bluuebunny/crossref_metadata_2025 huggingface dataset:
Linagliptin, a DPP‐4 inhibitor, activates AMPK/FOXO3a and suppresses NFκB to mitigate the debilitating effects of diethylnitrosamine exposure in rat liver: Novel mechanistic insights
Authors: Abdelhady Rasha , Mohammed Osama A. , Doghish Ahmed S. , Hamad Rabab S. , Abdel‐Reheim Mustafa Ahmed , Alamri Mohannad Mohammad S. , Alharthi Muffarah Hamid , Alfaifi Jaber , Adam Masoud I. E. , Alhalafi Abdullah Hassan , Mohammed Nahid A. , Isa Adamu Imam , Abdel‐Ghany Sameh , Attia Mohammed A. , Elmorsy Elsayed A. , AL‐Noshokaty Tohada M. , Nomier Yousra , El‐Dakroury Walaa A. , Saber Sameh
Published: February 2024

Accumulating evidence suggests that dysregulation of FOXO3a plays a significant role in the progression of various malignancies, including hepatocellular carcinoma (HCC). FOXO3a inactivation, driven by oncogenic stimuli, can lead to abnormal cell growth, suppression of apoptosis, and resistance to anticancer drugs. Therefore, FOXO3a emerges as a potential molecular target for the development of innovative treatments in the era of oncology. Linagliptin (LNGTN), a DPP‐4 inhibitor known for its safe profile, has exhibited noteworthy anti‐inflammatory and anti‐oxidative properties in previous in vivo studies. Several potential molecular mechanisms have been proposed to explain these effects. However, the capacity of LNGTN to activate FOXO3a through AMPK activation has not been investigated. In our investigation, we examined the potential repurposing of LNGTN as a hepatoprotective agent against diethylnitrosamine (DENA) intoxication. Additionally, we assessed LNGTN's impact on apoptosis and autophagy. Following a 10‐week administration of DENA, the liver underwent damage marked by inflammation and early neoplastic alterations. Our study presents the first experimental evidence demonstrating that LNGTN can reinstate the aberrantly regulated FOXO3a activity by elevating the nuclear fraction of FOXO3a in comparison to the cytosolic fraction, subsequent to AMPK activation. Moreover, noteworthy inactivation of NFκB induced by LNGTN was observed. These effects culminated in the initiation of apoptosis, the activation of autophagy, and the manifestation of anti‐inflammatory, antiproliferative, and antiangiogenic outcomes. These effects were concomitant with improved liver function and microstructure. In conclusion, our findings open new avenues for the development of novel therapeutic strategies targeting the AMPK/FOXO3a signaling pathway in the management of chronic liver damage.
A Brief Screening Tool for Risk of Self-Medication of Pain With Substance Use
Authors: Bush Nicholas J. , Ferguson Erin , Zale Emily , Boissoneault Jeff
Published: February 2024

Objectives

Substance use and pain are both growing public health concerns globally. Evidence suggests that individuals may use substances in order to self-medicate their pain. The Catastrophizing, Anxiety, Negative Urgency, and Expectancy model was developed to provide a theoretical foundation for the modifiable risk factors implicated in self-medication of pain with substance use. This study aimed to use the outcomes in the Catastrophizing, Anxiety, Negative Urgency, and Expectancy model to develop a brief clinical screening tool to identify individuals at risk for self-medication.

Methods

Participants (N = 520; Mage = 38.8) were adults who endorsed the past three-month use of at least one substance and completed an online questionnaire. Logistic regression and receiver operator characteristic analyses were used to reduce the initial 104-item questionnaire to the items needed to achieve a minimum accuracy score of 0.95 and 0.90.

Results

A 14-item and a 7-item questionnaire were derived from the initial larger questionnaire. Both of these questionnaires were significantly correlated with the outcome variables and were significantly associated with health risk and percent of use because of pain. The R
2 values between the 14- and 7-item versions were only significantly different for the percent of alcohol use because of pain.

Conclusions

The study provides two brief screening tools to screen for individuals at risk for self-medication of pain with substance use that can be easily implemented within clinical settings. Further, the screening tools provide insight into modifiable risk factors for self-medication and may also be valuable to monitor treatment response.
Fixed- Versus Variable-Dose Prothrombin Complex Concentrate for the Emergent Reversal of Vitamin K Antagonists: A Systematic Review and Meta-Analysis
Authors: Alwakeal Amr , Maas Matthew B. , Naidech Andrew M. , Jahromi Babak S. , Potts Matthew B.
Published: February 2024

OBJECTIVES:

Four-factor prothrombin complex concentrate (4-PCC) is recommended for rapid reversal of vitamin K antagonists (VKAs) such as warfarin, yet optimal dosing remains uncertain.

DATA SOURCES:

A systematic review was conducted of PubMed, Embase, and Ovid MEDLINE (Wolters Kluwer) databases from January 2000 to August 2023 for clinical studies comparing fixed- vs. variable-dose 4-PCC for emergent VKA reversal with at least one reported clinical outcome.

STUDY SELECTION:

Abstracts and full texts were assessed independently and in duplicate by two reviewers.

DATA EXTRACTION:

Data were extracted independently and in duplicate by two reviewers using predefined extraction forms.

