bluuebunny/crossref_metadata_2025 huggingface dataset:
The Efficacy of High-Fidelity Telesimulation in Preparing Nursing Students for Emergency and Critical Patient Care: A Prospective Study
Authors: PENG Yi-Chi , WU Hua-Shan
Published: October 2024

Background

High-fidelity telesimulation can address the gap in nursing education caused by the pandemic by providing a simulated environment for students to practice skills that closely mimic real-life scenarios.

Purpose

This study was designed to determine the effect of a high-fidelity telesimulation teaching program on emergency and critical patient care-related knowledge, self-confidence, and critical thinking skills in nursing students.

Methods

This randomized, single-blind controlled study was conducted on a sample of 84 nursing students who were evaluated using pretest and posttest measurements. The participants were randomized into a control group (n = 43) and an experimental group (n = 41). The control group received an in-person traditional teaching program, and the experimental group was taught using a high-fidelity telesimulation program. During the high-fidelity telesimulation, synchronous online tutorial learning and telesimulation were conducted every 100 and 300 minutes. The experimental group program included a lecture, simulation teaching videos, and demonstrations related to endotracheal intubation, 12-lead electrocardiography, protective clothing, and hybrid telesimulation learning. In each subgroup, the students executed a single high-fidelity telesimulation scenario in which they were assigned individual roles. The students in the other subgroups served as observers and engaged in the synchronous online debriefing. Teaching efficacy was evaluated using an objective structured clinical examination and a questionnaire designed for emergency and critical patient care.

Results

In the experimental group, levels of knowledge and self-confidence as well as critical thinking skills related to emergency and critical patient care were significantly higher than in the control group (p < .05).

Conclusions

High-fidelity telesimulation teaching is a feasible and reliable alternative to conventional in-person simulation for nursing students, particularly in situations where traditional clinical experiences are not possible.
An Alternative Approach to Low-Dose Buprenorphine Induction in Pregnancy and Postpartum
Authors: Koenigs Kathleen , Gray Jessica , Gale Evan , Siegel Molly , Schiff Davida , Bernstein Sarah
Published: October 2024

Low-dose buprenorphine induction, unlike traditional methods, does not require that individuals experience at least moderate withdrawal before initiation. This technique has been widely used and studied in the general population; however, research in pregnancy is limited. We aimed to evaluate obstetric and neonatal outcomes after low-dose buprenorphine induction. In this retrospective case series, we reviewed all cases of low-dose induction during pregnancy or within 6 weeks postpartum at an urban academic medical center over a 3-year period. Nine patients started buprenorphine using this method, and all but one completed induction. There was a high rate of treatment retention and no apparent associated adverse neonatal events. Four individuals are in sustained remission and currently parenting. Though further research is needed, low-dose buprenorphine induction appears effective in the obstetric population.
The human side of cancer care in Japan: barriers and challenges
Authors: Uchitomi Yosuke
Published: October 2024

Among the core concepts of psycho-oncology, “addressing the human aspects of cancer” is one of the most important. In particular, the enhancement of physicians' empathic communication is welcomed in Japan. In 2006, the enactment of the Cancer Control Act in Japan promoted psychosocial and palliative care to anyone. Thus, the designated cancer hospitals adopted a palliative care team, including a psycho-oncologist, as well as a communication skills training program practicing empathic communication. The Cancer Registry data have suggested regional disparities in suicides among patients with cancer in Japan, suggesting fragile regions of psycho-oncology. How can we deliver empathic communication to patients across the country, and how far will technological innovation, including AI, produce innovative support? Although constant efforts are needed to move closer to solutions, the human side of cancer must not be changed; however, clinical practice must continue to change over time.
Inferior Rectus Muscle Thermal Injury Following Transconjunctival Blepharoplasty Using Carbon Dioxide Laser
Authors: Choi Hee Young , Yang Seung Ahn , Ahn Jung Hyo
Published: October 2024

A 56-year-old woman was referred to the authors' hospital after the removal of the lower eyelid fat through a transconjunctival approach using a carbon dioxide laser. The patient was noted to have vertical diplopia in the primary position, with worsening diplopia on downgaze. Detachment of the right inferior rectus (IR) muscle from its insertion point was observed during exploratory surgery. The thermally damaged IR muscle fibers were attached to a location posterior to the original insertion point. At 6 months postoperatively, 8 prism diopters of right hypertropia in the primary position and a −3 degrees limitation on downgaze were still present. The patient underwent the vertical transposition of the lateral and medial rectus muscles to the IR muscle. After strabismus surgery, orthotropia was observed with no vertical diplopia in the primary gaze, but ocular motility limitation on the downgaze has permanently remained.
Draft genome sequence of a Lactiplantibacillus pentosus strain isolated from traditionally fermented rice
Authors: Cheruvari Athira , Kammara Rajagopal
Published: October 2024

Lactiplantibacillus pentosus is a probiotic bacterium reported to be present in various fermented foods, such as fermented olives, and it significantly influences human health. The present study concerns a lactic acid bacterial strain designated L. pentosus krglsrbmofpi2, isolated from traditional fermented rice, and which has been shown to have an assortment of beneficial attributes. Using Illumina technologies, we have sequenced and investigated the whole genome sequence of L. pentosus krglsrbmofpi2 to understand its functionality and safety. The chromosomal genome was 3.7 Mb in size with 46% GC content and 3192 protein-coding genes. Additional extensive bioinformatics investigations were carried out involving whole genome sequence assembly and annotation.
Bacteriological profile of community peritonitis operated in a Moroccan Hospital
Authors: BAZHAR SAMIA , Benaissa Elmostafa , Ziad Fatima , Laamara Leila , Ben Lahlou Yassine , Chadli Mariama , Elouennass Mostafa
Published: October 2024

