bluuebunny/crossref_metadata_2025 huggingface dataset:
Short-term effects and safety of a natural oral supplement containing glucosinolates, phytosterols, and citrus flavonoids compared with hormone treatment for the management of postmenopausal symptomatic women: a pilot single-center randomized phase 2 clinical trial
Authors: Villar-López Martha , Soto-Becerra Percy , Chedraui Peter , Osorio-Manyari Joel D. , Al-kassab-Córdova Ali , Osorio-Manyari Angel A. , Fernandez-Sosaya José L. , Moya-Silvestre Edith , Rojas Percy A. , Lugo-Martínez Gabriela , Mezones-Holguín Edward
Published: October 2023

Objective

This study aimed to evaluate the short-term efficacy and safety of an oral herbal supplement containing glucosinolates, phytosterols, and citrus flavonoids for menopausal symptoms in comparison with estrogen plus progestogen therapy (EPT) among postmenopausal women.

Methods

This was a pilot single-blinded, three-armed phase II randomized clinical trial, controlled with EPT. Sixty participants were randomly assigned to receive treatment for 3 months: (1) an oral herbal supplement of 1,500 mg/d (G1, n = 20), (2) an oral herbal supplement of 3,000 mg/d (G2, n = 20), or (3) conjugated equine estrogens 0.625 mg/d plus medroxyprogesterone acetate of 5 mg/d (EPT group, n = 20). The primary endpoint was the intensity of menopausal symptoms as measured using the Menopause-Specific Quality of Life Questionnaire (global and domain scores). The Menopause-Specific Quality of Life Questionnaire uses a 7-point scale to rate the symptom intensity, with higher scores indicating severity. The secondary endpoints were hormonal, lipid, and safety profiles.

Results

Fifty-four participants (n = 54) completed the study. The mean, model-estimated, and global menopausal symptom scores at 3 months were 85.8 in the EPT group, 61.3 in G1, and 62.5 in G2. Participants treated with the herbal compound had lower global (13.7 [6.9-20.4], P < 0.001) and physical symptom scores (6.6 [1.6-11.5], P = 0.002) on the second month and lower psychosocial symptom scores (3.8 [1.3 to 6.3], P < 0.001) on the third month of follow-up, compared with EPT. Conversely, participants receiving EPT showed better outcomes on vasomotor symptoms since the first month of treatment (−6.1 [−8.3 to −4.0], P < 0.001). The EPT group exhibited higher values of estradiol and lower follicle-stimulating hormone and luteinizing hormone since the first month of follow-up. Also, total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol were significantly higher in this group than in G2.

Conclusions

In this small single-blind exploratory trial, the oral herbal supplement was more efficacious in reducing global, physical, and psychosocial menopausal symptoms in the short term than EPT. However, further studies are needed to adequately assess the efficacy and safety of this herbal supplement in the treatment of menopausal symptoms.
FMO2 ameliorates nonalcoholic fatty liver disease by suppressing ER-to-Golgi transport of SREBP1
Authors: Ke Changle , Xiao Changchen , Li Jiamin , Wu Xianpeng , Zhang Yu , Chen Yongjian , Sheng Shuyuan , Fu Zaiyang , Wang Lingjun , Ni Cheng , Zhao Jing , Shi Yanna , Wu Yan , Zhong Zhiwei , Nan Jinliang , Zhu Wei , Chen Jinghai , Wu Rongrong , Hu Xinyang
Published: October 2023

Background and Aims:

NAFLD comprises a spectrum of liver disorders with the initial abnormal accumulation of lipids in hepatocytes called NAFL, progressing to the more serious NASH in a subset of individuals. Our previous study revealed that global flavin-containing monooxygenase 2 (FMO2) knockout causes higher liver weight in rats. However, the role of FMO2 in NAFLD remains unclear. Herein, we aimed to determine the function and mechanism of FMO2 in liver steatosis and steatohepatitis.

Approach and Results:

The expression of FMO2 was significantly downregulated in patients with NAFL/NASH and mouse models. Both global and hepatocyte-specific knockout of FMO2 resulted in increased lipogenesis and severe hepatic steatosis, inflammation, and fibrosis, whereas FMO2 overexpression in mice improved NAFL/NASH. RNA sequencing showed that hepatic FMO2 deficiency is associated with impaired lipogenesis in response to metabolic challenges. Mechanistically, FMO2 directly interacts with SREBP1 at amino acids 217–296 competitively with SREBP cleavage-activating protein (SCAP) and inhibits SREBP1 translocation from the endoplasmic reticulum (ER) to the Golgi apparatus and its subsequent activation, thus suppressing de novo lipogenesis (DNL) and improving NAFL/NASH.

Conclusions:

In hepatocytes, FMO2 is a novel molecule that protects against the progression of NAFL/NASH independent of enzyme activity. FMO2 impairs lipogenesis in high-fat diet-induced or choline-deficient, methionine-deficient, amino acid-defined high-fat diet-induced steatosis, inflammation, and fibrosis by directly binding to SREBP1 and preventing its organelle translocation and subsequent activation. FMO2 thus is a promising molecule for targeting the activation of SREBP1 and for the treatment of NAFL/NASH.
Prevalence of FXII-Deficiency and Its Relevance to Monitoring Anticoagulation in Adults Receiving Extracorporeal Membrane Oxygenation
Authors: Brock Roman , Kornfehl Andrea , Staudinger Thomas , Schellongowski Peter , Quehenberger Peter , Schwameis Michael , Buchtele Nina
Published: October 2023