DATA SYNTHESIS:

The analysis comprised three randomized trials and 16 cohort studies comprising a total of 323 participants in randomized trials (161 in fixed dosage and 162 in variable dosage) and 1912 patients in cohort studies (858 in fixed-dose and 1054 in variable dose). Extracranial bleeding was the predominant indication, while intracranial hemorrhage varied. Overall, a fixed-dose regimen may be associated with a lower dose of 4-PCC and results in a reduction in 4-PCC administration time compared with a variable-dose regimen. A fixed-dose regimen also likely results in increased clinical hemostasis. While there is no clear difference between the two regimens in terms of achieving a goal international normalized ratio (INR) less than 2, a fixed-dose regimen is less likely to achieve a goal INR less than 1.5. High certainty evidence indicates that the fixed-dose regimen reduces both mortality and the occurrence of thromboembolic events. Additional subgroup analyses provides exploratory data to guide future studies.

CONCLUSIONS:

A fixed-dose regimen for 4-PCC administration provides benefits over a variable-dose regimen in terms of dose reduction, faster administration time, improved clinical hemostasis, and reduced mortality and thromboembolic events. Further studies are warranted to better refine the optimal fixed-dose regimen.
Body work and body meanings in patient-centered care
Authors: Brizio Greta Elisabetta , Paolino Chiara
Published: February 2024

Background

This study integrates patient-centered care (PCC) research and body work studies to understand how a focus on physical and sensorial aspects in the relationship between health care professionals (HPs) and patients contribute to the implementation of PCC.

Purpose

To understand how HPs’ body work practices contribute to the implementation of PCC, we investigate the meanings HPs ascribe to their and to patients’ bodies. The goal is to grasp how these practices and meanings, rooted in unexplored sensorial perceptions, account for the emergence of a relationship of mutual acknowledgment between HPs and patients.

Methodology

Thirty-nine in-depth interviews were carried out with HPs, who interact with patients with disabilities in Italian hospitals.

Results

HPs engage in different body work practices: adopting a diagnostic gaze and an empathetic gaze, touching, and playing. The diagnostic gaze concurs to create a feeling of promptness between HPs and patients, but also a stronger distance with respect to other practices. The empathetic gaze, touching, and playing are associated with feelings of shared vulnerability and resilience. These shared perceptions and emotions build a common ground and shape a relationship focused on patients’ involvement.

Practice Implications

Voicing and feedback sessions can be arranged to listen to how HPs interpret their own and patients’ bodies. An organizational culture acknowledging emotions should be promoted to sponsor among HPs the consideration of the sensorial aspects of their connection with patients. The value of bricolage should be observed, where the HPs feel free to readjust tools, spaces, and routines. Sensitivity training exercises should be arranged to understand the interactions with patients with disabilities.
Laser vision correction after radial keratotomy: systematic review and meta-analysis
Authors: Koosha Nima , Riazi Mir-Siamak , Janfaza Parisa , Mohammadbeigy Iman , Rahimi Alireza , Khoshali Mehri , Pourazizi Mohsen , Peyman Alireza
Published: February 2024

Laser vision correction for residual refractive errors in patients with previous radial keratotomy (RK) presents a challenging task. Different techniques have been used with varying outcomes. This study aimed to systematically review published articles on refractive surgeries in post-RK patients by conducting a search on PubMed, Scopus, and Web of Science. The final analysis included 35 studies that described a total of 888 eyes. Our systematic review and meta-analysis demonstrated a significant improvement in uncorrected distance visual acuity (UDVA) for photorefractive keratectomy (PRK), topography-guided PRK, wavefront-guided PRK, and femtosecond laser-assisted in situ keratomileusis (LASIK) while mechanical microkeratome LASIK did not yield such significant improvements. Moreover, our results suggest that post-RK patients with hyperopia had a significant improvement in UDVA, whereas no such improvement was observed in patients with myopia.
Simultaneous total internal biliary diversion during liver transplantation for progressive familial intrahepatic cholestasis type 1: Standard of care?
Authors: Menon Jagadeesh , Shanmugam Naresh , Vij Mukul , Veerankutty Fadl H. , Rammohan Ashwin , Rela Mohamed
Published: February 2024

Patients post liver transplant (LT) with progressive familial intrahepatic cholestasis type 1 (PFIC-1) often develop progressive graft steatohepatitis, intractable diarrhea, and growth failure. A total internal biliary diversion (TIBD) during an LT may prevent or reverse these adverse events. Children with PFIC-1 who underwent an LT at our institute were divided into 2 groups, A and B based on the timeline where we started offering a TIBD in association with LT. Pre-LT parameters, intraoperative details, and posttransplant complications like graft steatosis and diarrhea were also analyzed between the 2 groups, and their growth velocity was measured in the follow-up period. Of 550 pediatric LT performed between 2011 and 2022, 13 children underwent LT for PFIC-1. Group A had 7 patients (A1–A7) and group B had 6 (B1–B6). Patients A1, A4, B4, and B5 had a failed partial internal biliary diversion before offering them an LT. Patients A1, A2, and A6 in group A died in the post-LT period (2 early allograft dysfunction and 1 posttransplant lymphoproliferative disorder) whereas A3, A4, and A5 had graft steatosis in the follow-up period. A4 was offered a TIBD 4 years after LT following which the graft steatosis fully resolved. In group B, B1, B2, B5, and B6 underwent TIBD during LT, and B3 and B4 had it 24 and 5 months subsequently for intractable diarrhea and graft steatosis. None of the patients in group B demonstrated graft steatosis or diarrhea and had good growth catch-up during follow-up. We demonstrate that simultaneous TIBD in patients undergoing LT should be a standard practice as it helps dramatically improve outcomes in PFIC-1 as it prevents graft steatosis and/or fibrosis, diarrhea, and improves growth catch-up.
Ataxia telangiectasia: a rare case report from Nepal
Authors: Upreti Apil , Mandal Prince , Upreti Amit , Sapkota Srijana , Acharya Sristi , Yogi Avash , Gauchan Bikash , Bhattarai Suman , Thapa Lekhjung
Published: February 2024

