bluuebunny/crossref_metadata_2025 huggingface dataset:
Factors Associated With Pelvic Organ Prolapse in Postmenopausal South Korean Women
Authors: Kim Tae-Ran , Jung Hee-Yeong , Kim Myoung-Hwan , Yuk Jin-Sung
Published: July 2024

Importance

This study identifies key risk factors for pelvic organ prolapse (POP) in Korean women, providing valuable insights for prevention and personalized care.

Objectives

The aim of this study was to identify risk factors for POP in Korean women.

Study Design

This retrospective case-control study analyzed 2003–2011 Korean health checkup data in postmenopausal women diagnosed with POP (cases) and age-matched controls without POP (1:4 ratio) to identify risk factors.

Results

Of 2,506,271 participants, 34,648 patients were selected for the POP group and 138,592 patients were selected for the control group. The risk of POP was found to be increased with overweight (body mass index, 23–24.9: odds ratio [OR], 1.146; 95% confidence interval [CI], 1.1–1.196; body mass index, 25–29.9: OR, 1.142; 95% CI, 1.097–1.189) and multiple childbirths (2 times: OR, 1.52; 95% CI, 1.39–1.653; ≥3: OR, 1.639; 95% CI, 1.493–1.8). The risk of POP was found to be decreased with smoking (OR, 0.769; 95% CI, 0.688–0.861), alcohol drinking (3–6/week: OR, 0.65; 95% CI, 0.557–0.758), and exercise (1–2/week: OR, 0.904; 95% CI, 0.862–0.947; 3–4/week: OR, 0.896; 95% CI, 0.844–0.951; 5–6/week: OR, 0.87; 95% CI, 0.788–0.96).

Conclusions

This study found that overweight and multiple childbirths were associated with an increased risk of POP. Smoking, alcohol drinking, and exercise reduced the risk of POP, but socioeconomic status, age at menarche, and age at menopause were not found to be associated with POP.
Atypical presentation of varicella-zoster virus reactivation in a lung transplant patient: a case report
Authors: Hoff Ingrid , Rath Eivind , Pena-Karan Slobodanka , Sivy Nginamau Elisabeth , Holm Are Martin , Thune Turid , Mustafa Tehmina
Published: July 2024

Background.Varicella-zoster virus (VZV) is a human neurotropic virus which commonly causes infection during childhood, presenting as chickenpox. Later in life it may reactivate as herpes zoster. We report a rare manifestation of reactivation of VZV infection presenting as cutaneous vasculitis and varicella pneumonia in a lung transplant recipient.

Case presentation.A 65-year-old man was lung transplanted bilaterally for emphysema and had repeated posttransplant chest infections and colonization withPseudomonas aeruginosa. Nine months post-transplant he presented with dyspnoea and a cutaneous vasculitis-like eruption with a predilection over face, thorax and distal extremities. Initially, VZV reactivation was not suspected due to absence of the typical vesicular eruptions. The diagnosis was confirmed by VZV PCR from the swabs of the ulcer after skin punch biopsy of a lesion and from bronchoalveolar lavage (BAL). The histology of skin biopsy demonstrated epithelial damage and vascular damage but no typical epithelial virus associated changes. The patient responded to antiviral therapy with total remission of rash and VZV DNA was finally not detectable from repeated BAL after 29 days of therapy. However, the pulmonary radiological features and dyspnoea persisted due to reasons possibly unrelated to the VZV infection.

Conclusion.Had it not been for the patient to mention the resemblance of the vasculitic rash with his primary VZV infection, the diagnosis would easily have been overlooked. In this case, the biopsy did not show typical histopathologic findings of VZV-vasculitis. What led the diagnosis was a PCR from the wound swab taken after the punch biopsy. This case serves as a reminder for atypical presentation of common conditions in immunosuppressed patients and that extensive diagnostic sampling may be warranted in this group.
Modulation of microglia activation after human donor retinal ganglion cell transplantation
Authors: Malechka Volha V. , Phay Monichan Hayes , Augustine Josy , Rivera John Dayron , Alt Clemens , Gregory-Ksander Meredith , Baranov Petr
Published: July 2024

Stem cell-derived retinal ganglion cell (RGC) transplantation therapy offers a promising avenue for restoring vision in patients with significant RGC loss. The major challenge in this therapeutic approach is ensuring the survival of transplanted human donor RGCs within the host retina. Previously, we demonstrated the pivotal role of host retinal microglia and macrophages in the acceptance and survival of human donor cells. This current study aimed to improve the survival and integration of human donor RGCs through modulation of the host retinal microglia. Pretreatment of human donor RGCs with annexin V and soluble FasL (sFasL) before transplantation significantly enhanced their acceptance and survival rate. Detailed analyses of the host mouse retina post- transplantation revealed morphological changes and activation patterns in microglia and macrophages. These findings indicate that sFasL and annexin V activate pro-survival pathways and foster a supportive environment for the acceptance and survival of transplanted human donor RGCs.
A computer vision-based approach for estimating carbon fluxes from sinking particles in the ocean
Authors: Amaral Vinícius J. , Durkin Colleen A.
Published: July 2024

