONS

CM volume reduction obtained by the DyeVertTMsystem is effective to prevent AKI in ACS patients undergoing invasive procedure.

Trial Registration

The study is registered withwww.clinicaltrial.gov(NCT04714736)

Clinical Perspective

What Is New?

Contrast media volume reduction obtained by the DyeVertTMsystem is effective to prevent acute kidney injury in acute coronary syndrome patients undergoing invasive procedure.

What Are the Clinical Implications?

Contrast media volume minimization is of outmost important in the attempt to prevent acute kidney injury. The DyeVert™ system is an “operator-independent” tool contributing to the contrast media-sparing approach.
Novel Liver Injury Phenotypes and Outcomes in Pulmonary Arterial Hypertension
Authors: Scott Jacqueline V , Moutchia Jude , McClelland Robin L , Al-Naamani Nadine , Weinberg Ethan , Palevsky Harold I , Minhas Jasleen , Appleby Dina K , Smith Akaya , Pugliese Steven C , Ventetuolo Corey E , Kawut Steven M
Published: September 2023

Background

Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are disorders of the pulmonary vasculature that cause right ventricular dysfunction. Systemic consequences of right ventricular dysfunction include damage to other solid organs, such as the liver. However, the profiles and consequences of hepatic injury due to PAH and CTEPH have not been well-studied.

Methods

We aimed to identify underlying patterns of liver injury in a cohort of PAH and CTEPH patients enrolled in 15 randomized clinical trials conducted between 1998 and 2012. We used unsupervised machine learning to identify liver injury clusters in 13 trials and validated the findings in two additional trials. We then determined whether these liver injury clusters were associated with clinical outcomes or treatment effect heterogeneity.

Results

Our training dataset included 4,219 patients and our validation dataset included 1,756 patients with complete liver laboratory panels (serum total bilirubin, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, and albumin). Using k-means clustering paired with factor analysis, we identified four unique liver phenotypes (no liver injury, hepatocellular injury, cholestatic injury, and combined injury patterns). Patients in the cholestatic injury liver cluster had the shortest time to clinical worsening and highest chance of worsening World Health Organization functional class. Randomization to the experimental arm was associated with a transition to healthier liver clusters compared to randomization to the control arm. The cholestatic injury group experienced the greatest placebo-corrected treatment benefit in terms of six-minute walk distance.

Conclusions

Liver injury patterns were associated with adverse outcomes in patients with PAH and CTEPH. Randomization to active treatment of pulmonary hypertension in these clinical trials had beneficial effects on liver health compared to placebo. The independent role of liver disease (often subclinical) in determining outcomes warrants prospective studies of the clinical utility of liver phenotyping for PAH prognosis and contribution to clinical disease.
Short term atrial fibrillation in different stroke entities
Authors: Boettger Priyanka , Kracht Till , Schulz Nils , Ott Kai , Klemm Philipp , Lange Uwe , Müller-Ladner Ulf , Rolf Andreas , Lemm Henning , Buerke Michael
Published: September 2023

Background

Stroke including ESUS is one of the most common causes of disability and death in the world. Atrial fibrillation (AF) of more than 30 sec is considered a reason for cardioembolic stroke. Nevertheless, shorter periods of AF might also be a possible risk factor.

Methods

We determined periods of AF within a range of 0-14 s, 15-30 s and > 30 s in patients with different stroke entities. We analysed all ischemic strokes and transient ischemic attacks at the Stroke Units/Emergency Room in Siegen within 6 months and classified them etiologically. All stroke patients were prospectively ECG monitored over a minimum of 24h and characterized for the different AF periods at the stroke unit. The stroke entities were then compared.

RESULTS

A number of 714 patients over 6 months were hospitalized suffering a stroke. Among them 163 (30.8%) had a cryptogenic Stroke, including 98 (19%) ESUS patients. Furthermore, 185 (26%) TIA, 209 (39%) cardioembolic, 110 (21%) atherosclerotic, 40 (8%) lacunar and 7 (1%) other specific strokes were registered. Manifest atrial fibrillation (>30s) showed a prevalence of 23% within our stroke population. Whereas 15% had an AF episode of 15-29 s and 16% presented AF episode of 0-14 s. Among cardioembolic infarcts, 45% had manifest atrial fibrillation (>30 s), 20% had an atrial fibrillation episode of 15-29 s, and 22% showed an atrial fibrillation episode of 0-14 s. Taken together, more than 90% of cardioembolic infarcts show an episode of atrial fibrillation of any duration. An AF episode of 15-29 s or 0-14 s was also found in almost 35% of ESUS patients: similar to cryptogenic infarctions. In 22% of the TIA patients manifest atrial fibrillation had been detected. 7% of TIA patients showed one or more episodes of AF of 15-29 s and 10% an episode of 0-14 s. Among the atherosclerotic infarctions, the proportion of AF >30 s is profoundly lower at 12%, however the percentage of AF for 15-29 s was 14. The smallest ratio of atrial fibrillation of any duration was formed by lacunar insults with a total of nearly 25%, of which only 13% had manifest AF.

