bluuebunny/crossref_metadata_2025 huggingface dataset:
Prevalence of Regret in Gender-Affirming Surgery
Authors: Ren Thomas , Galenchik-Chan Andre , Erlichman Zachary , Krajewski Aleksandra
Published: April 2024

Introduction

Gender-affirmation surgeries are a rapidly growing set of procedures in the field of plastic surgery. This study is novel in that a thorough analysis has not been performed quantifying, identifying, and recognizing the reasons and factors associated with regret in a largely US population.

Methods

A systematic review of several databases was conducted. After compiling the articles, we extracted study characteristics. From the data set, weighted proportions were generated and analyzed.

Results

A total of 24 articles were included in this study, with a population size of 3662 patients. A total of 3673 procedures were conducted in the United States, 514 in European nations, 97 in Asian nations, which included only Thailand, and 19 in South American nations, which included only Brazil. The pooled prevalence of regret was 1.94%. The prevalence of transfeminine regret was 4.0% while the prevalence of transmasculine regret was 0.8%.

Conclusions

Both transfeminine and transmasculine patients had significantly lower rates of regret in the United States when compared with the rest of the world. Our study largely excluded facial gender-affirming surgeries as most of its articles did not fall into our inclusion search criteria. To our knowledge, this is the most recent review performed on the topic of regret among gender-affirming surgery patients with an emphasis on a US cohort. This analysis can help shed light on better ways to enhance patient selection and surgical experience.
Synovial Lipomatosis With Extra-articular Extension in the Arthritic Wrist
Authors: Miller Rebecca L.R. , Donaldson Elsa K. , Giuffre Jennifer L.
Published: April 2024

Synovial lipomatosis is a rare condition characterized by adipocyte proliferation within joint synovial tissue. It most commonly affects the knee and is typically intra-articular. Only 5 published case reports describe extra-articular synovial lipomatosis of the wrist. We present a case of a sexagenarian patient seen for his wrist arthropathy. His x-ray revealed pan-wrist arthritis and inflammatory soft tissue swelling. The patient was slated for a wrist fusion and Darrach procedure. Following the dorsal skin incision in the operating room, an unusual adipose mass was identified infiltrating all extensor compartments: midcarpal, radiocarpal, and distal radioulnar joints. The mass was excised and sent to pathology prior to proceeding with the slated surgery. Synovial lipomatosis was diagnosed postoperatively based on histopathology. Six weeks postoperatively, the wrist fusion had healed clinically and radiographically, and his pain had improved. There was no evidence of recurrence. Synovial lipomatosis is a rare entity that may imitate multiple other pathologies. It is possible that synovial lipomatosis may represent a secondary occurrence following degenerative articular disease or trauma in older patients. This is the first case report to date describing synovial lipomatosis of the wrist with extra-articular extension in the setting of pan-carpal wrist arthritis.
Construction of a Lentiviral Vector for Fgfr2 Overexpression and its Impact on the Biological Behavior of Cranial Suture Mesenchymal Stem Cells
Authors: Yue Yingying , Chen Zong , Dong Xinhang , Song Guodong , Jin Xiaolei
Published: April 2024

Objective:

Suture mesenchymal stem cells (SuSCs), possessing self-renewal and multilineage differentiation abilities, play a crucial role in cranial bone growth. However, the impact of the disease-causing fibroblast growth factor receptor 2 (FGFR2) mutation on SuSCs in Crouzon syndrome has not been explored. This study aims to employ a lentivirus to overexpress Fgfr2 and investigate its role in the pathogenesis of Crouzon syndrome.

Methods:

Starting with the prevalent FGFR2 mutation site in patients with Crouzon syndrome, a lentiviral vector carrying the Fgfr2.C361Y mutation was developed and transfected into SuSCs, with a determined multiplicity of infection values. The experimental group, SuSCs+Fgfr2.C361Y, was compared with the empty vector and normal SuSC groups. Cell proliferation, cycle, apoptosis, and osteogenic functionality were assessed using CCK-8 assays, flow cytometry, ALP activity assays, and real-time quantitative polymerase chain reaction.

Results:

The lentiviral vector effectively infected SuSCs, leading to heightened Fgfr2 expression, with optimal multiplicity of infection values of 80. The experimental group demonstrated decreased proliferation activity and a higher apoptosis rate compared with controls (P < 0.05). After osteogenic induction, the experimental group showed significantly higher ALP activity than controls (P < 0.05). Real-time quantitative polymerase chain reaction indicated lower mRNA expression levels of Gli1, Axin2, Pcna, Cdk2, and Bcl-2 in the experimental group than controls, whereas Bax, Runx2, and Bmp-2 showed higher expression (P < 0.05).

Conclusion:

This study constructed a lentivirus vector to upregulate Fgfr2 expression in SuSCs, suppressing stem cell stemness by inhibiting proliferation, promoting apoptosis, and accelerating premature osteogenic differentiation, resulting in premature suture closure. These findings establish the groundwork for further understanding the pathogenesis of Crouzon syndrome.
Bispectral Index Monitoring in the Nursing of Patients With Paroxysmal Sympathetic Hyperactivity
Authors: Chen YuJing , Huang WenJing , Li ShuFang , Dong Lun , Zhang HengZhu , Shao Qiang , Hu Fei , Chen Lang
Published: April 2024

Aim:

To investigate the clinical nursing effect of bispectral index (BIS) monitoring for paroxysmal sympathetic hyperactivity (PSH) patients in the neurosurgical intensive care unit (NICU).

