bluuebunny/crossref_metadata_2025 huggingface dataset:
Review and analysis of history and utilization of pneumatic retinopexy after pneumatic retinopexy versus vitrectomy for the management of primary rhegmatogenous retinal detachment outcomes randomized trial (PIVOT)
Authors: Shah Serena , Chou Brandon , Patel Marissa , Watane Arjun , Shah Lea , Yannuzzi Nicolas , Sridhar Jayanth
Published: February 2024

Purpose of review

We describe the history and series results of pneumatic retinopexy (PnR)and provide an analysis of PnR utilization after publication of results of pneumatic retinopexy versus vitrectomy for the management of primary rhegmatogenous retinal detachment outcomes randomized trial (PIVOT).

Recent findings

No significant trends were found for average number of services (P = 0.153) of PnR after the publication of PIVOT results.

PnR is a rhegmatogenous retinal detachment (RRD) repair technique that was first described in the early 1900 s and has evolved over time to become a modern-day, minimally invasive, underutilized treatment option. Other repair techniques for RRD include scleral buckling and pars plana vitrectomy (PPV), which has been compared to the use of PnR in PIVOT. Results of PIVOT concluded that PnR offered superior visual acuity and noninferiority. PnR is underutilized in the United States even after publication of results of PIVOT deemed it a noninferior treatment. Lack of a significant increase in national utilization of PnR could be associated with multifactorial clinician, systems, and financial reasons in the real-world setting.
Dandy walker variant with agenesis of corpus callosum diagnosed late prenatally by fetal ultrasound: a case report
Authors: Paudel Sandip , Poudel Shree Krishna , Shah Ravi , Regmi Samiksha , Zoowa Ronit
Published: February 2024

Introduction and Importance:

Dandy walker variant is an intracranial disorder involving variable hypoplasia of cerebellar vermis without posterior fossa enlargement. An anomaly scan performed at mid second trimester has good sensitivity and specificity for detecting fetal congenital anomalies. Despite that, some cases like ours might go undiagnosed due to normal biometric parameters for that gestational age and may be detected later in intrauterine life.

Case Presentation:

A primi-gravid mother underwent sonographic evaluation at 20+4 weeks of gestation that revealed all fetal parameters within normal limits. Only at 30+2 weeks of gestation, a posterior fossa cyst communicating with forth ventricle was detected. Fetal MRI done at 8 days of life (DOL), confirmed these findings and diagnosis of Dandy Walker Variant with agenesis of corpus callosum was made.

Clinical Discussion:

Although the chances of a CNS anomaly is exceedingly low when fetal metrics like head circumference, atrial width and Cisterna Magna are within normal limits, some cases like ours may develop anomalies later in the intrauterine life which may lead to delayed diagnosis of the cases. Thorough performance of anomaly scan involving a multiplanar approach may help in prompt diagnosis of fetal anomalies.

Conclusion:

The risks of development of posterior fossa anomalies can exist even after second trimester scan, Clinicians should be aware of this possibility and assess the posterior fossa at repeat scans done later in intrauterine life. Early diagnosis can provide an option to couples of the termination of pregnancy which is complicated when detected later in the intrauterine life.
Surgical outcomes for carotid body tumor resection without preoperative embolization: A 10-year experience
Authors: Ridha Barzany , Aram Varin , Baram Aram , Hama Baqi Soren Younis , Yaldo Fitoon
Published: February 2024

Background:

Carotid body tumors (CBTs) are neoplasms originating from the paraganglionic cells of the carotid body. Excision is the main route of treatment. This study sought to assess the surgical outcomes of post-carotid body tumor resection without preoperative embolization and discern any underlying relationships between modified Shamblin classes (MSC) and related complications.

Methods:

A retrospective medical record review of prospectively collected data is performed at Sulaymaniyah Teaching Hospital between 2008 and 2019, for 54 patients. Pre and postsurgical variables such as comorbidities and complications were noted respectively.

Results:

Patient ages ranged between 26-60 years (x̄=40.06) with a minimal female predominance (57.4%). Complications included one minor stroke. MSC and postoperative complications were significantly related (P=<0.001). Our analyses also suggested a significant relationship between intraoperative blood loss and the incidence of postoperative complications (P=0.001, χ²=25). The MSC III subtype was significantly associated with intraoperative blood loss (P=0.000), length of stay (P=0.000), and operating time (P=0.001).

Conclusions:

Our study purports a strong relationship between greater MSC and complications of all types. As such, surgeons may benefit from preoperative strategies to minimize complications.
Unveiling the complexity of right middle lobe syndrome: a case series highlighting the association with asthma
Authors: Shhada Eman , Nahle Ali Alakbar , Hamdar Hussein , Jlailati Alaa , Jawad Ali , Nahle Zeinab , Ali Sawssan
Published: February 2024

Introduction and Importance:

Right middle lobe syndrome (MLS) is a rare lung disorder primarily affecting children with a history of asthma or atopy. It encompasses a range of pathological and clinical conditions, from recurrent collapses of the middle lobe to bronchiectasis. In this study, we present a case series featuring four individuals with MLS associated with asthma, aiming to deepen our understanding of this uncommon condition.