Introduction and importance:

Ataxia telangiectasia (A-T) is a rare autosomal recessive neurodegenerative disorder with early childhood onset. It’s characterized by ataxia, oculocutaneous telangiectasia, immunodeficiency, and lymphoid-origin cancer predisposition due to ATM gene mutations.

Case Presentation:

We present a 19-year-old girl with spastic movements since 18 months, leading to wheelchair dependence. Ocular telangiectasia, dystonic posture, and slurred speech were evident. Diagnosis involved elevated alpha-fetoprotein levels and typical brain imaging.

Clinical Discussion:

Ataxia telangiectasia due to ATM gene mutations located on chromosome 11q22-23. It has varied presentations categorized by age and features. Timely diagnosis relies on characteristic symptoms, lab findings, and imaging. Radiation sensitivity and increased cancer risk underscore cautious radiation use.

Conclusion:

Ataxia telangiectasia is a complex disorder with no cure. Genetic counseling for parents is vital. Its poor prognosis due to infection susceptibility and cancer risk necessitates supportive care. Comprehensive management, including genetic counseling and careful surveillance, is imperative.
“Therapeutic effect of ferrous sulfate in diabetic patients with iron deficiency anemia: A randomised controlled trial”
Authors: Taati Bahareh , Ganji Reza , Moradi Leila , Vosoughi Tina , Gisouee Amir
Published: February 2024

Iron deficiency anemia (IDA) and diabetes mellitus (DM) are most prevalent disease, that diabetic patients are more prone to IDA. Therefore, the main aim of this study was to investigate the relationship between patients with diabetes and IDA in relation to taking iron pills daily and every other day to reduce the effects related to it. 91 participants were enrolled and randomly divided into two groups, with a final analysis cohort of 72 patients. The primary focus was on changes in serum Hb and Ferritin levels. The screening phase lasted 24 weeks, leading to 72 eligible participants meeting the criteria for entry into the study. Additionally, the study examined alternations in Hb and Hb A1C levels after treating patients with iron deficiency. The Hb and ferritin level contrasts between groups were not significant (P = 0.096 and P = 0.500, respectively). The relationship between Hb A1C and Hb levels before and after treatment was positive and significant (r 2 = 0.187). The results of the present study show that although the effectiveness of using oral iron supplements did not have a significant difference in terms of increasing hemoglobin and ferritin, the use of oral iron once every other day was more effective than the use of oral iron every day, and also in this study Like other studies, this result concluded that there is a negative correlation between HbA1C and Hb, and to check the status of HbA1C in diabetics, the level of Hb should be considered first.
Beyond Dollars and Scars: The Influence of Wealth Inequality on Total Expenditure on Cosmetic Procedures in the United States
Authors: Kim Jaeyeon , Kang Daihun
Published: February 2024

The present study delves into the “beauty paradox,” a multifaceted phenomenon influenced by wealth inequality, societal norms, and consumer behaviors, specifically regarding spending on cosmetic procedures. Relying on data from the United States Census Bureau and the American Society of Plastic Surgeons, the research primarily focuses on the Gini coefficient, Mean Logarithmic Deviation (MLD), and income data for the lowest and top 5% quintiles of mean household income over a 15-year span. The analysis uncovers a significant correlation between Total Expenditures on Cosmetic Surgery and minimally invasive procedures and the wealth of the top 5% income quintile. The “Cosmetic Enhancement Cycle (CEC)” is proposed, indicating a symbiotic growth between wealth accumulation among the affluent and the plastic surgery industry. As such, the “beauty paradox” lays bare the multifaceted consequences of wealth inequality, necessitating a comprehensive approach that addresses socioeconomic dynamics, accessibility of cosmetic procedures, societal norms, and perceptions. This investigation underscores the imperative for further exploration into the myriad ways that wealth inequality sculpts societies and influences behaviors, including within the context of the CEC.
Plasticity of the Arabidopsis leaf lipidome and proteome in response to pathogen infection and heat stress
Authors: Scholz Patricia , Doner Nathan M. , Gutbrod Katharina , Herrfurth Cornelia , Niemeyer Philipp , Lim Magdiel S. S. , Blersch Katharina , Schmitt Kerstin , Valerius Oliver , Shanklin John , Feussner Ivo , Dörmann Peter , Braus Gerhard H. , Mullen Robert T. , Ischebeck Till
Published: February 2024