Methods:

From January 2022 to June 2023, a total of 30 patients with PSH secondary to moderate to severe craniocerebral injury in the NICU were monitored for BIS. The patients’ paroxysmal sympathetic hyperactivity-assessment measure (PSH-AM) scores were recorded. PSH patients generally appear in 3 states: calm state, seizure state, and postmedication state. Thirty PSH patients’ BIS values were recorded during the calm period, during the seizure state, and postmedication state, and these 3 different stages’ BIS values were divided into groups A, B, and C, using the Kruskal-Wallis H test to compare groups.

Results:

The Kruskal-Wallis H test yielded a value of H=22.599, P<0.001. H0 was rejected against the test standard of α=0.05, and the BIS values of groups A, B, and C differed. The BIS values of group A and group B differed after a pairwise comparison, and the difference was statistically significant (adjusted P=0.001). Group B and group C had different BIS values, and the difference was statistically significant (adjusted P=0.001); group A and Group C had no difference in BIS values, and the difference was not statistically significant (adjusted P=1.00).

Conclusions:

Taking BIS value as the nursing observation index for PSH patients can make nursing work more objective, reasonable, and accurate, reduce the inducing factors of PSH attack, further reduce the attack of PSH, save nursing resources, and help guide the safety assessment of sedative use.
Ictal Direct Current Shifts Preceded Much Earlier Than High Frequency Oscillations After Status: Is It the Effect of Status or Antiseizure Medication?
Authors: Kanazawa Kyoko , Kajikawa Shunsuke , Matsumoto Riki , Takatani Miwa , Nakatani Mitsuyoshi , Daifu-Kobayashi Masako , Imamura Hisaji , Kikuchi Takayuki , Kunieda Takeharu , Miyamoto Susumu , Takahashi Ryosuke , Matsuhashi Masao , Ikeda Akio
Published: April 2024

Purpose:

While spikes and sharp waves are considered as markers of epilepsy in conventional electroencephalography, ictal direct current (DC) shifts and high-frequency oscillations (HFOs) appear to be useful biomarkers for epileptogenicity. We analyzed how ictal DC shifts and HFOs were affected by focal status epilepticus and antiseizure medications (ASMs).

Methods:

A 20-year-old female patient who underwent long-term intracranial electrode implantation for epilepsy surgery presented with 72 habitual seizures and a focal status epilepticus episode lasting for 4 h. Ten, 3, and 10 consecutive habitual seizures were analyzed before the status, after the status, and after ASM (valproate) loading, respectively.

Results:

Before and immediately after the status, ictal DC shifts remained the same in terms of the amplitude, duration, and slope of DC shifts. High-frequency oscillations also remained the same in terms of the duration, frequency, and power except for the power of the lower frequency band. After ASM loading, the duration, amplitude, and slope of the ictal DC shift were significantly attenuated. The duration, frequency, and power of the HFOs were significantly attenuated. Furthermore, the interval between the DC onset and HFO onset was significantly longer and the interval between the HFO onset and ictal DC shift peak was significantly shorter.

Conclusions:

The attenuation of ictal DC shifts and HFOs after ASM loading implies that astrocyte and neuronal activity may be both attenuated by ASMs. This finding may help with our understanding of the pathophysiology of epilepsy and can aid with the discovery of new approaches for epilepsy management.
Molecular mechanisms behind the generation of pro-oncogenic HIV-1 matrix protein p17 variants
Authors: Zani Alberto , Messali Serena , Bugatti Antonella , Uggeri Matteo , Rondina Alessandro , Sclavi Leonardo , Caccuri Francesca , Caruso Arnaldo
Published: April 2024

HIV-1 matrix protein p17 variants (vp17s), characterized by amino acid insertions at the COOH-terminal region of the viral protein, have been recently identified and studied for their biological activity. Different from their wild-type counterpart (refp17), vp17s display a potent B cell growth and clonogenic activity. Recent data have highlighted the higher prevalence of vp17s in people living with HIV-1 (PLWH) with lymphoma compared with those without lymphoma, suggesting that vp17s may play a key role in lymphomagenesis. Molecular mechanisms involved in vp17 development are still unknown. Here we assessed the efficiency of HIV-1 Reverse Transcriptase (RT) in processing this genomic region and highlighted the existence of hot spots of mutation in Gag, at the end of the matrix protein and close to the matrix-capsid junction. This is possibly due to the presence of inverted repeats and palindromic sequences together with a high content of Adenine in the 322–342 nucleotide portion, which constrain HIV-1 RT to pause on the template. To define the recombinogenic properties of hot spots of mutation in the matrix gene, we developed plasmid vectors expressing Gag and a minimally modified Gag variant, and measured homologous recombination following cell co-nucleofection by next-generation sequencing. Data obtained allowed us to show that a wide range of recombination events occur in concomitance with the identified hot spots of mutation and that imperfect events may account for vp17s generation.
The causal role of early visual cortex in vividness of visual imagery
Authors: Silvanto Juha , Bona Silvia , Cattaneo Zaira
Published: April 2024