The gravitational settling of organic particles in the ocean drives long term sequestration of carbon from surface waters to the deep ocean. Quantifying the magnitude of carbon sequestration flux at high spatiotemporal resolution is critical for monitoring the ocean’s ability to sequester carbon as ecological conditions change. Here, we propose a computer vision-based method for classifying images of sinking marine particles and using allometric relationships to estimate the amount of carbon that the particles transport to the deep ocean. We show that our method reduces the amount of time required by a human image annotator by at least 90% while producing ecologically- informed estimates of carbon flux that are comparable to estimates based on purely human review and chemical bulk carbon measurements. This method utilizes a human-in-the-loop domain adaptation approach to leverage images collected from previous sampling campaigns in classifying images from novel campaigns in the future. If used in conjunction with autonomous imaging platforms deployed throughout the world’s oceans, this method has the potential to provide estimates of carbon sequestration fluxes at high spatiotemporal resolution while facilitating an understanding of the ecological pathways that are most important in driving these fluxes.
Neural correlates of phenomenological attitude toward perceptual experience
Authors: Nishida Satoshi , Hamada Hiro Taiyo , Niikawa Takuya , Miyahara Katsunori
Published: July 2024

Phenomenology is one of the most promising approaches to study conscious experience. It holds that a rigorous study of conscious experience requires a transition in the subject from the “natural attitude” (NA) to the “phenomenological attitude” (PA). NA describes our ordinary stance, in which our attention is directed at external objects and events. PA is a distinctive, reflective stance in which our attention is directed at our conscious experience itself. Despite its theoretical importance in philosophy and science of consciousness, the neural mechanisms underlying PA remain unknown. To clarify this point, we developed a novel behavioral task in which participants alternate between NA and PA in relation to their stimulus-evoked subjective experiences. Participants are presented with two sentences and requested to identify the one that best captures their experience. These sentences are designed to induce either NA or PA. We found that participants had lower error rates but slower reaction times in the PA condition compared to the NA condition, suggesting a difference beyond task difficulty. Using fMRI, we also found that multivoxel activation patterns in the premotor cortex, posterior parietal cortex, supplementary motor area, and cerebellum successfully classified the task conditions. Furthermore, the activation strength in these regions was lower in the PA condition, indicating that PA depends on neural processes that suppress action-related information. These findings provide the first evidence for the neural signature of PA, contributing to a better understanding of phenomenological method and its underlying neural mechanisms.

Significance statement

Phenomenology is one of the most promising approaches to study conscious experience. A key step is a transition from the natural attitude (NA)—where our attention is directed at external objects and events—to the phenomenological attitude (PA)—where our attention is directed toward our conscious experience itself. However, the neural processes underlying PA remain unclear. This study aimed to clarify this point by analyzing fMRI signals measured during a cognitive task that forced participants to repeatedly alternate between NA and PA. We observed that multiple action-related brain regions exhibited different activation patterns between NA and PA. Our findings provide the first neuroscientific evidence that illuminates the core process of the phenomenological method.
Computational simulations ofPachycrocutabite damage based on a ∼1.2 Ma ravaged hippopotamus femur from Fuente Nueva 3 (Orce, Granada, Spain)
Authors: Courtenay Lloyd A. , Serrano-Ramos Alexia , Barsky Deborah , Jiménez-Arenas Juan-Manuel , Yravedra José
Published: July 2024

Understanding the behaviour and interactions of extinct carnivoran species present a significant challenge in archaeological and palaeontological research, often limited by numerous constraints in the fossil record. Here we analyse a hippopotamus femur consumed by an extinct species of giant hyena, recovered from the open-air site Fuente Nueva 3 (∼1.2 Ma, Orce, Granada, Spain). Leveraging the use of advanced microscopic techniques to digitise the tooth marks observed on this specimen in three dimensions, the present study utilises artificially intelligent algorithms to then simulate the possible morphological variability of this carnivoran. This allows us to characterisePachycrocuta brevirostristooth pit morphology, so as to construct a diagnostic reference sample of this species. Our findings underscore the importance tooth mark size has on identifying the activity ofPachycrocuta, revealing the giant hyena to have produced remarkably large, deep, and circular tooth pits on dense cortical bone.
Hotspot of Exotic Benthic Marine Invertebrates Discovered in the Tropical East Atlantic: DNA Barcoding Insights from the Bijagós Archipelago, Guinea-Bissau
Authors: Moura Carlos J. , Wirtz Peter , Nhanquê Filipe T. , Barbosa Castro , Serrão Ester
Published: July 2024

Aim

This study aimed to explore and document putative exotic marine benthic invertebrate species in the Bijagós Archipelago, Guinea-Bissau, to enhance understanding of marine biodiversity and address the extent of marine species introductions.

Location

The research was conducted in the Bijagós Archipelago, a UNESCO Biosphere Reserve located in Guinea-Bissau.

Methods

The study involved the region’s first scuba-diving survey of marine biodiversity. DNA barcoding was employed to assist in the identification of benthic invertebrate species. Molecular phylogenetic analyses were conducted with the available DNA barcodes to ensure accurate taxonomic assignments, detect cryptic species, and investigate the phylogeography of the taxa.

Results

The survey resulted in the discovery of 28 new species records for the Bijagós Archipelago, including octocorals, scleractinians, hydroids, bryozoans, barnacles, and ascidians. Among these, seven species were documented for the first time in the East Atlantic:Stragulum bicolor,Tubastraea tagusensis,Nemalecium lighti,Diphasiasp.,Amathia alternata,A. distans, andSymplegma rubra. Molecular analyses revealed pervasive cryptic diversity within species previously listed as exotic, suggesting that some, such as the hydroidsPlumularia setacea,Obelia geniculata, andDynamena disticha, are not exotic due to their restricted biogeographic distributions. Many other species reported as introduced present only a few genetic lineages capable of long-distance dispersal due to human activities.