Plants must cope with a variety of stressors during their life cycle, and the adaptive responses to these environmental cues involve all cellular organelles. Among them, comparatively little is known about the contribution of cytosolic lipid droplets (LDs) and their core set of neutral lipids and associated surface proteins to the rewiring of cellular processes in response to stress. Here, we analyzed the changes that occur in the lipidome and proteome of Arabidopsis leaves after pathogen infection withBotrytis cinereaorPseudomonas syringae, or after heat stress. Analyses were carried out in wild-type plants and the oil-rich double mutanttgd1-1 sdp1-4that allowed for an allied study of the LD proteome in stressed leaves. Using liquid chromatography-tandem mass spectrometry-based methods, we show that a hyperaccumulation of the primary LD core lipid triacylglycerol is a general response to stress and that acyl chain and sterol composition are remodeled during cellular adaptation. Likewise, comparative analysis of the LD protein composition in stress-treated leaves highlighted the plasticity of the LD proteome as part of the general stress response. We further identified at least two additional LD-associated proteins, whose localization to LDs in leaves was confirmed by confocal microscopy of fluorescent protein fusions. Taken together, these results highlight LDs as dynamic contributors to the cellular adaptation processes that underlie how plants respond to environmental stress.

One sentence summary

Biotic and heat stress strongly alters the lipidome and proteome of Arabidopsis leaves including the proteome of lipid droplets.
The Diagnostic Potential of Combined Photoplethysmography and Ankle-Brachial Index in Peripheral Arterial Obstructive Disease: A Comparative Analysis with Doppler Ultrasound
Authors: Huang Han-Luen , Chang Chia-Hsiu , Lo Men-Tzung , Lin Chen
Published: February 2024

Background and aims

While ankle-brachial index (ABI) and photoplethysmography (PPG) have also shown adequate sensitivity in detecting PAOD, their accuracies can be compromised in detecting milder cases. We aim to evaluate the diagnostic value of combining ABI and PPG in detecting PAOD for subjects with high atherosclerotic cardiovascular risks compared to duplex sonography.

Methods

130 participants underwent ABI, PPG, and duplex sonography during the evaluation process. Two parameters were derived from the PPG-PPG amplitude ratio of the lower-to-upper extremities (PPGratio) and the PPG amplitude of the lower extremity (PPGamp). Sensitivity, specificity, accuracy, and the area under receiver operative curve (AUC) were calculated for PPG parameters and ABI, and the combination of both methods. Multivariate analysis was performed for adjusting other relevant risk factors.

Results

65 participants were diagnosed with PAOD based on duplex sonography. The ROC analysis revealed optimal cut-off values in diagnosing PAOD were 0.417 for PPGratioand 58 for PPGamp. Both PPGratioand PPGampdemonstrated significantly higher sensitivities, 78.4% and 75.7%, in comparison to 55.9% of ABI<0.9 (p<0.05). Lower PPGratioand PPGampremained independently associated with PAOD even after adjusting for confounding factors. The AUC of combination models, including model 1 (ABI and PPGratio), model 2 (ABI and PPGamp), and model 3 (ABI, PPGratio, and PPGamp), exhibited improved performance with AUCs of 0.922, 0.922, and 0.931 (all p<0.01) compared to that of ABI alone (AUC:0.822).

Conclusions

The combination of ABI and PPG increases the sensitivity and accuracy prominently in diagnosing PAOD compared to ABI or PPG alone.
Signatures of structural disorder in developing epithelial tissues
Authors: Cupo Christian , Allan Cole , Ailiani Vikram , Kasza Karen E.
Published: February 2024

Epithelial cells generate functional tissues in developing embryos through collective movements and shape changes. In some morphogenetic events, a tissue dramatically reorganizes its internal structure — often generating high degrees of structural disorder — to accomplish changes in tissue shape. However, the origins of structural disorder in epithelia and what roles it might play in morphogenesis are poorly understood. We study this question in theDrosophilagermband epithelium, which undergoes dramatic changes in internal structure as cell rearrangements drive elongation of the embryo body axis. Using two order parameters that quantify volumetric and shear disorder, we show that structural disorder increases during body axis elongation and is strongly linked with specific developmental processes. Both disorder metrics begin to increase around the onset of axis elongation, but then plateau at values that are maintained throughout the process. Notably, the disorder plateau values for volumetric disorder are similar to those for random cell packings, suggesting this may reflect a limit on tissue behavior. In mutant embryos with disrupted external stresses from the ventral furrow, both disorder metrics reach wild-type maximum disorder values with a delay, correlating with delays in cell rearrangements. In contrast, in mutants with disrupted internal stresses and cell rearrangements, volumetric disorder is reduced compared to wild type, whereas shear disorder depends on specific external stress patterns. Together, these findings demonstrate that internal and external stresses both contribute to epithelial tissue disorder and suggest that the maximum values of disorder in a developing tissue reflect physical or biological limits on morphogenesis.
DexDesign: A new OSPREY-based algorithm for designingde novoD-peptide inhibitors
Authors: Guerin Nathan , Childs Henry , Zhou Pei , Donald Bruce R.
Published: February 2024