While numerous studies have demonstrated objective accuracy in visual imagery tasks to involve the early visual cortex (V1/V2), the role of this region in imagery vividness remains unclear. We addressed this question by combining Transcranial Magnetic Stimulation (TMS) with a cross-adaptation paradigm in which visual adaptation modulates the ability to engage in visual imagery in the adapted part of the visual field. As previously shown, in the control (Vertex) condition, mental imagery accuracy was impaired when the mental image was generated in the adapted region of visual space. This effect was removed by TMS, indicating that the locus of adaptation was the early visual cortex. In contrast, analysis of vividness ratings (collected on trial-by-trial basis) showed no effects of adaptation, indicating that the imagery vividness is somewhat orthogonal to the fidelity of the mental image. The key finding was that TMS impacted vividness ratings on trials when participants performed incorrectly in the imagery task. Thus, the effects of TMS on accuracy and vividness were observed on different trial types: TMS impaired accuracy of trials associated with high baseline performance, but increased vividness on incorrect trials. Overall, our findings suggest that the early visual cortex plays a role in both accuracy and vividness of mental images, yet these processes are dissociable.
MyoVision-US: an Artificial Intelligence-Powered Software for Automated Analysis of Skeletal Muscle Ultrasonography
Authors: Calulo Rivera Zoe , González-Seguel Felipe , Horikawa-Strakovsky Arimitsu , Granger Catherine , Sarwal Aarti , Dhar Sanjay , Ntoumenopoulos George , Chen Jin , Bumgardner V. K. Cody , Parry Selina M. , Mayer Kirby P. , Wen Yuan
Published: April 2024

Introduction/Aims

Muscle ultrasound has high utility in clinical practice and research; however, the main challenges are the training and time required for manual analysis to achieve objective quantification of morphometry. This study aimed to develop and validate a software tool powered by artificial intelligence (AI) by measuring its consistency and predictability of expert manual analysis quantifying lower limb muscle ultrasound images across healthy, acute, and chronic illness subjects.

Methods

Quadriceps complex (QC [rectus femoris and vastus intermedius]) and tibialis anterior (TA) muscle ultrasound images of healthy, intensive care unit, and/or lung cancer subjects were captured with portable devices. Automated analyses of muscle morphometry were performed using a custom-built deep-learning model (MyoVision-US), while manual analyses were performed by experts. Consistency between manual and automated analyses was determined using intraclass correlation coefficients (ICC), while predictability of MyoVision -US was calculated using adjusted linear regression (adj.R2).

Results

Manual analysis took approximately 24 hours to analyze all 180 images, while MyoVision - US took 247 seconds, saving roughly 99.8%. Consistency between the manual and automated analyses by ICC was good to excellent for all QC (ICC:0.85–0.99) and TA (ICC:0.93–0.99) measurements, even for critically ill (ICC:0.91–0.98) and lung cancer (ICC:0.85–0.99) images. The predictability of MyoVision-US was moderate to strong for QC (adj.R2:0.56–0.94) and TA parameters (adj.R2:0.81–0.97).

Discussion

The application of AI automating lower limb muscle ultrasound analyses showed excellent consistency and strong predictability compared with human analysis. Future work needs to explore AI-powered models for the evaluation of other skeletal muscle groups.
Refining SARS-CoV-2 Intra-host Variation by Leveraging Large-scale Sequencing Data
Authors: Mostefai Fatima , Grenier Jean-Christophe , Poujol Raphäel , Hussin Julie G.
Published: April 2024

Understanding the evolution of viral genomes is essential for elucidating how viruses adapt and change over time. Analyzing intra-host single nucleotide variants (iSNVs) provides key insights into the mechanisms driving the emergence of new viral lineages, which are crucial for predicting and mitigating future viral threats. Despite the potential of next-generation sequencing (NGS) to capture these iSNVs, the process is fraught with challenges, particularly the risk of capturing sequencing artifacts that may result in false iSNVs. To tackle this issue, we developed a workflow designed to enhance the reliability of iSNV detection in large heterogeneous collections of NGS libraries. We use over 130,000 publicly available SARS-CoV-2 NGS libraries to show how our comprehensive workflow effectively distinguishes emerging viral mutations from sequencing errors. This approach incorporates rigorous bioinformatics protocols, stringent quality control metrics, and innovative usage of dimensionality reduction methods to generate representations of this high-dimensional dataset. We identified and mitigated batch effects linked to specific sequencing centers around the world and introduced quality control metrics that consider strand coverage imbalance, enhancing iSNV reliability. Additionally, we pioneer the application of the PHATE visualization approach to genomic data and introduce a methodology that quantifies how related groups of data points are within a two-dimensional space, enhancing our ability to explain clustering patterns based on their shared genetic characteristics. Our workflow sheds light on the complexities of viral genomic analysis with state-of-the-art sequencing technologies and advances the detection of accurate intra-host mutations, opening the door for an enhanced understanding of viral adaptation mechanisms.
Effect of diabetic kidney disease complications on fatigability in patients with type 2 diabetes mellitus
Authors: Hirano Yuma , Tsuriya Daisuke , Kono Kenichi , Fujikura Tomoyuki , Yamaguchi Tomoya , Matsushita Kento , Yokoyama Yurina , Yamauchi Katsuya , Nishida Yusuke
Published: April 2024

Purpose

Type 2 diabetes mellitus (T2DM) emphasizes the maintenance of high levels of physical activity and requires interventions tailored to the characteristics of each patient. We hypothesized that T2DM combined with diabetic kidney disease (DKD) could increase skeletal muscle fatigability, becoming a specific contributor to physical inactivity. This study aimed to determine the effects of DKD complications on fatigability and the relationship between fatigability and physical activity in patients with T2DM.