Introduction. Peritonitis is characterized by acute inflammation of the peritoneum, often resulting from digestive organ perforation or intra-abdominal septic focus. It may be either of infectious or noninfectious origin. The germs involved are those of the digestive flora (Enterobacteriaceae and Anaerobic), while gram-positive cocci and yeasts can be isolated in nosocomial infections. Our study aims to isolate and identify the germs involved in community-acquired peritonitis, in order to assess their susceptibility to the antibiotics available in our Country.
 
Methods. This is a retrospective study of bacteriological profile of community peritonitis in Rabat Morocco. A total of 150 adult patients with peritonitis, were admitted and samples were collected intraoperatively for bacteriological examination between July 1, 2022 and April 30, 2023.
 
Results. Among the 150 patients, 101 (67.8%) were males and 48 (32.2%) were females, with sex/ratio of 2.1. The mean age of the patients was 40.5 years +/- 20.12. The distribution of germs was dominated by Escherichia coli (44%). Overall, 70% of Escherichia coli isolated, had a resistance to Ampicillin but no resistance to Ampicillin has been reported by Enterococcus.
 
Discussion. In the present study, we were interested in the bacteriological profile of community peritonitis, in order to adapt the antibiotic therapy to our bacterial ecology. 
Our findings indicate a concerning trend of increasing resistance among Escherichia coli to the commonly used Amoxicillin/Clavulanic Acid combination in our clinical setting.
 
Conclusion. Consequently, there is a need to reassess the empiric antibiotic prescribed for the management of community-acquired peritonitis.
How the prospect of a clinical trial impacts decision-making for predictive genetic testing in amyotrophic lateral sclerosis
Authors: Fontaine Myriam , Horowitz Kayla , Anoja Nancy , Genge Angela , Salmon Kristiana
Published: October 2024

Objective

Genetic testing practices are rapidly evolving for people living with, or at-risk for, amyotrophic lateral sclerosis (ALS), due to emerging genotype-driven therapies. This study explored how individuals at-risk for familial ALS (fALS) perceive the opportunity to participate in a clinical trial, and to better understand how that may influence the decision-making process for predictive genetic testing.

Methods

This study used both quantitative and qualitative data analyses. Data were collected through an online questionnaire, followed by semi-structured interviews conducted with twelve (n=12) individuals at-risk for eitherSOD1-orC9orf72-ALS who had predictive testing prior to study participation. Interview data were analyzed using reflexive thematic analysis.

Results

Three overarching themes were conceptualized from the data: i) the psychosocial impact of fALS; ii) perspectives of at-risk individuals on research involvement; and iii) predictive genetic counselling and testing considerations. These results contribute perspectives of the lived experience to inform predictive genetic counselling and testing practices for individuals at-risk for fALS.

Conclusion

Individuals at-risk for fALS view potential participation in a presymptomatic clinical trial as an actionable measure that may increase their desire for predictive genetic testing. Genetic counselling was identified as a critical component of the predictive testing process given the life-changing implications associated with a positive result. Increased access to genetic counselling, and in a timely manner, is a significant need in the ALS population given potential access to gene-specific therapies in the presymptomatic stage.
Generalizable gesture recognition using magnetomyography
Authors: Yun Richy , Csaky Richard , Dash Debadatta , Gerrard Isabel , Gonzalez Gabriel , Kittle Evan , Taylor David , Soroushmojdehi Rahil , Labanowski Dominic , Deka Nishita
Published: October 2024

The progression of human-computer interfaces into immersive and touchless realities requires new ways of interacting with machines that are correspondingly intuitive and seamless. Among these are gesture-based systems that use natural hand movements to interact with and control digital devices. Today, these systems are most commonly implemented through the use of cameras or inertial sensors, which have drawbacks in environments that are poorly lit, in conditions where the hands are obscured, or for applications that require fine motor control. More recent studies have advocated for the use of surface electromyography (sEMG) to capture gesture information by sensing electrical activity generated by muscle contraction. While promising demonstrations have been shown, studies have also outlined limitations in sEMG when it comes to generalization across a population, largely due to physiological differences between individuals. Magnetomyography (MMG) is an alternative modality for measuring the same motor signals at the muscle, but is impervious to distortions caused by tissue, hair, and moisture; this indicates potential for lower variability caused by physiological differences and changes in skin conductivity, making MMG a promising generalizable solution for gesture control. To test this theory, we developed wristbands with magnetic sensors and implemented a signal processing pipeline for gesture classification. Using this system, we measured MMG across 30 participants performing a gesture task consisting of nine discrete gestures. We demonstrate average single-participant classification accuracy of 95.4%, rivaling state-of-the-art accuracy with sEMG. In addition, we achieved higher cross-session and cross-participant accuracy compared to sEMG studies. Given that these results were obtained with a non-ideal recording system, we anticipate significantly better results with better sensors. Together, these findings suggest that MMG can provide higher performance for control systems based on gesture recognition by overcoming limitations of existing techniques.
Longitudinal analysis of B- and T-cell responses to SARS-CoV-2 recombinant S-protein vaccine S-268019-b in phase 1/2 priming and booster study
Authors: Fujitani Masaya , Lu Xiuyuan , Shinnakasu Ryo , Inoue Takeshi , Kidani Yujiro , Seki Naomi M. , Ishida Satoru , Mitsuki Shungo , Ishihara Takeshi , Aoki Miwa , Suzuki Akio , Takahashi Koji , Takayama Masahiro , Ota Takeshi , Iwata Satoshi , Shibata Risa Yokokawa , Sonoyama Takuhiro , Ariyasu Mari , Kitano Ayumi , Terooatea Tommy , Villa Jordan Kelly , Yamashita Kazuo , Yamasaki Sho , Kurosaki Tomohiro , Omoto Shinya
Published: October 2024