With over 270 unique occurrences in the human genome, peptide-recognizing PDZ domains play a central role in modulating polarization, signaling, and trafficking pathways. Mutations in PDZ domains lead to diseases such as cancer and cystic fibrosis, making PDZ domains attractive targets for therapeutic intervention. D-peptide inhibitors offer unique advantages as therapeutics, including increased metabolic stability and low immunogenicity. Here, we introduce DexDesign, a novel OSPREY-based algorithm for computationally designingde novoD-peptide inhibitors. DexDesign leverages three novel techniques that are broadly applicable to computational protein design: the Minimum Flexible Set, K*-based Mutational Scan, and Inverse Alanine Scan, which enable exponential reductions in the size of the peptide sequence search space. We apply these techniques and DexDesign to generate novel D-peptide inhibitors of two biomedically important PDZ domain targets: CAL and MAST2. We introduce a new framework for analyzingde novopeptides—evaluation along a replication/restitution axis—and apply it to the DexDesign-generated D-peptides. Notably, the peptides we generated are predicted to bind their targets tighter than their targets’ endogenous ligands, validating the peptides’ potential as lead therapeutic candidates. We provide an implementation of DexDesign in the free and open source computational protein design software OSPREY.
Advanced Surface Passivation for High-Sensitivity Studies of Biomolecular Condensates
Authors: Yao Run-Wen , Rosen Michael K.
Published: February 2024

Biomolecular condensates are cellular compartments that concentrate biomolecules without an encapsulating membrane. In recent years, significant advances have been made in the understanding of condensates through biochemical reconstitution and microscopic detection of these structures. Quantitative visualization and biochemical assays of biomolecular condensates rely on surface passivation to minimize background and artifacts due to condensate adhesion. However, the challenge of undesired interactions between condensates and glass surfaces, which can alter material properties and impair observational accuracy, remains a critical hurdle. Here, we introduce an efficient, generically applicable, and simple passivation method employing self-assembly of the surfactant Pluronic F127 (PF127). The method greatly reduces nonspecific binding across a range of condensates systems for both phase-separated droplets and biomolecules in dilute phase. Additionally, by integrating PF127 passivation with the Biotin-NeutrAvidin system, we achieve controlled multi-point attachment of condensates to surfaces. This not only preserves condensate properties but also facilitates long-time FRAP imaging and high-precision single-molecule analyses. Using this method, we have explored the dynamics of polySIM molecules within polySUMO/polySIM condensates at the single-molecule level. Our observations suggest a potential heterogeneity in the distribution of available polySIM-binding sites within the condensates.

Significance Statement

The understanding of biomolecular condensates has significantly benefited from biochemical reconstitution with microscopy detection. Here, we present a novel surface passivation method utilizing self-assembly of Pluronic F127 on hydrophobic surfaces. This approach not only effectively minimizes non-specific binding without altering the physical properties of the condensates but also offers universal passivation across a variety of condensate systems. It demonstrates high resistance to different treatments and enables condensate immobilization through controlled anchor points. This allows for highly sensitive analytical techniques, including single-molecule imaging. The simplicity and high-performance of this method, coupled with time and cost efficiencies, could facilitate robustness and throughput of experiments, and could broaden the accessibility of biochemical phase separation studies to a wider scientific community.
The genomic landscape of Acute Respiratory Distress Syndrome: a meta-analysis by information content of genome-wide studies of the host response
Authors: Millar Jonathan E , Clohisey-Hendry Sara , McMannus Megan , Zechner Marie , Wang Bo , Parkinson Nick , Jungnickel Melissa , Zaki Nureen Mohamad , Pairo-Castineira Erola , Rawlik Konrad , Rogers Joshua , Russell Clark D , Bos Lieuwe DJ , Meyer Nuala J , Calfee Carolyn , McAuley Daniel F , Shankar-Hari Manu , Baillie J Kenneth
Published: February 2024

Acute respiratory distress syndrome (ARDS) is a clinically defined syndrome of acute hypoxaemic respiratory failure secondary to non-cardiogenic pulmonary oedema. It arises from a diverse set of triggers and encompasses marked biological heterogeneity, complicating efforts to develop effective therapies. An extensive body of recent work (including transcriptomics, proteomics, and genome-wide association studies) has sought to identify proteins/genes implicated in ARDS pathogenesis. These diverse studies have not been systematically collated and interpreted.

To solve this, we performed a systematic review and computational integration of existing omics data implicating host response pathways in ARDS pathogenesis. We identified 40 unbiased studies reporting associations, correlations, and other links with genes and single nucleotide polymorphisms (SNPs), from 6,856 ARDS patients.

We used meta-analysis by information content (MAIC) to integrate and evaluate these data, ranking over 7,000 genes and SNPs and weighting cumulative evidence for association. Functional enrichment of strongly-supported genes revealed cholesterol metabolism, endothelial dysfunction, innate immune activation and neutrophil degranulation as key processes. We identify 51 hub genes, most of which are potential therapeutic targets. To explore biological heterogeneity, we conducted a separate analysis of ARDS severity/outcomes, revealing distinct gene associations and tissue specificity. Our large-scale integration of existing omics data in ARDS enhances understanding of the genomic landscape by synthesising decades of data from diverse sources. The findings will help researchers refine hypotheses, select candidate genes for functional validation, and identify potential therapeutic targets and repurposing opportunities. Our study and the publicly available computational framework represent an open, evolving platform for interpretation of ARDS genomic data.
Simulating desegregation through affordable housing development: an environmental health impact assessment of Connecticut zoning law
Authors: Prasanth Saira , Oloyede Nire , Zhang Xuezhixing , Chen Kai , Carrión Daniel
Published: February 2024