Main Conclusions

The study highlights considerable gaps in the knowledge of West African marine biodiversity and suggests a substantial underestimation of the anthropogenic trade in exotic marine species between the Tropical East Atlantic and the Americas, and between the Indo-Pacific and West Africa. Detailed taxonomic and genomic analyses are necessary for understanding marine exotic species’ biogeography and adaptive traits. Our findings challenge current classifications of exotic species and underscore the need for improved monitoring and management to prevent the spread of non-native marine species.
Accelerated Missense Mutation Identification in Intrinsically Disordered Proteins using Deep Learning
Authors: Seth Swarnadeep , Bhattacharya Aniket
Published: July 2024

We use a combination of Brownian dynamics (BD) simulation results and Deep Learning (DL) strategies for rapid identification of large structural changes caused by missense mutations in intrinsically disordered proteins (IDPs). 2000 IDP sequences from DisProt database of length 20 −300 are used to obtain gyration radii from BD simulation on a coarse-grained single bead amino acid model (HPS model) used by us and others [Sethet al. J. Chem. Phys.160, 014902 (2024), Dignonet al. PLOS Comp. Biology, 14, 2018, Teseiet al. PNAS, 118, 2021] to generate the training sets for the DL algorithm. Using the gyration radii ⟨Rg⟩ of the simulated IDPs as the training set, we develop a multilayer perceptron neural net (NN) architecture that predicts the gyration radii of 33 IDPs previously studied using BD simulation with 95% accuracy from the sequence and the corresponding parameters from the HPS model. We now utilize this NN to predict gyration radii of every permutation of missense mutations in IDPs. Our approach successfully identifies mutation-prone regions that induce significant alterations in the radius of gyration when compared to the wild-type IDP sequence. We further validate the prediction by running BD simulations on the subset of identified mutants. The neural network yields a (104− 105)-fold faster computation in the search space for potentially harmful mutations. Our findings have substantial implications for rapid identification and understanding diseases related to missense mutations in IDPs and for the development of potential therapeutic interventions. The method can be extended to accurate predictions of other mutation effects in disordered proteins.
Synchronous assembly of peptide anisosome
Authors: Zhou Laicheng , Zhu Longcheng , Wang Cong , Xu Tengyan , Wang Jing , Zhang Bin , Zhang Xin , Wang Huaimin
Published: July 2024

Biomolecular condensates, formed by liquid-liquid phase separation (LLPS) of proteins or the complex of protein and nucleic acids, play key roles in regulating physiological events in biological system. However, the formation of mono-component yet inhomogeneous condensates is limited, and the underlying mechanism remains unclear. Here, we report the symmetrical core-shell structural biomolecular condensates formed through the LLPS by programming a tetra-peptide library. Mechanistic studies reveal that the tryptophan (W) is critical for the formation of core-shell structure because of its stronger homotypical π-π interaction compared with other amino acids, which endow us to modulate the droplets from core-shell to homogeneous structures by encoding the amino acid composition. Using molecular dynamics (MD) simulation and molecular engineering, we find that the inner core of LLPS is composed of dynamic and reversible fibers surrounded by liquid-like shells, resulting in a stable core-shell LLPS. Furthermore, we could control the multiphasic droplet formation by an intrinsic redox reaction or post-translational modification of peptide through phosphorylation, which facilitates the rational design of synthetic LLPS with various applications on demand.
Dihydromyricetin alleviated the damage of hypoxia-induced mouse neurons by reducing ROS levels and inhibiting the expression of PAR and γH2AX
Authors: Du Xueping , Guo Yanjun , Yang Junzheng
Published: July 2024

Objective

To investigate the effect of dihydromyricetin on hypoxia-induced neurons, to understand the effect of dihydromyricetin on hypoxic-ischemic encephalopathy (HIE).

Methods

Cortical neurons were isolated from C57BL/6j mice (24 hour-year old), cultured, and subjected to 4h hypoxia and 20h reoxygenation to mimic the neonatal hypoxic-ischemic encephalopathy. After dihydromyricetin (20μmol/L) treatment of hypoxia-induced neurons for 2h, CCK-8 assay was used to analyze the neuronal viability, Hoechst33342/PI double staining assay was used to analyze the neuronal death, Western blotting was used to analyze the expression of Poly ADP-ribose (PAR) polymer protein andγH2AX, comet assay was used to detect DNA damage, immunofluorescence staining was used to observe the nuclear translocation of apoptosis inducing factor, and 2’,7’-dichlorodihydrofluorescein diacetate was used to detect the expression of reactive oxygen species (ROS).

Results

Compared with the control groups, hypoxia-treated neurons exhibited significantly lower activity, higher neuronal death rate and the high expressions of PAR andγH2AX, hypoxia could also induce AIF nuclear translocation, increase tail DNA content and tail length, increase the expression of ROS in neurons; after dihydromyricetin treatment, neuronal activity were significantly increased, neuronal death rate, ROS levels, and the expressions of PAR andγH2AX were also decreased, AIF nuclear translocation was inhibited, the tail DNA content and tail length were also decreased.