Case Presentation:

Four pediatric patients with right MLS exhibited symptoms of persistent cough, dyspnea, and recurrent asthma exacerbations. Radiographic evaluations confirmed features consistent with right MLS, and bronchoscopy revealed mucus plugs and edematous airways obstructing the right middle lobe bronchus. Treatment with bronchodilators, antibiotics, and corticosteroids led to symptom improvement and resolution of atelectasis.

Clinical Discussion:

MLS is a rare condition characterized by chronic collapse of the right middle lobe and bronchiectasis. It is challenging to diagnose MLS, but CT scans provide detailed lung images for confirmation. Treatment focuses on addressing the underlying cause, such as infections or mucus obstruction. Lobectomy may be considered in severe cases. This case series emphasizes the need for further research on MLS, as its rarity and characteristics remain unclear.

Conclusion:

Our cases exhibited obstructive MLS with and without asthma. Accurate diagnosis is challenging, requiring imaging techniques. MLS has clinical implications, particularly in asthma patients. Future studies should focus on understanding the etiology of non-obstructive MLS.
ctDNA predicts recurrence and survival in stage I and II HPV-associated head and neck cancer patients treated with surgery
Authors: Naegele Saskia , Das Dipon , Hirayama Shun , Shalhout Sophia Z. , Lee Hang , Richmon Jeremy D. , Faden Daniel L.
Published: February 2024

Human papillomavirus-associated oropharyngeal squamous cell carcinomas (HPV+OPSCC) release circulating tumor HPV DNA (ctHPVDNA) into the blood which we, and others, have shown is an accurate real-time biomarker of disease status. In a prior prospective observational trial of 34 patients with AJCC 8 stage I-II HPV+OPSCC treated with surgery, we reported that ctHPVDNA was rapidly cleared within hours of surgery in patients who underwent complete cancer extirpation, yet remained elevated in those with macroscopic residual disease. The primary outcomes of this study were to assess 2-year OS and RFS between patients with and without molecular residual disease (MRD) following completion of treatment in this prospective cohort. MRD was defined as persistent elevation of ctHPVDNA at two consecutive time points, without clinical evidence of disease. The secondary outcomes were 2-year OS and RFS between patients with and without detectable MRD after surgery. We observed that patients with MRD after treatment completion were more likely to recur compared to patients without MRD, while there was no difference in recurrence rates between patients with MRD and without MRD on postoperative day 1. OS did not significantly differ between patients with MRD after surgery or treatment completion compared to patients without MRD; however, time to death was significantly different between the groups in both settings, suggesting that with a larger sample size OS would differ significantly between the groups or that the impact of MRD detection on survival is time dependent.
A Qualitative Evidence Synthesis Exploring Caregiver Information Needs and Experiences Caring for a Child with Chronic Heart Failure
Authors: Cunningham Chentel , Schroeder Katie , Plesuk Tabatha , Conway Jennifer , Haykowsky Mark J , Scott Shannon D.
Published: February 2024

Aim: To synthesize qualitative studies relating to caregivers' information needs and experiences caring for a child with chronic heart failure. Background: Children with chronic heart failure (HF) place a considerable burden on healthcare systems each year and is associated with significant stress for caregivers. Despite substantial knowledge generation and implementation amongst healthcare providers in this field, knowledge translation strategies that target caregiver audiences have lagged. To date, little is known about what literature exists about caregiver's information needs and experiences caring for a child with HF. Design: Qualitative evidence synthesis Methods: Sandelowski and Barroso's Handbook for Synthesizing Qualitative Research guided our review, cross-referencing the ENTREQ statement to report our findings. With librarian guidance, seven databases were searched in November 2023. Search results were imported into Microsoft Excel from EndNote 21. Two independent reviewers (CC, KS), supervised by a senior author (SDS), conducted the initial title/abstract and secondary full-text screens. Results: One study met the inclusion criteria outlined in our synthesis, identifying three themes and ten subthemes. Our findings impeded the ability to conduct any analysis. Conclusion: This review was the first of its kind, looking to synthesize caregiver's information needs and experiences caring for a child with chronic HF. One article met the inclusion criteria. This synthesis highlights a significant knowledge gap in caregivers' experiences and information needs when caring for a child affected by chronic heart failure. This study emphasizes that previous educational tools were not designed using research evidence about parent experience. This also validates the critical need for qualitative interviews with parents about their information needs and experiences to provide more relevant and understandable information to parents in this difficult situation.
From Pre-test and Post-test Probabilities to Medical Decision Making
Authors: Nixon Michelle P. , Momotaz Farhani , Smith Claire , Smith Jeffrey S. , Sendak Mark , Polage Christopher , Silverman Justin D.
Published: February 2024