Methods

The participants were 50 patients with T2DM aged 40–65 years with an estimated glomerular filtration rate of 30 ml/min/1.73 m2 or higher. An experimental protocol was performed using a isokinetic dynamometer to assess muscle function. Fatigability (maximal voluntary concentric contraction [ΔMVCC] velocity, maximal voluntary isometric contraction [ΔMVIC] torque) was calculated, indicating the decrease in angular velocity and muscle strength associated with the exercise task. The patient characteristics, physical activity (IPAQ-SV), knee extension strength, and skeletal muscle index were evaluated. Participants were divided into two groups (DKD and non-DKD) according to the presence or absence of DKD, and ΔMVCC velocity and ΔMVIC torque were compared.

Results

ΔMVCC velocity was significantly higher in the DKD group than that in the non-DKD group (p<0.05). Similarly, ΔMVIC torque was significantly higher in the DKD group compared with the non-DKD group (p<0.05). Subgroup analysis showed that ΔMVCC velocity was independently associated with physical activity in the DKD group (odds ratio: 0.045, 95% confidence interval: 0.913–0.999).

Conclusion

Fatigability increased with DKD in patients with T2DM and may be related to physical activity.
Novel Insights for Radiation Risk Assessment Unveiled by Deep Learning
Authors: Liu Zhenqiu , Shuryak Igor , Brenner David J , Ullrich Robert L
Published: April 2024

Contemporary radiation risk assessment predominantly depends on nonlinear parametric models, which typically include a baseline term, a dose-response term, and an effect modifier term. Despite their widespread application in estimating tumor risks, parametric models face a notable drawback: their rigid model structure can be overly restrictive, potentially introducing bias and inaccuracies into risk estimations.

In this study, we analyze data on solid tumors and leukemia from the Life Span Study (LSS) to compare the performance of deep neural network (DNN) and nonlinear parametric (NLP) models in assessing ERRs. DNN presents novel perspectives for radiation risk assessment. Our findings indicate that DNN can perform better than the traditional parametric models. Even if DNN and NLP models exhibit similar performance in predicting tumor incidence, they diverge significantly in their estimated ERRs. Standard NLP models tend to underestimate ERRs directly linked to radiation dose, overestimate ERRs for individuals at younger attained ages and ages at exposure, and underestimate ERRs for those at older attained ages. Furthermore, DNN consistently identifies radiation dose as the primary and predominant risk factor for ERRs in leukemia and solid tumors, underscoring the critical role of radiation dose in risk assessment. The insights from DNN could enhance low-dose radiation risk assessment and improve parametric model development.
Social-media based health education plus exercise programme (SHEEP) to improve muscle function among young-old adults with possible sarcopenia in the community: A feasibility study protocol
Authors: Shi Ya , Stanmore Emma , McGarrigle Lisa , Todd Chris
Published: April 2024

Background

Despite the comparatively high prevalence of possible sarcopenia among young-old adults in the community, there is currently no available and effective social media-based intervention to increase the awareness and behaviour of the target population in order to prevent sarcopenia. Using co-design methodology, we developed a multicomponent intervention strategy of health education and exercise for sarcopenia prevention utilizing the TikTok platform.

Objectives

Primary purpose of this study is to examine the feasibility and acceptability of the social media-based intervention to enhance muscle function in community-dwelling young-old adults with possible sarcopenia.

Methods

This protocol outlines the entire research procedure for a prospective single-arm pre-post feasibility study employing a mixed-method design, which will be conducted between May 2024 and September 2024. 35 older adults aged 60-69 years with possible sarcopenia will be recruited from two communities in Changsha, China. Based on the TikTok platform, participants will be required to view a total of seven health education videos in the first week, and each video lasts four to six minutes. Then, participants will receive six-week multi-component exercise through TikTok, with at least three sessions/week, 30 minutes/session, and moderate intensity. Finally, six-week follow-up will be conducted. Data collection will be conducted at baseline, post-intervention and follow-up period. The primary outcome will include evaluating recruitment capability, data collection procedure, outcome measurement, intervention procedures’ acceptability, researchers’ ability to manage and implement the study, etc. The secondary outcome is to compare standard measures for muscle function (e.g. handgrip strength, skeletal muscle mass, physical performance), body composition (e.g. body fat, body mass index, bone mineral), and other measures (e.g. perceived knowledge, personal motivation, behavioural skills). Finally, all participants will be offered a semi-structured interview to assess their in-depth experiences with the intervention and research process.

Discussion

This study will be the first social-media based multicomponent intervention program for community young-old adults with possible sarcopenia to improve their muscle function, awareness and behaviour of preventing sarcopenia. Findings will generate new evidence regarding to the use of social media in health education for impoving awareness of sarcopenia prevention, as well as the feasibility of using social media to influence participants’ behavioural changes through exercise. This may help researchers identify ways to optimise acceptability and efficacy of the SHEEP intervention for the targeted population.