During extracorporeal membrane oxygenation (ECMO) blood is exposed to artificial surfaces, resulting in contact activation of the intrinsic coagulation pathway initiated by coagulation factor XII (FXII). Little is known about the prevalence of acquired FXII-deficiency, especially during ECMO. The primary outcome was the prevalence of acquired FXII-deficiency (FXII activity <60%) during ECMO. Secondary outcomes included differences in hemorrhagic/thromboembolic complications, doses of unfractionated heparin administered, and time points of anticoagulation within target ranges between patients with and without FXII-deficiency. Of 193 adults receiving ECMO therapy between 2013 and 2021, FXII testing was performed in 64 (33%) patients. Of these, 89% (n = 57) had an acquired FXII-deficiency. Median complication-free intervals were not different between patients with and without acquired FXII-deficiency (bleeding: 28 days [6–145] vs. 12 days [11–not available], p = 0.85; thromboembolism: 16 days [8–54] vs. 13 days [3–15], p = 0.053). Patients with acquired FXII-deficiency received less heparin (16,554 IU/day vs. 25,839 IU/day; p = 0.009) and were less likely to be within aPTT-target ranges (23.1% [14.3%–36.4%] vs. 37.8% [33.7%–58.3%], p = 0.005). Acquired FXII-deficiency is common during ECMO and may affect monitoring of anticoagulation. The impact of FXII-activity on complications needs to be determined in future studies.
International Communication of Acupuncture and Moxibustion Popular in the West
Authors: Qiao Huijun , Liu Jingyuan , Hu Weiguo , Yang Yuyang
Published: October 2023

With the development of TCM acupuncture and moxibustion, research on acupuncture and moxibustion in the western world is deepening. The concept of acupuncture and moxibustion popular in the West is formed. By investigating the localization of acupuncture and moxibustion in the western world， this paper introduces several kinds of acupuncture and moxibustion popular in the West and concludes the spread of acupuncture and moxibustion popular in the West through hospitals and clinics, academic works, social organizations, education and training. This paper provides a global vision developing domestic acupuncture and moxibustion and promoting academic prosperity and technical progress of world acupuncture and moxibustion system.
Symptomatic flatfoot in cerebral palsy
Authors: Lenhart Rachel L. , Goodbody Christine M.
Published: October 2023

Purpose of review

The purpose of this review is to evaluate the current literature and best practices in the evaluation and treatment of symptomatic flatfoot in cerebral palsy.

Recent findings

While techniques to reconstruct the neuromuscular flatfoot and reestablish bony levers have remained similar over time, the concept of surgical dosing has helped guide appropriate interventions based on the magnitude of disease and functional level of the child. Moreover, the utilization of multisegment foot modeling in motion analysis has allowed quantitative description of such deformities and their impact on gait.

Future research should focus on refining operative indications and interventions with larger, multicenter, prospective cohorts to provide more robust evidence in surgical decision making. Long-term data are needed to confirm and compare efficacy of procedures. Radiographic data alone are not sufficient for describing functional foot position. Gait analysis with foot modeling and pedobarography along with patient-centered subjective outcomes will be needed in such investigations to make conclusive recommendations.
Innovations in Nursing Workforce Management
Authors: Blouin Ann Scott
Published: October 2023

Addressing the current and future nursing workforce shortage is the most pressing topic on healthcare leaders' agenda. The pandemic worsened a looming problem, driven both by supply and demand. Classic strategies deployed in past shortages are useful but are not sufficient to guide scarce resource management in the future. Emerging innovative technology solutions, carefully selected and evaluated, can supplement and enhance past strategies.
Male responses to sperm competition risk associated with increased macronutrient intake and reduced lifespan
Authors: Simmons Leigh W. , Chan Hwei-Ling
Published: October 2023

Increased expenditure on the ejaculate is a taxonomically widespread male response to sperm competition. Increased ejaculate expenditure is assumed to come at a cost to future reproduction, otherwise males should always invest maximally. However, the life-history costs of strategic ejaculation are not well documented. Macronutrient intake is known to affect the trade-off between reproduction and lifespan. Intakes of protein and carbohydrate that maximize reproduction often differ from those that maximize lifespan. Here, we asked whether strategic expenditure on the ejaculate by male crickets,Teleogryllus oceanicus, is mediated by macronutrient intake, and whether it comes at a cost of reduced lifespan. Males were exposed to rival song throughout their lifespan or were held in a silent non-competitive environment. Males exposed to song had a higher intake of both protein and carbohydrate, they reached adulthood sooner, produced ejaculates of higher quality, and died sooner than males living in a silent environment. Our findings provide a rare example of both the mechanisms and life-history costs associated with strategic ejaculation.
The Impact of Continuous Positive Airway Pressure Therapy on the Recurrence of Atrial Fibrillation in Patients with Obstructive Sleep Apnea after pulmonary vein isolation
Authors: Fan Jun , Sun Shao-Xi , Cao Li-li , Luo Shao-ling , Wang Shao-hua , Li Wei-jie , Pan Yi-chao , Wu Tian-yuan , Liu Jian , Yu Bing-Bo
Published: October 2023

Background

Despite the recognized risk of atrial fibrillation (AF) recurrence after pulmonary vein isolation (PVI) in patients with obstructive sleep apnea (OSA), the effect of continuous positive airway pressure (CPAP) remains inconsistent across studies, necessitating further examination.