Conclusion

Non-valvular atrial fibrillation presents the most common cause of cardiac cerebral embolism. In our study, AF showed the largest ratio among cardioembolic strokes with 48%. Overall, AF of any duration occurred in nearly 90% of this group. Since a manifest AF is an exclusion criterion for ESUS, conversely, none of the ESUS patients suffered from manifest AF. However, it is striking that 15% of ESUS patients had an AF episode of 15-29 s and 18% had an AF episode of 0-15 s. Similar results were observed in cryptogenic strokes. Possibly, the definition of AF has to be adjusted, since the stroke subgroups with short term AF did not receive proper anticoagulation treatment. However, at least advanced rhythm monitoring should be provided. This should be investigated in future prospective studies.
Cerebral microbleeds in critically ill patients with respiratory failure or sepsis: a scoping review
Authors: Chen Bing Yu , Dang Johnny , Cho Sung-Min , Harnegie Mary Pat , Uchino Ken
Published: September 2023

Background

Cerebral microbleeds (CMB) have been described in critically ill patients with respiratory failure, acute respiratory distress syndrome (ARDS), or sepsis. This scoping review aimed to systematically summarize existing literature on critical illness-associated CMBs.

Methods

Studies reporting on adults admitted to the intensive care unit for respiratory failure, ARDS or sepsis with evidence of CMBs on magnetic resonance imaging were included for review following a systematic search across five databases (MEDLINE, Embase, CENTRAL, Scopus, and Web of Science) and a two-stage screening process. Studies were excluded if patients’ CMBs were clearly explained by another process of neurological injury.

Results

Forty-eight studies reporting on 216 critically ill patients (mean age 57.9, 18.4% female) with CMBs were included. Of 216, 197 (91.2%) patients developed respiratory failure or ARDS, 5 (2.3%) developed sepsis, and 14 (6.5%) developed both respiratory failure and sepsis. Of 211 with respiratory failure, 160 (75.8%) patients had Coronavirus Disease 2019 (COVID-19). The prevalence of CMBs among critically ill patients with respiratory failure or ARDS was 30.0% (111 of 370 patients in cohort studies). The corpus callosum and juxtacortical area were the most frequently involved sites for CMBs (64.8% and 41.7% of all 216 patients, respectively).

Functional outcomes were only reported in 48 patients, among whom 31 (64.6%) were independent at discharge, 4 (8.3%) were dependent at discharge, and 13 (27.1%) did not survive until discharge. Cognitive outcomes were only reported in 11 of 216 patients (5.1%), all of which showed cognitive deficits (9 patients with executive dysfunction, 2 patients with memory deficits).

Conclusions

CMBs are commonly reported in patients with critical illness due to respiratory failure, ARDS, or sepsis. CMBs had a predilection for the corpus callosum and juxtacortical area, which may be specific to critical illness-associated CMBs. Functional and cognitive outcomes of these lesions are largely unknown.
Genotypic and resistance profile analysis of two oat crown rust differential sets urge coordination and standardisation
Authors: Nguyen Duong T. , Henningsen Eva C. , Lewis David , Mago Rohit , McNeil Meredith , Suchecki Radoslaw , Boden Scott , Sperschneider Jana , Kianian Shahryar F. , Dodds Peter N. , Figueroa Melania
Published: September 2023

Puccinia coronataf. sp.avenae(Pca) is the causal agent of the disease known as crown rust which represents a bottleneck in oat production worldwide. Characterisation of pathogen populations often involves race (pathotype) assignments using differential sets, which are not uniform across countries. This study compared virulence profiles of 25Pcaisolates from Australia using two host differential sets, one from Australia and one from the USA. These differential sets were also genotyped using DArT sequencing technology. Phenotypic and genotypic discrepancies were detected on eight out of 29 common lines between the two sets, indicating that pathogen race assignments based on those lines are not comparable. To further investigate molecular markers that could assist in the stacking of rust resistance genes important for Australia, four publishedPc91-linked markers were validated across the differential sets and then screened across a collection of 150 oat cultivars. Drover, Aladdin, and Volta were identified as putative carriers of thePc91locus. This is the first report to confirm that the cultivar ‘Volta’ carriesPc91and demonstrates the value of implementing molecular markers to characterise materials in breeding pools of oat. Overall, our findings highlight the necessity of examining seed stocks using pedigree and molecular markers to ensure seed uniformity and bring robustness to surveillance methodologies.
ASSESSMENT OF STABILIZING FEEDBACK CONTROL OF WALKING, A TUTORIAL
Authors: van Dieën Jaap , Bruijn Sjoerd , Afschrift Maarten
Published: September 2023

