bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessing the diagnostic impact of blood transcriptome profiling in a pediatric cohort previously assessed by genome sequencing
Authors: Hou Huayun , Yuki Kyoko E. , Costain Gregory , Szuto Anna , Barnes Sierra , Ramani Arun K. , Celik Alper , Braga Michael , Gloven-Brown Meagan , Stavropoulos Dimitri J. , Bowdin Sarah , Cohn Ronald D , Mendoza-Londono Roberto , Scherer Stephen W. , Brudno Michael , Marshall Christian R. , Meyn M. Stephen , Shlien Adam , Dowling James J. , Wilson Michael D. , Kyriakopoulou Lianna
Published: December 2024

Despite advances in diagnostic testing and genome sequencing, the majority of individuals with rare genetic disorders remain undiagnosed. As a complement to genome sequencing, transcriptional profiling can provide insight into the functional consequences of DNA variants on RNA transcript expression and structure. Here we assessed the utility of blood derived RNA-seq in a well-studied, but still mostly undiagnosed, cohort of individuals who enrolled in the SickKids Genome Clinic study. This cohort was established to benchmark the ability of genome sequencing technologies to diagnose genetic diseases and has been subjected to multiple analyses. We used RNA-seq to profile whole blood RNA expression from all probands for whom a blood sample was available (n=134). Our RNA-centric analysis included differential gene expression, alternative splicing, and allele specific expression. In one third of the diagnosed individuals (20/61), RNA-seq provided additional evidence supporting the pathogenicity of the variant found by prior DNA-based analyses. In 2/61 cases, RNA-seq changed the GS-derived genetic diagnosis (EPG5toLZTR1in an individual with a Noonan syndrome-like disorder) and discovered an additional relevant gene (CEP120in addition toSONin an individual with ZTTK syndrome). In ∼7% (5/73) of the undiagnosed participants, RNA-seq provided at least one plausible, potentially diagnostic candidate gene. This study illustrates the benefits and limitations of using whole-blood RNA profiling to support existing molecular diagnoses and reveal candidate molecular mechanisms underlying undiagnosed genetic disease.
Trajectories of Cognitive Function in First-Episode Psychosis: Associations to Clinical Outcomes and Biomarkers
Authors: Lee Maria , Cullen Alexis E. , Matheson Granville J. , Lu Zheng-An , Bergen Sarah E. , Sellgren Carl M. , Erhardt Sophie , Fatouros-Bergman Helena , Cervenka Simon
Published: December 2024

Aims

Cognitive dysfunction in psychotic disorders is common. At disorder onset, this impairment varies greatly between individuals, which may reflect different levels of decline compared to pre-morbid levels. Diverse trajectories in cognitive change prior to psychosis onset have been hypothesized to represent different underlying pathological processes. Our primary aim was to model cognitive change over time in a sample of individuals with first-episode psychosis (FEP) and controls. The secondary aim was to explore whether cognitive change was associated with clinical outcomes, and biological markers that have shown associations with disease progression.

Methods

Our sample consisted of 73 individuals with FEP who had undergone cognitive assessment at psychosis onset and 53 controls. Using school grades from registry data as a proxy for pre-morbid cognitive ability, we modelled change in cognition using linear mixed-effects models. The resulting change scores were correlated to polygenic risk scores, cerebrospinal fluid levels of complement protein C4A and clinical outcomes.

Results and Conclusions

Groups did not differ in school performance prior to psychosis. Psychosis onset was associated with a large cognitive decline in FEP and thereafter they performed significantly worse than controls. Among FEP individuals, there was a large degree of variability in cognitive change leading up to psychosis onset. Degree of cognitive change was not associated to the selected biological variables but did predict worse clinical outcomes. The results indicate that individual cognitive trajectories may be a clinically relevant topic for further study, but given the exploratory nature of the analysis, replication in an independent sample is required.
A Multicenter Retrospective Observational Cohort Study of Seizure Freedom before Lennox-Gastaut Syndrome (the “Gap”). Opportunities for Prevention
Authors: Deering Laura , Nelson Aaron , Yozawitz Elissa , Wolf Steven , McGoldrick Patricia , Wu Alan , Basma Natasha , Grinspan Zachary
Published: December 2024

Objective

Lennox-Gastaut Syndrome (LGS) is a severe, often treatment-resistant epilepsy syndrome typically diagnosed in early childhood. Many have seizures before diagnosis. Some have periods of seizure freedom before treatment resistance, i.e., a “gap.” Review of these gaps may identify early candidate biomarkers of LGS and/or highlight opportunities for intervention.

