bluuebunny/crossref_metadata_2025 huggingface dataset:
Exploring Parent Experiences With Early Palliative Care Practices in the NICU
Authors: Quinn Megan , Gephart Sheila , Crist Janice
Published: February 2024

Background:

The anxiety and uncertain outcome of an admission of a seriously ill infant to the neonatal intensive care unit (NICU) can cause great stress for parents and contribute to poor mental health outcomes. Early implementation of family-centered palliative care (PC) may provide support for NICU parents. Key concepts of early PC in the NICU include shared decision-making, care planning, and support for coping with distress.

Purpose:

The purpose of this study was to explore parent experiences during their child's NICU admission with the early PC practices of shared decision-making, care planning, and coping with distress.

Methods:

Qualitative descriptive methodology was used. Strategies of reflexive journaling, peer debriefing, and data audits were used to enhance trustworthiness. Parents (N = 16) were interviewed, and data were analyzed by conventional content analysis. Targeted recruitment of fathers occurred to ensure they comprised 25% of sample.

Results:

Parents' descriptions of decision-making were contextualized in gathering information to make a decision, the emotional impact of the decision, and influences on their decision-making. In experiences with care planning, parents described learning to advocate, having a spectator versus participant role, and experiencing care planning as communication. Key themes expressed regarding parental coping were exposure to trauma, survival mode, and a changing support network.

Implications for Practice and Research:

These findings highlight key areas for practice improvement: providing more support and collaboration in decision-making, true engagement of parents in care planning, and encouraging peer support and interaction in the NICU and in online communities.
Clinical research on Tai Chi: a review of health benefits
Authors: Teng Yuke , Luo Weiming , Zhou Jun , Wang Muchen , Wu Jinghan , Nie Xiaoqian , Sun Cong , Liang Ziyan , Liu Baiyang , Zhang Furong , Liu Tianyu , Zhao Shi , Liang Fanrong , Yang Xiaofan , Wu Jianwei , Li Zhengjie
Published: February 2024

Tai Chi, a traditional Chinese martial art and health exercise, has gained significant global attention and recognition. The clinical benefits of Tai Chi have been studied extensively in recent decades. We conducted a systematic search of PubMed, Web of Science, EMBASE databases, and the China National Knowledge Infrastructure, identifying and reviewing 241 clinical trials on the benefits of Tai Chi from their inception to June 1, 2023. Most of these studies have consistently demonstrated the positive impact of Tai Chi on balance, cognitive function, mood regulation, sleep quality, pain relief, cardiorespiratory function, and overall health. In the future, the key to fostering the ongoing development of this field lies in comprehensive research on standardized study designs and reporting, the scope of Tai Chi applications, and the core factors influencing its efficacy.
Vasoactive-Inotropic Score as a Promising Predictor of Acute Kidney Injury in Adult Patients Requiring Extracorporeal Membrane Oxygenation
Authors: Zhang Dandan , Li Lu , Huang Weipeng , Hu Chang , Zhu Weiwei , Hu Bo , Li Jianguo
Published: February 2024

Acute kidney injury (AKI) is a common complication in patients supported by extracorporeal membrane oxygenation (ECMO). Vasoactive-Inotropic Score (VIS) serves as an indicator of the extent of cardiovascular drug support provided. Our objective is to assess the relationship between the VIS and ECMO-associated AKI (EAKI). This single-center retrospective study extracted adult patients treated with ECMO between August 2016 and September 2022 from an intensive care unit (ICU) in a university hospital. A total of 126 patients requiring ECMO support were included in the study, of which 76% developed AKI. Multivariate logistic regression analysis identified VIS-max Day1 (odds ratio [OR]: 1.025, 95% confidence interval [CI]: 1.007–1.044, p = 0.006), VIS-max Day2 (OR: 1.038, 95% CI: 1.007–1.069, p = 0.015), VIS-mean Day1 (OR: 1.048, 95% CI: 1.013–1.084, p = 0.007), and VIS-mean Day2 (OR: 1.059, 95% CI: 1.014–1.107, p = 0.010) as independent risk factors for EAKI. VIS-max Day1 showing the best predictive effect (Area under the receiver operating characteristic curve (AUROC): 0.80, sensitivity: 71.87%, specificity: 80.00%) for EAKI with a cutoff value of 33.33. Surprisingly, VIS-mean Day2 was also excellent at predicting 7 day mortality (AUROC: 0.77, sensitivity: 87.50%, specificity: 56.38%) with a cutoff value of 8.67. In conclusion, VIS could independently predict EAKI and 7 day mortality in patients with ECMO implantation, which may help clinicians to recognize the poor prognosis in time for early intervention.
Unpacking the navigation toolbox: insights from comparative cognition
Authors: Jeffery Kate J. , Cheng Ken , Newcombe Nora S. , Bingman Verner P. , Menzel Randolf
Published: February 2024