The durability of vaccine-induced immune memory to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is crucial for preventing infection, especially severe disease. This follow-up report from a phase 1/2 study of S-268019-b (a recombinant spike protein vaccine) after homologous booster vaccination confirms its long-term safety, tolerability, and immunogenicity. Booster vaccination with S-268019-b resulted in an enhancement of serum neutralizing antibody (NAb) titers and a broad range of viral neutralization. Single-cell immune profiling revealed persistent and mature antigen-specific memory B cells and T follicular helper cells, with increased B-cell receptor diversity. The expansion of B- and T-cell repertoires and presence of cross-reactive NAbs targeting conserved epitopes within the receptor-binding domain following a booster accounted for the broad-spectrum neutralizing activity. These findings highlight the potential of S-268019-b to provide broad and robust protection against a range of SARS-CoV-2 variants, addressing a critical challenge in the ongoing fight against coronavirus disease 2019 (COVID-19).
Sex differences in the clinical manifestation of autosomal dominant frontotemporal dementia
Authors: Memel Molly , Staffaroni Adam M , Ilan-Gala Ignacio , Castro Jesús Garcia , Kornak John , Tartaglia Carmela M , Saloner Rowan , VandeBunte Anna M , Paolillo Emily W , Cadwallader Claire J , Chen Coty , Gorno-Tempini Maria Luisa , Mandelli Malu , Apostolova Liana , Graff-Radford Neil , Litvan Irene , Bayram Ece , Pressman Peter S , Miyagawa Toji , Mackenzie Ian , Goldman Jill , Darby Richard R. , Appleby Brian S , Petrucelli Len , Gendron Tania , Heuer Hilary W , Forseberg Leah K , Rojas Julio C , Boeve Brad F , Brushaber Nellie , Domoto-Reilly Kimiko , Ghoshal Nupur , Lapid Maria , Pascual Belen , Lee Suzee , Ramos Eliana Marisa , Ramanan Vijay , Rademakers Rosa , Rascovsky Katya , Pantelyat Alex , Masdeu Joseph C , Snyder Allison , Boxer Adam L , Rosen Howard J , Casaletto Kaitlin
Published: October 2024

INTRODUCTION

Sex differences are apparent in neurodegenerative diseases, but have not been comprehensively characterized in frontotemporal dementia (FTD).

METHODS

Participants included 337 adults with autosomal dominant FTD enrolled in the ALLFTD Consortium. Clinical assessments and plasma were collected annually for up to six years. Linear mixed-effects models investigated how sex and disease stage associated with longitudinal trajectories of cognition, function, and neurofilament light chain (NfL).

RESULTS

While sex differences were not apparent at asymptomatic stages, females showed more rapid declines across all outcomes in symptomatic stages compared to males. In asymptomatic participants, the association between baseline NfL and clinical trajectories was weaker in females versus males, a difference that attenuated in symptomatic participants.

DISCUSSION

In genetic FTD, females show cognitive resilience in early disease stages followed by steeper clinical declines later in disease. Baseline NfL may be a less sensitive prognostic tool for clinical progression in females with FTD-causing mutations.
Top-down feedback matters: Functional impact of brainlike connectivity motifs on audiovisual integration
Authors: Tugsbayar Mashbayar , Li Mingze , Muller Eilif B. , Richards Blake
Published: October 2024

Artificial neural networks (ANNs) are an important tool for studying neural computation, but many features of the brain are not captured by standard ANN architectures. One notable missing feature in most ANN models is top-down feedback, i.e. projections from higher-order layers to lower-order layers in the network. Top-down feedback is ubiquitous in the brain, and it has a unique modulatory impact on activity in neocortical pyramidal neurons. However, we still do not understand its computational role. Here we develop a deep neural network model that captures the core functional properties of top-down feedback in the neocortex, allowing us to construct hierarchical recurrent ANN models that more closely reflect the architecture of the brain. We use this to explore the impact of different hierarchical recurrent architectures on an audiovisual integration task. We find that certain hierarchies, namely those that mimic the architecture of the human brain, impart ANN models with a light visual bias similar to that seen in humans. This bias does not impair performance on the audiovisual tasks. The results further suggest that different configurations of top-down feedback make otherwise identically connected models functionally distinct from each other, and from traditional feedforward-only models. Altogether our findings demonstrate that modulatory top-down feedback is a computationally relevant feature of biological brains, and that incorporating it into ANNs affects their behavior and helps to determine the solutions that the network can discover.
A simple action reduces high fat diet intake and obesity in mice
Authors: Barrett M. R. , Pan Y. , Murrell Chantelle , Karolczak Eva O. , Wang Justin , Fang Lisa , Thompson Jeremy M. , Chang Yu-Hsuan , Casey Eric , Czarny J. , So Wang Lok , Reichenbach Alex , Stark Romana , Taghipourbibalan Hamid , Penna Suzanne R. , McCullough Katherine B. , Westbrook Sara , Matikainen-Ankney Bridget , Cazares Victor A , Delevich Kristen , Fobbs Wambura , Maloney Susan , Sutton Hickey Ames , McCutcheon James E. , Andrews Zane , Creed Meaghan C. , Krashes Michael J. , Kravitz Alexxai V.
Published: October 2024