Methods

We reviewed charts of children diagnosed with LGS born in 2008-2010 and diagnosed with LGS by 2014 at five academic medical centers in New York City using the RENYC (Rare Epilepsies in New York City) database. We collected dates of events of potential biomarkers by chart abstraction, including onset of slow spike-and-wave (SSW) and onset and offset of seizure freedom. Seizure-free periods (“gaps”) were defined as greater than 30 days without unprovoked seizures.

Results

Thirty-three children had LGS (52% male; etiology 33% structural-acquired, 6% structural-congenital, 3% genetic-structural, 24% genetic, 33% unknown). Twenty-two (67%) had a gap before diagnosis. Eight of these twenty-two (36%) had SSW described before the gap, five (23%) during the gap, and six (27%) after the gap. A history of infantile epileptic spasms syndrome (IESS), age at seizure onset, and age of tonic seizure onset were not different between those with and without a gap. Of 20 (61%) with a history of IESS, 10 (30% of the full cohort) had not received recommended therapy (i.e., ACTH, prednisolone, or vigabatrin) as first-line treatment.

Conclusions

The appearance of SSW, even in seizure-free children, may herald the development of LGS in high-risk children. Further studies on its predictive value are warranted. Our findings also highlight use of recommended first-line therapy for infantile spasms as a potentially modifiable treatment gap in children who subsequently develop LGS.
Not the Models You Are Looking For: Traditional ML Outperforms LLMs in Clinical Prediction Tasks
Authors: Brown Katherine E. , Yan Chao , Li Zhuohang , Zhang Xinmeng , Collins Benjamin X. , Chen You , Clayton Ellen Wright , Kantarcioglu Murat , Vorobeychik Yevgeniy , Malin Bradley A.
Published: December 2024

Objectives

To determine the extent to which current Large Language Models (LLMs) can serve as substitutes for traditional machine learning (ML) as clinical predictors using data from electronic health records (EHRs), we investigated various factors that can impact their adoption, including overall performance, calibration, fairness, and resilience to privacy protections that reduce data fidelity.

Materials and Methods

We evaluated GPT-3.5, GPT-4, and ML (as gradient-boosting trees) on clinical prediction tasks in EHR data from Vanderbilt University Medical Center and MIMIC IV. We measured predictive performance with AUROC and model calibration using Brier Score. To evaluate the impact of data privacy protections, we assessed AUROC when demographic variables are generalized. We evaluated algorithmic fairness using equalized odds and statistical parity across race, sex, and age of patients. We also considered the impact of using in-context learning by incorporating labeled examples within the prompt.

Results

Traditional ML (AUROC: 0.847, 0.894 (VUMC, MIMIC)) substantially outperformed GPT-3.5 (AUROC: 0.537, 0.517) and GPT-4 (AUROC: 0.629, 0.602) (with and without in-context learning) in predictive performance and output probability calibration (Brier Score (ML vs GPT-3.5 vs GPT-4): 0.134 versus 0.384 versus 0.251, 0.042 versus 0.06 versus 0.219). Traditional ML is more robust than GPT-3.5 and GPT-4 to generalizing demographic information to protect privacy. GPT-4 is the fairest model according to our selected metrics but at the cost of poor model performance.

Conclusion

These findings suggest that LLMs are much less effective and robust than locally-trained ML for clinical prediction tasks, but they are getting better over time.
Co-prescription of Metformin and Antipsychotics in Severe Mental Illness: A UK Primary Care Cohort Study
Authors: Farache Trajano Luiza , Hayes Joseph F. , Launders Naomi , Davies Neil M. , Osborn David P. J. , Richards-Belle Alvin
Published: December 2024

Background

Metformin is a pharmacological candidate to mitigate second-generation antipsychotic (SGA)-induced weight gain in patients with severe mental illnesses (SMI).