The study of navigation is informed by ethological data from many species, laboratory investigation at behavioural and neurobiological levels, and computational modelling. However, the data are often species-specific, making it challenging to develop general models of how biology supports behaviour. Wiener
et al
. outlined a framework for organizing the results across taxa, called the ‘navigation toolbox’ (Wiener
et al.
In
Animal thinking: contemporary issues in comparative cognition
(eds R Menzel, J Fischer), pp. 51–76). This framework proposes that spatial cognition is a hierarchical process in which sensory inputs at the lowest level are successively combined into ever-more complex representations, culminating in a metric or quasi-metric internal model of the world (cognitive map). Some animals, notably humans, also use symbolic representations to produce an external representation, such as a verbal description, signpost or map that allows communication of spatial information or instructions between individuals. Recently, new discoveries have extended our understanding of how spatial representations are constructed, highlighting that the hierarchical relationships are bidirectional, with higher levels feeding back to influence lower levels. In the light of these new developments, we revisit the navigation toolbox, elaborate it and incorporate new findings. The toolbox provides a common framework within which the results from different taxa can be described and compared, yielding a more detailed, mechanistic and generalized understanding of navigation.
Regional and fine-scale local adaptation in salinity tolerance in
Daphnia
inhabiting contrasting clusters of inland saline waters
Authors: Brans Kristien I. , Vad Csaba F. , Horváth Zsófia , Santy Luca , Cuypers Kiani , Ptacnik Robert , De Meester Luc
Published: February 2024

Understanding the spatial scales at which organisms can adapt to strong natural and human-induced environmental gradients is important. Salinization is a key threat to biodiversity, ecosystem functioning and the provision of ecosystem services of freshwater systems. Clusters of naturally saline habitats represent ideal test cases to study the extent and scale of local adaptation to salinization. We studied local adaptation of the water flea
Daphnia magna
, a key component of pond food webs, to salinity in two contrasting landscapes—a dense cluster of sodic bomb crater ponds and a larger-scale cluster of soda pans. We show regional differentiation in salinity tolerance reflecting the higher salinity levels of soda pans versus bomb crater ponds. We found local adaptation to differences in salinity levels at the scale of tens of metres among bomb crater pond populations but not among geographically more distant soda pan populations. More saline bomb crater ponds showed an upward shift of the minimum salt tolerance observed across clones and a consequent gradual loss of less tolerant clones in a nested pattern. Our results show evolutionary adaptation to salinity gradients at different spatial scales, including fine-tuned local adaptation in neighbouring habitat patches in a natural landscape.
Darwin review: the evolution of virulence in human pathogens
Authors: Gupta Sunetra
Published: February 2024

By definition, all pathogens cause some level of harm to their hosts. If this harm occurs while the pathogen is transmitting, it can negatively affect the pathogen's fitness by shortening the duration over which transmission can occur. However, many of the factors that increase virulence (i.e. harm to host) also promote transmission, driving the pathogen population towards an optimal state of intermediate virulence. A wider spectrum of virulence may be maintained among pathogen populations which are structured into multiple discrete strains though direct resource and immune-mediated competition. These various evolutionary outcomes, and the effects of medical and public health interventions, are best understood within a framework that recognizes the complex relationship between transmission and virulence in the context of the antigenic diversity of the pathogen population.
Season of death, pathogen persistence and wildlife behaviour alter number of anthrax secondary infections from environmental reservoirs
Authors: Dolfi Amélie C. , Kausrud Kyrre , Rysava Kristyna , Champagne Celeste , Huang Yen-Hua , Barandongo Zoe R. , Turner Wendy C.
Published: February 2024

An important part of infectious disease management is predicting factors that influence disease outbreaks, such as
R
, the number of secondary infections arising from an infected individual. Estimating
R
is particularly challenging for environmentally transmitted pathogens given time lags between cases and subsequent infections. Here, we calculated
R
for
Bacillus anthracis
infections arising from anthrax carcass sites in Etosha National Park, Namibia. Combining host behavioural data, pathogen concentrations and simulation models, we show that
R
is spatially and temporally variable, driven by spore concentrations at death, host visitation rates and early preference for foraging at infectious sites. While spores were detected up to a decade after death, most secondary infections occurred within 2 years. Transmission simulations under scenarios combining site infectiousness and host exposure risk under different environmental conditions led to dramatically different outbreak dynamics, from pathogen extinction (
R
< 1) to explosive outbreaks (
R
> 10). These transmission heterogeneities may explain variation in anthrax outbreak dynamics observed globally, and more generally, the critical importance of environmental variation underlying host–pathogen interactions. Notably, our approach allowed us to estimate the lethal dose of a highly virulent pathogen non-invasively from observational studies and epidemiological data, useful when experiments on wildlife are undesirable or impractical.
PackDock: a Diffusion Based Side Chain Packing Model for Flexible Protein-Ligand Docking
Authors: Zhang Runze , Jiang Xinyu , Cao Duanhua , Yu Jie , Chen Mingan , Fan Zhehuan , Kong Xiangtai , Xiong Jiacheng , Zhang Zimei , Zhang Wei , Ni Shengkun , Wang Yitian , Gao Shenghua , Zheng Mingyue
Published: February 2024