Residential segregation shapes access to health-promoting resources and drives health inequities in the United States. Connecticut’s Section 8-30g incentivizes municipalities to develop a housing stock that is at least 10% affordable housing. We used this implicit target to project the impact of increasing affordable housing across all 169 Connecticut municipalities on all-cause mortality among low-income residents. We modeled six ambient environmental exposures: fine particulate matter (PM2.5), ozone (O3), nitrogen dioxide (NO2), summertime daily maximum heat index, greenness, and road traffic noise. We allocated new affordable housing to reach the 10% target in each town and simulated random movement of low-income households into new units using an inverse distance weighting penalty. We then quantified exposure changes and used established exposure-response functions to estimate deaths averted stratified by four ethnoracial groups: Asian, Hispanic or Latino, non-Hispanic Black, and non-Hispanic White. We quantified racialized segregation by computing a multi-group index of dissimilarity at baseline and post-simulation. Across 1,000 simulations, in one year (2019) we found on average 169 (95% CI: 84, 255) deaths averted from changes in greenness, 71 (95% CI: 49, 94) deaths averted from NO2, 9 (95% CI: 4, 14) deaths averted from noise, and marginal impacts from other exposures, with the highest rates of deaths averted observed among non-Hispanic Black and non-Hispanic White residents. Multi-group index of dissimilarity declined on average in all eight Connecticut counties post-simulation. Sensitivity analyses simulating a different population movement strategy and modeling a different year (2018) yielded consistent results. Strengthening desegregation policy may reduce deaths from environmental exposures among low-income residents. Further research should explore non-mortality impacts and additional mechanisms by which desegregation may advance health equity.
Mapping Evidence on Road Safety Information Management Systems in Sub-Saharan Africa: Scoping Review Protocol
Authors: Amme Shemsedin , Seid Sheka Shemsi , Bogale Mekonen , Amdisa Demuma , Husen Abdusemed , Tilahun Getachew , Jibat Nega , Mamo Getachew
Published: February 2024

Background

Road safety information management systems (RSIMS) play a vital role in improving road safety in sub-Saharan Africa (SSA) by providing reliable and timely data and information for evidence-based decision making. However, little is known about RSIMS in SSA.

Objective

The objective of this scoping review is to map the extent and type of evidence on RSIMS in Sub-Saharan Africa.

Inclusion criteria

This review will include sources that report on the application of RSIMS in SSA. The source of information that have considered the use of electronic data systems or software related to any aspects of the road safety management will be included irrespective of their designs or methods. Sources that focused on other populations, concepts, or context will be excluded.

Methods

A comprehensive search of published studies in electronic databases such as Scopus, PubMed, Embase, PubMed, RSKC, ARSO, Lens, and in the sources of grey literature will be carried out to identify relevant sources of information reported in English from 2019 onwards. A scoping review will be performed based on the JBI frameworks using Parsifal platform. Reviewers will independently screen the sources for eligibility, extract data using a JBI-adapted tool, analyze data using descriptive statistics and thematic analysis. The results will be presented in tables, figures, diagrams, and a narrative summary.

Registration details

This protocol for this scoping review has been registered on OSF,https://osf.io/6e2mx/.
Proteomic Signature of HIV-Associated Subclinical Left Atrial Remodeling and Incident Heart Failure
Authors: Peterson Tess E , Hahn Virginia S , Moaddel Ruin , Zhu Min , Haberlen Sabina A , Palella Frank J , Plankey Michael , Bader Joel S , Lima Joao AC , Gerszten Robert E , Rotter Jerome I , Rich Stephen S , Heckbert Susan R , Kirk Gregory D , Piggott Damani A , Ferrucci Luigi , Margolick Joseph B , Brown Todd T , Wu Katherine C , Post Wendy S
Published: February 2024

Background

People living with HIV (PLWH) are at higher risk of heart failure (HF) and preceding subclinical cardiac abnormalities, including left atrial dilation, compared to people without HIV (PWOH). Hypothesized mechanisms include premature aging linked to chronic immune activation. We leveraged plasma proteomics to identify potential novel contributors to HIV-associated differences in indexed left atrial volume (LAVi) among PLWH and PWOH and externally validated identified proteomic signatures with incident HF among a cohort of older PWOH.

Methods

We performed proteomics (Olink Explore 3072) on plasma obtained concurrently with cardiac magnetic resonance imaging among PLWH and PWOH in the United States. Proteins were analyzed individually and as agnostically defined clusters. Cross-sectional associations with HIV and LAVi were estimated using multivariable regression with robust variance. Among an independent general population cohort, we estimated associations between identified signatures and LAVi using linear regression and incident HF using Cox regression.

Results

Among 352 participants (age 55±6 years; 25% female), 61% were PLWH (88% on ART; 73% with undetectable HIV RNA) and mean LAVi was 29±9 mL/m2. Of 2594 analyzed proteins, 439 were associated with HIV serostatus, independent of demographics, hepatitis C virus infection, renal function, and substance use (FDR<0.05). We identified 73 of these proteins as candidate contributors to the independent association between positive HIV serostatus and higher LAVi, enriched in tumor necrosis factor (TNF) signaling and immune checkpoint proteins regulating T cell, B cell, and NK cell activation. We identified one protein cluster associated with LAVi and HIV regardless of HIV viral suppression status, which comprised 42 proteins enriched in TNF signaling, ephrin signaling, and extracellular matrix (ECM) organization. This protein cluster and 30 of 73 individual proteins were associated with incident HF among 2273 older PWOH (age 68±9 years; 52% female; 8.5±1.4 years of follow-up).