Conclusion

Dihydromyricetin could alleviate the damage of hypoxia-induced neurons through decreasing the levels of ROS and inhibiting the expressions of PAR andγH2AX, suggesting that dihydromyricetin may have the protective effect on HIE.
Identification of the sequences responsible for maternalH19-ICR hypermethylation with Beckwith-Wiedemann syndrome-like overgrowth in mice
Authors: Hara Satoshi , Matsuhisa Fumikazu , Kitajima Shuji , Yatsuki Hitomi , Kubiura-Ichimaru Musashi , Soejima Hidenobu
Published: July 2024

Beckwith-Wiedemann syndrome (BWS) is caused by a gain of methylation (GOM) at the imprinting control region within theIgf2-H19domain on the maternal allele (H19-ICR GOM). Mutations in the binding sites of several transcription factors are involved inH19-ICR GOM and BWS. However, the responsible sequence(s) forH19-ICR GOM with BWS-like overgrowth has not been identified in mice. Here, we report that a mutation in the SOX-OCT binding site (SOBS) causes partialH19-ICR GOM, which does not extend beyond CTCF binding site 3 (CTS3). Moreover, simultaneously mutating both SOBS and CTS3 causes complete GOM of the entireH19-ICR, leading to the misexpression of the imprinted genes, and frequent BWS-like overgrowth. In addition, CTS3 is critical for CTCF/cohesin-mediated chromatin conformation. These results indicate that SOBS and CTS3 are the sequences responsible forH19-ICR GOM leading to BWS-like overgrowth and are essential for maintaining the unmethylated state of maternalH19-ICR.
Hippocampal-prefrontal communication subspaces align with behavioral and network patterns in a spatial memory task
Authors: Young Ryan A. , Shin Justin D. , Guo Ziyi , Jadhav Shantanu P.
Published: July 2024

Rhythmic network states have been theorized to facilitate communication between brain regions, but how these oscillations influence communication subspaces, i.e, the low-dimensional neural activity patterns that mediate inter-regional communication, and in turn how subspaces impact behavior remains unclear. Using a spatial memory task in rats, we simultaneously recorded ensembles from hippocampal CA1 and the prefrontal cortex (PFC) to address this question. We found that task behaviors best aligned with low-dimensional, shared subspaces between these regions, rather than local activity in either region. Critically, both network oscillations and speed modulated the structure and performance of this communication subspace. Contrary to expectations, theta coherence did not better predict CA1-PFC shared activity, while theta power played a more significant role. To understand the communication space, we visualized shared CA1-PFC communication geometry using manifold techniques and found ring-like structures. We hypothesize that these shared activity manifolds are utilized to mediate the task behavior. These findings suggest that memory-guided behaviors are driven by shared CA1-PFC interactions that are dynamically modulated by oscillatory states, offering a novel perspective on the interplay between rhythms and behaviorally relevant neural communication.
Elucidating Interactome Dynamics of the A2A Adenosine Receptor
Authors: Lee Wonseok , Son Ahrum , Kim Woojin , Park Jongham , Cho Ja-Young , Kim Ju-Won , Kim Young-Ok , Kong Hee Jeong , Kim Hyunsoo
Published: July 2024

Polydeoxyribonucleotide (PDRN) is a tissue regeneration substance that resembles human DNA and is present in human cells, mullets, salmons, and flatfish. It stimulates physiological regeneration and metabolic activity. The regenerative and metabolic effects of PDRN are attributed to the activation of Adenosine A2A receptors (ADORA2A), which increases the production of angiogenesis factors and growth factors. Activation of ADORA2A leads to the activation of ADORA2A-interacting proteins with similar functions. To investigate the changes and dynamics of proteins in the presence of PDRN, we conducted selected reaction monitoring-mass spectrometry (SRM-MS) to quantify 491 proteins, 3,852 peptides. Through peptide-level analysis, we founded 374 proteins and 1,193 peptides demonstrating both up-regulation and down-regulation in expression. We conducted gene ontology (GO) analysis and physical network analysis and discovered a novel network of proteins related to neuronal differentiation among the ADORA2A-interacting protein. Based on network analysis, we found indirect interactions with MAPK1 and MP2K1, which are known to influence neuronal cell differentiation and suggest the formation of a network involving MAPK signaling transduction. Finally, using AlphaFold multimer, we were able to predict interaction sites among ADORA2A-interacting proteins in the network associated with neuronal cell differentiation. Specifically, we predicted five interaction sites between ADORA2A and NTRK1 (which interacts with ADORA2A), forming the edge. Thus, we provided indicators for further research using ADORA2A present in robust network and highlighted the potential of PDRN to impact neuronal differentiation.
50 years of antibody numbering schemes: a statistical and structural evaluation reveals key differences and limitations
Authors: Zhu Zirui , Olson Katherine S. , Magliery Thomas J.
Published: July 2024

The complementarity determining region (CDR) of antibodies represents the most diverse region both in terms of sequence and structural characteristics, playing the most critical role in antibody recognition and binding for immune responses. Over the past decades, several numbering schemes have been introduced to define CDRs based on sequence. However, the existence of diverse numbering schemes has led to potential confusion, and a comprehensive evaluation of these schemes is lacking. We employ statistical analyses to quantify the diversity of CDRs compared to the framework regions. Comparative analyses across different numbering schemes demonstrates notable variations in CDR definitions. The Kabat and AbM numbering schemes tend to incorporate more conserved residues into their CDR definitions, whereas CDRs defined by the Chothia and IMGT numbering schemes display greater diversity, sometimes missing certain loop residues. Notably, we identify a critical residue, L29, within the kappa light chain CDR1, which appears to act as a pivotal structural point within the loop. In contrast, most numbering schemes designate the topological equivalent point in the lambda light chain as L30, suggesting the need for further refinement in the current numbering schemes. These findings shed light on regional sequence and structural conservation within antibody sequence databases while also highlighting discrepancies stemming from different numbering schemes. These insights yield valuable guidelines for the precise delineation of antibody CDRs and the strategic design of antibody repertoires, with practical implications in developing innovative antibody-based therapeutics and diagnostics.