Background: A central goal of modern evidence-based medicine is the development of simple and easy to use tools that help clinicians integrate quantitative information into medical decision-making. The Bayesian Pre-test/Post-test Probability (BPP) framework is arguably the most well known of such tools and provides a formal approach to quantify diagnostic uncertainty given the result of a medical test or the presence of a clinical sign. Yet, clinical decision-making goes beyond quantifying diagnostic uncertainty and requires that that uncertainty be balanced against the various costs and benefits associated with each possible decision. Despite increasing attention in recent years, simple and flexible approaches to quantitative clinical decision-making have remained elusive. Methods: We extend the BPP framework using concepts of Bayesian Decision Theory. By integrating cost, we can expand the BPP framework to allow for clinical decision-making. Results: We develop a simple quantitative framework for binary clinical decisions (e.g., action/inaction, treat/no-treat, test/no-test). Letpbe the pre-test or post-test probability that a patient has disease. We show thatr^*=(1-p)/prepresents a critical value called a decision boundary. In terms of the relative cost of under- to over-acting,r^*represents the critical value at which action and inaction are equally optimal. We demonstrate how this decision boundary can be used at the bedside through case studies and as a research tool through a reanalysis of a recent study which found widespread misestimation of pre-test and post-test probabilities among clinicians. Conclusions: Our approach is so simple that it should be thought of as a core, yet previously overlooked, part of the BPP framework. Unlike prior approaches to quantitative clinical decision making, our approach requires little more than a hand-held calculator, is applicable in almost any setting where the BPP framework can be used, and excels in situations where the costs and benefits associated with a particular decision are patient specific and difficult to quantify.
Bone tracers for transthyretin amyloid cardiomyopathy: are [99mTc]Tc-DPD and [99mTc]Tc-HMDP truly equivalent?
Authors: Dubois Julien , Kucharczak Florentin , Mariano-Goulart Denis , Paunet Tom
Published: February 2024

Background

The management of transthyretin amyloid cardiomyopathy (ATTR-CM) has revolved around the scintigraphic diagnosis since the introduction of a specific treatment; however, the equivalency of the bone radiotracers remains unclear. This retrospective monocentric observational study compared [99mTc]Tc-3,3-diphosphono-1,2-propanodicarboxylic acid ([99mTc]Tc-DPD) and [99mTc]Tc-hydroxy-methylene diphosphonate ([99mTc]Tc-HMDP) for ATTR-CM diagnosis.

Methods

One hundred and twenty-nine patients who underwent single photon emission computed tomography (SPECT/CT) after intravenous injection of [99mTc]Tc-DPD or [99mTc]Tc-HMDP for ATTR-CM were included. The patients’ current visual Perugini grades were retrieved. Regions of interest (ROI) were measured on the heart (H) and on contralateral mediastinum (CM), and H/CM ratios were calculated.

Results

Although the distribution of quantitative assessments of heart to contralateral mediastinum ratios is wider with [99mTc]Tc-DPD, suggesting a trend towards improved diagnosis, no difference in Perugini grades was found between [99mTc]Tc-DPD or [99mTc]Tc-HMDP for the diagnosis of ATTR-CM in evocative/non-evocative conditions. There was no difference in ATTR-CM diagnosis between the 2 tracers with a threshold of 1.5 (p-value = 3.316*10−10for [99mTc]Tc-HMDP and p-value = 2.59*10−15for [99mTc]Tc-DPD).

Conclusions

We show in our local cohort that [99mTc]Tc-DPD and [99mTc]Tc-HMDP for amyloidosis diagnostic are equivalent for ATTR-CM diagnosis based on the Perugini grading scale. With [99mTc]Tc-DPD, a wider range of the H/CM ratio was noted, which may be considered as a better discrimination of the disease by this bone tracer. Additional research with a final diagnosis of the disease is necessary to evaluate the utility of this quantitative evaluation.
Phylogenomic and genomic analysis reveals unique and shared genetic signatures of Mycobacterium kansasii complex species
Authors: Machado Edson , Vasconcellos Sidra , Gomes Lia , Catanho Marcos , Ramos Jesus , de Carvalho Luciana , Goldenberg Telma , Dalcolmo Margareth , Redner Paulo , Caldas Paulo , Campos Carlos , Lourenco Maria Cristina , Lasunskaia Elena , Mussi Vinicius , Spinasse Lizania , Vinhas Solange , Rigouts Leen , Cogneau Sari , de Rijk Pim , Utpatel Christian , Kaustova Jarmila , van der Laan Tridia , de Neeling Han , Rastogi Nalin , Levina Klavdia , Kutt Marge , Mokrousov Igor , Zhuravlev Viacheslav , Makhado Ndivhu , Zolnir-Dovc Manca , Jankovic Vera , de Waard Jacobus , Sisco Maria , van Soolingen Dick , Niemann Stefan , de Jong Bouke C. , Meehan Conor J , Suffys Philip
Published: February 2024