Structure-based drug design (SBDD) relies on accurate knowledge of protein structure and ligand-binding conformations. However, most of the static conformations obtained by advanced methods such as structural biology and de novo protein folding algorithms often don’t meet the needs for drug design. We introduce PackDock, a flexible docking method that combines “conformation selection” and “induced fit” mechanisms in a two-stage docking pipeline. The core module of this method is PackPocket, which uses a diffusion model to explore the side-chain conformation space in ligand binding pockets, both with or without a ligand. We evaluate our method using several tests that reflect real-world application scenarios. (1) Side-chain packing and Re-docking experiments validate the ability of PackDock to predict accurate side-chain conformations and ligand conformations. (2) Cross-docking experiments withapoand non-homologous ligand-inducedholostructures align with real docking scenarios, demonstrating PackDock’s practical value. (3) Docking experiments with hypothetical models show that PackPocket can potentially conduct SBDD starting from protein sequence information only. Additionally, we found that PackDock can identify key amino acid conformation changes, which may provide insights for lead compound optimization. We demonstrate PackDock can accurately predict the complex conformations in various application scenarios, by combining the conformation selection theory and the induced fit theory, and by using the ability of PackPocket to accurately predict the side chain conformations in the pocket region. We believe this method can improve the usability of existing structures, providing a new perspective for the SBDD community.
Novel spirocyclic dimer, SpiD3, targets chronic lymphocytic leukemia survival pathways with potent preclinical effects
Authors: Eiken Alexandria P , Smith Audrey L , Skupa Sydney A , Schmitz Elizabeth , Rana Sandeep , Singh Sarbjit , Kumar Siddhartha , Mallareddy Jayapal Reddy , de Cubas Aguirre A , Krishna Akshay , Kalluchi Achyuth , Rowley M Jordan , D’Angelo Christopher R , Lunning Matthew A , Bociek R Gregory , Vose Julie M , Natarajan Amarnath , El-Gamal Dalia
Published: February 2024

Chronic lymphocytic leukemia (CLL) cell survival and growth is fueled by the induction of B-cell receptor (BCR) signaling within the tumor microenvironment (TME) driving activation of NF- κB signaling and the unfolded protein response (UPR). Malignant cells have higher basal levels of UPR posing a unique therapeutic window to combat CLL cell growth using pharmacological agents that induce accumulation of misfolded proteins. Frontline CLL therapeutics that directly target BCR signaling such as Bruton-tyrosine kinase (BTK) inhibitors (e.g., ibrutinib) have enhanced patient survival. However, resistance mechanisms wherein tumor cells bypass BTK inhibition through acquired BTK mutations, and/or activation of alternative survival mechanisms have rendered ibrutinib ineffective, imposing the need for novel therapeutics. We evaluated SpiD3, a novel spirocyclic dimer, in CLL cell lines, patient-derived CLL samples, ibrutinib-resistant CLL cells, and in the Eµ-TCL1 mouse model. Our integrated multi-omics and functional analyses revealed BCR signaling, NF-κB signaling, and endoplasmic reticulum stress among the top pathways modulated by SpiD3. This was accompanied by marked upregulation of the UPR and inhibition of global protein synthesis in CLL cell lines and patient-derived CLL cells. In ibrutinib-resistant CLL cells, SpiD3 retained its anti-leukemic effects, mirrored in reduced activation of key proliferative pathways (e.g., PRAS, ERK, MYC). Translationally, we observed reduced tumor burden in SpiD3-treated Eµ-TCL1 mice. Our findings reveal that SpiD3 exploits critical vulnerabilities in CLL cells including NF-κB signaling and the UPR, culminating in profound anti-tumor properties independent of TME stimuli.

STATEMENT OF SIGNIFICANCE

SpiD3 demonstrates cytotoxicity in CLL partially through inhibition of NF-κB signaling independent of tumor-supportive stimuli. By inducing the accumulation of unfolded proteins, SpiD3 activates the UPR and hinders protein synthesis in CLL cells. Overall, SpiD3 exploits critical CLL vulnerabilities (i.e., the NF-κB pathway and UPR) highlighting its use in drug-resistant CLL.

VISUAL ABSTRACT
Family Leaders Communicate Risk During Cascade Screening after Sudden Cardiac Death in the Young
Authors: Dellefave-Castillo Lisa M. , Hinkamp Franceska , Shah Lisa , Scherr Courtney L. , Young Jennifer , Webster Gregory , Duquette Debra
Published: February 2024

Introduction

Relatives of a victim of sudden cardiac death in the young (SCDY) may be at risk for hereditary cardiomyopathies and arrhythmias. Family leaders are often responsible for communicating risk to surviving family at a difficult time.

Purpose

Explore barriers and facilitators to communication about cascade screening in families who have lost a family member to SCDY

Methods

Semi-structured interviews (n = 14) were conducted with family members of a SCDY decedent. Participants were recruited from the Sudden Arrhythmia Death Syndrome advocacy group. Interviews were conducted until data saturation was reached. Interviews were audio recorded, transcribed, and analyzed using conventional content analysis.

Results

Five categories were identified from the interviews: 1. Participants understood fundamental risks but the clinical variability in arrhythmia and cardiomyopathy was difficult to interpret and convey; 2. Family leaders felt some family disregarded risk information; 3. Grief interfered with communication; 4. Communication aids were insufficient stand-alone interventions; 5. Families advocated for a “genetic family navigator”.

Conclusion

The five categories provide practical strategies to improve clinical care and communication for families after a SCDY and emphasize the need for genetic family navigators to facilitate cascade screening.