Diets that are high in fat cause over-eating and weight gain in multiple species of animals, suggesting that high dietary fat is sufficient to cause obesity. However, high-fat diets are typically provided freely to animals in obesity experiments, so it remains unclear if high-fat diets would still cause obesity if they required more effort to obtain. We hypothesized that unrestricted and easy access is necessary for high-fat diet induced over-eating, and the corollary that requiring mice to perform small amounts of work to obtain high-fat diet would reduce high-fat diet intake and associated weight gain. To test this hypothesis, we developed a novel home-cage based feeding device that either provided high-fat diet freely, or after mice poked their noses into a port one time – a simple action that is easy for them to do. We tested the effect of this intervention for six weeks, with mice receiving all daily calories from high-fat diet, modifying only how they accessed it. Requiring mice to nose-poke to access high-fat diet reduced intake and nearly completely prevented the development of obesity. In follow up experiments, we observed a similar phenomenon in mice responding for low-fat grain-based pellets that do not induce obesity, suggesting a general mechanism whereby animals engage with and consume more food when it is freely available vs. when it requires a simple action to obtain. We conclude that unrestricted access to food promotes overeating, and that a simple action such as a nose-poke can reduce over-eating and weight gain in mice. This may have implications for why over-eating and obesity are common in modern food environments, which are often characterized by easy access to low-cost unhealthy foods.
Tunable ligand discrimination via kinetic sorting
Authors: Dixit Purushottam , Goetz Andrew , Madsen Ralitsa
Published: October 2024

Kinetic proofreadingis a class of non-equilibrium mechanisms that allow biochemical sensing networks to discriminate between cognate and non-cognate ligands. Proofreading is typically invoked in the context of error correction and therefore is often inflexible in its discrimination in favor of the cognate ligand. This discrimination is achieved when a multi-step and energy consuming reaction pathway is irreversibly restarted with a rate proportional to the thermodynamic stability of the ligand-bound complex. Here, we present a novel non-equilibrium and tunablekinetic sortingmechanism that allows signaling networks to modulate ligand discrimination in direction as well as in magnitude. In our model, the ‘restart cycle’ associated with traditional proofreading is coupled with a topologically distinct and ligand-identity independent cycle, e.g., through receptor degradation or activity-induced desensitization. The signaling network cankinetically sortthe non-equilibrium flux of receptors bound to one of the ligands towards degradation/desensitization and the other through the restart cycle. This preferential diversion of the non-equilibrium flux allows the network to switch its ligand discrimination by altering biochemical processes that are not specific to the identity of the bound ligand, thereby allowing cells to respond to ligands in a context-specific manner. Our model recapitulates several observations related to paradoxical ligand discrimination by the Epidermal Growth Factor pathway. Given the ubiquity of receptor degradation, activity-induced desensitization, and other similar cycles in cellular signaling networks, tunable ligand discrimination usingkinetic sortingis likely to be broadly applicable.
Efficacy of photodynamic therapy using 5-aminolevulinic acid-induced photosensitization is enhanced in pancreatic cancer cells with acquired drug resistance
Authors: Liu Yiran , Mensah Sally Kyei , Farias Sergio , Khan Shakir , Hasan Tayyaba , Celli Jonathan P.
Published: October 2024

The use of 5-aminolevulinic acid (ALA) as a precursor for protoporphyrin IX (PpIX) is an established photosensitization strategy for photodynamic therapy (PDT) and fluorescence guided surgery. Ongoing studies are focused on identifying approaches to enhance PpIX accumulation as well as to identify tumor sub-types associated with high PpIX accumulation. In this study, we investigated PpIX accumulation and PDT treatment response with respect to nodule size in 3D cultures of pancreatic cancer cells (Panc1) and a derivative subline (Panc1OR), which has acquired drug resistance and exhibits increased epithelial mesenchymal transition. In monolayer and 3D culture dose response studies the Panc1OR cells exhibit significantly higher cell killing at lower light doses than the drug naïve cells. Panc1OR also exhibits increased PpIX accumulation. Further analysis of cell killing efficiency per molecule of intracellular PpIX indicates that the drug resistant cells are intrinsically more responsive to PDT. Additional investigation using exogenous delivery of PpIX also shows higher cell killing in drug resistant cells, under conditions which achieve approximately the same intracellular PpIX. Overall these results are significant as they demonstrate that this example of drug-resistant cells associated with aggressive disease progression and poor clinical outcomes, show increased sensitivity to ALA-PDT.
mRNA expression is co-regulated by non-nucleolar RNA polymerase I
Authors: Carter Lucas M , Gong Ruyi , Acosta Nicolas , Li Wing Shun , Pujadas Liwag Emily , Kuo Tiffany , Minh Uyen Phan Lam , MacQuarrie Kyle , Huang Sui , Kanemaki Masato T. , Almassalha Luay , Backman Vadim
Published: October 2024