Conclusion

Proteomic signatures that may contribute to HIV-associated LA remodeling were enriched in immune checkpoint proteins, cytokine signaling, and ECM organization. These signatures were also associated with incident HF among older PWOH, suggesting specific markers of chronic immune activation, systemic inflammation, and fibrosis may identify shared pathways in HIV and aging that contribute to risk of HF.
Phosphorylation code of human nucleophosmin includes four cryptic sites for hierarchical binding of 14-3-3 proteins
Authors: Kapitonova Anna A. , Perfilova Kristina V. , Cooley Richard B. , Sluchanko Nikolai N.
Published: February 2024

Nucleophosmin (NPM1) is the 46th most abundant human protein with many functions whose dysregulation leads to various cancers. Pentameric NPM1 resides in the nucleolus but can also shuttle to the cytosol. NPM1 is regulated by multisite phosphorylation, yet molecular consequences of site-specific NPM1 phosphorylation remain elusive. Here we identify four 14-3-3 protein binding sites in NPM1 concealed within its oligomerization and α-helical C-terminal domains that are found phosphorylatedin vivo. By combining mutagenesis, in-cell phosphorylation and PermaPhos technology for site-directed incorporation of a non-hydrolyzable phosphoserine mimic, we show how phosphorylation promotes NPM1 monomerization and partial unfolding, to recruit 14-3-3 dimers with low-micromolar affinity. Using fluorescence anisotropy we quantified pairwise interactions of all seven human 14-3-3 isoforms with four recombinant NPM1 phosphopeptides and assessed their druggability by fusicoccin. This revealed a complex hierarchy of 14-3-3 affinities toward the primary (S48, S293) and secondary (S106, S260) sites, differentially modulated by the small molecule. As three of these 14-3-3 binding phospho-sites in NPM1 reside within signal sequences, this work highlights a key mechanism of NPM1 regulation by which NPM1 phosphorylation promotes 14-3-3 binding to control nucleocytoplasmic shuttling. It also provides further evidence that phosphorylation-induced structural rearrangements of globular proteins serve to expose otherwise cryptic 14-3-3-binding sites that are important for cellular function.
Caspase-2 kills cells with extra centrosomes
Authors: Rizzotto Dario , Vigorito Vincenza , Rieder Patricia , Gallob Filip , Moretta Gian Mario , Soratroi Claudia , Riley Joel , Bellutti Florian , Li Veli Stefano , Mattivi Alessia , Lohmueller Michael , Herzog Sebastian , Bornhauser Beat C. , Jacotot Etienne D. , Villunger Andreas , Fava Luca L.
Published: February 2024

Centrosomes are membrane-less organelles that orchestrate a wide array of biological functions by acting as microtubule organizing centers. Here, we report that caspase-2-driven apoptosis is elicited in blood cells failing cytokinesis and that extra centrosomes are necessary to trigger this cell death. Activation of caspase-2 depends on the PIDDosome multi-protein complex and priming of PIDD1 at extra centrosomes is necessary for this pathway. Accordingly, loss of its centrosomal adapter, ANKRD26, allows for cell survival and unrestricted polyploidization in response to cytokinesis failure. Mechanistically, cell death is initiated upstream of mitochondria via caspase-2-mediated processing of the BCL2 family protein BID, driving BAX/BAK-dependent mitochondrial outer membrane permeabilization (MOMP). Remarkably, BID-deficient cells enforce apoptosis by engaging p53-dependent pro-apoptotic transcriptional responses initiated by caspase-2. Consistently, BID and MDM2 act as shared caspase-2 substrates, with BID being kinetically favored. Our findings document that the centrosome limits its own unscheduled duplication by the induction of PIDDosome-driven mitochondrial apoptosis to avoid potentially pathogenic polyploidization events.
Trial-by-trial detection of cognitive events in neural time-series
Authors: Weindel Gabriel , van Maanen Leendert , Borst Jelmer P.
Published: February 2024

Measuring the time-course of neural events that make up cognitive processing is crucial to understand the relation between brain and behavior. To this aim, we formulated a method to discover a trial-wise sequence of events in multivariate neural signals such as electro- or magneto-encephalograpic (E/MEG) recordings. This sequence of events is assumed to be represented by multivariate patterns in neural time-series, with the by-trial inter-event intervals following probability distributions. By estimating event-specific multivariate patterns, and between-event time interval distributions, the method allows to recover the by-trial location of brain responses. We demonstrate the properties and robustness of this hidden multivariate pattern (HMP) method through simulations, including robustness to low signal-to-noise ratio, as typically observed in EEG recordings. The applicability of HMP is illustrated using three previously published datasets. We show how HMP provides, for any experiment or condition, an estimate of the number of events, the sensors contributing to each event (e.g. EEG scalp topography), and the intervals between each event. Traditional exploration of tasks’ cognitive structures and electrophysiological analyses can thus be enhanced by HMP estimates.
The RNA-binding activity of the TRIM-NHL protein NHL-2 is essential for miRNA-mediated gene regulation
Authors: Saadat Nasim , Colson Rhys N. , Grimme Acadia L. , Seroussi Uri , Anderson Joshua W. , Claycomb Julie M. , Wilce Matthew C. J. , McJunkin Katherine , Wilce Jacqueline A. , Boag Peter R.
Published: February 2024