Walking without falling requires stabilization of the trajectory of the body center of mass relative to the base of support. Model studies suggest that this requires active, feedback control, i.e., the nervous system must process sensory information on the state of the body to generate descending motor commands to the muscles to stabilize walking, especially in the mediolateral direction. Stabilization of bipedal gait is challenging and can be impaired in older and diseased individuals. In this tutorial, we illustrate how gait analysis can be used to assess the stabilizing feedback control of gait. We present methods ranging from those that require limited input data (e.g. position data of markers placed on the feet and pelvis only) to those that require full-body kinematics and electromyography. Analyses range from simple kinematics analyses to inverse dynamics. These methods assess stabilizing feedback control of human walking at three levels: 1) the level of center of mass movement and horizontal ground reaction forces, 2) the level of center of mass movement and foot placement and 3) the level of center of mass movement and the joint moments or muscle activity. We show how these can be calculated and provide a GitHub repository (https://github.com/VU-HMS/Tutorial-stabilizing-walking) which contains open access Matlab and Python code to calculate these. Finally, we discuss what information on feedback control can be learned from each of these.
Brainstem astrocytes regulate breathing and may affect arousal state in rats
Authors: Bishop Mitchell , SheikhBahei Shahriar
Published: September 2023

Variations in arousal levels can impact respiratory patterns. However, whether changes in breathing behaviors can influence arousal state is not fully understood. In this study, we investigated the role of astrocytes in the preBötzinger complex (preBötC) in modulating arousal states via breathing in adult conscious rats. Using viral vector tools, we selectively interfered with astrocytic signaling in the preBötC. Rats with inhibited astrocytic signaling exhibited slower breathing rates and behaviors indicative of a calmer state, whereas enhanced purinergic signaling in preBötC astrocytes led to faster breathing and heightened arousal. Our findings reveal a key role for astrocyte-mediated mechanism in the preBötC that influences both respiratory behaviors and higher-order brain functions like arousal, suggesting a bidirectional link between breathing behaviors and mental states.

Highlights

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In this study, we used molecular approaches to interfere with vesicular signaling in preBötC astrocytes.

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We showed that inhibiting vesicular release mechanisms in preBötC astrocytes are associated with calm behaviors: lower breathing and sigh rates, and longer sniffing time.

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We showed that enhancing vesicular release mechanisms in preBötC astrocytes are associated with more aroused behaviors: higher breathing and sigh rates as well as shorter sniffing time.
Clinal variation in drought response is consistent across life stages but not between native and non-native ranges
Authors: Nagy Dávid U. , Thoma Arpad E. , Al-Gharaibeh Mohammad , Callaway Ragan M. , Flory S. Luke , Frazee Lauren J. , Hartmann Matthias , Hensen Isabell , Jandová Kateřina , Khasa Damase P. , Lekberg Ylva , Pal Robert W. , Samartza Ioulietta , Shah Manzoor A. , Sheng Min , Slate Mandy , Stein Claudia , Tsunoda Tomonori , Rosche Christoph
Published: September 2023

Clinal variation, i.e., intraspecific variation that corresponds to environmental gradients, is common in widely distributed species. Studies on clinal variation across multiple ranges and life stages are lacking, but can enhance our understanding of specieś adaptive potential to abiotic environments and may aid in predicting future species distributions.

This study examined clinal variation in drought responses of 59Conyza canadensispopulations across large aridity gradients from the native and non-native ranges in three greenhouse studies. Experimental drought was applied to recruitment, juveniles, and adult stages.

Drought reduced growth at all three life stages. However, contrasting patterns of clinal variation emerged between the two ranges. Native populations from xeric habitats were less inhibited by drought than mesic populations, but such clinal variation was not apparent for non-native populations. These range-specific patterns of clinal variation were consistent across the life stages.