Trial registration

ISRCTN registry,ISRCTN17269170, Registered 14 September 2023
Characterization of the mesendoderm progenitors in the gastrulating mouse embryo
Authors: Masamsetti V. Pragathi , Salehin Nazmus , Kim Hani Jieun , Santucci Nicole , Weatherstone Megan , Knowles Hilary , Sun Jane , McMahon Riley , Studdert Josh B. , Aryamanesh Nader , Wang Ran , Jing Naihe , Yang Pengyi , Osteil Pierre , Tam Patrick P.L
Published: April 2024

A population of putative mesendoderm progenitor cells that can contribute cellular descendants to both mesoderm and endoderm lineages is identified. These progenitor cells are localized to the anterior primitive streak and the adjacent epiblast of E7.0-E7.5 mid-to late-gastrula stage embryos. Lineage tracing in vivo revealed that putative mesendoderm progenitors that are marked byMixl1andMesp1activity contribute descendants to the endoderm layer. Analysis of the role of Mixl1 transcription factor in endoderm differentiation of the mouse epiblast stem cells revealed the choice for endoderm or mesoderm cell fate depends on the timing of activation ofMixl1upon exit from pluripotency, suggesting Mixl1 function may underpin the divergence of the mesendoderm progenitor to mesoderm and endoderm lineages. The knowledge gained on the spatial, temporal, and lineage attribute of mesendoderm progenitors enriches our mechanistic understanding of germ layer allocation and endoderm differentiation of mesendoderm progenitor in embryonic development and lineage allocation of primed state pluripotent stem cells in vitro.
Sustained Vaccine Exposure Elicits More Rapid, Consistent, and Broad Humoral Immune Responses to Multivalent Influenza Vaccines
Authors: Saouaf Olivia M. , Ou Ben S. , Song Ye Eun , Carter Joshua J. , Yan Jerry , Jons Carolyn K. , Barnes Christopher O. , Appel Eric A.
Published: April 2024

With the ever-present threat of pandemics, it is imperative we develop vaccine technologies eliciting broad and durable immunity to high-risk pathogens. Yet, current annual influenza vaccines, for example, fail to provide robust immunity against the 3-4 homologous strains they contain, let alone heterologous strains. Herein, we demonstrate that sustained delivery of multivalent influenza vaccines from an injectable polymer-nanoparticle (PNP) hydrogel technology induces more rapid, consistent, and potent humoral immune responses against multiple homologous viruses, as well as potent responses against heterologous viruses and potential pandemic subtypes H5N1, H7N9 and H9N2. Further, admixing PNP hydrogels with commercial influenza vaccines results in stronger hemagglutination inhibition against both heterologous and homologous viruses. We show this enhanced potency and breadth arises from higher affinity antibodies targeting both the hemagglutinin stem and head. Overall, this simple and effective sustained delivery platform for multivalent annual influenza vaccines generates durable, potent, and remarkably broad immunity to influenza.
Unifying community-wide whole-brain imaging datasets enables robust automated neuron identification and reveals determinants of neuron positioning inC. elegans
Authors: Sprague Daniel Y. , Rusch Kevin , Dunn Raymond L. , Borchardt Jackson M. , Ban Steven , Bubnis Greg , Chiu Grace C. , Wen Chentao , Suzuki Ryoga , Chaudhary Shivesh , Lee Hyun Jee , Yu Zikai , Dichter Benjamin , Ly Ryan , Onami Shuichi , Lu Hang , Kimura Koutarou D. , Yemini Eviatar , Kato Saul
Published: April 2024

We develop a data harmonization approach forC. elegansvolumetric microscopy data, still or video, consisting of a standardized format, data pre-processing techniques, and a set of human-in-the-loop machine learning based analysis software tools. We unify a diverse collection of 118 whole-brain neural activity imaging datasets from 5 labs, storing these and accompanying tools in an online repository called WormID (wormid.org). We use this repository to train three existing automated cell identification algorithms to, for the first time, enable accuracy in neural identification that generalizes across labs, approaching human performance in some cases. We mine this repository to identify factors that influence the developmental positioning of neurons. To facilitate communal use of this repository, we created open-source software, code, web-based tools, and tutorials to explore and curate datasets for contribution to the scientific community. This repository provides a growing resource for experimentalists, theorists, and toolmakers to (a) study neuroanatomical organization and neural activity across diverse experimental paradigms, (b) develop and benchmark algorithms for automated neuron detection, segmentation, cell identification, tracking, and activity extraction, and (c) inform models of neurobiological development and function.
Evidence for multiple forms of heritable RNA silencing
Authors: Chey Mary S. , Raman Pravrutha , Ettefa Farida , Jose Antony M.
Published: April 2024

Heritable gene silencing has been proposed to rely on DNA methylation, histone modifications, and/or non-coding RNAs in different organisms. Here we demonstrate that multiple RNA-mediated mechanisms with distinct and easily detectable molecular signatures can underlie heritable silencing of the same open-reading frame in the nematodeC. elegans. Using two-gene operons, we reveal three cases of gene-selective silencing that provide support for the transmission of heritable epigenetic changes through different mechanisms of RNA silencing independent of changes in chromatin that would affect all genes of an operon equally. Different heritable epigenetic states of a gene were associated with distinct populations of stabilized mRNA fragments with untemplated poly-UG (pUG) tails, which are known intermediates of RNA silencing. These ‘pUG signatures’ provide a way to distinguish the multiple mechanisms that can drive heritable RNA silencing of a single gene.
A Causal Role of the Right Dorsolateral Prefrontal Cortex in Random Exploration
Authors: Toghi Armin , Chizari Mojtaba , Khosrowabadi Reza
Published: April 2024

Our brain faces the dilemma of exploiting familiar options to gain immediate rewards or exploring new options to increase probable future rewards, in many real-life decisions, and solves it by direct and random exploration. Previous studies show that these two explorative strategies have dissociable neural correlates in the brain. Using the continuous theta burst stimulation (cTBS) and horizon task, we investigate the causal role of the right dorsolateral prefrontal cortex (rDLPFC) in direct and random exploration. Twenty-five healthy right-handed adult participants underwent cTBS, and vertex stimulation sessions, and then completed the horizon tasks. Both model-free and model-based analysis showed that cTBS over rDLPFC selectively reduced random exploration, but not direct exploration. This suggests a causal role for rDLPFC especially in random exploration, and further supports dissociable neural implementations for direct and random exploration. © 2024 The Author(s)
DNA damage and senescence in the aging and Alzheimer’s disease cortex are not uniformly distributed
Authors: Gutta Gnanesh , Mehta Jay , Kingston Rody , Xie Jiaan , Brenner Eliana , Ma Fulin , Herrup Karl
Published: April 2024