The relationship between gene transcription and chromatin organization is an area of active study. Due to its role in mRNA synthesis, many studies have focused on the regulaton of RNA polymerase II (Pol-II) function by supranucleosomal structure and vice-versa. In contrast, there is little work on the function of RNA polymerase I (Pol-I) in non-nucleolar chromatin. Prior work has shown that Pol-I engages with components of Pol-II on rDNA, but it’s role in global transcription and chromatin structure beyond the nucleolus has largely been ignored. By pairing auxin-inducible degron technology with nanoscopic imaging, RNA-Seq, and Hi-C, we found that Pol-I and Pol-II co-regulate conformationally defined chromatin domains and mRNA synthesis. Mechanistically, Pol-I maintains the positioning of intronic and intergenic chromatin within domains for the proper expression of exon elements. Consequently, Pol-I loss disrupts genome connectivity,in situchromatin domains, and the expression of mRNA, genome-wide.
A stableNetrin-1fluorescent reporter chicken reveals cell-specific molecular signatures during optic fissure closure
Authors: Chan Brian Ho Ching , Hardy Holly , Requena Teresa , Findlay Amy , Ioannidis Jason , Meunier Dominique , Toms Maria , Moosajee Mariya , Raper Anna , McGrew Mike , Rainger Joe
Published: October 2024

NTN1is expressed in a wide range of developmental tissues and is essential for normal development. Here we describe the generation of a Netrin-1 reporter chicken line (NTN1-T2A-eGFP) by targeting green fluorescent protein into theNTN1locus using CRISPR/Cas9 methodology. Our strategy gave 100% transmission of heterozygous (NTN1T2A-eGFP/+) embryos in which GFP localisation faithfully replicated endogenousNTN1expression in the optic fissure and neural tube floorplate. Furthermore, allNTN1T2A-eGFP/+embryos and hatched birds appeared phenotypically normal. We applied this resource to a pertinent developmental context - coloboma is a structural eye malformation characterised by failure of epithelial fusion during optic fissure closure (OFC) andNTN1is specifically expressed in fusion pioneer cells at the edges of the optic fissure. We therefore optimised the isolation of GFP expressing cells from embryonicNTN1T2A-eGFP/+eyes using spectral fluorescence cell-sorting and applied transcriptomic profiling of pioneer cells, which revealed multiple new OFC markers and novel pathways for developmental tissue fusion and coloboma. This work provides a novel fluorescentNTN1chicken reporter line with broad experimental utility and is the first to directly molecularly characterise pioneer cells during OFC.
Robust Bayesian analysis of animal networks subject to biases in sampling intensity and censoring
Authors: Sosa Sebastian , Brooke McElreath Mary , Redhead Daniel , Ross Cody T.
Published: October 2024

Data collection biases are a persistent issue for studies of social networks. This issue has been particularly important in Animal Social Network Analysis (ASNA), where data are unevenly sampled and such biases may potentially lead to incorrect inferences about animal social behavior. Here, we address the issue by developing a Bayesian generative model, which not only estimates network structure, but also explicitly accounts for sampling and censoring biases. Using a set of simulation experiments designed to reflect various sampling and observational biases encountered in real-world scenarios, we systematically validate our model and evaluate it’s performance relative to other common ASNA methodologies. By accounting for differences in node-level censoring (i.e., the probability of missing an individual interaction.), our model permits the recovery of true latent social connections, even under a wide range of conditions where some key individuals are intermittently unobserved. Our model outperformed all other existing approaches and accurately captured network structure, as well as individual-level and dyad-level effects. Antithetically, permutation-based and simple linear regression aprroaches performed the worst across many conditions. These results highlight the advantages of generative network models for ASNA, as they offer greater flexibility, robustness, and adaptability to real-world data complexities. Our findings underscore the importance of generative models that jointly estimate network structure and adjust for measurement biases typical in empirical studies of animal social behaviour.
Detecting the body’s reproductive hormonal brake against tissue overgrowth: micrin/SgII-70
Authors: Hart John E , Davies Keith G , Mundy Christopher R , Hart Aurelia C , Howlett David R , Newton Russell P
Published: October 2024

A new humoral factor has been detected, within a project aiming to disclose the body’s reproductive hormonal brake against tissue overgrowth, micrin (‘my-crin’). It is hypothesized that micrin braking, gonadal and hypothalamic, is lifted at puberty and wanes with age, bringing on prostatic enlargement and cancers. Factor purification has involved fractionation of ovine and bovine ovarian follicular fluid and blood plasma and serum, with evaluation via rat bioassays in vivo and in vitro. Analysis averse, the molecular effector provided a chemical conundrum. Evidence from mass spectrometry (MS) has been problematic, with spectra from MALDI-TOF, the only productive MS modality, confused by a target polypeptide exhibiting artefacts during processing, storage and MALDI set-up in terms of C-terminal truncation and water losses, together with N-terminal grand fragmentations and dimerizations (factor fragments doubled up). Evidence from chemical sequencing of amino acid (aa) residues was likewise baffling, but consistent with a spiralised depolymerisation within the Edman reaction chamber of a unitary polypeptide. Data decryption has overcome molecular intractability, supported by the results of tryptic digestion and epitope mapping using immunohistochemistry (IHC). The detected inhibitory factor is sleuthed to relate to secretogranin II (SgII), the neurosecretory prohormone, in the form of a secreted acidic 70-aa polypeptide derivative called here SgII-70 (‘sig two seventy’). The product of peptide splicing, micrin/SgII-70 is potentially an amphipathic molecular ampersand (&), with ends entwined (via salt bridging), the knotty totality compromising Edman and MALDI analyses and molecular modelling whilst conferring protease and heat resistance. The two ends of the factor are conceptualised as binding at the same time to a dimeric cellular receptor, to stoichiometric effect, providing fewer smaller cells within a counting mechanism of tissue-mass regulation. Hexapeptide mimetics simulating both ends of the hormone together have been demonstrated in different species and settings, in the cause of antiorganotrophism (tissue reduction) and reproductive modulation. Therapeutic exploitation beckons for mimetics of the body’s hormonal brake, micrin/SgII-70, in tissue overgrowth conditions such as endometriosis, PCOS, BPH and cancer, and in infertility.
Differential composition of lymphocyte subpopulations and activation between the hypertensive Bph/2 and normotensive Bpn/3 mouse strains
Authors: Dattmore Devon , McDonald Paiton , Chowdhury Afrin , Awali Saamera , Boss Allison P. , Jin Yining , Sather Lisa , Lauver D. Adam , Rockwell Cheryl E.
Published: October 2024