Methods

Utilizing databases encompassing Web of Science, Pubmed and OVID, we implemented a meta-analysis dedicated to investigating the role of OSA in post-PVI AF recurrence and the preventative properties of CPAP.

Results

Our meta-analysis of OSA patients undergoing PVI suggests an AF recurrence risk with a RR (risk ratio) of 1.67 (95% CI: 1.52-1.83). For patients with no atrial size difference, the risk is RR=2.13 (95% CI: 1.63-2.79), and with size difference, it’s RR=1.78 (95% CI: 1.46-2.17). Diagnoses from the Berlin questionnaire and polysomnography yielded RRs of 1.71 (95% CI: 1.37-2.14) and 1.75 (95% CI: 1.40-2.18), respectively. Non-CPAP usage increases AF recurrence risk by 67% and especially in cases of significant atrial size difference (RR=1.63, 95%CI:1.32-2.03). Conversely, when atrial size difference is absent, the impact of CPAP appears to be insignificant (RR=1.22, 95%CI: 0.98-3.02). Co-existence of paroxysmal and non-paroxysmal AF indicates a significant CPAP effect (RR=1.78, 95% CI: 1.50-2.09), contrary to one study on paroxysmal AF patients (RR=1.3, 95%CI: 0.71-1.50).

Conclusion

Our meta-analysis found a significant risk of AF recurrence in patients with OSA following PVI. However, OSA had an insignificant impact on AF recurrence in paroxysmal AF patients. Non-CPAP usage generally increased recurrence risk. Yet, in subgroups without prominent atrial size difference and paroxysmal AF, CPAP’s influence was not significant. Keywords: CPAP; Atrial Fibrillation; Obstructive Sleep Apnea; Pulmonary vein isolation
Diagnostic and prognostic value of the gasdermins in gastric cancer
Authors: Xu Yeqiong , Wan Chuandan , Wang Ping , Gu yulan
Published: October 2023

Background

Pyroptosis has been drawn attention owing to its contributory role in various cancers. Recently, the participator of pyroptosis, gasdermins (GSDMs) have been reported associated with of multiple types of cancers. However, the role of GSDMs expression in diagnosis and prognosis of gastric cancer (GC) has not been well elucidated. Moreover, the mechanisms underlying the carcinogenesis of GC are still obscure.

Methods

Herein we analyzed the transcriptional, prognostic information and the role of GSDMs in patients with GC from TIMER, UALCAN, Human Protein Atlas (HPA), GEPIA and Kaplan-Meier plotter databases. The cBioPortal online tool was used to analyze the GSDMs alterations, correlations, and networks. Furthermore, String, Cytoscape and TIMER were conducted to explore the functional enrichment and immune modulation. The statistical analysis was carried out in the R environment, andP-value < 0.05 was considered statistically significant.

Results

GSDMB, GSDMC, GSDMD, GSDME were with higher expression in GC than normal tissue in TIMER database. Moreover, survival analyses via two databases both demonstrated that high expression of GSDME was related to shorter overall survival (OS) in patients with GC. Additionally, functional enrichment revealed that GSDMs might be involved in endopeptidase activity, peptidase regulator activity, cysteine-type peptidase activity. Besides, GSDMs were correlated with infiltration levels of immune cells in GC, and GSDME was correlated with the infiltrating level of CD4+ T, CD8+ T, neutrophils, macrophages and dendritic cells.

Conclusions

The study systematically indicated the potential diagnostic and prognostic value of GSDMs in GC. Our results showed that GSDME might play a considerably oncogenic role in GC diagnosis and prognosis. However, our bioinformatics analyses should be further validated in more prospective studies.
A Deep Dive into Single-Cell RNA Sequencing Foundation Models
Authors: Boiarsky Rebecca , Singh Nalini , Buendia Alejandro , Getz Gad , Sontag David
Published: October 2023

Large-scale foundation models, which are pre-trained on massive, unlabeled datasets and subsequently fine-tuned on specific tasks, have recently achieved unparalleled success on a wide array of applications, including in healthcare and biology. In this paper, we explore two foundation models recently developed for single-cell RNA sequencing data, scBERT and scGPT. Focusing on the fine-tuning task of cell type annotation, we explore the relative performance of pre-trained models compared to a simple baseline, L1-regularized logistic regression, including in the few-shot setting. We perform ablation studies to understand whether pretraining improves model performance and to better understand the difficulty of the pre-training task in scBERT. Finally, using scBERT as an example, we demonstrate the potential sensitivity of fine-tuning to hyperparameter settings and parameter initializations. Taken together, our results highlight the importance of rigorously testing foundation models against well established baselines, establishing challenging fine-tuning tasks on which to benchmark foundation models, and performing deep introspection into the embeddings learned by the model in order to more effectively harness these models to transform single-cell data analysis. Code is available athttps://github.com/clinicalml/sc-foundation-eval.
High pathogenicity avian influenza A (H5N1) clade 2.3.4.4b virus infection in a captive Tibetan black bear (Ursus thibetanus): investigations based on paraffin-embedded tissues, France, 2022
Authors: Bessière Pierre , Gaide Nicolas , Croville Guillaume , Crispo Manuela , Fusade-Boyer Maxime , Abou Monsef Yanad , Dirat Malorie , Beltrame Marielle , Dendauw Philippine , Lemberger Karin , Guérin Jean-Luc , Le Loc’h Guillaume
Published: October 2023