Objective

To evaluate the incidence, prevalence, and demographic patterns of metformin co-prescription among patients diagnosed with SMI initiating SGAs. To estimate the impact of co-prescription on weight.

Methods

A cohort study of patients diagnosed with SMI initiating aripiprazole, olanzapine, quetiapine, or risperidone in 2005-2019 using primary care data from Clinical Practice Research Datalink. We estimated cumulative incidence and period prevalences of co-prescription and explored prescribing differences by demographic and clinical factors. We compared weight change among patients prescribed an SGA only versus an SGA plus metformin, accounting for confounders using linear regression.

Findings

Among 26,537 patients initiating SGAs, 4652 were ever prescribed metformin and 21,885 were not. Two-year incidence of first metformin prescription was 3.3%. The SGA plus metformin group were more ethnically diverse, had greater social deprivation, more comorbidities, and higher baseline weight (mean 90.4 vs. 76.8 kg). By two years post-SGA initiation, mean weight in the SGA- only group had changed by +4.16% (95% CI, -1.26 to +9.58) compared to -0.65% (95% CI, -4.26 to +2.96) in the SGA plus metformin group. After confounder adjustment, the two-year mean difference in weight with metformin co-prescription was -1.48 kg (95% CI, -4.03 to 1.07) among females and -1.84 kg (95% CI, -4.67 to 0.98) among males.

Conclusion

Metformin is infrequently co-prescribed, despite established efficacy and guidelines.

Clinical implications

Primary and secondary care collaboration should be strengthened and barriers to co-prescribing addressed.
Expanding the HP1a-binding consensus and molecular grammar for heterochromatin assembly
Authors: Colmenares Serafin U. , Tsukamoto Shingo , Hickmann Collin , Brennan Lucy D. , Khavani Mohammad , Mofrad Mohammad R. K. , Karpen Gary H.
Published: December 2024

The recruitment of Heterochromatin Protein 1 (HP1) partners is essential for heterochromatin assembly and function, yet our knowledge regarding their organization in heterochromatin remains limited. Here we show that interactors engage the Drosophila HP1 (HP1a) dimer through a degenerate and expanded form of the previously identified PxVxL motif, which we now term HP1a Access Codes (HACs). These HACs reside in disordered regions, possess high conservation among Drosophila homologs, and contain alternating hydrophobic residues nested in a cluster of positively charged amino acids. These findings and molecular dynamics simulations identify key electrostatic interactions that modulate HP1a-binding strength and provide a dramatically improved HP1a-binding consensus motif that can reveal protein partners and the molecular grammar involved in heterochromatin assembly. We propose HP1a acts as a scaffold for other heterochromatin components containing HAC motifs, which in turn may regulate the function and higher order structure of the heterochromatin compartment.
Harnessing the FBXW7 somatic mutant R465C for targeted protein degradation
Authors: Basu Ananya A. , Zhang Chenlu , Rouhimoghadam Milad , Vasudevan Anil , Reitsma Justin M. , Zhang Xiaoyu
Published: December 2024

Targeted protein degradation (TPD) is a pharmacological strategy that eliminates specific proteins from cells by harnessing cellular proteolytic degradation machinery. In proteasome-dependent TPD, expanding the repertoire of E3 ligases compatible with this approach could enhance the applicability of this strategy across various biological contexts. In this study, we discovered that a somatic mutant of FBXW7, R465C, can be exploited by heterobifunctional compounds for targeted protein degradation. This work demonstrates the potential of utilizing mutant E3 ligases that occur exclusively in diseased cells for TPD applications.
Structure of Bifunctional Variediene Synthase Yields Unique Insight on Biosynthetic Diterpene Assembly and Cyclization
Authors: Wenger Eliott S. , Christianson David W.
Published: December 2024