GRAPHIC ABSTRACT

HIGHLIGHTS

Amino acid distribution analysis conducted on 124,317 sequences archived in the abYsis database showed lower conservation among CDR residues, as defined by Kabat numbering, compared to the framework region.

Both LCDR3 and HCDR3 exhibited particularly high levels of diversity compared to the other four CDR loops, highlighting additional functional roles of the CDR3 loops relative to the others.

Two distinct residues, L29 and H30, displayed highly conserved hydrophobic side chain characteristics and played unique conformational roles within the CDR1 loop, contributing to the formation of an ‘M-shaped’ structure. This residue divides the C-terminus CDR1 loop, which was observed to be less conserved and have greater length diversity, and the N-terminus CRD1 loop.

The Kabat numbering scheme appears to overestimate the LCDR2 and HCDR2 loops and underestimate HCDR1, only encompassing the C-terminal loop of the ‘M-shaped’ CDR1 loop.

Structural analysis revealed that a residue within LCDR1 was numbered differently in the two subtypes (kappa and lambda) of the variable light domain. This discrepancy suggests the need for further refinement in the current major numbering schemes.
Large Language Models in Pathology: A Comparative Study of ChatGPT and Bard with Pathology Trainees on Multiple-Choice Questions
Authors: Du Wei , Jin Xueting , Harris Jaryse Carol , Brunetti Alessandro , Johnson Erika , Leung Olivia , Li Xingchen , Walle Selemon , Yu Qing , Zhou Xiao , Bian Fang , McKenzie Kajanna , Kanathanavanich Manita , Ozcelik Yusuf , El-Sharkawy Farah , Koga Shunsuke
Published: July 2024

Large language models (LLMs), such as ChatGPT and Bard, have shown potential in various medical applications. This study aimed to evaluate the performance of LLMs, specifically ChatGPT and Bard, in pathology by comparing their performance with those of pathology trainees, and to assess the consistency of their responses. We selected 150 multiple-choice questions from 15 subspecialties, excluding those with images. Both ChatGPT and Bard were tested on these questions across three separate sessions between June 2023 and January January 2024, and their responses were compared with those of 14 pathology trainees (8 junior and 6 senior) from two hospitals. Questions were categorized into easy, intermediate, and difficult based on trainee performance. Consistency and variability in LLM responses were analyzed across three evaluation sessions. ChatGPT significantly outperformed Bard and trainees, achieving an average total score of 82.2% compared to Bard’s 49.5%, junior trainees’ 45.1%, and senior trainees’ 58.3%. ChatGPT’s performance was notably stronger in difficult questions (61.8%-70.6%) compared to Bard (29.4%-32.4%) and trainees (5.9%-44.1%). For easy questions, ChatGPT (88.9%-94.4%) and trainees (75.0%-100.0%) showed similar high scores. Consistency analysis revealed that ChatGPT showed a high consistency rate of 80%-85% across three tests, whereas Bard exhibited greater variability with consistency rates of 54%-61%. ChatGPT consistently outperformed Bard and trainees, especially on difficult questions. While LLMs show significant promise in pathology education and practice, continued development and human oversight are crucial for reliable clinical application.
Genomic characterization of Dengue virus circulation in Ethiopia
Authors: Abera Adugna , Tegally Houriiyah , Tasew Geremew , Wilkinson Eduan , Ali Abraham , Regasa Feyisa , Bitew Molalegne , Chabuka Lucious , Mwanyika Gaspary , Tshiabuila Derek , Giandhari Jennifer , Pillay Sureshnee , Poogavanan Jenicca , Moir Monika , Kraemer Moritz U.G. , Khan Kamran , Huber Carmen , Tollera Getachew , Wit Tobias F. Rinke de , Baxter Cheryl , Lessells Richard , Wolday Dawit , Beyene Dereje , de Oliveira Tulio ,   CLIMADE Consortium
Published: July 2024

In Ethiopia, dengue virus (DENV) infections have been reported in several regions, however, little is known about the circulating genetic diversity. Here, we conducted clinical surveillance for DENV during the 2023 nationwide outbreak and sequenced DENV whole genomes for the first time in Ethiopia. We enrolled patients at three sentinel hospital sites. Using RT-PCR, we screened serum samples for three arboviruses followed by serotyping and sequencing for DENV-positive samples (10.4% of samples). We detected two DENV serotypes (DENV1 and DENV3). Phylogenetic analysis identified one transmission cluster of DENV1 (genotype III major lineage A), and two clusters of DENV3 (genotype III major lineage B). The first showed close evolutionary relationship to the 2023 Italian outbreak and the second cluster to Indian isolates. Co-circulation of DENV1 and DENV3 in some regions of Ethiopia highlights the potential for severe dengue. Intensified surveillance and coordinated public health response are needed to address the threat of severe dengue outbreaks.
The incidence and prevalence of Dupuytren’s disease in primary care: Results from a text mining approach on registration data
Authors: van Straalen Roel J. M. , de Boer Michiel R. , Vos Francine , Werker Paul M. N. , Broekstra Dieuwke C.
Published: July 2024

Background

The focus of research and management of Dupuytren’s disease (DD) is shifting from relieving symptoms in the later stages of disease towards the prevention of contractures. Treatment services might likewise shift towards primary care. Studying characteristics of DD patients who seek medical care for the first time, may identify a symptomatic target group for early DD treatments. We present the first study that estimates the incidence and prevalence of DD in primary care by applying a text-mining algorithm to registration data.