High pathogenicity avian influenza viruses H5Nx (HPAIVs) of clade 2.3.4.4b have been circulating increasingly in both wild and domestic birds in recent years. In turn, this has led to an increase in the number of spillovers events affecting mammals. In November 2022, a HPAIV H5N1 caused an outbreak in a zoological park in the south of France, resulting in the death of a Tibetan black bear (Ursus thibetanus) and several captive and wild bird species. We detected the virus in various tissues of the bear and a wild black-headed gull found dead in its enclosure using histopathology, two differentin-situdetection techniques and next generation sequencing, all performed on formalin fixed paraffin embedded tissues. Phylogenetic analysis performed on HA gene segment showed that bear and gull strains shared 99.998% genetic identity, making the bird strain the closest related one. We detected the PB2 E627K mutation in minute quantities in the gull, whereas it predominated in the bear, which suggests that this mammalian adaptation marker was selected during the bear infection. Our results provide the first molecular and histopathological characterization of an H5N1 virus infection in this bear species.
Assessing Perceptual Chromatic Equiluminance Using a Reflexive Pupillary Response
Authors: Ye Liu , Mahony Bridget W. , Wang Xiaochun , Daye Pierre , Wang Wei , Cavanagh Patrick , Pouget Pierre , Andolina Ian Max
Published: October 2023

Equiluminant stimuli help assess the integrity of colour perception and the relationship of colour to other visual features. As a result of individual variation, it is necessary to calibrate experimental visual stimuli to suit each individual’s unique equiluminant ratio. Most traditional methods rely on training observers to report their subjective equiluminance point. Such paradigms cannot easily be implemented on pre-verbal or non-verbal observers. Here, we present a novel Pupil Frequency-Tagging Method (PFTM) for detecting a participant’s unique equiluminance point without verbal instruction and with minimal training. PFTM analyses reflexive pupil oscillations induced by slow (< 2 Hz) temporal alternations between coloured stimuli. Two equiluminant stimuli will induce a similar pupil dilation response regardless of colour; therefore, an observer’s equiluminant point can be identified as the luminance ratio between two colours for which the oscillatory amplitude of the pupil at the tagged frequency is minimal. We compared pupillometry-based equiluminance ratios to those obtained with two established techniques in humans: minimum flicker and minimum motion. In addition, we estimated the equiluminance point in non-human primates, demonstrating that this new technique can be successfully employed in non-verbal subjects.

Key Points

Measuring equiluminance is challenging in non-verbal subjects.

The pupil diameter varies as perceived brightness changes.

Utilising oscillatory pupillometry, PFTM provides a way to measure equiluminance points without training or the need for a subjective report.
First Genome-Scale Metabolic Modeling ofBrucella abortusPredicts Pathogen Gene Essentiality and New Drug Target
Authors: Pinto Bruno Ribeiro , Guimarães de Oliveira Filipe Vilaça , Fernandes Miquéias , Ranieri Lima Alex Jerônimo , de Oliveira Mendes Tiago Antônio
Published: October 2023

Bovine brucellosis, a globally widespread disease, imposes substantial economic burdens on livestock production. The pathogen,Brucella abortus, has a particular affinity for infecting cattle and can also impact humans, potentially posing a public health risk in regions where the disease persists. To gain a deeper understanding of the pathogen’s biology and its interactions with the host, Pathogen-specific Genome-Scale Metabolic Models offer valuable insights. They aid in identifying novel pharmacological targets and biomarkers, which can inform innovative brucellosis control strategies. In this study, we developed and validated the first Genome-Scale Metabolic Model ofB. abortus2308, named iBP932, encompassing 932 genes, 1,140 reactions, and 999 metabolites. Furthermore, iBP932 capability to predict potential drug targets was demonstrated.
It’s not the spoon that bends: Internal states of the observer determine serial dependence
Authors: Ozkirli Ayberk , Pascucci David
Published: October 2023

Traditional views suggest that human perception handles uncertainty using optimal strategies. For instance, when prior stimuli are more reliable than current ones, perceptual decisions rely more on the past, leading to stronger serial dependence. Here, we report findings that challenge this view. We asked human observers to reproduce the average orientation of an ensemble of stimuli under varying stimulus uncertainty. Contrary to optimal strategies, we found that serial dependence is stronger when prior stimuli are more uncertain. We hypothesize that fluctuations in stimulus uncertainty may influence internal states of observers, such as participants expectations about uncertainty and beliefs about their own performance. A striking finding is that manipulating these internal states through rigged feedback can yield drastic effects on serial dependence, even when external input (i.e., stimulus uncertainty) remained constant. Our findings suggest that phenomena like serial dependence can be better understood by considering internal states of the observer, beyond fixed computations and optimal strategies.
Mammalian circadian clock proteins form dynamic interacting microbodies distinct from phase separation
Authors: Xie Pancheng , Xie Xiaowen , Ye Congrong , Dean Kevin M. , Laothamatas Isara , Taufique S K Tahajjul , Takahashi Joseph , Yamazaki Shin , Xu Ying , Liu Yi
Published: October 2023