Species belonging to the Mycobacterium kansasii complex (MKC) are frequently isolated from humans and the environment and can cause serious diseases. The most common MKC infections are caused by the species M. kansasii (stricto sensu), leading to tuberculosis-like disease. However, a broad spectrum of virulence, antimicrobial resistance and pathogenicity of these non-tuberculous mycobacteria (NTM) are observed across the MKC. Many genomic aspects of the MKC that relate to these broad phenotypes are not well elucidated. Here, we performed genomic analyses from a collection of 665 MKC strains, isolated from environmental, animal and human sources. We inferred the MKC pangenome, mobilome, resistome, virulome and defense systems and show that the MKC species harbors unique and shared genomic signatures. High frequency of presence of prophages and different types of defense systems was observed. We found that the M. kansasii species splits into four lineages, of which three are lowly represented and mainly in Brazil, while one lineage is dominant and globally spread. Moreover, we show that four sub-lineages of this most distributed M. kansasii lineage emerged during the 20th century. Further analysis of the M. kansasii genomes revealed almost 300 regions of difference contributing to genomic diversity, as well as fixed mutations that may explain the M. kansasii's increased virulence and drug resistance.
Community stability increases the predictability of microeukaryote community coalescence outcomes
Authors: Vass Máté , Székely Anna , Carlsson-Graner Ulla , Wikner Johan , Andersson Agneta
Published: February 2024

Mixing of entire microbial communities represents a frequent, yet understudied phenomenon. Here, we mimicked estuarine condition in a microcosm experiment by mixing a freshwater river community with a brackish sea community and assessed the effects of both environmental and community coalescences induced by varying mixing processes on microeukaryotic communities. Signs of shifted community composition of coalesced communities towards the sea parent community suggest asymmetrical community coalescence outcome, which, in addition, was generally less impacted by environmental coalescence. Diatoms were negatively impacted by coalescence, while fungi, ciliates, and cercozoans were promoted to varying extents, depending on the mixing ratios of the source (i.e., river or sea) communities. Community stability, inferred from community cohesion, suggests that the more stable parent community (i.e., community with greater negative cohesion attributed to competitive interactions) dominates the final, coalesced community, but the fate of its community members is influenced by mixing ratios and frequencies (i.e., one-time versus repeated coalescence). Generally, community coalescence increased alpha diversity and promoted competition from the introduction (or emergence) of additional (or rare) species. These competitive interactions in turn had community stabilizing effect as evidenced by the increased proportion of negative cohesion. Our study suggests that the predictability of coalescence outcomes was greater when the more stable parent community (i.e., sea microbes) dominated the final community and this predictability was further enhanced when communities collided repeatedly.
Experimental evolution for improved post-infection survival selects for increased disease resistance inDrosophila melanogaster
Authors: Basu Aabeer , Tekade Kimaya , Singh Aparajita , Das Paresh Nath , Prasad Nagaraj Guru
Published: February 2024

Disease resistance (defined as the host capacity to limit systemic infection intensity) and disease tolerance (defined as the host capacity to limit infection-induced damage) are two complementary defense strategies that help the hosts maximize their survival and fitness when infected with pathogens and parasites. In addition to the underlying physiological mechanisms, existing theory postulates that these two strategies differ in terms of the conditions under which each strategy evolves in host populations, their evolutionary dynamics, and the ecological and epidemiological consequences of their evolution. Here we explored if one or both of these strategies evolve when host populations are subjected to selection for increased post-infection survival. We experimentally evolvedDrosophila melanogasterpopulations, selecting for the flies that survived an infection with the entomopathogenEnterococcus faecalis, and found that the host populations evolved increased disease resistance in response. This was despite the physiological costs associated with increased resistance. We did not find evidence of any change in disease tolerance in the host populations. We have therefore demonstrated that in an experimental evolution set-up, where insect hosts must survive an infection with a pathogenic bacterium, the hosts evolve improved disease resistance but not disease tolerance.
Multi-ancestry polygenic risk scores using phylogenetic regularization
Authors: Layne Elliot , Zabad Shadi , Li Yue , Blanchette Mathieu
Published: February 2024

Accurately predicting phenotype using genotype across diverse ancestry groups remains a significant challenge in human genetics. Many state-of-the-art polygenic risk score models are known to have difficulty generalizing to genetic ancestries that are not well represented in their training set. To address this issue, we present a novel machine learning method for fitting genetic effect sizes across multiple ancestry groups simultaneously, while leveraging prior knowledge of the evolutionary relationships among them. We introduce DendroPRS, a machine learning model where SNP effect sizes are allowed to evolve along the branches of the phylogenetic tree capturing the relationship among populations. DendroPRS outperforms existing approaches at two important genotype-to-phenotype prediction tasks: expression QTL analysis and polygenic risk scores. We also demonstrate that our method can be useful for multi-ancestry modelling, both by fitting population-specific effect sizes and by more accurately accounting for covariate effects across groups. We additionally find a subset of genes where there is strong evidence that an ancestry-specific approach improves eQTL modelling.
A flow cytometry protocol for accurate and precise measurement of plant genome size using frozen material
Authors: Soni Abhishek , Constantin Lena , Furtado Agnelo , Henry Robert J
Published: February 2024

Flow cytometry is a technique widely applied to infer the ploidy and genome size of plant nuclei. The conventional approach of sample preparation, reliant on fresh plant material to release intact nuclei, requires protocol optimisation for application to many species. The approach often results in poor yields of nuclei, impeding the accurate measurement of genome size and confines the optimal resource allocation and efficiency in genome sequencing which relies on genome size estimation. Here, we present a novel method using frozen plant material that facilitates the release of intact nuclei for genome size estimation. Genome estimates from frozen material are similar to those from fresh material. Accurate and precise estimates can be made by complementing the fluorescence of frozen nuclei with histogram modelling and debris compensation algorithms. This method of nuclei isolation from frozen plant material for flow cytometry-based genome size estimations has special value in estimating the genome size of samples collected and frozen for use in plant genome sequencing. Plant material can be conveniently stored, resampled, and used for DNA or RNA extractions.