Methods

This is a population-based cohort study using electronic health records from Dutch general practices involved in a regional research network. Descriptive statistics were used to describe sex, age, comorbidities and lifestyle factors, the latter two were identified via International Classification of Primary Care (ICPC) codes. Incidence rate was calculated as number of patients with a first contact for DD/1000 person years for the years 2017 to 2021, point prevalence as the percentage of patients with a contact for DD in 2021. DD contacts were identified using a text-mining algorithm.

Results

The incidence ranged between 1.41 to 1.72/1000 person years and the overall prevalence was 1.99%. Incidence and prevalence are higher among males and increase with age, peaking between 61 to 80 years.

Conclusions

Our results of prevalence and incidence of DD in primary care give an insight into the relevant population of patients with symptomatic DD that might be the future target group for potential disease controlling treatments.
The telemedical platform MyaLink for remote monitoring in myasthenia gravis: Rationale and protocol for a proof of concept study
Authors: Stein Maike , Meisel Andreas , Moench Maximilian , Narayanaswami Pushpa , Sun Haoqi , Herdick Meret , Gerischer Lea , Lehnerer Sophie
Published: July 2024

Rationale: Myasthenia gravis (MG) is a rare, chronic neurological disorder leading to fluctuating muscle weakness and potentially life-threatening crises. Patients often require life-long specialized treatment, but timely interventions are frequently hindered by the limited availability of specialists. Telemedical solutions at specialized centers enabling patient-physician interaction hold promise in bridging this gap, but are not yet available for MG. We developed 'MyaLink,' a remote monitoring platform tailored for MG, and outline the study design assessing the platform and clinical outcomes regarding telemedical intervention. Additionally, we present study results on care-related aspects in MG prior to telemedical intervention to identify challenges in the current care provision process. Design: The platform comprises a patient app and a physician portal, enabling systematic symptom monitoring using data from patient-reported outcome measures (PROMs), coupled devices and a communication module. The randomized controlled study included 45 study participants (SP) over a 12-weeks period, including a group receiving standard care (15 MG patients) and a group with additional telemedical treatment (30 MG patients) including assessment of PROMs, wearable data collection and telemedical check-ups. Questions regarding care-related aspects were assessed at baseline visit. Results: Many SP (N=33, 73.3%) communicate with the physician managing their MG via email. 73.3% (N=33) of SP identify areas for improvement in their MG care including symptom monitoring (N=23, 69.7%), specialist appointment availability (N=22, 66.7%), medication (N=22, 66.7%) and specialist accessibility (N=20, 60.6%). Additionally, 73.3% (N=33) reported that the effort required to manage their MG was high. Conclusion: Our results emphasize the high demand of affected MG patients for continuous telemedicine services. MyaLink can provide such a service through personalized support based on the exchange of health data. Telemedicine solutions such as MyaLink promise to improve myasthenia care by providing accessible, patient-centred care that enables early detection of worsening symptoms and non-response to treatment.
Analysis of HER2-low breast cancer in Aotearoa New Zealand: a nationwide retrospective cohort study
Authors: Lasham Annette , Ramsaroop Reenadevi , Wrigley Abbey , Knowlton Nicholas
Published: July 2024

Aim

To perform the first national analysis of demographic and clinicopathological features associated with the HER2 positive, HER2-low and HER2-zero invasive breast cancers in New Zealand. The study will inform the proportion of women who benefit from new HER2-targeted antibody drug conjugate (ADC) therapies.

Methods

Utilising data from Te Rēhita Mate Ūtaetae (Breast Cancer Foundation NZ National Register), the study analysed data from women diagnosed with invasive breast cancer over a 21-year period. The HER2 status of tumours was classified into three categories – HER2-zero, -low, - positive.

Results

From 2009-2021, 94% of women underwent HER2 testing, with 14% diagnosed with HER2-positive breast cancer. For advanced-stage disease, 38% formerly classified as HER2-negative were reclassified as HER2-low. Including HER2-positive breast cancers, this indicates 60% of women with advanced breast cancer would be eligible for the new HER2-directed ADCs (approximately 120 women per year). In future, these therapies may provide a targeted option for 40% of women with early-stage triple negative breast cancer now classified as HER2-low.

Conclusion

The findings suggest a significant proportion of women with invasive breast cancer in New Zealand could benefit from new HER2-targeted treatments. There is a need to standardise HER2 testing to enhance personalised treatment and improve outcomes.
Nocturnal systolic blood pressure dipping among people living with HIV and people without HIV: a cross-sectional study in Rural Uganda
Authors: Sekitoleko Isaac , Kansiime Sheila , Mugamba Viola , Kawooya Ismael , Ntabadde Kauthra , Nakyeyune Rena , Bannink Femke , Nyirenda Moffat , Niwaha Anxious J , Byrd James Brian
Published: July 2024

Background

In this study, we investigated sleep quality, depression and stress symptoms as hypothesized factors affecting the association between HIV status and nocturnal blood pressure dipping status in rural Uganda.