Alzheimer’s disease (AD) is a neurodegenerative illness with a typical age of onset exceeding 65 years of age. The age-dependency of the condition led us to track the appearance of DNA damage in the frontal cortex of individuals who died with a diagnosis of AD. The focus on DNA damage was motivated by evidence that increasing levels of irreparable DNA damage are a major driver of the aging process. The connection between aging and the loss of genomic integrity is compelling because DNA damage has also been identified as a possible cause of cellular senescence. The number of senescent cells has been reported to increase with age, and their senescence-associated secreted products are likely contributing factors to age-related illnesses. We tracked DNA damage with 53BP1 and cellular senescence with p16 immunostaining of human post-mortem brain samples. We found that DNA damage is significantly increased in the BA9 region of the AD cortex when compared to the same region of unaXected controls (UC). In the AD but not UC cases, the density of cells with DNA damage increased with distance from the pia mater up to approximately layer V then decreased in deeper areas. This pattern of DNA damage was overlaid with the pattern of cellular senescence, which also increased with cortical depth. On a cell-by-cell basis, we found that the intensity of the two markers was tightly linked in the AD, but not the UC brain. To test whether DNA damage was a causal factor in the emergence of the senescence program, we used etoposide treatment to damage the DNA of cultured mouse primary neurons. While DNA damage increased after treatment, after 24 hours no change in the expression of senescence-associated markers was observed. Our work suggests that DNA damage and cellular senescence are both increased in the AD brain and increasingly coupled. We propose that in vivo the relationship between the two age-related processes is more complex than previously thought.
GLP-1R associates with VAPB and SPHKAP at ERMCSs to regulate β-cell mitochondrial remodelling and function
Authors: Austin Gregory , Oqua Affiong I. , Eid Liliane El , Zhu Mingli , Manchanda Yusman , Peres Priyanka , Coyle Helena , Poliakova Yelyzaveta , Bouzakri Karim , Montoya Alex , Withers Dominic J. , Solimena Michele , Jones Ben , Millership Steven J. , Burgold Steffen , Gaboriau David C.A. , Majorovits Endre , Prokopenko Inga , Nixon-Abell Jonathon , Müller Andreas , Tomas Alejandra
Published: April 2024

Glucagon-like peptide-1 receptor (GLP-1R) agonists (GLP-1RAs) ameliorate mitochondrial health by increasing mitochondrial turnover in metabolically relevant tissues. Mitochondrial adaptation under metabolic stress is crucial to maintain pancreatic β-cell function and prevent type 2 diabetes (T2D) progression. While the GLP-1R is well known to stimulate cAMP production leading to Protein Kinase A (PKA) and Exchange Protein Activated by cyclic AMP 2 (Epac2) activation, there is a lack of understanding of the molecular mechanisms that link GLP-1RA-induced signalling with mitochondrial remodelling and functional adaptation. Here, we present a comprehensive study in β-cells and primary mouse and human islets that demonstrates that, following GLP-1RA stimulation, GLP-1R-positive endosomes associate with the endoplasmic reticulum (ER) membrane contact site (MCS) tether VAPB at ER-mitochondria MCSs (ERMCSs), where active GLP-1R engages with SPHKAP, an A-kinase anchoring protein (AKAP) linked to T2D and adiposity risk in genome-wide association studies (GWAS). The inter-organelle complex formed by endosomal GLP-1R, ER VAPB and SPHKAP triggers a pool of ERMCS-localised cAMP/PKA signalling which leads to the phosphorylation of the mitochondrial contact site and cristae organising system (MICOS) complex component MIC19 and is accompanied by mitochondrial remodelling and modulation of mitochondrial function, with important consequences for β-cell function and survival to oxidative stress.
“Regulation of Obesity and Fatty Liver by Moringa oleifera: Insights into Inflammatory Pathways”
Authors: Ibrahim Nihal A. , Buabeid Manal A. , Arafa El-Shaimaa A. , Murtaza Ghulam
Published: April 2024

Obesity and fatty liver are relatively benign states but continued inflammatory stress and its metabolic implications turn them into one of the most devastating diseases of humankind. Generally, obesity and fatty liver precede diabetes mellitus, cardiovascular problems and malignant growths. The present research aimed to explore the efficacy of methanolic extract ofMoringa Olifera(Me.MO) for the management of obesity and fatty liver and related inflammatory state that prime the body for devastating effects. A series ofin-vitroandin-vivostudies were employed. Data from HPLC analysis confirmed the presence of flavonoids and phenolic acids. Rats were fed on either normal diet (ND) or high fat diet (HFD and streptozocin (STZ) in the presence or absence ofMe.Mo(250 mg/kg & 500 mg/kg) or metformin (70 mg/kg). Findings showed that rats received 500 mg/kgMe.MOshowed a significant (p> 0.01) decrease in body weights, liver weights, and plasma glucose level. Laboratory data exhibited a significant (p< 0.05) inhibitory effect onMe.MOon pro-inflammatory mediators (IL-1B and TNF) and caused a sharp increase in anti-inflammatory cytokines levels (IL-10, IL-6 and COX-2) in all treatment groups. Histopathological analysis exhibited no structural and functional alteration in the liver and adipose tissues. Altogether,Me.MOameliorates experimentally induced obesity accompanying fatty liver and inflammatory stress. However, further investigations are still needed to confirm the safety and efficacy ofMoringaβ olifera(MO) for clinical application.
Autonomous multicolor bioluminescence imaging in bacteria, mammalian, and plant hosts
Authors: Kusuma Subhan Hadi , Hattori Mitsuru , Nagai Takeharu
Published: April 2024