Numerous studies point to a role for the immune system in various animal models of hypertension. However, little is known about the immune system of Bph/2 mice, a spontaneously hypertensive strain. To address this, we conducted a comprehensive comparison of immune cell composition and response to polyclonal T cell activation in hypertensive Bph/2 mice and normotensive Bpn/3 control mice. We quantified immune cell populations by flow cytometry from spleen and inguinal, brachial and mesenteric lymph nodes. While composition of myeloid immune cell types was largely comparable between strains, we observed differences in B and T cell subpopulations. Specifically, we found an increased percentage of IgM+ IgDLoand IgM+ IgD-B cells in Bph/2 mice, suggesting greater baseline B cell activation. In addition, we observed a decreased percentage of CD4 effector memory T cells and CD8 central memory T cells. The diminished proportion of memory T cells in Bph/2 mice correlated with decreased proliferation and cytokine response of splenic T cells to polyclonal T cell activation. In splenic T cells from Bph/2 mice 24 h after activation we observed a pronounced decrease in the majority of T cell cytokines. At 120 h after activation, the Th1 and Th17 cytokine responses of splenic T cells from Bph/2 mice were decreased, but other T cell cytokines were largely comparable. Overall, the data suggest a decreased percentage of memory T cells in Bph/2 mice that correlates with markedly diminished proliferation and a reduced cytokine response to polyclonal activation.
Brainstem neurons coordinate the bladder and urethra sphincter for urination
Authors: Li Xing , Li Xianping , Li Jun , Qin Han , Liang Shanshan , Li Jun , Jian Tingliang , Wang Xia , Yin Lingxuan , Yuan Chunhui , Liao Xiang , Jia Hongbo , Chen Xiaowei , Yao Jiwei
Published: October 2024

Urination, a vital and conserved process of emptying urine from the urinary bladder in mammals, requires precise coordination between the bladder and external urethra sphincter (EUS) that is tightly controlled by a complex neural network. However, the specific subpopulation of neurons that accounts for such coordination remains unidentified, limiting the development of target-specific therapies for certain urination disorders, e.g. detrusor-sphincter dyssynergia. Here, we find that cells expressing estrogen receptor 1 (ESR1+) in the pontine micturition center (PMC) initiate voiding when activated and suspend ongoing voiding when suppressed, each at 100% reliability, respectively. Transection of either the pelvic or the pudendal nerve does not impair PMCESR1+control of the downstream target through the other nerve at all. Anatomically, PMCESR1+cells possess two subpopulations projecting to either the pelvic or pudendal nerve and a third, dual-projecting subpopulation, locking in the coordination of bladder contraction and sphincter relaxation in a rigid temporal order. We identify a cell type in the brainstem that controls the bladder-urethra coordination for urination.
Tbc1d15 knockdownin vivoalleviates α-synuclein-induced neurotoxicity by promoting autophagy
Authors: Siddiqi F. H. , Raval N. R. , Palner M. , Nielsen J. E. , Pocock R. , Rubinsztein D. C. , Ejlerskov P.
Published: October 2024

Parkinson’s disease is a neurodegenerative disease, which is associated with accumulation of α-synuclein protein aggregates and Lewy Body formation. These neurotoxic inclusions are especially harmful for dopamine-producing neurons in the substantia nigra of the brain. The cellular degradation system autophagy can reduce neurotoxicity caused by accumulated α-synuclein, by targeting it for degradation. Previously, we demonstrated that human TBC1D15 inhibits autophagyin vitro, resulting in accumulation of neurotoxic protein aggregates. Conversely, lowering the TBC1D15 expression promotes autophagy and degradation of α-synuclein and huntingtin proteins in various cell models. Here we show that knockdown of murine Tbc1d15in vivoactivates autophagy, reduces α-synuclein-mediated neurotoxicity, and improves motor performance. Thus, targeting Tbc1d15 expression may be a therapeutic avenue for neurodegenerative diseases.
ProteusAI: An Open-Source and User-Friendly Platform for Machine Learning-Guided Protein Design and Engineering
Authors: Funk Jonathan , Machado Laura , Bradley Samuel A. , Napiorkowska Marta , Gallegos-Dextre Rodrigo , Pashkova Liubov , Madsen Niklas G. , Webel Henry , Phaneuf Patrick V. , Jenkins Timothy P. , Acevedo-Rocha Carlos G.
Published: October 2024