An unusual family of bifunctional terpene synthases has been discovered in which both catalytic domains – a prenyltransferase and a cyclase – are connected by a long, flexible linker. These enzymes are unique to fungi and catalyze the first committed steps in the biosynthesis of complex terpenoid natural products: the prenyltransferase assembles 5-carbon precursors to form C20geranylgeranyl diphosphate (GGPP), and the cyclase converts GGPP into a polycyclic hydrocarbon product. Weak domain-domain interactions as well as linker flexibility render these enzymes refractory to crystallization and challenge their visualization by cryo-EM. Despite these challenges, we now present the first experimentally-determined structure of a massive, 495-kD bifunctional terpene synthase revealing the assembly of all catalytic domains. The cryo-EM structure of variediene synthase fromEmericella variecolor(EvVS) exhibits a bollard-like architecture, consisting of a hexameric prenyltransferase core sandwiched between two triads of cyclase domains. Although prenyltransferase and cyclase active sites are relatively close together, enzymological measurements indicate that GGPP is not channeled from one to the other. Surprisingly, however, the individual cyclase domain from another bifunctional diterpene synthase, fusicoccadiene synthase fromPhomopsis amygdali, preferentially receives GGPP from the EvVS prenyltransferase in substrate competition experiments. Our previous studies of fusicoccadiene synthase suggest that GGPP channeling occurs through transient binding of cyclase domains to the sides of the prenyltransferase oligomer. The bollard-like architecture of EvVS leaves the sides of the prenyltransferase oligomer open and accessible, suggesting that a non-native cyclase could bind to the sides of the prenyltransferase oligomer to achieve GGPP channeling.
Human stem cell-derived GABAergic interneuron development reveals early emergence of subtype diversity followed by gradual electrochemical maturation
Authors: Bershteyn Marina , Zhou Hongjun , Fuentealba Luis , Chen Chun , Subramanyam Geetha , Cherkowsky Daniel , Salvatierra Juan , Sezan Meliz , Maury Yves , Havlicek Steven , Kriks Sonja , Lee Seonok , Watson Michael , Au Wai , Qiu Yuechen , Nesterova Anastasia , Anderson Derek , Feld Brianna G , Kuzmenko Olga , Grimmett Maria Elena , Hosford Victoria , Jung Ji-Hye , Kowal Tia , Bulfone Alessandro , Banik Gautam , Priest Catherine , Palop Jorge , Nicholas Cory R.
Published: December 2024

Medial ganglionic eminence-derived inhibitory GABAergic pallial interneurons (MGE-pINs) are essential regulators of cortical circuits; their dysfunction is associated with numerous neurological disorders. We developed human (h) MGE-pINs from pluripotent stem cells for the treatment of drug-resistant epilepsy. Here, we analyzed xenografted hMGE-pINs over the lifespan of host mice using single nuclei RNA sequencing. Comparative transcriptomics against endogenous human brain datasets revealed that 97% of grafted cells developed into somatostatin (SST) and parvalbumin (PVALB) subtypes, including populations that exhibit selective vulnerability in Alzheimer’s disease. Transplanted hMGE-pINs demonstrated rapid emergence of subclass features, progressing through distinct transcriptional states sequentially involving neuronal migration, synapse organization, and membrane maturation. We present molecular, electrophysiological, and morphological data that collectively confirm the derivation of diversebona-fidehuman SST and PVALB subtypes, providing a high-fidelity model to study human MGE-pIN development and functional maturation as well as a compositional atlas for regenerative cell therapy applications.
An algorithm for predicting per-cell proteomic properties
Authors: Arroyo José Ignacio , Kempes Chris
Published: December 2024

Proteomic studies have traditionally focused on population-level analyses with an emphasis on the relative abundance of various proteins. Such studies have been useful in uncovering physiological differences across diverse species, the physiological response of individual species to distinct environmental conditions, and the function of individual proteins in the context of cellular networks. However, the absolute value of protein abundance in a cell is important for understanding single-cell physiology, detailed biophysical considerations, connecting diverse quantitative data, and for comparisons across species. Such detailed quantification will naturally occur as singlecell proteomics becomes more prevalent, but it is also of current interest to leverage population studies. There are several challenges here. First, most population studies do not measure the quantity of cells associated with a proteome. Second, recent work has shown that cell physiology radically shifts with cell size, and these effects need to be accounted for in going from population to single-cell estimates. Here we develop and implement a method to estimate the basic properties of proteomes, based on well-established scaling relationships among cell components, including genome size, cell size, and proteome volume. Our method estimates similar but higher total proteins per cell compared to previous theoretical and empirical estimations. Our algorithm has applications for interpreting proteomes, analyzing environmental samples, and designing artificial cells. While focusing on prokaryotes, we discuss how the method can be extended to unicellular and multicellular eukaryotes.
Age-specific control and Alzheimer’s disease reference curves and z-scores for glial fibrillary acidic protein in blood
Authors: Halbgebauer Steffen , Fazeli Badrieh , Klose Veronika , Nagel Gabriele , Rosenbohm Angela , Rothenbacher Dietrich , Bachhuber Franziska , Jesse Sarah , Otto Markus , Landwehrmeyer G. Bernhard , Abdelhak Ahmed , Petzold Axel , Ludolph Albert C. , Tumani Hayrettin ,   the ALS Registry Swabia study group
Published: December 2024