Liquid-liquid phase separation (LLPS) underlies diverse biological processes. Because most LLPS studies were performed in vitro or in cells that overexpress protein, the physiological relevance of LLPS is unclear. PERIOD proteins are central mammalian circadian clock components and interact with other clock proteins in the core circadian negative feedback loop. Different core clock proteins were previously shown to form large complexes. Here we show that when transgene was stably expressed, PER2 formed nuclear phosphorylation-dependent LLPS condensates that recruited other clock proteins. Super-resolution microscopy of endogenous PER2, however, revealed formation of circadian-controlled, rapidly diffusing microbodies that were resistant to protein concentration changes, hexanediol treatment, and loss of phosphorylation, indicating that they are distinct from the LLPS condensates caused by overexpression. Surprisingly, only a small fraction of endogenous PER2 microbodies transiently interact with endogenous BMAL1 and CRY1, a conclusion that was confirmed in cells and in mice tissues, suggesting an enzyme-like mechanism in the circadian negative feedback process. Together, these results demonstrate that the dynamic interactions of core clock proteins is a key feature of mammalian circadian clock mechanism and the importance of examining endogenous proteins in LLPS and circadian studies.
CryoTransformer: A Transformer Model for Picking Protein Particles from Cryo-EM Micrographs
Authors: Dhakal Ashwin , Gyawali Rajan , Wang Liguo , Cheng Jianlin
Published: October 2023

Cryo-electron microscopy (cryo-EM) is a powerful technique for determining the structures of large protein complexes. Picking single protein particles from cryo-EM micrographs (images) is a crucial step in reconstructing protein structures from them. However, the widely used template-based particle picking process requires some manual particle picking and is labor-intensive and time-consuming. Though machine learning and artificial intelligence (AI) can potentially automate particle picking, the current AI methods pick particles with low precision or low recall. The erroneously picked particles can severely reduce the quality of reconstructed protein structures, especially for the micrographs with low signal-to-noise (SNR) ratios. To address these shortcomings, we devised CryoTransformer based on transformers, residual networks, and image processing techniques to accurately pick protein particles from cryo-EM micrographs. CryoTransformer was trained and tested on the largest labelled cryo-EM protein particle dataset - CryoPPP. It outperforms the current state-of-the-art machine learning methods of particle picking in terms of the resolution of 3D density maps reconstructed from the picked particles as well as F1-score and is poised to facilitate the automation of the cryo-EM protein particle picking.
Fast myosin binding protein C knockout in skeletal muscle alters length-dependent activation and myofilament structure
Authors: Hessel Anthony L. , Kuehn Michel , Han Seong-Won , Ma Weikang , Irving Thomas C. , Momb Brent A. , Song Taejeong , Sadayappan Sakthivel , Linke Wolfgang A. , Palmer Bradley M.
Published: October 2023

In striated muscle, some sarcomere proteins regulate crossbridge cycling by varying the propensity of myosin heads to interact with actin. Myosin-binding protein C (MyBP-C) is bound to the myosin thick filament and is predicted to interact and stabilize myosin heads in a docked position against the thick filament and limit crossbridge formation, the so-called OFF state. Via an unknown mechanism, MyBP-C is thought to release heads into the so-called ON state, where they are more likely to form crossbridges. To study this proposed mechanism, we used the C2-/-mouse line to knock down fast-isoform MyBP-C completely and total MyBP-C by ∼24%, and conducted mechanical functional studies in parallel with small-angle X-ray diffraction to evaluate the myofilament structure. We report that C2−/−fibers presented deficits in force production and reduced calcium sensitivity. Structurally, passive C2-/-fibers presented altered SL-independent and SL-dependent regulation of myosin head ON/OFF states, with a shift of myosin heads towards the ON state. Unexpectedly, at shorter sarcomere lengths, the thin filament was axially extended in C2-/-vs. non-transgenic controls, which we postulate is due to increased low-level crossbridge formation arising from relatively more ON myosins in the passive muscle that elongates the thin filament. The downstream effect of increasing crossbridge formation in a passive muscle on contraction performance is not known. Such widespread structural changes to sarcomere proteins provide testable mechanisms to explain the etiology of debilitating MyBP-C-associated diseases.
Ribosome demand links transcriptional bursts to protein expression noise
Authors: Pal Sampriti , Ray Upasana , Dhar Riddhiman
Published: October 2023

Stochastic variation in protein expression generates phenotypic heterogeneity in a cell population and has an important role in antibiotic persistence, mutation penetrance, tumor growth and therapy resistance. Studies investigating molecular origins of noise have predominantly focused on the transcription process. However, the noise generated in the transcription process is further modulated by translation. This influences the expression noise at the protein level which eventually determines the extent of phenotypic heterogeneity in a cell population. Studies across different organisms have revealed a positive association between translational efficiency and protein noise. However, the molecular basis of this association has remained unknown. In this work, through stochastic modeling of translation in single mRNA molecules and empirical measurements of protein noise, we show that ribosome demand associated with high translational efficiency in a gene drives the correlation between translational efficiency and protein noise. We also show that this correlation is present only in genes with bursty transcription. Thus, our work reveals the molecular basis of how coding sequence of genes, along with their promoters, can regulate noise. These findings have important implications for investigating protein noise and phenotypic heterogeneity across biological systems.
Mu opioid receptors gate the locus coeruleus pain generator
Authors: Norris Makenzie R. , Kuo Chao-Cheng , Dunn Samantha S. , Kim Jenny R. , Becker Léa J. , Borges Gustavo , Thang Loc V. , Parker Kyle E. , McCall Jordan G.
Published: October 2023