Bioluminescence imaging has become a valuable tool in biological research, offering several advantages over fluorescence-based techniques, including the absence of phototoxicity and photobleaching, along with a higher signal-to-noise ratio. Common bioluminescence imaging methods often require the addition of an external chemical substrate (luciferin), which can result in a decrease in luminescence intensity over time and limit prolonged observations. Since the bacterial bioluminescence system is genetically encoded for luciferase-luciferin production, it enables autonomous bioluminescence (auto-bioluminescence) imaging. However, its application to multiple reporters is restricted due to a limited range of color variants. Here, we report five colors auto-bioluminescence system named Nano-lanternX (NLX), which can be expressed in bacterial, mammalian, and plant hosts, thereby enabling auto-bioluminescence in various living organisms. We have also expanded the applications of the NLX system, such as multiplexed auto-bioluminescence imaging for gene expression, protein localization, and dynamics of biomolecules within living mammalian cells.
Comparative investigations of cellular dynamics in the development of medusae (Cnidaria: Medusozoa)
Authors: Travert Matthew , Winata Kent , Cartwright Paulyn
Published: April 2024

Medusozoans are characterized by the presence of a medusa (jellyfish) stage as part of the life cycle. Despite being a prominent trait in medusozoan evolution, the mechanisms underlying the emergence of this life cycle stage are poorly understood. Characterizing cell proliferation, cell migration and programmed cell death in several disparate species, we found that the development of the medusa displays distinct cellular mechanisms between the scyphozoan and hydrozoan lineages. Using Edu labeling, hydroxyurea treatments and cell tracing we found that in hydrozoans, the development of the medusa relies on extensive cell migration and a distinct pattern of cell proliferation. Using TUNEL assays and pan-caspase inhibitor treatments, we found that in all surveyed hydrozoans apoptosis does not play a role in the development or release of medusa. By contrast, the surveyed scyphozoan medusae undergo extensive apoptosis, and subsequent cell proliferation is required for the formation of the medusa and many of their adult structures. Our results suggest that the difference in medusa developmental trajectories between scyphozoans and hydrozoans stems from distinct cellular mechanisms. Characterization of the medusa stage at different levels of biological organization is thus required to investigate the origin of this complex life cycle stage.
ECG-derived global longitudinal strain using artificial intelligence: A comparative study with transthoracic echocardiography
Authors: Choi Hong-Mi , Kim Joonghee , Park Jiesuck , Park Jun-Bean , Kim Hyung-Kwan , Choi Hye Jung , Yoon Yeonyee E. , Cho Goo-Yeong , Cho Youngjin , Hwang In-Chang
Published: April 2024

Background

Despite the versatility of the left ventricular (LV) global longitudinal strain (LVGLS), its complex measurement and interpretation make it difficult to use. An artificial intelligence (AI)-generated electrocardiography (ECG) score for LVGLS estimation (ECG-GLS score) may offer a cost-effective alternative.

Objectives

We evaluated the potential of an AI-generated ECG-GLS score to diagnose LV systolic dysfunction and predict the prognosis of patients with heart failure (HF).

Methods

A convolutional neural network-based deep-learning algorithm was trained to estimate the echocardiography-derived GLS (LVGLS) using retrospective ECG data from a tertiary hospital (n=2,882). ECG-GLS score performance was evaluated using data from an acute HF registry at another tertiary hospital (n=1,186).

Results

In the validation cohort, the ECG-GLS score could identify patients with impaired LVGLS (≤12%) (area under the receiver-operating characteristic curve [AUROC], 0.82; sensitivity, 85%; specificity, 59%). ECG-GLS performance in identifying patients with an LV ejection fraction (LVEF) of <40% (AUROC, 0.85) was comparable to that for LVGLS (AUROC, 0.83) (p=0.08). Five-year outcomes (all-cause death; composite of all-cause death and hospitalization for HF) occurred significantly more frequently in patients with low ECG-GLS scores. Low ECG-GLS score was a significant risk factor for these outcomes after adjustment for other clinical risk factors and LVEF. The prognostic performance of the ECG-GLS score was comparable to that of the LVGLS.

Conclusions

The ECG-GLS score demonstrates a strong correlation with the LVGLS and is effective in risk stratification for the long-term prognosis after acute HF, suggesting its potential role as a practical alternative to the LVGLS.

Condensed abstract

This study is the first to attempt to estimate the left ventricular global longitudinal strain (LVGLS) from electrocardiography (ECG) data using an artificial intelligence-based algorithm (ECG-GLS score). The ECG-GLS score was correlated with the LVGLS and performed as well as the LVGLS in predicting the long-term prognosis of patients with heart failure. Thus, the ECG-GLS score has potential as practical alternative to the LVGLS on echocardiography, with reductions in time and effort.