Abstract

Protein design and engineering are crucial for advancements in biotechnology, medicine, and sustainability. Machine learning (ML) models are used to design or enhance protein properties such as stability, catalytic activity, and selectivity. However, many existing ML tools require specialized expertise or lack open-source availability, limiting broader use and further development. To address this, we developed ProteusAI, a user-friendly and open-source ML platform to streamline protein engineering and design tasks. ProteusAI offers modules to support researchers in various stages of the design-build-test-learn (DBTL) cycle, including protein discovery, structure-based design, zero-shot predictions, and ML-guided directed evolution (MLDE). Our benchmarking results demonstrate ProteusAI’s efficiency in improving proteins and enyzmes within a few DBTL-cycle iterations. ProteusAI democratizes access to ML-guided protein engineering and is freely available for academic and commercial use. Future work aims to expand and integrate novel methods in computational protein and enzyme design to further develop ProteusAI.
Environmental polysulfides promote protein disulfide bond formation of microorganisms growing under anaerobic condition
Authors: Xin Yuping , Wang Qingda , Yang Jianming , Wu Xiaohua , Xia Yongzhen , Xun Luying , Liu Huaiwei
Published: October 2024

Polysulfides are rich in anaerobic and microbial metabolism active environments. Anaerobic survival of microorganisms requires the formation of protein disulfide bond (DSB). The relation between environmental polysulfides and anaerobic DSB formation has not been studied so far. Herein, we discovered that environmental polysulfides can efficiently mediate protein DSB formation of microorganisms under anaerobic condition. We used polysulfides to treat proteins including roGFP2, Trx1, and DsbA under anaerobic condition and found that all three proteins formed intramolecular DSBin vitro. The growth ofE. coliΔdsbBwas reduced and the amount of its intracellular protein DSB was decreased under anaerobic condition. However, treating the mutant strain with polysulfides recovered the growth and reversed DSB decrease. TreatingE. coliΔdsbAwith polysulfides promoted DSB formation of its periplasmic roGFP2 and recovered its growth under anaerobic condition. In addition, treatingSchizosaccharomyces pombewith polysulfides led to increase of the intracellular protein DSB content. Thus, our study reveals that environmental polysulfides can promote DSB formation independent of the enzymatic DSB mediating system and oxygen. In this aspect, environmental polysulfides are beneficial for the survival of microorganisms in anaerobic habitats.

IMPORTANCE

How polysulfides benefit adaption of microorganisms to anaerobic environments are unclear. Our study reveals that environmental polysulfides efficiently facilitate protein DSB formation under anaerobic condition. Polysulfides contain zero valent sulfur atoms (S0), which can be transferred to the thiol group of cysteine residue. This S0atom gets two electrons from two cysteine residues and becomes reduced H2S, leaving two cysteine residues in disulfide bond form. Anaerobic growth of microorganisms was benefited from the formation of DSB. This finding paves the way for a deeper understanding of the intricate relationship between polysulfides and microorganisms in environmental contexts.
Investigation of cell metabolism dysfunction in autism spectrum disorders using genome-scale metabolic network analysis of neuronal development
Authors: Pourmajidian Moohebat , Marashi Sayed-Amir
Published: October 2024

Autism Spectrum Disorders (ASDs) are a group of highly heterogeneous neurodevelopmental conditions characterized by impairments in social interactions and repetitive behaviors. In spite of extensive efforts, known genetic mutations can hardly explain the ASD cases, which signifies the highly heterogeneous nature of ASDs and calls for shifting to a more holistic approach for understanding the mechanism of these disorders. Several studies have reported that a wide range of metabolic markers is present in blood, urine and brain samples of ASD patients. In this study, using transcriptome data of neurons derived from ASD and control individuals, we reconstructed neuron-specific metabolic network models for two neurodevelopmental time points representing late neural progenitor stage and mature neurons. We simulate gene inactivation in these networks to investigate the altered metabolic fluxes and biological pathways in ASD metabolism. We further examine these networks using reporter metabolite analysis to identify those metabolites around which significant gene expression changes occur. Briefly, our model was successful in predicting previously reported metabolites and pathways implicated in ASD metabolism, including oxidative phosphorylation and fatty acid oxidation, and points to a new finding concerning alterations in the less studied pathways like keratan sulfate degradation pathway and N/O-glycosylation in ASD. Finally, by employing the robust metabolic transformation algorithm (rMTA) we set to find potential drug targets that can reverse the ASD metabolic state into a healthy one. Interestingly, our model found phosphatidic phosphatase enzyme, as well as phosphatidylethaolamine and phosphatidylserine transfer proteins as targets that could recover the healthy metabolic state.
Decreased hippocampal neurite density in middle-aged/aging adults following prenatal exposure to higher levels of maternal inflammation
Authors: Mohyee Raana A. , Elliott Blake L. , Pike Madeline R. , Smith Emma , Kring Ann M. , Olson Ingrid R. , Breen Elizabeth C. , Cohn Barbara A. , Cirillo Piera M. , Krigbaum Nickilou Y. , Olino Thomas M. , D’Esposito Mark , Cogan Ashby B. , Patwardan Bhakti P. , Ellman Lauren M.
Published: October 2024