The experiments suggest that invaders may succeed without complete local adaptation to their new abiotic environments, and that long-established invaders may still be evolving to the abiotic environment. These findings may explain lag times in some invasions and raise concern about future expansions.
Plastic food packaging from five countries contains endocrine and metabolism disrupting chemicals
Authors: Stevens Sarah , Mcpartland Molly , Bartosova Zdenka , Skåland Hanna Sofie , Völker Johannes , Wagner Martin
Published: September 2023

Plastics are complex chemical mixtures of polymers and various intentionally and non-intentionally added substances. Despite the well-established links between certain plastic chemicals (bisphenols, phthalates) and adverse health effects, the composition and toxicity of real-world mixtures of plastic chemicals is not well understood. To assess both, we analyzed the chemicals from 36 plastic food contact articles from five countries using nontarget high-resolution mass spectrometry and reporter gene assays for four nuclear receptors that represent key components of the endocrine and metabolic system. We found that chemicals activating the pregnane X receptor (PXR), peroxisome proliferator receptor gamma (PPARγ), estrogen receptor alpha (ERα) and inhibiting the androgen receptor (AR) are prevalent in plastic packaging. We detected up to 9936 chemical features in a single product but found that each product has a rather unique chemical fingerprint. To tackle this chemical complexity, we used stepwise partial least squares regressions and prioritized and tentatively identified the chemical features associated with receptor activity. Our findings demonstrate that most plastic food packaging contains endocrine and metabolism disrupting chemicals. This shows that plastics are a relevant source of exposure to toxic chemicals and further supports the notion that plastic products designed for food contact cannot be considered safe.
Thermal environment and ecological interactions modulate the importance of evolution in response to warming
Authors: Faillace Cara A. , Álvarez-Codesal Soraya , Garreau Alexandre , Bestion Elvire , Montoya José M.
Published: September 2023

Understanding the interaction between evolutionary history, the current abiotic environment, and biotic interactions is critical for a more nuanced understanding of the response of communities to anthropogenic stressors. We leveraged a long term experiment manipulating temperature in mesocosms containing communities of phytoplankton and zooplankton to examine how evolution in response to long-term community warming affects consumer-resource dynamics at different temperatures. We showed that the evolution in response to warming depends on both the current thermal environment, as well as the presence of interactions between consumers and resources. We also demonstrated that evolution influences the outcomes of current ecological dynamics. For each consumer–resource pair, the effects of evolution were temperature-dependent, but both the effects and the temperature dependence itself additionally depended upon the identity of evolving species in each pair. Evolution resulted on a win-win situation for the first resource species: across all temperatures, this resource was more fit and the consumer was less successful, with fitness gains peaking at intermediate temperatures. For this resource species our results supported the “hotter is better” hypothesis, especially at moderate or intermediate temperatures, while “hotter is worse” for the consumer. In the second species pair, patterns were more complex. Warm-origin populations of both the second resource and the consumer generally failed to show improved fitness. Overall, our results show that evolution altered resource and consumer fitness, but these effects were dependent on the current combination of abiotic and biotic conditions.
Integrated organismal responses induced by ecologically-relevantpCO2and temperature exposures in developing lake sturgeon
Authors: Belding L. D. , Thorstensen M. J. , Quijada-Rodriguez A. R. , Bugg W. S. , Yoon G. R. , Loeppky A. R. , Allen G. J. P. , Schoen A. N. , Earhart M. L. , Brandt C. , Ali J. L. , Weihrauch D. , Jeffries K. M. , Anderson W. G.
Published: September 2023

Atmospheric CO2and temperature are rising concurrently, and may have profound impacts on the transcriptional, physiological, and behavioral responses of aquatic organisms. Further, spring snow melt may cause transient increases ofpCO2in freshwater systems. Lake sturgeon (Acipenser fulvescens) groups were raised in current and projected levels of warming andpCO2. Following an overwintering period, lake sturgeon were exposed to a transient increase inpCO2, simulating a spring melt. Diverging transcriptional patterns were found in each group and metabolic rate was lower in the combined stressor group compared to others. Behavioral assays revealed no effect of environment on alarm cue responses or boldness, but there was a decrease in total activity following an acute CO2exposure. These results demonstrate compensatory and compounding mechanisms ofpCO2and warming dependent on developmental conditions of a freshwater fish, and provide key information for responses to future climate change.
Transcriptome analysis in a humanized mouse model of familial dysautonomia reveals tissue-specific gene expression disruption in the peripheral nervous system
Authors: Harripaul Ricardo , Morini Elisabetta , Salani Monica , Logan Emily , Kirchner Emily , Bolduc Jessica , Chekuri Anil , Currall Benjamin , Yadav Rachita , Erdin Serkan , Talkowski Michael E. , Gao Dadi , Slaugenhaupt Susan
Published: September 2023