Highlight

Frozen leaf material can be used to isolate nuclei for the accurate estimation of genome size The method proved suitable for difficult samples and did not require specific optimization. The method was especially useful where plant material could not be immediately processed through flow cytometry and allowed the same sample to be used for genomes size estimation and genome sequencing.
Striatal Dopamine Can Enhance Learning, Both Fast and Slow, and Also Make it Cheaper
Authors: Westbrook Andrew , van den Bosch Ruben , Hofmans Lieke , Papadopetraki Danae , Maatta Jessica I , Collins Anne Gabrielle Eva , Frank Michael J. , Cools Roshan
Published: February 2024

Associations can be learned incrementally, via reinforcement learning (RL), or stored instantly in working memory (WM). While WM is fast, it is also capacity-limited and effortful. Striatal dopamine may promote RL plasticity, and WM, by facilitating updating and effort exertion. Yet, prior studies have failed to distinguish between dopamine's effects on RL versus WM. N = 100 participants completed a paradigm isolating these systems in a double-blind study measuring dopamine synthesis with [18F]-FDOPA imaging and manipulating dopamine with methylphenidate and sulpiride. Learning is enhanced among high synthesis capacity individuals and by methylphenidate, but impaired by sulpiride. Methylphenidate also blunts effort cost learning. Computational modeling reveals that individuals with high dopamine synthesis rely more on WM, while methylphenidate boosts their RL rates. The D2 antagonist sulpiride reduces accuracy due to diminished WM involvement and faster WM decay. We conclude that dopamine enhances both slow RL, and fast WM, by promoting plasticity and reducing effort sensitivity. These results also highlight the need to control for dopamine's effects on WM when testing its effects on RL.
Systemically targeting monocytic MDSCs using dendrimers and their cell-level biodistribution kinetics
Authors: Littrell Chad A. , Takacs Gregory P. , Sankara Chenikkayala Siva , Sherman Alexandra , Rubach Kai A. , Garcia Julia S. , Bell Coral , Harrison Jeffrey K. , Zhang Fan
Published: February 2024

The focus of nanoparticlesin vivotrafficking has been mostly on their tissue-level biodistribution and clearance. Recent progress in the nanomedicine field suggests that the targeting of nanoparticles to immune cells can be used to modulate the immune response and enhance therapeutic delivery to the diseased tissue. In the presence of tumor lesions, monocytic-myeloid-derived suppressor cells (M-MDSCs) expand significantly in the bone marrow, egress into peripheral blood, and traffic to the solid tumor, where they help maintain an immuno-suppressive tumor microenvironment. In this study, we investigated the interaction between PAMAM dendrimers and M-MDSCs in two murine models of glioblastoma, by examining the cell-level biodistribution kinetics of the systemically injected dendrimers. We found that M-MDSCs in the tumor and lymphoid organs can efficiently endocytose hydroxyl dendrimers. Interestingly, the trafficking of M-MDSCs from the bone marrow to the tumor contributed to the deposition of hydroxyl dendrimers in the tumor. M-MDSCs showed different capacities of endocytosing dendrimers of different functionalitiesin vivo. This differential uptake was mediated by the unique serum proteins associated with each dendrimer surface functionality. The results of this study set up the framework for developing dendrimer-based immunotherapy to target M-MDSCs for cancer treatment.
Genome-AC-GAN: Enhancing Synthetic Genotype Generation through Auxiliary Classification
Authors: Ahronoviz Shaked , Gronau Ilan
Published: February 2024

In recent years, there have been increasing attempts to develop computational methods for generating synthetic genomic data that aim to mimic real genomic datasets. Artificial genomes (AGs) generated by these methods have emerged as a promising potential solution for privacy concerns raised by public genomic datasets and as means to provide adequate representation of under-sampled populations. However, existing methods for generating AGs provide a very limited capability for faithfully capturing features of different sub-populations within a larger cohort. In this study, we propose a novel method called the Genome Auxiliary Classifier Generative Adversarial Network (Genome-AC-GAN), which generates AGs tailored to specific sub-populations. We conducted experiments to evaluate the performance of the Genome-AC-GAN and compare the AGs it generates with real genomic data as well as with AGs generated by previously published methods. The Genome-AC-GAN outperforms other methods and faithfully models population structure, which is not adequately captured by existing methods. We also demonstrate the use of AGs generated by the Genome-AC-GAN in augmentation of datasets used as training sets for classifying genomes into populations. These experiments demonstrate the benefits of AGs in enhancing classification accuracy, especially when dealing with under-sampled and closely related populations.
Modeling disease progression and placebo response in Huntington's Disease: Insights from Enroll-HD and GENERATION HD1 cohorts
Authors: Boareto Marcelo , Yamamoto Yumi , Long Jeffrey D , Sampaio Cristina , McColgan Peter , Diack Cheikh , Sanwald Ducray Patricia
Published: February 2024