GRAPHICAL ABSTRACT
Humoral and cellular immune responses after 6 months of a heterologous SARS-CoV-2 booster with the protein-based PHH-1V vaccine in a phase IIb trial
Authors: Corominas Júlia , Garriga Carme , Prenafeta Antoni , Moros Alexandra , Cañete Manuel , Barreiro Antonio , González-González Luis , Madrenas Laia , Güell Irina , Clotet Bonaventura , Izquierdo-Useros Nuria , Raïch-Regué Dàlia , Gallemí Marçal , Blanco Julià , Pradenas Edwards , Trinité Benjamin , Prado Julia G , Pérez-Caballero Raúl , Bernad Laia , Plana Montserrat , Esteban Ignasi , Aurrecoechea Elena , Taleb Rachel Abu , McSkimming Paula , Soriano Alex , Nava Jocelyn , Anagua Jesse Omar , Ramos Rafel , Lluch Ruth Martí , Comes Aida Corpes , Romero Susana Otero , Martínez-Gómez Xavier , Camacho-Arteaga Lina , Molto Jose , Benet Susana , Bailón Lucía , Arribas Jose R , Borobia Alberto M , Parada Javier Queiruga , Navarro-Pérez Jorge , Giner Maria José Forner , Lucas Rafael Ortí , Jiménez María del Mar Vázquez , Fernández María Jesús López , Alvarez-Mon Melchor , Troncoso Daniel , Arana-Arri Eunate , Meijide Susana , Imaz-Ayo Natale , García Patricia Muñoz , de la Villa Sofía , Fernández Sara Rodríguez , Prat Teresa , Torroella Èlia , Ferrer Laura
Published: February 2024

The HIPRA-HH-2 was a multicentre, randomized, active-controlled, double-blind, non-inferiority phase IIb clinical trial to compare the immunogenicity and safety of a heterologous booster with PHH-1V adjuvanted recombinant vaccine versus a homologous booster with mRNA vaccine. Interim results showed a strong humoral and cellular immune response against the SARS-CoV-2 Wuhan-Hu-1 strain and the Beta, Delta, and Omicron BA.1 variants up to day 98 after dosing. Here we report that these humoral and cellular responses after PHH-1V dosing are sustained up to 6 months. These results are observed both when including or not participants who reported SARS-CoV-2 infection and in a high-risk population (≥65 years). Additional analysis revealed a non-inferiority of PHH-1V booster in eliciting neutralizing antibodies also for SARS-CoV-2 Omicron XBB.1.5 when compared to mRNA vaccine after 6 months. The PHH-1V vaccine provides long-lasting protection against a wide variety of SARS-CoV-2 emerging variants to prevent severe COVID-19.

ClinicalTrials.govIdentifier

NCT05142553
Enhancing mitochondrial pyruvate metabolism ameliorates myocardial ischemic reperfusion injury
Authors: Visker Joseph R. , Cluntun Ahmad A. , Velasco-Silva Jesse N. , Eberhardt David R. , Shankar Thirupura S. , Hamouche Rana , Ling Jing , Kwak Hyoin , Hillas Yanni , Aist Ian , Tseliou Eleni , Navankasattusas Sutip , Chaudhuri Dipayan , Ducker Gregory S. , Drakos Stavros G. , Rutter Jared
Published: February 2024

The established clinical therapy for the treatment of acute myocardial infarction is primary percutaneous coronary intervention (PPCI) to restore blood flow to the ischemic myocardium. PPCI is effective at reperfusing the ischemic myocardium, however the rapid re-introduction of oxygenated blood also can cause ischemia-reperfusion (I/R) injury. Reperfusion injury is the culprit for up to half of the final myocardial damage, but there are no clinical interventions to reduce I/R injury. We previously demonstrated that inhibiting the lactate exporter, monocarboxylate transporter 4 (MCT4), and re-directing pyruvate towards oxidation can blunt isoproterenol-induced hypertrophy. Based on this finding, we hypothesized that the same pathway might be important during I/R. Here, we establish that the pyruvate-lactate metabolic axis plays a critical role in determining myocardial salvage following injury. Post-I/R injury, the mitochondrial pyruvate carrier (MPC), required for pyruvate oxidation, is upregulated in the surviving myocardium following I/R injury. MPC loss in cardiomyocytes caused more cell death with less myocardial salvage, which was associated with an upregulation of MCT4 in the myocardium at risk of injury. We deployed a pharmacological strategy of MCT4 inhibition with a highly selective compound (VB124) at the time of reperfusion. This strategy normalized reactive oxygen species (ROS), mitochondrial membrane potential (Δψ), and Ca2+, increased pyruvate entry to TCA cycle, and improved myocardial salvage and functional outcomes following I/R injury. Altogether, our data suggest that normalizing the pyruvate-lactate metabolic axis via MCT4 inhibition is a promising pharmacological strategy to mitigate I/R injury.

GRAPHICAL ABSTRACT
Ready, set, yellow! Color Preference of Indian Free-ranging Dogs
Authors: Roy Anamitra , Lahiri Aesha , Nandi Srijaya , Manchalwar Aayush , Siddharth S , Abishek J V R , Bulhan Indira , Sengupta Shouvanik , Kumar Sandeep , Chakravarty Tushnim , Bhadra Anindita
Published: February 2024

Most of the research on color vision related behaviors in dogs has involved training the dogs to perform visual discrimination tasks. We investigated the meaning of color to untrained Indian free-ranging dogs (FRDs). Using one-time multi-option choice tests for color preference in 134 adult dogs, we found the dogs to prefer yellow objects over blue or gray ones (p < 0.001, Cramer’s V = 0.433) while there was no preference between blue and gray (N = 102, p = 0.165). We next pitted a yellow object against a gray object that had food. Here, the dogs ignored the food to approach the yellow object first, both when the food was biscuit (N = 52, p < 0.001, Cramer’s V = 0.576) and chicken (N = 61, p < 0.001, Cramer’s V = 0.540), indicating the color preference to be quite strong. Color preference has previously been investigated in many other animals and has implications for behaviors like mate choice and foraging. Our study provides a new perspective into the ecology of Indian FRDs and might have implications for pet dogs as well, if they too show this preference.