The conserved TRIM-NHL protein, NHL-2, plays a key role in small RNA pathways inCaenorhabditis elegans. NHL-2 has been shown to interact with U-rich RNA through its NHL domain, but the importance to its biological function is unknown. We defined the crystal structure of the NHL domain to 1.4 Å resolution and identified residues that affect affinity for U-rich RNA. Functional analysis of an NHL-2 RNA-binding loss-of-function mutant demonstrated defects in the heterochronic pathway, suggesting that RNA binding is essential for its role in this miRNA pathway. Processing bodies were enlarged in the NHL-2 RNA-binding mutant, suggesting a defect in mRNA decay. We also identified the eIF4E binding protein IFET-1 as a strong synthetic interactor with NHL-2 and the DEAD box RNA helicase CGH-1 (DDX6), linking NHL-2 function to translation repression. We demonstrated that in the absence of NHL-2, there was an enrichment of miRNA transcripts associated with the miRNA pathway Argonaute proteins ALG-2 and ALG-2. We demonstrate that NHL-2 RNA-binding activity is essential forlet-7family miRNA-mediated translational repression. We conclude that the NHL-2, CGH-1, and IFET-1 regulatory axes work with the core miRISC components to form an effector complex that is required for some, but not all, miRNAs.
Bacteria use spatial sensing to direct chemotaxis on surfaces
Authors: Wheeler James H. R. , Foster Kevin R. , Durham William M.
Published: February 2024

Planktonic bacteria navigate chemical gradients using temporal sensing to detect changes in concentration over time as they swim. Here we show that surface-attached bacteria use a fundamentally different mode of sensing during chemotaxis. We combined microfluidic experiments, massively parallel cell tracking, and fluorescent reporters to study howPseudomonas aeruginosasenses chemical gradients during pili-based “twitching” chemotaxis on surfaces. First, we asked whether surface-attached cells use temporal sensing by exposing them to temporal chemical gradients generated via Taylor-Aris dispersion. However, we find that temporal changes in concentration do not induce changes in motility, indicating that twitching cells do not sense chemical gradients like swimming bacteria do. We, therefore, designed experiments to test whether cells can detect chemical gradients across the length of their bodies. In these experiments, we follow the localisation of a fluorescent protein fusion to quantify the chemotactic behaviour of stationary cells in an alternating chemical gradient. We find thatP. aeruginosacells can directly sense differences in concentration across the lengths of their bodies, even in the presence of strong temporal fluctuations. Our work reveals thatP. aeruginosacells are capable of spatial sensing, thus overturning the widely held notion that bacterial cells are too small to directly sense chemical gradients in space.
The cellular representation of temperature across the somatosensory thalamus
Authors: Leva Tobias , Whitmire Clarissa J. , Sauve Ilaria , Bokiniec Phillip , Memler Charlene , Horn Bibiana M. , Vestergaard Mikkel , Carta Mario , Poulet James F.A.
Published: February 2024

Although distinct thalamic nuclei encode sensory information for almost all sensory modalities, the existence of a thalamic representation of temperature with a role in thermal perception remains unclear. To address this, we performed high-density electrophysiological recordings across the entire forelimb somatosensory thalamus in awake mice, and identified an anterior and a posterior representation of temperature that spans three thalamic nuclei. We found that these parallel representations show fundamental differences in the cellular encoding of temperature which reflects their cortical output targets. While the anterior representation encodes cool only and the posterior both cool and warm; in both representations cool was more densely represented and showed shorter latency, more transient responses as compared to warm. Moreover, thalamic inactivation showed a major role in thermal perception. Our comprehensive dataset identifies the thalamus as a key structure in thermal processing and highlights a novel posterior pathway in the thalamic representation of warm and cool.
Microglia/macrophage-specific deletion of TLR-4 protects against neural effects of diet-induced obesity
Authors: Liu Jiahui , Zaidi Ali , Pike Christian J.
Published: February 2024

Obesity is associated with numerous adverse neural effects, including reduced neurogenesis, cognitive impairment, and increased risks for developing Alzheimer’s disease (AD) and vascular dementia. Obesity is also characterized by chronic, low-grade inflammation that is implicated in mediating negative consequences body-wide. Toll-like receptor 4 (TLR4) signaling from peripheral macrophages is implicated as an essential regulator of the systemic inflammatory effects of obesity. In the brain, obesity drives chronic neuroinflammation that involves microglial activation, however the contributions of microglia-derived TLR4 signaling to the consequences of obesity are poorly understood. To investigate this issue, we first generated mice that carry an inducible, microglia/macrophage-specific deletion of TLR4 that yields long-term TLR4 knockout only in brain indicating microglial specificity. Next, we analyzed the effects of microglial TLR4 deletion on systemic and neural effects of a 16-week of exposure to control versus obesogenic high-fat diets. In male mice, TLR4 deletion generally yielded limited effects on diet-induced systemic metabolic dysfunction but significantly reduced neuroinflammation and impairments in neurogenesis and cognitive performance. In female mice maintained on obesogenic diet, TLR4 deletion partially protected against weight gain, adiposity, and metabolic impairments. Compared to males, females showed milder diet-induced neural consequences, against which TLR4 deletion was protective. Collectively, these findings demonstrate a central role of microglial TLR4 signaling in mediating the neural effects of obesogenic diet and highlight sexual dimorphic responses to both diet and TLR4.