Objective: The objective of this study was to quantify longitudinal changes in Unified Huntington's Disease Rating Scale (UHDRS) clinical scores and evaluate their susceptibility to placebo response, improving our understanding of disease progression and the ability to optimize clinical trials in Huntington's disease. Methods: We utilized data from the Enroll-HD and GENERATION HD1 placebo arm cohorts to model the natural history of the disease and placebo response for functional, motor and cognitive clinical scores. Baseline patient characteristics available in both cohorts were analyzed as potential predictors of progression rate. Results: We identified distinct trajectories for each clinical measurement throughout the course of the disease, with baseline characteristics serving as strong predictors of progression rate. Interestingly, we observed a weak correlation between progression rates among different endpoints, highlighting the need for careful selection of endpoints, as they may not have the same relevance for different patient populations. To quantify placebo response, we compared disease progression in the largest Huntington's clinical trial to date (GENERATION HD1 placebo arm) to the Enroll-HD cohort. We found a strong initial improvement in motor and cognitive scores in GENERATION HD1, which remained constant during the dosing period of the trial. We show that this initial improvement in motor and cognitive scores can be quantified, enabling the simulation of changes in endpoints in a placebo arm for distinct subpopulations. Interpretation: Our model successfully captures essential aspects of disease progression and placebo response in Huntington's disease, providing valuable guidance for the design and analysis of upcoming clinical trials.
Biological Factors Influencing Individual Responses to Propylene Oxide: A Systematic Review of Exogenous Exposure, Endogenous Production and Detoxification
Authors: Gabashvili Irene S.
Published: February 2024

Objective

This systematic review aims to synthesize current knowledge on Propylene Oxide (PO) in human exhaled breath, examining its presence across various biological matrices and exploring methodologies for its analysis. It seeks to elucidate the sources of PO in the human body and understand individual variability in detoxification processes.

Methods

A comprehensive literature search was conducted across 12 databases and specialized repositories, spanning over 10,000 publications without language restrictions until May 16, 2024. Seventeen AI tools were employed to enhance study identification and analysis, focusing on both direct mentions and indirect evidence of PO behavior and detection in the human body. Assessment tools for risk of bias included SYRCLE’s tool for animal studies, the Newcastle-Ottawa Scale for cohort and case-control studies, and the ROBINS-I tool for non-randomized studies. The selection process yielded 89 studies, encompassing a range of research types and species, supplemented by reviews, monographs, and editorials to provide a comprehensive overview.

Results

The search revealed limited direct evidence on PO concentrations in exhaled breath, with only one reference providing concrete data (0.083 ppb to 0.3 ppb following exposures to 10-25 ppm of propylene). A study of ours, published separately, indicated significantly higher PO concentrations (hundreds of ppb or even ppm) in individuals with environmental sensitivities. Numerous references offered indirect insights into PO’s persistence and detection in blood and urine. The review highlights the enzymes involved in PO metabolism, the evolution of analytical methodologies, and the challenges and potential of AI tools in systematic reviews.

Conclusions

The scarcity of direct evidence on PO in exhaled breath underscores a significant gap in the literature and existing databases. Directly and indirectly relevant sources indicate variability in environmental compound concentrations in exhaled breath, influenced by genetics, health status, metabolism, and the microbiome. The review emphasizes the difficulties in synthesizing data on PO effects due to heterogeneous inputs and complex exposure scenarios. It underscores the need for advanced AI capabilities in literature reviews to capture nuanced, indirect evidence more effectively and calls for targeted research and technological innovation in environmental health sciences. Enhancing AI tools to navigate scientific literature with greater efficacy can leverage PRISMA guidelines and diverse data sources to minimize bias and enhance reliability. This approach will aid in addressing the complex interplay of biological and environmental factors in PO metabolism and toxicity, ultimately improving risk assessments and intervention strategies.
Revealing nanoscale structure and interfaces of protein and polymer condensates via cryo-electron microscopy
Authors: RIZVI AOON , Favetta Bruna , Jaber Nora , Lee Yun-kyung , Jiang Jennifer , Idris Nehal , Schuster Benjamin S. , Dai Wei , Patterson Joseph P
Published: February 2024