Highlights

Indian free-ranging dogs (FRDs) show preference toward the color yellow over blue and gray.

Indian FRDs show no preference between blue and gray colors.

Attraction towards a yellow object can be stronger than attraction towards food rewards for Indian FRDs.
Iron deficiency causes aspartate-sensitive metabolic and proliferative dysfunction in CD8+ T cells
Authors: Teh Megan R. , Gudgeon Nancy , Frost Joe N. , Sinclair Linda V. , Smith Alastair L. , Millington Christopher L. , Kronsteiner Barbara , Roberts Jennie , Marzullo Bryan P. , Preston Alexandra E. , Rehwinkel Jan , Milne Thomas A. , Tennant Daniel A. , Dunachie Susanna J. , Armitage Andrew E. , Dimeloe Sarah , Drakesmith Hal
Published: February 2024

Iron is an irreplaceable co-factor for metabolism. Iron deficiency affects >1 billion people, causing symptoms including anaemia and impaired immunity. Nevertheless, precisely how iron deprivation impacts immune cell function remains poorly characterised. We therefore interrogated how physiologically low iron availability affected activated CD8+ T cell metabolism and function, using multi-omic and metabolic labelling approaches. Iron limitation profoundly stalled proliferation without influencing cell viability, altered histone methylation status and disrupted mitochondrial membrane potential. Consistently, metabolism of glucose and glutamine in the TCA cycle was limited, indeed TCA cycle activity was partially reversed to a reductive trajectory. Previous studies have shown mitochondria-derived aspartate is crucial for proliferation of transformed cells. Surprisingly, we found aspartate was increased in stalled iron deficient CD8+ T-cells, but was not utilised cytosolically for nucleotide synthesis, likely due to trapping within depolarised mitochondria. Conversely, exogenous aspartate, which directly accesses the cytosol, markedly rescued the clonal expansion of even severely iron-deficient CD8+ T-cells. Overall, iron scarcity creates a mitochondrial-located metabolic bottleneck impairing T-cells, which can be bypassed by resupplying inhibited biochemical processes with aspartate. These findings reveal molecular consequences of iron deficiency for CD8+ T cell function, providing mechanistic insight into the basis for immune impairment during iron deficiency.
Excitation/Inhibition balance relates to cognitive function and gene expression in Temporal Lobe Epilepsy: an hdEEG assessment with aperiodic exponent
Authors: Duma Gian Marco , Cuozzo Simone , Wilson Luc , Danieli Alberto , Bonanni Paolo , Pellegrino Giovanni
Published: February 2024

Patients with epilepsy are characterized by a dysregulation of excitation-inhibition balance (E/I). The assessment of E/I may inform clinicians during the diagnosis and therapy management, even though it is rarely performed. An accessible measure of the E/I of the brain represents a clinically relevant feature. Here we exploited the exponent of the aperiodic component of the power spectrum of EEG signal as a noninvasive and cost-effective proxy of the E/I balance. We recorded resting-state activity with high-density EEG from 65 patients with temporal lobe epilepsy (TLE) and 35 controls. We extracted the exponent of the aperiodic fit of the power spectrum from source-reconstructed EEG and tested differences between TLE and controls. Spearman’s correlation was performed between the exponent and clinical variables (age of onset, epilepsy duration and neuropsychology) and cortical expression of epilepsy-related genes derived from Human Allen Brain Atlas. Patients with TLE showed a significantly larger exponent, corresponding to an inhibition directed E/I balance, in bilateral frontal and temporal regions. Lower E/I in the left entorhinal, and bilateral dorsolateral prefrontal cortices corresponded to a lower performance of short term verbal memory. Limited to TLE, we detected a significant correlation between the exponent and the cortical expression of GABRA1, GRIN2A, GABRD, GABRG2, KCNA2and PDYN. EEG aperiodic exponent maps the E/I balance non-invasively in patients with epilepsy and reveals a tight relationship between altered E/I patterns, cognition and genetics.
Perceived association of mood and symptom severity in adults with mitochondrial diseases
Authors: Kelly Catherine , Junker Alex , Englestad Kris , Hirano Michio , Trumpff Caroline , Picard Martin
Published: February 2024

Individuals with genetic mitochondrial diseases suffer from multisystemic symptoms that vary in severity from day-to-day and week-to-week, but the underlying causes of symptomatic fluctuations are not understood. Based upon observations that: i) patients and their families frequently report that stressful life events either trigger exacerbations of existing symptoms or the onset of new symptoms, ii) psychological states and stress hormones influence mitochondrial energy production capacity, and iii) epidemiological reports document a robust connection between traumatic/stressful life events and various neurologic disorders, we hypothesized that mitochondrial disease symptom severity may vary according to participant’s mood. To investigate this we administered the Stress, Health and Emotion Survey (SHES) in 70 adults (majority white (84%) cisgender women (83%), ages 18-74) with self-reported mitochondrial diseases (MELAS, 18%; CPEO, 17%; Complex I deficiency, 13%). Participants rated the severity of each of their symptom(s) over the past year on either good or bad days. On days marked by more stress, sadness and other negative emotions, some but not all symptoms were reported to be worse, including fatigue, exercise intolerance, brain fog, and fine motor coordination. By contrast, on days marked by happiness and calmness, participants reported these and other symptoms to be better, or less severe. Other symptoms including diminished sweating, hearing problems, and dystonia were in general unrelated to mood. Thus, some individuals living with mitochondrial diseases, at times perceive a connection between their mood and symptom severity. These preliminary associative results constitute an initial step towards developing more comprehensive models of the factors that influence the clinical course of mitochondrial diseases.
Common genetic variants associated with urinary phthalate levels in children: a genome-wide study
Authors: Bustamante Mariona , Balagué Laura , Buko Zsanett , Sakhi Amrit Kaur , Casas Maribel , Maitre Lea , Andrusaityte Sandra , Grazuleviciene Regina , Gützkow Kristine B , Brantsæter Anne Lise , Heude Barbara , Philippat Claire , Chatzi Leda , Vafeiadi Marina , Yang Tiffany C , Wright John , Hough Amy , Ruiz-Arenas Carlos , Nurtdinov Ramil , Escaramís Geòrgia , Gonzalez Juan Ramon , Thomsen Cathrine , Vrijheid Martine
Published: February 2024