Methods

Individuals living with HIV (PLHIV) and people without HIV (PwoHIV) underwent 24-hour ambulatory blood pressure monitoring (ABPM) and classified as extreme dippers, dippers and non-dippers based on a percentage nocturnal drop in mean systolic and diastolic blood pressure. Ordinal logistic regression models were used to assess the effect of different exposure variables (HIV status, sleep quality and other covariates) on the outcome (dipping status).

Results

The median age was 45 years (IQR: 35-54) and 80% of the participants were female. 24% of PwoHIV and 16% of PLHIV were overweight, 10% of HIV negative and 3% of the HIV positive individuals were obese. Depression was prevalent in both PLHIV and PwoHIV. Additionally, poor sleep quality was more prevalent in PLHIV compared to PwoHIV (70% versus 58%, P= 0.046). The study found that 53% of participants had normal dipping, while 35.1% were non-dippers, with non-dipping being more prevalent in PwoHIV individuals (34.9% vs 29.7%, P<0.001). PLHIV had 3.6 times the odds of being extreme dippers compared to PwoHIV (OR 3.64, 95% CI: 1.40 – 9.44).

Conclusion

This study identified high proportions of non-dipping BP profiles among both PLHIV and PwoHIV. However, the odds of being extreme dippers were higher among PLHIV compared to PwoHIV. Further research is needed to understand the underlying mechanisms contributing to extreme dipping patterns in PLHIV.
Modulating immune cell fate and inflammation through CRISPR-mediated DNA methylation editing
Authors: Valcárcel Gemma , López-Rubio Anna V. , Lazarenkov Aleksey , Berenguer Clara , Calafell Josep , Rodríguez-Ubreva Javier , Ballestar Esteban , Sardina José Luis
Published: July 2024

DNA methylation is traditionally associated with gene silencing, but its causal relationship and role in shaping cell fate decisions still need to be fully elucidated. Here, we conducted a genome-wide analysis to investigate the relationship between DNA methylation and geneexpressionat gene regulatory regions in human immune cells. By utilizing CRISPR-dCas9 DNA methylation editing tools, we successfully established a cause-and-effect relationship between the methylation levels of the promoter of the Interleukin1-receptor antagonist (IL1RN) gene and its expression. Notably, we observed that modifying the DNA methylation status of theIL1RNpromoter is sufficient to alter the acquisition of the human myeloid cell fate and change the cellular response to inflammatory stimuli, resulting in abnormal cytokine release and distinctive capacity to support cancer growth.
Transient Naive Treatment (TNT) iPS cells do not feature Sendai virus expression: Response to Sendai virus persistence questions the transient naive reprogramming method for iPSC generation
Authors: Buckberry Sam , Liu Xiaodong , Poppe Daniel , Tan Jia Ping , Faulkner Geoffrey J. , Polo Jose M , Lister Ryan
Published: July 2024

The Transient Naive Treatment (TNT) reprogramming method involves a brief period of culturing in naive media early in the reprogramming process. Through conducting extensive molecular, epigenetic, and functional analyses on numerous induced pluripotent stem cell lines, we have demonstrated that TNT reprogramming facilitates epigenetic memory erasure and produces induced pluripotent stem (iPS) cells more similar to embryonic stem (ES) cells than conventional reprogramming methods1. In 2024, De Los Angeleset al. posted a ‘contradictory results’ preprint onbioRxivtitled ‘Sendai virus persistence questions the transient naive reprogramming method for iPSC generation’2. Their claims include: 1) that Sendai virus expression in naive cultured cells questions the TNT reprogramming method, 2) the possible selection of cells (clonal expansion) with Sendai virus expression during TNT reprogramming, 3) Sendai virus genes being expressed in control samples implying a potential sample mix-up. Here, we demonstrate these claims are not directly supported by the data, and emphasize that we assessed the possibility of cell sub-population selection experimentally in Buckberryet al. (2023). Moreover, our re-analyses of the data in the context of Sendai virus expression during reprogramming actually highlight the advantages of TNT reprogramming concerning the timing of the naive media treatment and the absence of detectable Sendai virus gene expression.
TDP-43 mutations-induced defects in miRNA biogenesis and cytotoxicity by differentially obstructing Dicer activity inDrosophilaand in vitro
Authors: Long Xiang , Jiang Mengni , Miao Yongzhen , Du Huanhuan , Zhang Ting , Ma Zhuoya , Li Jiao , Liu Chunfeng , Meng Hongrui
Published: July 2024

Mutations in the DNA/RNA-binding protein 43 (TDP-43) can cause amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD). As an RNA-binding protein, TDP-43 plays a diverse physiological role in RNA processing and is potentially involved in the pathological progression caused by disease mutations. However, the precise mechanisms linking RNA dysregulation and TDP-43 mutations, which propel disease progression, are not yet fully understood. Here, we demonstrate that TDP-43 and itsDrosophilahomolog, TBPH, whose mutations crucially perturb Dicer presentation, result in dysregulated miRNA profiles. Genetically modulating the expression or pharmacologically activating Dicer implies unique interactions of TDP-43 A315T and M337V with the Dicer protein, suggesting a specific mechanism of C-terminal disease mutations contributes to the pathological process. Unlike TDP-43 A315T, the M337V mutation causes the assembly of aggregates and reorganizes but functionally preserves the Dicer activity in miRNA processing. Mutations in TDP-43 disrupt miRNA biogenesis by hindering its interaction with Dicer, leading to cytotoxicity and providing mechanistic insight into the pathogenic mutations associated with ALS-FTD.
GlyT2-positive interneurons regulate timing and variability of information transfer in a cerebellar-behavioural loop
Authors: Palacios Ensor Rafael , Houghton Conor , Chadderton Paul
Published: July 2024