Liquid-liquid phase separation (LLPS) is a ubiquitous demixing phenomenon observed in various molecular solutions, including in polymer and protein solutions. Demixing of solutions results in condensed, phase separated droplets which exhibit a range of liquid-like properties driven by transient intermolecular interactions. Understanding the organization within these condensates is crucial for deciphering their material properties and functions. This study introduces a streamlined methodology for imaging three different classes of condensates, proteins, complex coacervates, and non-ionic block copolymer coacervates, using cryo-electron microscopy (cryo-EM). The method involves initiating condensate formation on electron microscopy grids to control droplet size and stage in the phase separation process. Results from cryo-EM reveal distinct nanoscale networks and interfaces in the condensate samples. We further investigate these structures using cryo-electron tomography which provides 3D reconstructions, uncovering porous internal structures, unique core-shell morphologies, and inhomogeneities within the nanoscale organization of protein condensates. Comparison with dry-state transmission electron microscopy emphasizes the importance of preserving the hydrated structure for accurate structural analysis. We correlate the internal structure of condensates with their material properties by performing viscosity measurements that support that more viscous condensates exhibit denser internal assemblies. Our findings contribute to a comprehensive understanding of condensate structure and this streamlined methodology provides a versatile tool for exploring various phase-separated systems and their nanoscale structures.
Meiotic recombination in Leptosphaeria maculans favours the rise of transgressive isolates adapted to a nonhost species, Brassica carinata
Authors: Noah Julie M , Gorse Mathilde , Romain Carole-Anne , Gay Elise J , Rouxel Thierry , Balesdent Marie-Helene , Soyer Jessica L
Published: February 2024

Leptosphaeria maculans is one of the major fungal pathogens on oilseed rape (Brassica napus), causing stem canker disease. The closely related Brassica species Brassica nigra, Brassica juncea, and Brassica carinata display extreme resistance toward stem canker. In this study, we demonstrate the nonhost status of B. carinata toward L. maculans in France through field experiments and inoculations performed in controlled conditions. A few isolates moderately adapted to B. carinata, in controlled conditions, were recovered in the field on B. nigra leaves, allowing us to investigate the unusual B. carinata / L. maculans interactions using molecular, macroscopic, and microscopic analyses. A cross between a L. maculans isolate adapted to B. napus and an isolate moderately adapted to B. carinata allowed the generation, in the lab, of recombinant L. maculans strains better adapted to B. carinata than the natural parental isolate obtained from B. nigra, and highlighted the polygenic determinism of the adaptation of L. maculans to B. carinata and B. napus. This biological material will allow further investigation of the molecular determinants of the adaptation of L. maculans to nonhost species and elucidate the genetic resistance basis of B. carinata.
Fusion, fission, and scrambling of the bilaterian genome in Bryozoa
Authors: Lewin Thomas D. , Liao Isabel Jiah-Yih , Chen Mu-En , Bishop John D. D. , Holland Peter W. H. , Luo Yi-Jyun
Published: February 2024

Groups of orthologous genes are commonly found together on the same chromosome over vast evolutionary distances. This extensive physical gene linkage, known as macrosynteny, is seen between bilaterian phyla as divergent as Chordata, Echinodermata, Mollusca, and Nemertea. Here, we report a unique pattern of genome evolution in Bryozoa, an understudied phylum of colonial invertebrates. Using comparative genomics, we reconstruct the chromosomal evolutionary history of five bryozoans. Multiple ancient chromosome fusions followed by gene mixing led to the near-complete loss of bilaterian linkage groups in the ancestor of extant bryozoans. A second wave of rearrangements, including chromosome fission, then occurred independently in two bryozoan classes, further scrambling bryozoan genomes. We also discover at least five derived chromosomal fusion events shared between bryozoans and brachiopods, supporting the traditional but highly debated Lophophorata hypothesis. Finally, we show that chromosome fusion and fission processes led to the partitioning of genes from bryozoan Hox clusters onto multiple chromosomes. Our findings demonstrate that the canonical bilaterian genome structure has been lost across all studied representatives of an entire phylum; reveal that linkage group fission can occur very frequently in specific lineages; and provide a powerful source of phylogenetic information.
Predicting cell type-specific epigenomic profiles accounting for distal genetic effects
Authors: Murphy Alan E , Beardall William , Rei Marek , Phuycharoen Mike , Skene Nathan G
Published: February 2024

Understanding genetic variants effects on the epigenome is crucial for interpreting genome-wide association studies (GWAS) results, yet profiling these effects across the non-coding genome remains challenging due to the scalability limits of experimental methods. This necessitates accurate computational models. Existing machine learning approaches, while progressively improving, are confined to the cell types they were trained on, limiting their applicability. Here, we propose the development of a deep learning model, Enformer Celltyping, which can both incorporate distal effects of DNA interactions, up to 100,000 base-pairs away, and predict epigenetic signals in a cell type-agnostic fashion. We demonstrate that Enformer Celltypings predictions of the epigenome out-perform the current best-in-class approach, have strong performance in a range of different cell types and biological regions and generalise to cell types assayed independently of the original training set. Finally, we propose an approach to test epigenetic models performance on genetic variant effect predictions using regulatory quantitative trait loci mapping studies, highlighting Enformer Celltypings and other genomic deep learning models limitations for this task. Our work introduces a new, accurate model for cell type-agnostic histone mark predictions and highlights the benefit of transfer learning for more efficient model development for deep learning in genomics. We make our customisable and efficient transfer learning approach for Enformer available to the community.
Neutral transcriptome rewiring promotes QDR evolvability at the species level
Authors: Delplace Florent , Khafif Mehdi , Stam Remco , Barbacci Adelin , Raffaele Sylvain
Published: February 2024