Introduction

Phthalates, or dieters of phthalic acid, are a ubiquitous type of plasticizer used in a variety of common consumer and industrial products. They act as endocrine disruptors and are associated with increased risk for several diseases. Once in the body, phthalates are metabolized through partially known mechanisms, involving phase I and phase II enzymes.

Objective

In this study we aimed to identify common single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) associated with the metabolism of phthalate compounds in children through genome-wide association studies (GWAS).

Methods

The study used data from 1,044 children with European ancestry from the Human Early Life Exposome (HELIX) cohort. Ten phthalate metabolites were assessed in a two-void urine pool collected at the mean age of 8 years. Six ratios between secondary and primary phthalate metabolites were calculated. Genome-wide genotyping was done with the Infinium Global Screening Array (GSA) and imputation with the Haplotype Reference Consortium (HRC) panel. PennCNV was used to estimate copy number variants (CNVs) and CNVRanger to identify consensus regions. GWAS of SNPs and CNVs were conducted using PLINK and SNPassoc, respectively. Subsequently, functional annotation of suggestive SNPs (p-value <1E-05) was done with the FUMA web-tool.

Results

We identified four genome-wide significant (p-value <5E-08) loci at chromosome (chr) 3 (FECHP1for oxo-MiNP_oh-MiNP ratio), chr6 (SLC17A1for MECPP_MEHPP ratio), chr9 (RAPGEF1for MBzP), and chr10 (CYP2C9for MECPP_MEHPP ratio). Moreover, 113 additional loci were found at suggestive significance (p-value <1E-05). Two CNVs located at chr11 (MRGPRX1for oh-MiNP andSLC35F2for MEP) were also identified. Functional annotation pointed to genes involved in phase I and phase II detoxification, molecular transfer across membranes, and renal excretion.

Conclusion

Through genome-wide screenings we identified known and novel loci implicated in phthalate metabolism in children. Genes annotated to these loci participate in detoxification and renal excretion.

Graphical abstract

Highlights

The genetic variation involved in phthalate detoxification in humans is partially known.

We identified four loci at genome-wide significance, and 113 at suggestive significance, some of them being novel.

Two copy number variants were also identified.

Functional annotation highlighted genes in phase I and II detoxification and renal excretion.
μSim: A goal-driven framework for elucidating the neural control of movement through musculoskeletal modeling
Authors: Almani Muhammad Noman , Lazzari John , Chacon Andrea , Saxena Shreya
Published: February 2024

How does the motor cortex (MC) produce purposeful and generalizable movements from the complex musculoskeletal system in a dynamic environment? To elucidate the underlying neural dynamics, we use a goal-driven approach to model MC by considering its goal as a controller driving the musculoskeletal system through desired states to achieve movement. Specifically, we formulate the MC as a recurrent neural network (RNN) controller producing muscle commands while receiving sensory feedback from biologically accurate musculoskeletal models. Given this real-time simulated feedback implemented in advanced physics simulation engines, we use deep reinforcement learning to train the RNN to achieve desired movements under specified neural and musculoskeletal constraints. Activity of the trained model can accurately decode experimentally recorded neural population dynamics and single-unit MC activity, while generalizing well to testing conditions significantly different from training. Simultaneous goal- and data- driven modeling in which we use the recorded neural activity as observed states of the MC further enhances direct and generalizable single-unit decoding. Finally, we show that this framework elucidates computational principles of how neural dynamics enable flexible control of movement and make this framework easy-to-use for future experiments.
Disrupted mitochondrial response to nutrients is a presymptomatic event in the cortex of the APPSAAknock-in mouse model of Alzheimer’s disease
Authors: Norambuena Andrés , Sagar Vijay Kumar , Wang Zhuoying , Raut Prakash , Feng Ziang , Wallrabe Horst , Pardo Evelyn , Kim Taylor , Alam Shagufta Rehman , Hu Song , Periasamy Ammasi , Bloom George S.
Published: February 2024

Introduction

Reduced brain energy metabolism, mTOR dysregulation, and extracellular amyloid-β oligomer (xcAβO) buildup characterize AD; how they collectively promote neurodegeneration is poorly understood. We previously reported that xcAβOs inhibitNutrient-inducedMitochondrialActivity (NiMA) in cultured neurons. We now report NiMA disruptionin vivo.

Methods

Brain energy metabolism and oxygen consumption were recorded in APPSAA/+mice using two-photon fluorescence lifetime imaging and multiparametric photoacoustic microscopy.