The locus coeruleus (LC) plays a paradoxical role in chronic pain. Although largely known as a potent source of endogenous analgesia, increasing evidence suggests injury can transform the LC into a chronic pain generator. We sought to clarify the role of this system in pain. Here, we show optogenetic inhibition of LC activity is acutely antinociceptive. Following long-term spared nerve injury, the same LC inhibition is analgesic – further supporting its pain generator function. To identify inhibitory substrates that may naturally serve this function, we turned to endogenous LC mu opioid receptors (LC-MOR). These receptors provide powerful LC inhibition and exogenous activation of LC-MOR is antinociceptive. We therefore hypothesized that endogenous LC-MOR-mediated inhibition is critical to how the LC modulates pain. Using cell type-selective conditional knockout and rescue of LC-MOR receptor signaling, we show these receptors bidirectionally regulate thermal and mechanical hyperalgesia – providing a functional gate on the LC pain generator.
No evidence of “social immune memory” in Acorn ants (Temnothoax nylanderi)
Authors: Robinson Jaya , Pull Christopher D.
Published: October 2023

Social organisms are predicted to experience higher rates of infectious disease, as the likelihood of transmission increases with higher spatial and temporal proximity of potential hosts. In social insects, this risk is counteracted through a social immune system, where altruistic and collective anti-pathogen behaviours reduce or eliminate the impact of disease at the colony, or ‘superorganism’, level. Superorganismal immune strategies are often analogous to immune responses in metazoan organisms, suggesting that disease may have played a crucial role in shaping multiple major evolutionary transitions. In this study, we investigated whether acorn ants use prior experience with a pathogen to perform more efficient social immunity behaviours upon pathogen reencounter, a potential parallel to metazoan immune memory that we term ‘social immune memory’. UsingTemnothorax nylanderiants, we created experience with the fungal pathogenMetarhizium brunneumboth individually and in groups, to investigate the effect of prior experience when presented with the same pathogen. We further examined the effect of prior pathogen experience when groups of ants differ in their pathogen-experience levels. We found no evidence for social immune memory in our experiments, suggesting positive results in previous studies may be due to sublethal infections, rather than cognitive effects. Alternatively, ants may employ different immune defence strategies depending on context or species, with potential differences in immune system flexibility across major evolutionary scales.
Prdm1 Positively Regulates Liver Group 1 ILCs Cancer Immune Surveillance and Preserves Functional Heterogeneity
Authors: He Jitian , Gao Le , Wang Peiying , Chan Wing Keung , Zheng Yiran , Zhang Yumo , Sun Jiaman , Li Xue , Wang Jiming , Li Xiaohong , Chen Huaiyong , Yang Zhouxin , Wang Youwei
Published: October 2023

Group 1 innate lymphoid cells (ILCs) comprise conventional natural killer (cNK) cells and type 1 innate lymphoid cells (ILC1s). The main functions of liver cNK cells and ILC1s not only include directly killing target cells but also regulating local immune microenvironment of the liver through the secretion of cytokines. Uncovering the intricate mechanisms by which transcriptional factors regulate and influence the functions of liver cNK cells and ILC1s, particularly within the context of liver tumors, presents a significant opportunity to amplify the effectiveness of immunotherapies against liver malignancies. Using Ncr1-drived conditional knockout mouse model, our study reveals the regulatory role ofPrdm1in shaping the composition and maturation of cNK cells. AlthoughPrdm1did not affect the killing function of cNK cells in anin vivocytotoxicity model, a significant increase in cancer metastasis was observed inPrdm1knockout mice. Interferon-gamma (IFN-γ), granzyme B, and perforin secretion decreased significantly inPrdm1deficient cNK cells and liver ILC1s. scRNA sequencing data also provided evidences that Prdm1 maintains functional subsets of cNK cells and liver ILC1s and facilitates communications between cNK cells, liver ILC1s and macrophages. The present study unveiled a novel regulatory mechanism of Prdm1 in cNK cells and liver ILC1s, showing promising potential for developing innovative immune therapy strategies against liver cancer.

Graphical abstract
Multiomics characterization of cell type repertoires for urine liquid biopsies
Authors: Vorperian Sevahn K. , DeFelice Brian C. , Buonomo Joseph A. , Chinchinian Hagop J. , Gray Ira J. , Yan Jia , Mach Kathleen E. , La Vinh , Lee Timothy J. , Liao Joseph C. , Lafayette Richard , Loeb Gabriel B. , Bertozzi Carolyn R. , Quake Stephen R.
Published: October 2023

Urine is assayed alongside blood in medicine, yet current clinical diagnostic tests utilize only a small fraction of its total biomolecular repertoire, potentially foregoing high-resolution insights into human health and disease. In this work, we characterized the joint landscapes of transcriptomic and metabolomic signals in human urine. We also compared the urine transcriptome to plasma cell-free RNA, identifying a distinct cell type repertoire and enrichment for metabolic signal. Untargeted metabolomic measurements identified a complementary set of pathways to the transcriptomic analysis. Our findings suggest that urine is a promising biofluid yielding prognostic and detailed insights for hard-to-biopsy tissues with low representation in the blood, offering promise for a new generation of liquid biopsies.
Geographic risk assessment ofBatrachochytrium salamandrivoransinvasion in Costa Rica as a means of informing emergence management and mitigation
Authors: Adams Henry C. , Markham Katherine E. , Madden Marguerite , Gray Matthew J. , Vives Federico Bolanos , Chaves Gerardo , Hernandez Sonia M.
Published: October 2023