Background

Serum glial fibrillary acidic protein (GFAP) is a biomarker for astrocytic injury and astrogliosis. Concentrations are elevated in numerous neurological disorders, including a pronounced increase in Alzheimer’s disease (AD). However, GFAP levels in the serum also increase with age. Consequently, the integration of GFAP levels into clinical routine and their interpretation demands age-adjusted reference values.

Methods

Serum from 1273 subjects (952 non-inflammatory and non-neurodegenerative neurological controls and 321 subjects with AD) were analyzed for GFAP using the microfluidic Ella system. Age-dependent serum GFAP reference values were calculated by additive quantile regression analysis. Percentiles and z-scores were employed for the presentation of GFAP levels as a function of age.

Results

All patients within the AD continuum exhibited statistically elevated serum GFAP levels in comparison to the control cohort (p<0.0001). This remained the case when the newly generated age-corrected z-scores were applied (p<0.0001). In the control cohort, a non-linear elevation of serum GFAP with increasing age was observed (Spearman correlation coefficient (r) 0.62, 95%CI 0.58-0.66, p<0.0001). In contrast, the AD cohort exhibited a more linear increase in serum GFAP levels (0.16, 95%CI 0.05-0.26, p=0.004). Age-dependent cut-offs for serum GFAP were calculated for different AD age groups. The calculated areas under the curve (AUC 0.97) demonstrated excellent diagnostic test performance in the early onset age group. This effect was less marked in the elderly subjects (AUC 0.72).

Conclusions

Our novel GFAP z-scores enable the integration and interpretation of serum GFAP levels in clinical practice, moving from group to individual level. They support both intra- and interindividual interpretation of single GFAP levels in neurological diseases with astrocytic pathology, including an accurate discrimination of Alzheimer’s disease.
Transcriptome regulation analysis in osteoarthritis primary tissues identifies high-confidence effector genes
Authors: Katsoula Georgia , Arruda Ana Luiza , Tutino Mauro , Kreitmaier Peter , Shah Karan M , Swift Diane , Southam Lorraine , Wilkinson J Mark , Zeggini Eleftheria
Published: December 2024

Osteoarthritis, a whole-joint degenerative disorder, is a major public health burden that affects nearly 600 million individuals worldwide. Molecular profiling of relevant tissues is crucial for understanding the biological mechanisms underlying disease development. We present the first comprehensive map of transcriptional regulation of disease-relevant primary tissues from knee osteoarthritis patients: macroscopically intact (low-grade, N=263) and degenerated (high-grade, N=216) cartilage, synovium (N=278), and fat pad (N=94). Of 9,738 unique expression quantitative trait loci (eQTL)-associated genes, 60.6% have not been reported previously. We identify 51 genes with directional evidence of tissue-specific colocalization and causal association with knee osteoarthritis, 25 of which are new high-confidence effector genes for osteoarthritis (includingMUSTN1, which is implicated in cartilage integrity). Our study provides valuable insights into the tissue-specific and shared molecular mechanisms underlying osteoarthritis and offers drug repurposing opportunities.