Graphical Abstract
EVALUATING THE IMPACT OF COVID-19 ON THE PREGNANCY AND POSTNATAL PERIOD FOR UK WOMEN
Authors: Nye Gareth A , Deb George Abou , Dunne Seóna
Published: April 2024

INTRODUCTION

Pregnancy is a crucial period which ultimately directly impacts two individuals health and wellbeing. Within the UK, a standardised pattern of care is established with collaborations across disciplines to the benefit of women and babies. During the COVID19 pandemic, this pattern of care was disrupted to align with protective protocols which until now, has not been formally reported.

METHODS

A retrospective, mixed methods study of UK based women pregnant between the years 2012 and 2022 inclusive with no known complications was conducted to collate opinions and experiences of pregnancy with and without the impact of COVID19 restrictions. Quantitative results were analysed using the statistical package GraphPad Prism 9.2.0 and presented as mean values +/- standard deviation were appropriate. In addition, we used a phased approach to open ended questions.

RESULTS

Our results showed no significant difference in either the number of appointments or the time of first appointment however an increased percentage of women reported the use of private services during the COVID pandemic. There was no change in the number of midwife appointments during the postnatal period during COVID but there was a significant reduction in the number of health visitor appointments. Overall, the COVID pandemic led to women feeling less satisfied with their care both during their pregnancy and postnatally, but they reported that they continued to be listened to and remained feeling in control of their pregnancy.

DISCUSSION

Generally, the changes implemented during the COVID pandemic did not impact women’s pregnancy journey substantially although we have no evidence of the long-term impact on child health and development. Clear themes have been established which can be used to further improve services in maternity and there are key elements to focus on for the future of UK maternity services.
Polyadenylated RNA sequencing analysis helps establish a reliable catalog of circular RNAs – a bovine example
Authors: Robic Annie , Hadlich Frieder , Monteiro Moreira Gabriel Costa , Clark Emily Louise , Plastow Graham , Charlier Carole , Kühn Christa
Published: April 2024

The aim of this study was to compare the circular transcriptome of divergent tissues in order to understand: i) the presence of circular RNAs (circRNAs) that are not exonic circRNAs, i.e. originated from backsplicing involving known exons and, ii) the origin of artificial circRNA (artif_circRNA), i.e. circRNA not generatedin-vivo. CircRNA identification is mostly anin-silicoprocess, and the analysis of data from the BovReg project (https://www.bovreg.eu/) provided an opportunity to explore new ways to identify reliable circRNAs. By considering 117 tissue samples, we characterized 23,926 exonic circRNAs, 337 circRNAs from 273 introns (191 ciRNAs, 146 intron circles), 108 circRNAs from small non-coding genes and nearly 36.6K circRNAs classified as other_circRNAs. We suggestedin-vivocopying of specific exonic circRNAs by an RNA-dependent RNA polymerase (RdRP) to explain the 20 identified circRNAs with reverse-complement exons. Furthermore, for 63 of those samples we analyzed in parallel data from total-RNAseq (ribosomal RNAs depleted prior to library preparation) with paired mRNAseq (library prepared with poly(A)-selected RNAs). The high number of circRNAs detected in mRNAseq, and the significant number of novel circRNAs, mainly other_circRNAs, led us to consider all circRNAs detected in mRNAseq as artificial. This study provided evidence that there were 189 false entries in the list of exonic circRNAs: 103 artif_circRNAs identified through comparison of total-RNAseq/mRNAseq using two circRNA tools, 26 probable artif_circRNAs, and 65 identified through deep annotation analysis. This study demonstrates the effectiveness of a panel of highly expressed exonic circRNAs (5-8%) in analyzing the diversity of the bovine circular transcriptome.
Crystallographic fragment screening and deep mutational scanning of Zika virus NS2B-NS3 protease enable development of resistance-resilient inhibitors
Authors: Ni Xiaomin , Richardson R. Blake , Godoy Andre Schutzer , Ferla Matteo P. , Kikawa Caroline , Scheen Jenke , Hannon William W , Capkin Eda , Lahav Noa , Balcomb Blake H , Marples Peter G , Fairhead Michael , Wang Siyi , Williams Eleanor P , Tomlinson Charlie W.E. , Aschenbrenner Jasmin Cara , Lithgo Ryan M , Winokan Max , Giroud Charline , Chandran Anu V , Walsh Martin , Thompson Warren , Bloom Jesse D , Barr Haim , Kirkegaard Karla , Koekemoer Lizbé , Fearon Daren , Evans Matthew J. , von Delft Frank
Published: April 2024

The Zika viral protease NS2B-NS3 is essential for the cleavage of viral polyprotein precursor into individual structural and non-structural (NS) proteins and is therefore an attractive drug target. Generation of a robust crystal system of co-expressed NS2B-NS3 protease has enabled us to perform a crystallographic fragment screening campaign with 1076 fragments. 47 fragments with diverse scaffolds were identified to bind in the active site of the protease, with another 6 fragments observed in a potential allosteric site. To identify binding sites that are intolerant to mutation and thus suppress the outgrowth of viruses resistant to inhibitors developed from bound fragments, we performed deep mutational scanning of NS2B-NS3 protease. Merging fragment hits yields an extensive set of ‘mergers’, defined as synthetically accessible compounds that recapitulate constellations of observed fragment-protein interactions. In addition, the highly sociable fragment hits enable rapid exploration of chemical space via algorithmic calculation and thus yield diverse possible starting points that maximally explore the binding opportunities to NS2B-NS3 protease, facilitating its resistance-resilient antiviral development.