Remotely-sensed risk assessments of emerging, invasive pathogens are key to targeted surveillance and outbreak responses. The recent emergence and spread of the fungal pathogen,Batrachochytrium salamandrivorans(Bsal), in Europe has negatively impacted multiple salamander species. Scholars and practitioners are increasingly concerned about the potential consequences of this lethal pathogen in the Americas, where salamander biodiversity is higher than anywhere else in the world. AlthoughBsalhas not yet been detected in the Americas, certain countries have already proactively implemented monitoring and detection plans in order to identify areas of greatest concern and enable efficient contingency planning in the event of pathogen detection. To predict areas in Costa Rica with a highBsaltransmission risk, we employed ecological niche modeling combined with biodiversity and tourist visitation data to ascertain the specific risk to a country with world renowned biodiversity. Our findings indicate that approximately 23% of Costa Rica’s landmass provides suitable conditions forBsal, posing a threat to 37 salamander species. The Central and Talamanca mountain ranges, in particular, have habitats predicted to be highly suitable for the pathogen. To facilitate monitoring and mitigation efforts, we identified eight specific protected areas that we believe are at the greatest risk due to a combination of high biodiversity, tourist visitation, and suitable habitat forBsal. We advise regular monitoring utilizing remotely-sensed data and ecological niche modeling to effectively targetin-situsurveillance and as places begin implementing educational efforts.
CellTracksColab — A platform for compiling, analyzing, and exploring tracking data
Authors: Gómez-de-Mariscal Estibaliz , Grobe Hanna , Pylvänäinen Joanna W. , Xénard Laura , Henriques Ricardo , Tinevez Jean-Yves , Jacquemet Guillaume
Published: October 2023

In life sciences, tracking objects from movies enables researchers to quantify the behavior of single particles, organelles, bacteria, cells, and even whole animals. While numerous tools now allow automated tracking from video, a significant challenge persists in compiling, analyzing, and exploring the large datasets generated by these approaches. Here, we introduce CellTracksColab, a platform tailored to simplify the exploration and analysis of tracking data. CellTracksColab facilitates the compiling and analysis of results across multiple fields of view, conditions, and repeats, ensuring a holistic dataset overview. CellTracksColab also harnesses the power of high-dimensional data reduction and clustering, enabling researchers to identify distinct behavioral patterns and trends without bias. Finally, CellTracksColab also includes specialized analysis modules enabling spatial analyses (clustering, proximity to specific regions of interest). We demonstrate CellTracksColab capabilities with three use cases, including T-cells and cancer cell migration, as well as filopodia dynamics. CellTracksColab is available for the broader scientific community athttps://github.com/CellMigrationLab/CellTracksColab.
Do macroinvertebrate abundance and community structure depend on the quality of ponds located in peri-urban areas?
Authors: Hulot Florence D. , Hanot Christophe , Nélieu Sylvie , Lamy Isabelle , Karolak Sara , Delarue Ghislaine , Baudry Emmanuelle
Published: October 2023

Contamination is one of the major threats to freshwater biodiversity. Compared to other aquatic ecosystems, peri-urban ponds are unique because they are embedded in human-dominated areas. However, it is poorly understood how different land uses such as urban or agricultural contribute multiple pollutants to ponds and thus affect pond biodiversity. In this work, 12 ponds located in a peri-urban area (Ile-de-France region, France) were monitored for 2 consecutive years in spring and fall. We surveyed macroinvertebrates and measured the physicochemical parameters and contaminants of different classes (trace elements, pharmaceuticals, pesticides and polycyclic aromatic hydrocarbons) in both water and sediment. The objective was twofold: (1) to explore local and regional macroinvertebrate spatiotemporal diversity and (2) to understand the effects of contaminants on community structure. We observed 236 macroinvertebrate morphotaxa, none of which were rare or sensitive to pollutants. Morphotaxa richness showed small differences between ponds but no difference between there was no effect of field campaign. There was no effect of ponds and field campaign on morphotaxa diversity and equitability. We did not observe a relationship between land use around the pond (agricultural, urban, or semi-natural) and diversity indices with the exception of the proportion of agricultural land in the vicinity of the pond on equitability. Regional beta diversity (between ponds) showed that differences in morphotaxa composition reflected species replacement more than differences in species richness; these were primarily due to the high abundance of pollutant-tolerant species in some of the ponds. The effects of environmental parameters on community structure were studied using partial redundancy analysis based on the presence-absence of morphotaxa, showing that community assemblages are shaped by sediment levels of pharmaceuticals, water conductivity and ammonium concentration. In conclusion, ponds in peri-urban areas are exposed to various human activities, with our results suggesting that this exposure leads to chronic and diverse contaminations that affect morphotaxa communities.
Genome of the glacier algaAncylonemaand its insights into the evolution of streptophyte life on ice and land
Authors: Bowles Alexander M. C. , Williams Tom A. , Donoghue Philip C. J. , Campbell Douglas A. , Williamson Christopher J.
Published: October 2023

Contemporary glaciers and ice sheets are home to communities of streptophyte glacier algae that must balance their requirements for photosynthesis and growth with tolerance of extremes in temperature, desiccation and UV radiation. These same environmental challenges have been hypothesized as the driving force behind the evolution of land plants from streptophyte algal ancestors in the Cryogenian (720–635 million years ago). Here, we sequence, assemble and analyze the metagenome-assembled genome (MAG) of the glacier algaAncylonema nordenskiöldiito investigate its adaptations to life in ice, and whether this represents a vestige of Cryogenian anydrophyte exaptations. Phylogenetic analysis confirms the placement of glacier algae within the sister lineage to land plants, Zygnematophyceae. The MAG is characterized by an expansion of genes involved in high irradiance and UV light tolerance, whilst lineage-specific diversification led to the novel screening pigmentation of glacier algae. We found no support for the hypothesis of a common genomic basis for adaptations to ice and to land in streptophytes. Comparative genomic analysis revealed that reductive genome evolution in the ancestor of Zygnematophyceae correlates with their reductive morphological evolution. This first genome-scale data for glacier algae supports anAncylonema-specific adaptation to the cryosphere, as well as shedding light on the genome evolution of land plants and Zygnematophyceae.
Metagenome Assembled Genomes (MAG) Facilitate a Better Understanding of Microbially-mediated Heavy Metal Resistance in Soils from a Former Nuclear Materials Production Facility
Authors: Kommu Navya , Stothard Paul , Chukwujindu Christian , Pathak Ashish , Chauhan Ashvini
Published: October 2023