Graphical abstract
Optimal intervention strategies for a new pandemic: The case of Covid-19*
Authors: Holden Steinar , Rø Gunnar , Hjort Ingrid
Published: December 2024

We present an age-stratified SEIR-type model of the Norwegian population, which is extended to include the effects of broad types of Non-Pharmaceutical Interventions (NPIs) like general lockdown-policies, contact tracing and quarantine and border control. The model can be used to explore the spread of a new virus with given virulence and transmissibility, and to assess the main costs of the disease and the NPIs in terms of lost health and welfare as well as economic losses. We define the optimal strategy as the intervention policy which minimizes the total costs from the pandemic, including health, economic and other welfare effects. We find that the optimal policy typically is a “bang-bang-strategy”, where costly interventions are either so strict that the pandemic is suppressed to a low level, or they are not used at all. Strict interventions may be used to stop the disease at the herd immunity level (i.e prevent pandemic overshoot), while mitigation policies aimed at merely slowing the spread of the pandemic are not optimal in our baseline simulations. We explore how the optimal strategy depends on the properties of the virus, healthcare capacity, intervention costs, population behavior and other relevant variables. These results are informative for decisions regarding costly investments and interventions. In addition, we explore the consequences of policy errors and delays, providing guidance for decision making in the uncertain early stages of a new pandemic.
The essential host genome forCryptosporidiumintracellular survival exposes metabolic dependencies that can be leveraged for treatment
Authors: Marzook N. Bishara , Song Ok-Ryul , Baumgärtel Lotta , Bernitz Netanya , Mkandawire Tapoka T. , Watson Lucy C. , Nunes Vanessa , Warchal Scott , MacRae James I. , Howell Michael , Sateriale Adam
Published: December 2024

Mapping how pathogens interact with their host cells can reveal unexpected pathogen and host cell biology, paving the way for new treatments.Cryptosporidiumis an intracellular parasite of intestinal epithelial cells, and a leading cause of diarrheal death and disease in infants worldwide. Despite this, very little is known about the cell biology of infection of this eukaryotic pathogen. Here, we designed and implemented a unique microscopy-based arrayed CRISPR-Cas9 screen to interrogate the effects of the loss of every protein-coding human gene on aCryptosporidiuminfection. As the experimental readout is image-based, we extracted multiple phenotypic features of infection, including parasite growth, progression of the parasite to its sexual life stage, and recruitment of host actin to ‘pedestals’ beneath the parasite vacuole. Using this dataset, we discovered a tipping point in the host cholesterol biosynthesis pathway that controlsCryptosporidiuminfection. Parasite growth can either be inhibited or promoted by the intermediary metabolite squalene. A build-up of squalene in epithelial cells creates a reducing environment, with more reduced host glutathione available for uptake by the parasite. BecauseCryptosporidiumhas lost the ability to synthesise glutathione, this uptake from the host cell is required for growth and progression through its life cycle. We demonstrate that this dependency can be leveraged for treatment with the abandoned drug lapaquistat, an inhibitor of host squalene synthase that has efficacy againstCryptosporidium in vitroandin vivo.
PITHD1: An Endogenous Inhibitor of the 26S Proteasome During Cellular Dormancy
Authors: Amann Sascha J. , Dong Ken , Roehsner Josef , Krall Dominik , Grishkovskaya Irina , Kotisch Harald , Schleiffer Alexander , Roitinger Elisabeth , Pauli Andrea , Martin Andreas , Haselbach David
Published: December 2024

Cellular dormancy represents a state of regulated growth arrest essential for diverse biological processes, from reproduction to cancer progression. While mechanisms controlling protein synthesis in dormant cells have been identified, how cells regulate protein degradation during dormancy remains unclear. Using zebrafish oocytes, eggs and embryos as a model system, we discovered PITHD1 as an endogenous inhibitor of the 26S proteasome. Our high-resolution cryoEM structure reveals that PITHD1 simultaneously blocks three crucial functional sites on the 19S regulatory particle which are required for ubiquitin recognition, processing, and substrate translocation. This triple-lock mechanism effectively prevents protein degradation in dormant cells. Given PITHD1’s evolutionary conservation across species, this mechanism likely represents a general strategy for reversible proteasome regulation during cellular dormancy. Our findings establish a new paradigm for controlling proteostasis in quiescent states.
Glucose-Sensing ChREBP Protein in the Pathogenesis of Diabetic Retinopathy
Authors: Starr Christopher R. , Zhylkibayev Assylbek , Gorbatyuk Oleg , Nuotio-Antar Alli M. , Mobley James , Grant Maria B. , Gorbatyuk Marina
Published: December 2024