Familial dysautonomia (FD) is a rare recessive neurodevelopmental disease caused by a splice mutation in the Elongator acetyltransferase complex subunit 1 (ELP1) gene. This mutation results in a tissue-specific reduction of ELP1 protein, with the lowest levels in the central and peripheral nervous systems (CNS and PNS, respectively). FD patients exhibit complex neurological phenotypes due to the loss of sensory and autonomic neurons. Disease symptoms include decreased pain and temperature perception, impaired or absent myotatic reflexes, proprioceptive ataxia, and progressive retinal degeneration. While the involvement of the PNS in FD pathogenesis has been clearly recognized, the underlying mechanisms responsible for the preferential neuronal loss remain unknown. In this study, we aimed to elucidate the molecular mechanisms underlying FD by conducting a comprehensive transcriptome analysis of neuronal tissues from the phenotypic mouse modelTgFD9;Elp1Δ20/flox. This mouse recapitulates the same tissue-specificELP1mis-splicing observed in patients while modeling many of the disease manifestations. Comparison of FD and control transcriptomes from dorsal root ganglion (DRG), trigeminal ganglion (TG), medulla (MED), cortex, and spinal cord (SC) showed significantly more differentially expressed genes (DEGs) in the PNS than the CNS. We then identified genes that were tightly co-expressed and functionally dependent on the level of full-lengthELP1transcript. These genes, defined asELP1dose-responsive genes, were combined with the DEGs to generate tissue-specific dysregulated FD signature genes and networks. Within the PNS networks, we observed direct connections between Elp1 and genes involved in tRNA synthesis and genes related to amine metabolism and synaptic signaling. Importantly, transcriptomic dysregulation in PNS tissues exhibited enrichment for neuronal subtype markers associated with peptidergic nociceptors and myelinated sensory neurons, which are known to be affected in FD. In summary, this study has identified critical tissue-specific gene networks underlying the etiology of FD and provides new insights into the molecular basis of the disease.
Iron-sulfur cluster loss in mitochondrial CISD1 mediates PINK1 loss-of-function phenotypes
Authors: Bitar Sara , Baumann Timo , Weber Christopher , Abusaada Majd , Rojas-Charry Liliana , Ziegler Patrick , Schettgen Thomas , Randerath Isabella Eva , Venkataramani Vivek , Michalke Bernhard , Hanschmann Eva-Maria , Arena Giuseppe , Krüger Rejko , Zhang Li , Methner Axel
Published: September 2023

Parkinson’s disease (PD) is characterized by the progressive loss of dopaminergic neurons in the substantia nigra of the midbrain. Familial cases of PD are often caused by mutations of PTEN-induced kinase 1 (PINK1) and the ubiquitin ligase Parkin, both pivotal in maintaining mitochondrial quality control. CISD1, a homodimeric mitochondrial iron-sulfur-binding protein, is a major target of Parkin-mediated ubiquitination. We here discovered a heightened propensity of CISD1 to form dimers in Pink1 mutant flies and in dopaminergic neurons from PINK1 mutation patients. The dimer consists of two monomers that are covalently linked by a disulfide bridge. In this conformation CISD1 cannot coordinate the iron-sulfur cofactor. Overexpressing Cisd, the Drosophila orthologue of CISD1, and a mutant Cisd incapable of binding the iron-sulfur cluster in Drosophila reduced climbing ability and lifespan. This was more pronounced with mutant Cisd and aggravated in Pink1 mutant flies. Complete loss of Cisd, in contrast, rescued all detrimental effects of Pink1 mutation on climbing ability, wing posture, dopamine levels, lifespan, and mitochondrial ultrastructure. Our results suggest that Cisd, probably iron-depleted Cisd, operates downstream of Pink1 shedding light on PD pathophysiology and implicating CISD1 as a potential therapeutic target.
A tipping point in West Antarctica in 2023’s circumpolar 5-sigma event? a glimpse from the emperor penguin’s perspective
Authors: Krüger Lucas , Vianna Juliana A. , Le Bohec Céline , Cárdenas César A.
Published: September 2023

Emperor penguins are one of the seabird species most vulnerable to climate change in Antarctica, as they depend on stable sea ice for breeding and molting. Recent extremes of warming have taken to the lowest records of sea ice in West Antarctica in 2022 and 2023, raising concerns to the extent that emperor penguins have been affected. We evaluated historical satellite data (1985-2022) of sea ice around the 10 emperor penguin breeding colonies, identified so far along the coast of the Amundsen and Bellingshausen Seas, and compared them to recent sea ice cover (2022-2023) to identify where and when critical thresholds of sea ice cover have been crossed. We found that the sea ice retreated below the critical thresholds in 2022-2023 during the chick-rearing and in some cases failed to return at the start of the following breeding season, hence likely affecting 9 of the 10 emperor penguin colonies in the region. This is an unprecedented climatic phenomena affecting breeding habitat of emperor penguin colonies over a large area, potentially affecting numerically important colonies in West Antarctica.
Label-free visualization and quantification of the drug-type-dependent response of tumor spheroids by dynamic optical coherence tomography
Authors: El-Sadek Ibrahim Abd , Morishita Rion , Mori Tomoko , Makita Shuichi , Mukherjee Pradipta , Matsusaka Satoshi , Yasuno Yoshiaki
Published: September 2023