Quantitative disease resistance (QDR) is an immune response limiting pathogen damage in plants. It involves transcriptomic reprogramming of numerous genes, each having a small contribution to plant immunity. Despite QDR broad-spectrum nature, the evolution of its underlying transcriptome reprogramming remains largely uncharacterized. Here, we analyzed global gene expression in response to the necrotrophic fungusSclerotinia sclerotiorumin 23Arabidopsis thalianaaccessions of diverse origin and contrasted QDR phenotype. Over half of the species pan-transcriptome displayed local responses toS. sclerotiorum, with global reprogramming patterns incongruent with accessions phylogeny. Due to frequent small-amplitude variations, only ∼11% of responsive genes were common across all accessions, defining a core transcriptome enriched in highly-responsive genes. Co-expression and correlation analyses showed that QDR phenotypes result from the integration of numerous genes expression. Promoter sequence comparisons revealed that variation in DNA-binding sites within cis-regulatory regions contributing to gene expression rewiring. Finally, transcriptome-phenotype maps revealed abundant neutral networks connecting diverse QDR transcriptomes with no loss of resistance, hallmarks of robust and evolvable traits. This navigability associated with regulatory variation in core genes highlights their role in QDR evolvability. This work provides insights into the evolution of complex immune responses, informing models for plant disease dynamics.

Classification: Biological Sciences, Plant Biology
Bottlebrush polyethylene glycol nanocarriers translocate across human airway epithelium via molecular architecture enhanced endocytosis
Authors: He Zhi-Jian , Huang Baiqiang , Cai Li-Heng
Published: February 2024

Pulmonary drug delivery is critical to the treatment of respiratory diseases. However, the human airway surface presents multiscale barriers to efficient drug delivery. Here we report a bottlebrush polyethylene glycol (PEG-BB) nanocarrier that can translocate across all barriers within the human airway surface. Guided by the molecular theory, we design a PEG-BB molecule consisting of a linear backbone densely grafted by many (∼1,000) low molecular weight (∼1000 g/mol) PEG chains; this results in a highly anisotropic, wormlike nanocarrier featuring a contour length of ∼250 nm, a cross-section of ∼20 nm, and a hydrodynamic diameter of ∼40 nm. Using the classic air-liquid-interface culture system to recapitulate essential biological features of the human airway surface, we show that PEG-BB rapidly penetrates through endogenous airway mucus and periciliary brush layer (mesh size of 20-40 nm) to be internalized by cells across the whole epithelium. By quantifying the cellular uptake of polymeric carriers of various molecular architectures and manipulating cell proliferation and endocytosis pathways, we show that the translocation of PEG-BB across the epithelium is driven by bottlebrush architecture enhanced endocytosis. Our results demonstrate that large, wormlike bottlebrush PEG polymers, if properly designed, can be used as a novel carrier for pulmonary and mucosal drug delivery.

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Enterobacterial repetitive intergenic consensus (ERIC)-PCR analysis as a trace for Burkholderia pseudomallei in Myanmar
Authors: Chantratita Narisara , Su Khine Khine , Tribuddharat Chanwit , Aung Nay Myo
Published: February 2024

Melioidosis is a potentially fatal disease caused by Burkholderia pseudomallei, which is endemic in Southeast Asia, including Myanmar. The typeability of enterobacterial repetitive intergenic consensus (ERIC)-PCR assessed for 21 B. pseudomallei, they used the results of sequence types (STs) of the multilocus sequence typing (MLST) method. Among 5 soil and 16 clinical B. pseudomallei isolates, the most significant bands were similar in position but different in minor band formation. ST 90 of two soil strains (Tontae_NMBP001 and Tontae_NMBP002) displayed the same ERIC banding pattern, while ST 56 of two clinical isolates (MMBP005 and MMBP010) from different regions exhibited a single type. The same ST found both clusters in the MLST method. The shared group STs showed four or three satellite variants in the MLST scheme. One novel studied ST (ST 1729) and regarded it as an out-group in the ERIC pattern. ERIC PCR demonstrated high discriminatory power, while MLST provided more discrimination for genetic diversity. MLST requires extensive sequencing and bioinformatics analysis, making it challenging to implement in resource-limited settings. More isolates are needed to validate these findings. Despite its limitations, ERIC PCR represents a valuable and cost-effective alternative to MLST for molecular typing of B. pseudomallei in resource-limited settings.
Open educational resources on how to conduct randomised clinical trials: a protocol for a landscape analysis
Authors: Boesen Kim , Klingenberg Sarah Louise , Gluud Christian
Published: February 2024

This is a protocol for the project entitled, “Open educational resources on how to conduct randomised clinical trials”.