Shotgun metagenomes is a repository of all the genes present in an environmental sample. With recent advancements in bioinformatic techniques, it is now possible to in-silico retrieve sequences that belong to specific taxa, followed by assembly and annotation and the obtained sequences are called as metagenome-assembled genome (MAG), which facilitates better understanding of metabolic and other traits without having to culture the microorganism. We applied the MAG technique using the nf-core/mag pipeline on shotgun metagenome sequences obtained from a soil ecosystem that has long-term co-contamination with radionuclides (mainly uranium), heavy metals (mercury, nickel etc.) and organic compounds. Annotation of MAGs was performed using SPAdes and MEGAHIT and genomes were binned and taxonomically classified using the GTDBTk and CAT toolkits within nf-core/mag. Additional annotations were done using Prokka and Prodigal and the dRep program was used to choose specific MAGs for further analysis. Initial analysis resulted in a total of 254 MAGs which met the high-quality standard with the completeness > 95% and contamination < 5%, accounting for 26.67% of all the MAGs (Fig SI-1). After bin refinement and de-replication, 27 MAGs (18 from Winter season and 9 from Summer season) were reconstructed. These 27 MAGs span across 6 bacterial phyla and the most predominant ones were Proteobacteria, Bacteroidetes, and Cyanobacteria regardless of the season. Overall, theArthrobacterMAG was found to be one that was robust for further analysis. Over 1749 genes putatively involved in crucial metabolism of elements viz. nitrogen, phosphorous, sulfur and 598 genes encoding enzymes for metals resistance from cadmium, zinc, chromium, arsenic and copper. In summary, this project enhances our understanding of genes conferring resistance to heavy metals in uranium contaminated soils.
A homeostatic gut-to-brain insulin antagonist restrains neuronally stimulated fat loss
Authors: Liu Chung-Chih , Khan Ayub , Seban Nicholas , Littlejohn Nicole , Srinivasan Supriya
Published: October 2023

InC. elegansmechanisms by which peripheral organs relay internal state information to the nervous system remain unknown, although strong evidence suggests that such signals do exist. Here we report the discovery of a peptide of the ancestral insulin superfamily called INS-7 that functions as an enteroendocrine peptide and is secreted from specialized cells of the intestine. INS-7 secretion increases during fasting, and acts as a bona fide gut-to-brain homeostatic signal that attenuates neuronally induced fat loss during food shortage. INS-7 functions as an antagonist at the canonical DAF-2 receptor in the nervous system, and phylogenetic analysis suggests that INS-7 bears greater resemblance to members of the broad insulin/relaxin superfamily than to conventional mammalian insulin and IGF peptides. The discovery of an endogenous insulin antagonist secreted by specialized intestinal cell with enteroendocrine functions suggests that much remains to be learned about the intestine and its role in directing neuronal functions.
Combining Blood-Based Biomarkers and Structural MRI Measurements to Distinguish Persons With and Without Significant Amyloid Plaques
Authors: Chen Yanxi , Su Yi , Wu Jianfeng , Chen Kewei , Atri Alireza , Caselli Richard J , Reiman Eric M. , Wang Yalin ,   the Alzheimer’s Disease Neuroimaging Initiative
Published: October 2023

Background

Amyloid-β (Aβ) plaques play a pivotal role in Alzheimer’s disease. The current positron emission tomography (PET) is expensive and limited in availability. In contrast, blood-based biomarkers (BBBMs) show potential for characterizing Aβ plaques more affordably. We have previously proposed an MRI-based hippocampal morphometry measure to be an indicator of Aβ-plaques.

Objective

To develop and validate an integrated model to predict brain amyloid PET positivity combining MRI feature and plasma Aβ42/40 ratio.

Methods

We extracted hippocampal multivariate morphometry statistics (MMS) from MR images and together with plasma Aβ42/40 trained a random forest classifier to perform a binary classification of participant brain amyloid PET positivity. We evaluated the model performance using two distinct cohorts, one from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and the other from the Banner Alzheimer’s Institute (BAI), including prediction accuracy, precision, recall rate, F1 score and AUC score.

Results

Results from ADNI (mean age 72.6, Aβ+ rate 49.5%) and BAI (mean age 66.2, Aβ+ rate 36.9%) datasets revealed the integrated multimodal (IMM) model’s superior performance over unimodal models. The IMM model achieved prediction accuracies of 0.86 in ADNI and 0.92 in BAI, surpassing unimodal models based solely on structural MRI (0.81 and 0.87) or plasma Aβ42/40 (0.73 and 0.81) predictors.

Conclusion

Our IMM model, combining MRI and BBBM data, offers a highly accurate approach to predict brain amyloid PET positivity. This innovative multiplex biomarker strategy presents an accessible and cost-effective avenue for advancing Alzheimer’s disease diagnostics, leveraging diverse pathologic features related to Aβ plaques and structural MRI.