We demonstrate label-free dynamic optical coherence tomography (D-OCT)-based visualization and quantitative assessment of patterns of tumor spheroid response to three anti-cancer drugs. The study involved treating human breast adenocarcinoma (MCF-7 cell-line) with paclitaxel (PTX), tamoxifen citrate (TAM), and doxorubicin (DOX) at concentrations of 0 (control), 0.1, 1, and 10 μM for 1, 3, and 6 days. In addition, fluorescence microscopy imaging was performed for reference. The D-OCT imaging was performed using a custom-built OCT device. Two algorithms, namely logarithmic intensity variance (LIV) and late OCT correlation decay speed (OCDSl) were used to visualize the tissue dynamics. The spheroids treated with 0.1 and 1 μM TAM appeared similar to the control spheroid, whereas those treated with 10 μM TAM had significant structural corruption and decreasing LIV and OCDSlover treatment time. The spheroids treated with PTX had decreasing volumes and decrease of LIV and OCDSlsignals over time at most PTX concentrations. The spheroids treated with DOX had decreasing and increasing volumes over time at DOX concentrations of 1 and 10 μM, respectively. Meanwhile, the LIV and OCDSlsignals decreased over treatment time at all DOX concentrations. The D-OCT, particularly OCDSl, patterns were consistent with the fluorescence microscopic patterns. The diversity in the structural and D-OCT results among the drug types and among the concentrations are explained by the mechanisms of the drugs. The presented results suggest that D-OCT is useful for evaluating the difference in the tumor spheroid response to different drugs and it can be a useful tool for anti-cancer drug testing.
Socially plastic responses in females are robust to evolutionary manipulations of adult sex ratio and adult nutrition
Authors: McConnell N , Haerty W , Gage MJG , Chapman T
Published: September 2023

Background

Socially plastic behaviours are widespread among animals and can have a significant impact on fitness. Here we investigated whether the socially plastic responses of femaleDrosophila melanogastercan evolve in predictable ways following long term manipulation of adult sex ratio and adult nutrient availability. Previous reports show that femaleD. melanogasterrespond plastically to their immediate same-sex social environment by altering their fecundity, laying fewer eggs after they mate if previously exposed to other females, Fecundity is also highly sensitive to a female’s immediate nutritional status, being significantly reduced when dietary protein in particular is scarce. On this basis, we predicted that an evolutionary history of exposure to variation in adult sex ratio and adult nutritional environment would select strongly upon a female’s plastic fecundity responses.

Results

We used females that had been drawn from replicated lines that had experienced an evolutionary history of male biased, female biased or equal adult sex ratios and either standard or low-quality adult nutrition. We tested the specific predictions that a history of elevated competition among females (in female-biased regimes) would select for increasingly sensitive plastic fecundity responses to the presence of conspecifics, and that these would be magnified under poor nutritional resource regimes. In contrast to the expectations, we found that the plastic responses in females were strikingly robust to perturbations of both sexual competition and nutrient availability and did not differ significantly across any of the evolutionary regimes. The lack of response is not explained by an insufficient strength of selection. For example, among females held in isolation prior to mating, we did observe significant evolutionary responses in virgin egg according to nutritional regime and in virgin egg retention to sex ratio regime.

Conclusion

The lack of variation in the existence and magnitude of predicted plasticity is consistent with the idea that the costs of maintaining fecundity plasticity in females are low, benefits high, and that plasticity itself can be hard wired.
Targeting lignocellulolytic gene clusters in novelTrichoderma atrovirideandTrichoderma harzianumstrains through Bac-guided analysis
Authors: Campiteli Paulo Henrique , Horta Maria Augusta , Rosolen Rafaela Rossi , Mendes Juliano Sales , da Silva Carla Cristina , Sforça Danilo , de Souza Anete Pereira
Published: September 2023