Results

NiMA is inhibited in APPSAA/+mice before other defects are detected in these amyloid-β-producing animals that do not overexpress APP or contain foreign DNA inserts into genomic DNA. GSK3β signals through mTORC1 to regulate NiMA independently of mitochondrial biogenesis. Inhibition of GSK3β with lithium or TWS119 stimulates NiMA in cultured human neurons, and mitochondrial activity and oxygen consumption in APPSAAmice.

Conclusion

NiMA disruptionin vivooccurs before histopathological changes and cognitive decline in APPSAAmice, and may represent an early stage in human AD.
Small RNAs positively and negatively control transcription elongation through modulation of Rho utilization site accessibility
Authors: Farley Kristen R. , Buechler Andrew K. , Bianco Colleen M. , Vanderpool Carin K.
Published: February 2024

Bacteria use a multi-layered regulatory strategy to precisely and rapidly tune gene expression in response to environmental cues. Small RNAs (sRNAs) form an important layer of gene expression control and most act post-transcriptionally to control translation and stability of mRNAs. We have shown that at least five different sRNAs inEscherichia coliregulate the cyclopropane fatty acid synthase (cfa) mRNA. These sRNAs bind at different sites in the long 5’ untranslated region (UTR) ofcfamRNA and previous work suggested that they modulate RNase E-dependent mRNA turnover. Recently, thecfa5’ UTR was identified as a site of Rho-dependent transcription termination, leading us to hypothesize that the sRNAs might also regulatecfatranscription elongation. In this study we find that a pyrimidine-rich region flanked by sRNA binding sites in thecfa5’ UTR is required for premature Rho-dependent termination. We discovered that both the activating sRNA RydC and repressing sRNA CpxQ regulatecfaprimarily by modulating Rho-dependent termination ofcfatranscription, with only a minor effect on RNase E-mediated turnover ofcfamRNA. A stem-loop structure in thecfa5’ UTR sequesters the pyrimidine-rich region required for Rho-dependent termination. CpxQ binding to the 5’ portion of the stem increases Rho-dependent termination whereas RydC binding downstream of the stem decreases termination. These results reveal the versatile mechanisms sRNAs use to regulate target gene expression at transcriptional and post-transcriptional levels and demonstrate that regulation by sRNAs in long UTRs can involve modulation of transcription elongation.

Importance

Bacteria respond to stress by rapidly regulating gene expression. Regulation can occur through control of messenger RNA (mRNA) production (transcription elongation), stability of mRNAs, or translation of mRNAs. Bacteria can use small RNAs (sRNAs) to regulate gene expression at each of these steps, but we often do not understand how this works at a molecular level. In this study, we find that sRNAs inEscherichia coliregulate gene expression at the level of transcription elongation by promoting or inhibiting transcription termination by a protein called Rho. These results help us understand new molecular mechanisms of gene expression regulation in bacteria.
Sex Differences in the Brain’s White Matter Microstructure during Development assessed using Advanced Diffusion MRI Models
Authors: Benavidez Sebastian M. , Abaryan Zvart , Kim Gaon S. , Laltoo Emily , McCracken James T. , Thompson Paul M. , Lawrence Katherine E.
Published: February 2024

Typical sex differences in white matter (WM) microstructure during development are incompletely understood. Here we evaluated sex differences in WM microstructure during typical brain development using a sample of neurotypical individuals across a wide developmental age (N=239, aged 5-22 years). We used the conventional diffusion-weighted MRI (dMRI) model, diffusion tensor imaging (DTI), and two advanced dMRI models, the tensor distribution function (TDF) and neurite orientation dispersion density imaging (NODDI) to assess WM microstructure. WM microstructure exhibited significant, regionally consistent sex differences across the brain during typical development. Additionally, the TDF model was most sensitive in detecting sex differences. These findings highlight the importance of considering sex in neurodevelopmental research and underscore the value of the advanced TDF model.
Are the sterile insect technique and the incompatible insect techniques effective in reducingAedesmosquito populations?
Authors: Olive Marie-Marie , Le Goff Gilbert , Baldet Thierry , Roiz David
Published: February 2024

Background

The control ofAedes aegyptiandAedes albopictusmosquitoes, the main vectors of dengue, chikungunya and Zika viruses, presents several challenges. The difficulties encountered in acquiring funding, implementing measures, obtaining community participation, acceptability and effectiveness, and the problem of insecticide resistance demonstrate the need to develop and optimise innovative vector control strategies. The sterile insect technique (SIT), the incompatible insect technique (IIT) and a combination of both (SIT-IIT) show promise. Numerous trials are being carried out worldwide to obtain evidence of their effectiveness before implementing them in large-scale, integrated vector-control strategies. The main objective of our study is to build an analytical framework for the identification and standardisation of appropriate entomological indicators that could be used to compare the relative effectiveness of the SIT, IIT and SIT-IIT methods in reducingAedesvector populations.

Methods

We reviewed the available scientific literature to compare the characteristics, methodologies, effectiveness indicators and results of various trials with the aim of standardising and comparing the indicators used in the trials, such as reductions in the egg hatch rate and in the adult populations.

Results

Seventeen trials, either published in peer-reviewed journals or posted as preprints, were selected. We found wide variation among them in experimental design, field implementation and the methods of calculating the indicators. Although limited by the amount of available published data, our results suggest that a reduction in egg hatching greater than 45% results in up to 60% fewer females, greater than 60% results in over 80% fewer females, and greater than 70% results in over 90% fewer females. Therefore, the quality of implementation, assessed on the basis of egg hatch reduction, is statistically associated with effectiveness, assessed on the basis of the reduction inAedesfemales.