GlyT2-positive interneurons, Golgi and Lugaro cells, reside in the input layer of the cerebellar cortex in a key position to influence information processing. Here, we examine the contribution of GlyT2-positive interneurons to network dynamics in Crus 1 of mouse lateral cerebellar cortex during free whisking. We recorded neuronal population activity using NeuroPixels probes before and after chemogenetic downregulation of GlyT2-positive interneurons. Under resting conditions, cerebellar population activity reliably encoded whisker movements. Reductions in the activity of GlyT2-positive cells produced mild increases in neural activity which did not significantly impair these sensorimotor representations. However, reduced Golgi and Lugaro cell inhibition did increase the temporal alignment of local population network activity at the initiation of movement. These network alterations had variable impacts on behaviour, producing both increases and decreases in whisking velocity. Our results suggest that inhibition mediated by GlyT2-positive interneurons primarily governs the temporal patterning of population activity, which in turn is required to support downstream cerebellar dynamics and behavioural coordination.

SIGNIFICANCE STATEMENT

The cerebellum has a simple and conserved structure which has tantalised neurobiologists wishing to understand its function. Here we look at the role of granule cell layer inhibitory interneurons, Golgi and Lugaro cells, in the cerebellar cortex. We selectively turned down the activity of these cells in the awake cerebellum to characterise their influence on network activity and behaviour. We show that downregulation of Golgi and Lugaro cells has very little influence on sensorimotor representations in the cerebellum (i.e.,whatis represented), but instead modulates the timing of cortical population activity (i.e.,wheninformation is represented). Our results indicate that inhibitory interneurons in the granule cell layer are necessary to appropriately pace changes in cerebellar activity to match ongoing behaviour.
Mobius Assembly for Plant Systems highlights promoter-coding sequences-terminator interaction in gene regulation
Authors: Kocaoglan Elif Gediz , Andreou Andreas , Nirkko Jessica , Ochoa-Villarreal Marisol , Loake Gary , Nakayama Naomi
Published: July 2024

Plants are the primary biological platforms for producing food, energy, and materials in agriculture; however, they remain a minor player in the recent synthetic biology-driven transformation in bioproduction. Molecular tools and technologies for complex, multigene engineering in plants are as yet limited, with the challenge to enhance their stability and predictivity. Here, we present a new standardized and streamlined toolkit for plant synthetic biology, Mobius Assembly for Plant Systems (MAPS). It is based on small plant binary vectors pMAPs, which contain a fusion origin of replication that enhances plasmid yield in bothEscherichia coliandRhizobium radiobacter. MAPS includes a new library of promoters and terminators with different activity levels; part sizes were minimized to improve construct stability and transformation efficiency. These promoters and terminators were characterized using a high-throughput protoplast expression assay. We observed a significant influence of terminators on gene expression, as the strength of a single promoter can change more than seven-folds in combination with different terminators. Changing the coding sequence changed the relative strength of promoter and terminator pairs, thus uncovering combinatorial gene regulation among all parts of a transcriptional unit. We further gained insights into the mechanisms of such interactions by analyzing RNA folding, with which we suggest a design principle for more predictive and context-independent genetic parts in synthetic biology of plant systems and beyond.
Maternal obesity and offspring neurodevelopment are associated with hypoxic gene expression in term human placenta
Authors: Gunter-Rahman Fatima , Mallett Shayna , White Frédérique , Jacques Pierre-Étienne , Raju Ravikiran M. , Hivert Marie-France , Lee Eunjung Alice
Published: July 2024

One third of women in the United States are affected by obesity during pregnancy. Maternal obesity (MO) is associated with an increased risk of neurodevelopmental and metabolic disorders in the offspring. The placenta, located at the maternal-fetal interface, is a key organ determining fetal development and likely contributes to programming of long-term offspring health. We profiled the term placental transcriptome in humans (pre-pregnancy BMI 35+ [MO condition] or 18.5-25 [lean condition]) using single-nucleus RNA-seq to compare expression profiles in MO versus lean conditions, and to reveal potential mechanisms underlying offspring disease risk. We recovered 62,864 nuclei of high quality from 10 samples each from the maternal-facing and fetal-facing sides of the placenta. On both sides in several cell types, MO was associated with upregulation of hypoxia response genes. On the maternal-facing side only, hypoxia gene expression was associated with offspring neurodevelopmental measures, in Gen3G, an independent pregnancy cohort with bulk placental tissue RNA-seq. We leveraged Gen3G to determine genes that correlated with impaired neurodevelopment and found these genes to be most highly expressed in extravillous trophoblasts (EVTs). EVTs further showed the strongest correlation between neurodevelopment impairment gene scores (NDIGSs) and the hypoxia gene score. We reanalyzed gene expression of cultured EVTs, and found increased NDIGSs associated with exposure to hypoxia. Among EVTs, accounting for the hypoxia gene score attenuated 44% of the association between BMI and NDIGSs. These data suggest that hypoxia in EVTs may be a key process in the neurodevelopmental programming of fetal exposure to MO.