Lignocellulosic biomass is known as a challenging substrate for enzymatic hydrolysis, increasing the processing cost in biorefineries. In nature, filamentous fungi, including those of the genusTrichoderma, naturally degrade lignocellulose by using an arsenal of hydrolytic and oxidative enzymes that act synergistically with biomass degradation. This work explored the genome organization of target genes ofTrichoderma atrovirideandTrichoderma harzianumthat are able to promote hydrolysis by identifying regions enriched in degradative enzyme-encoding genes, namely, hydrolytic clusters. We employed bacterial artificial chromosome (BAC) methodology to target specific genomic regions to explore their genetic organization, proximal gene context, and gene expression under degradative conditions. Using this tool, it was possible to inspect the linear structure and expression data of target hydrolytic-rich genomic regions. The results offered a genomic perspective of the organization of genome regions related to carbohydrate metabolism, revealing novel genome regions and genes that are positively regulated during cellulose degradation and contributing to elucidating differences in gene organization amongTrichodermaspecies.

Highlights

High-quality genomic regions were selected using closely related species CAZyme targets.

RNA-seq data were used to quantify BAC genes expression.

Relevant regions were identified by combining functional and differential expression data.

Novel targets for future characterization identified via differential expression.
Toxin-Triggered Liposomes for the Controlled Release of Antibiotics to Treat Infections Associated with Gram-Negative Bacteria
Authors: Li Ziang , Baidoun Rani , Brown Angela C.
Published: September 2023

Antibiotic resistance has become an urgent threat to health care in recent years. The use of drug delivery systems provides advantages over conventional administration of antibiotics and can slow the development of antibiotic resistance. In the current study, we developed a toxin- triggered liposomal antibiotic delivery system, in which the drug release is enabled by the leukotoxin (LtxA) produced by the Gram-negative pathogen,Aggregatibacter actinomycetemcomitans. LtxA has previously been shown to mediate membrane disruption by promoting a lipid phase change in nonlamellar lipids, such as 1,2-dioleoyl-sn-glycero-3- phosphoethanolamine-N-methyl (N-methyl-DOPE). In addition, LtxA has been observed to bind strongly and nearly irreversibly to membranes containing large amounts of cholesterol. Here, we designed a liposomal delivery system composed of N-methyl-DOPE and cholesterol to take advantage of these interactions. Specifically, we hypothesized that liposomes composed of N- methyl-DOPE and cholesterol, encapsulating antibiotics, would be sensitive to LtxA, enabling controlled antibiotic release. We observed that liposomes composed of N-methyl-DOPE were sensitive to the presence of low concentrations of LtxA, and cholesterol increased the extent and kinetics of content release. The liposomes were stable under various storage conditions for at least 7 days. Finally, we showed that antibiotic release occurs selectively in the presence of an LtxA-producing strain ofA. actinomycetemcomitansbut not in the presence of a non-LtxA- expressing strain. Together, these results demonstrate that the designed liposomal vehicle enables toxin-triggered delivery of antibiotics to LtxA-producing strains ofA. actinomycetemcomitans.
The function of juvenile-adult transition axis in female sexual receptivity ofDrosophila melanogaster
Authors: Li Jing , Ning Chao , Liu Yaohua , Deng Bowen , Wang Bingcai , Shi Kai , Wang Rencong , Fang Ruixin , Zhou Chuan
Published: September 2023

Female sexual receptivity is essential for reproduction of a species. Neuropeptides play the main role in regulating female receptivity. However, whether neuropeptides regulate female sexual receptivity during the neurodevelopment is unknown. Here we found the peptide hormone prothoracicotropic hormone (PTTH), which belongs to the insect PG axis, negatively regulated virgin female receptivity through ecdysone during neurodevelopment inDrosophila melanogaster. We identified PTTH neurons as doublesex-positive neurons, they regulated virgin female receptivity before the metamorphosis during the 3rd-instar larval stage. PTTH deletion resulted in the increased EcR-A expression in the whole newly formed prepupae. Furthermore, the ecdysone receptor EcR-A in pC1 neurons positively regulated virgin female receptivity during metamorphosis. The decreased EcR-A in pC1 neurons induced abnormal morphological development of pC1 neurons without changing neural activity. Among all subtypes of pC1 neurons, the function of EcR-A in pC1b neurons was necessary for virgin female copulation rate. These suggested that the changes of synaptic connections between pC1b and other neurons decreased female copulation rate. Moreover, female receptivity significantly decreased when the expression of PTTH receptor Torso was reduced in pC1 neurons. This suggested that PTTH not only regulates female receptivity through ecdysone but also through affecting female receptivity associated neurons directly. The PG axis has similar functional strategy as the HPG axis in mammals to trigger the juvenile–adult transition. Our work suggests a general mechanism underlying which the neurodevelopment during maturation regulates female sexual receptivity.
GENERATION OF FUNCTIONAL NEURONS FROM ADULT HUMAN MUCOSAL OLFACTORY ENSHEATHING GLIA BY DIRECT LINEAGE CONVERSION
Authors: Portela-Lomba María , Simón Diana , Callejo-Móstoles Marta , de la Fuente Gemma , Fernández de Sevilla David , García-Escudero Vega , Moreno-Flores M. Teresa , Sierra Javier
Published: September 2023