In animal models, exposure to heightened maternal inflammation in utero is associated with altered offspring hippocampal development, including reduced dendritic arborization and density. However, the effects of prenatal maternal inflammation (PNMI) on offspring hippocampal microstructure in humans remains unclear. Here, we examined the relationship between exposure to PNMI and neurite density in the hippocampus and its subfields among offspring during late middle age. Participants included 72 mother-offspring dyads from the Child Health and Development Studies (CHDS) cohort. Data for four inflammatory biomarkers (IL-6, IL-8, IL-1 receptor antagonist [IL-1RA], and soluble TNF receptor-II [sTNF-RII]) were available from first and second trimester maternal sera. Neurite density in the offspring hippocampus and its subfields was estimated using microstructural modeling of offsprings’ diffusion-weighted Magnetic Resonance Imaging data (mean age of offspring at imaging = 59 years; 51% male). We estimated the relationship between each biomarker and region-of-interest’s neurite density. Higher first trimester maternal IL-1RA and IL-6 levels were associated with lower offspring hippocampal neurite density. These relationships were specific to the CA3, CA4, dentate gyrus, and subiculum subfields. In addition, higher second trimester IL-6 was associated with lower subiculum neurite density. Our findings reveal that exposure to heightened prenatal levels of maternal inflammation is linked to altered offspring hippocampal microstructure in late middle age, which could have implications for memory decreases during this period and may be relevant for understanding risk of aging-related cognitive changes.

Significance Statement

The contribution of prenatal maternal inflammation (PNMI) to offspring brain microstructure in later life is well established in animal models, but poorly understood in humans. Our study discovered long-lasting impacts of elevated PNMI during early-mid gestation on the structural integrity of the hippocampus in offspring during late middle age. Our findings underscore the potential role of developmental programming in aging-related neurological and cognitive decline, as the observed degradation in hippocampal microstructure is present over half a century following exposure.
TYK2 inhibition enhances Treg differentiation and function while preventing Th1 and Th17 differentiation
Authors: Tuomela Karoliina , Garcia Rosa V. , Boardman Dominic A. , Tavakoli Pedram , Ancheta-Schmit Maria , Sham Ho Pan , Cheng Lihong , Struthers Mary , Bressler Brian , Vallance Bruce A. , Zhao Qihong , Levings Megan K.
Published: October 2024

Janus kinase (JAK) inhibitors are widely use to inhibit inflammatory cytokine signalling in autoimmune and inflammatory diseases but their effect on regulatory T cells (Tregs) is poorly characterized. We investigated the effect of JAK inhibition on human Treg differentiation, phenotype, and function using a JAK inhibitor, upadacitinib, in comparison to BMS-986202, a selective Tyrosine kinase 2 (TYK2) inhibitor. Both upadacitinib and BMS-986202 blocked the differentiation of naïve CD4+T cells into Th1 and Th17 cells, but only BMS-986202 spared IL-2 signalling and Treg differentiation. BMS-986202 also increased Treg suppressive function and stability under Th1- and Th17-polarizing conditions, whereas upadacitinib significantly impaired the phenotype and viability ofex vivoTregs. Analysis of lamina propria mononuclear cells from patients with inflammatory bowel disease revealed that, under Th17 polarizing conditions, BMS-986202 redirected CD4+T cells towards a Treg phenotype. The Treg-sparing and enhancing properties of TYK2 inhibition suggest that TYK2 inhibitors are a promising pharmacological approach for tolerance induction.

eTOC SUMMARY

Tuomela et al. report that TYK2 inhibition does not affect human Treg induction from naïve CD4+T cells, promotes Treg differentiation in lamina propria-derived T cells, and increases blood-derived Treg stability/function. In contrast, JAK inhibition strongly impairs Treg function.
Reconstruct a Connectome of Single Neurons in Mouse Brains by Cross-Validating Multi-Scale Multi-Modality Data
Authors: Xiong Feng , Liu Lijuan , Peng Hanchuan
Published: October 2024

Brain networks, often referred to as connectomes, are crucial to findings in brain science and have inspired the development of numerous technologies at macro-, meso-, and micro-scales. With the growing prevalence of single-cell analysis, there is an urgency to generate connectomes of individual neurons that project to brain-wide regions. This work reports a scalable approach to build neuron connection networks of mouse brains by mapping whole-brain single-neuron connectivity using two complementary methods at sub-neuronal levels. We first generated an arbor-net by partitioning and probabilistically pairing dendritic and axonal arbors of 20,247 neurons registered to the Allen Brain Atlas. We also produced a bouton-net based on 2.57 million putative boutons detected along single axons of 1,877 fully reconstructed neurons and probabilistic pairing of these full-morphology datasets. Our cross-validation of both the arbor-net and bouton-net showed statistical consistency in the spatially and anatomically modular distributions of neuronal connections, which also corresponded to functional modules of the mouse brain. Our single-neuron connections were also validated by two existing independent connectomes of coarser resolution based on viral tracing of neuron populations and barcoding-and-sequencing, as well as an independent synaptome containing the relative density distribution of synapses. We further found that single neuronal connections correlated more strongly with gene co-expression at both the brain region and single-cell levels than the previous full-brain mesoscale connectome of a mouse brain. Our findings allow the assembly of a new whole-brain scale single-neuron resolution connectome for all brain regions, called SEU-net. We studied the properties of our connectomes in comparison with other potential brain architectures and found a series of non-random subnetwork patterns in the form of consistent triad motifs. Overall, our data indicate a rich granularity and strong modular diversity in the brain networks of mice.