Conclusion

We present results suggesting that, when implemented effectively, the incompatible and sterile insect techniques are substantially effective in reducingAedesmosquito populations. Furthermore, these techniques are species specific, non-insecticidal and environmentally friendly. However, it has yet to be shown that they can be scaled up as cost-effective operational tools for vector control and that they substantially reduce arbovirus transmission.
Underestimation of SARS-CoV-2 in wastewater due to single or double mutations in the N1 qPCR probe binding region
Authors: Sun Jianxian , Yang Minqing Ivy , Peng Jiaxi , Khan Ismail , Lopez Jhoselyn Jaramillo , Chan Ronny , Edwards Elizabeth , Peng Hui
Published: February 2024

Wastewater surveillance using RT-qPCR has now been widely adopted to track circulating levels of SARS-CoV-2 virus in many sewer sheds. The CDC qPCR assays targeting two regions (N1 and N2) within the N gene are commonly used, but a discrepancy between the two biomarkers has been noticed by many groups using this method since late 2021. The reason is presumed to be due to mutations in regions targeted by the qPCR probe. In this study, we systematically investigated and unequivocally confirmed that the underlying reason for this discrepancy was mutations in the N1 probe target, and that a single mutation could cause a significant drop in signal. We first confirmed the proportion of related mutations in wastewater samples (Jan 2021-Dec 2022) using nested PCR and LC-MS. Based on relative proportion of N1 alleles, we separated the wastewater data into four time periods corresponding to different variant waves: Period I (Alpha and Delta waves with 0 mutation), Period II (BA.1/BA.2 wave with a single mutation found in all Omicron strains), Period III (BA. 5.2* wave with two mutations), and Period IV (BQ.1* wave with two mutations). Significantly lower N1 copies relative to N2 copies in samples from Periods II-IV compared to those from Period I was observed in wastewater. To further pinpoint the extent to which each mutation impacted N1 quantification, we compared the qPCR response among different synthetic oligomers with corresponding mutations. This study highlighted the impact of even just one or two mutations on qPCR-based wastewater surveillance of SARS-CoV-2.
Elevated Activity in Left Homologous Music Circuits is Maladaptive for Music Perception but Mediated by Decoupled Structure and Function
Authors: Wang Yucheng , Jin Zhishuai , Huyang Sizhu , Lian Qiaoping , Wu Daxing
Published: February 2024

Music is inherent in human life and is a significant topic of cognitive neuroscience. Previous studies focused on amusia suggested that two frontotemporal circuits engage in music processing. Structure-function coupling is an important feature of human brain, which is associated with cognition and allows for a more sensitive investigation of brain-behavior association. However, we still have limited knowledge about the relation between structure-function coupling, music processing and other regional neural profiles. We recruited 106 participants (43 subjects were diagnosed with congenital amusia) and measured their music perception by Montreal Battery of Evaluation of Amusia (MBEA). Then we utilized support vector regression algorithm and mediation analysis, and employed amplitude of low frequency fluctuation (ALFF), structural/functional degree centrality (DC) and structure-function coupling to explore their relation with global averaged MBEA score. We found structure-function coupling of widespread brain regions in both hemispheres, rather than ALFF or DC, contributed to predict MBEA score. Left middle frontal gyrus, bilateral inferior temporal gyrus and right insula were most predictive regions, and these regions were involved in memory and cognitive control according to meta-analysis. Further, coupling of left middle frontal gyrus, a region that is homologous to and is connected with typical music circuits, fully mediated the negative relation between ALFF and MBEA score. Our findings provide further understanding for the neural basis of music, and have implications for neural plasticity, neuromodulation therapy and cognitive causes of amusia.

Highlights

Our study first applies structure-function coupling to investigate the neural correlates of music perception, and predicting modeling indicate structure-function coupling is more effective than regional activity and connectivity.

Elevated activity of contralateral homologous of music circuits might be maladaptive rather than compensatory.

Elevated spontaneous regional activity disrupts their connections, which might be a specific expression of neural plasticity for certain regions.

Our findings have implications for cognitive causes (abnormal memory and/or cognitive control to music salients) of amusia.
Spin squeezing with itinerant dipoles: A case for shallow lattices
Authors: Wellnitz David , Mamaev Mikhail , Bilitewski Thomas , Rey Ana Maria
Published: February 2024

Entangled spin squeezed states generated via dipolar interactions in lattice models provide unique opportunities for quantum enhanced sensing and are now within reach of current experiments. A critical question in this context is which parameter regimes offer the best prospects under realistic conditions. Light scattering in deep lattices can induce significant decoherence and strong Stark shifts, while shallow lattices face motional decoherence as a fundamental obstacle. Here we analyze the interplay between motion and spin squeezing in itinerant fermionic dipoles in one dimensional chains using exact matrix product state simulations. We demonstrate that shallow lattices can achieve more than 5 dB of squeezing, outperforming deep lattices by up to more than 3 dB, even in the presence of low filling, loss, and decoherence. We relate this finding to SU(2)-symmetric superexchange interactions, which keep spins aligned and protect collective correlations. We show that the optimal regime is achieved for small repulsive off-site interactions, with a trade-off between maximal squeezing and optimal squeezing time.

Published by the American Physical Society
2024