A recent approach to promote central nervous system (CNS) regeneration after injury or disease is direct conversion of somatic cells to neurons. This is achieved by transduction of viral vectors that express neurogenic transcription factors. In this work we propose adult human mucosal olfactory ensheathing glia (hmOEG) as a candidate for direct reprogramming to neurons due to its accessibility and to its well-characterized neuro-regenerative capacity. After induction of hmOEG with the single neurogenic transcription factor NEUROD1, the cells under study exhibited morphological and immunolabeling neuronal features, fired action potentials and expressed glutamatergic and GABAergic markers. In addition, after engraftment of transduced hmOEG cells in mouse hippocampus, these cells showed specific neuronal labeling. Thereby, if we add to the neuro-regenerative capacity of hmOEG cultures the conversion to neurons of a fraction of their population through reprogramming techniques, the engraftment of hmOEG and hmOEG induced neurons could be a procedure to enhance neural repair after central nervous system injury.
Simulating Interclonal Interactions in Diffuse Large B-Cell Lymphoma
Authors: Ganesh Siddarth , Roth Charles M. , Parekkadan Biju
Published: September 2023

Diffuse large B-cell lymphoma (DLBCL) is one of the most common types of cancers, accounting for 37% of B-cell tumors globally. DLBCL is known to be a heterogeneous disease, resulting in variable clinical presentations and the development of drug resistance. One underexplored aspect of drug resistance is the evolving dynamics between parental and drug-resistant clones with the same microenvironment. In this work, the effects of interclonal interactions between two cell populations - one sensitive to treatment and another resistant to treatment - on tumor growth behaviors were explored through a mathematical model.In vitrocultures of mixed DLBCL populations demonstrated cooperative interactions and revealed the need for modifying the model to account for complex interactions. Multiple best-fit models derived fromin vitrodata indicated a difference in steady-state behaviors based on therapy administrations in simulations. The model and methods may serve as a tool in understanding the behaviors of heterogeneous tumors and in identifying the optimal therapeutic regimen to eliminate cancer cell populations using computer-guided simulations.

Importance

The cellular makeup of tumors can play a vital role in its growth and cancer development. In this work, two different types of cell populations of diffuse large B-cell lymphoma (DLBCL) were studied together to understand how they interact with each other in cultures. In mixed cultures, both types of cells cooperated with each other and increased their growth in complex manners. A mathematical model was created to simulate the growth behavior of mixed cultures. The model can potentially be used to predict future cell behavior and help in identifying more effective therapy regimens to maximize tumor cell reduction.
Comparative genomics of a novelErwiniaspecies associated with the Highland midge (Culicoides impunctatus)
Authors: Pilgrim Jack
Published: September 2023

2.

Erwinia(Enterobacterales: Erwiniaceae) are a group of cosmopolitan bacteria best known as the causative agents of various plant diseases. However, other species in the group have been found to play important roles as insect endosymbionts supplementing the diet of their hosts. Here, I describeCandidatusErwinia impunctatus (Erwimp) associated with the Highland midgeCulicoides impunctatus(Diptera: Ceratopogonidae), an abundant biting pest in the Scottish Highlands. The genome of this newErwiniaspecies was assembled using hybrid long and short read techniques, and a comparative analysis was undertaken with other members of the genus to understand its potential ecological niche and impact. Genome composition analysis revealed that Erwimp is similar to other endophytic and ectophytic species in the genus and is unlikely to be restricted to its insect host. Evidence for an additional plant host includes the presence of a carotenoid synthesis operon implicated as a virulence factor in plant-associated members in the sister genusPantoea. Unique features of Erwimp include several copies of intimin-like proteins which, along with signs of genome pseudogenization and a loss of certain metabolic pathways, suggests an element of host restriction seen elsewhere in the genus. Furthermore, a screening of individuals over two field seasons revealed the absence of the bacteria inC. impunctatusin the second year indicating this microbe-insect interaction is likely to be transient. These data suggest thatCulicoides impunctatusmay have an important role to play beyond a biting nuisance, as an insect vector transmitting Erwimp alongside any conferred impacts to surrounding biota.