Glucose-sensing ChREBP and MondoA are transcriptional factors involved in lipogenic, inflammatory, and insulin signaling pathways implicated in metabolic disorders; however, limited ocular studies have been conducted on these proteins. We aimed to investigate the potential role of ChREBP in pathogenesis of diabetic retinopathy (DR). We used diabetic human and mouse retinal cryosections analyzed by immunohistochemistry. qRT-PCR was performed to quantify gene expression. To explore the role of ChREBP in rods, we generated caChREBPRPmice with constitutively active (ca) ChREBP. These mice underwent retinal function testing, followed by proteomic analysis using LC-MS. Furthermore, ARPE-19 cells were infected with lentiviral particles expressing human ChREBP (ARPE-19ChREBP) and subjected to global proteomics. Our results demonstrate that both pro-teins were expressed across the retina, although with distinct distribution patterns: MondoA was more prominently expressed in cones, while ChREBP was broadly expressed throughout the retina. Elevated expression of both proteins was observed in DR. This may have contributed to rod photo-receptor degeneration as we observed diminished scotopic ERG amplitudes detected in caChREB-PRPmice at P35. The retinal proteomic landscape indicated a decline in KEGG pathways associated with phototransduction, amino acid metabolism, and cell adhesion. Furthermore, rod-specific ca-ChREBP induced TXNIP expression. Consistent with altered retinal proteomics, ARPE-19ChREBPcells displayed a metabolic shift toward increased glyoxylate signaling, sugar metabolism, and lysosomal activation. Our study demonstrates that ChREBP overexpression causes significant metabolic reprograming triggering retinal functional loss in mice
High resolution imaging and interpretation of three-dimensional RPE sheet structure
Authors: Donaldson Kevin J. , Chrenek Micah A. , Boatright Jeffrey H. , Nickerson John M.
Published: December 2024

The retinal pigment epithelium (RPE), a monolayer of pigmented cells, is critical for visual function through its interaction with the neural retina. In healthy eyes, RPE cells exhibit a uniform hexagonal arrangement, but under stress or disease, such as age-related macular degeneration (AMD), dysmorphic traits like cell enlargement and apparent multinucleation emerge. Multinucleation has been hypothesized to result from cellular fusion, a compensatory mechanism to maintain cell to cell contact, barrier function, and conserve resources in unhealthy tissue. However, traditional two-dimensional (2D) imaging using apical border markers alone may misrepresent multinucleation due to the lack of lateral markers.

We present high-resolution confocal images enabling three-dimensional (3D) visualization of apical (ZO-1) and lateral (alpha-catenin) markers alongside nuclei. In two RPE damage models, we find that seemingly multinucleated cells are often single cells with displaced neighboring nuclei and lateral membranes. This emphasizes the need for 3D analyses to avoid misinterpreting multinucleation and underlying fusion mechanisms. Lastly, images from the NaIO3 oxidative damage model reveal variability in RPE damage, with elongated, dysmorphic cells showing increased ZsGreen reporter protein expression driven by EMT-linked CAG promoter activity, while more regular RPE cells displayed somewhat reduced green signal more typical of epithelial phenotypes.
Convergence of autism proteins at the cilium
Authors: Kostyanovskaya Elina , Lasser Micaela C. , Wang Belinda , Schmidt James , Bader Ethel , Buteo Chad , Arbelaez Juan , Sindledecker Aria Rani , McCluskey Kate E. , Castillo Octavio , Wang Sheng , Dea Jeanselle , Helde Kathryn A. , Graglia J. Michael , Brimble Elise , Kastner David B. , Ehrlich Aliza T. , State Matthew W. , Willsey A. Jeremy , Willsey Helen Rankin
Published: December 2024

Hundreds of high-confidence autism genes have been identified, yet the relevant etiological mechanisms remain unclear. Gene ontology analyses have repeatedly identified enrichment of proteins with annotated functions in gene expression regulation and neuronal communication. However, proteins are often pleiotropic and these annotations are inherently incomplete. Our recent autism functional genetics work has suggested that these genes may share a common mechanism at the cilium, a membrane-bound organelle critical for neurogenesis, brain patterning, and neuronal activity–all processes strongly implicated in autism. Moreover, autism commonly co-occurs with conditions that are known to involve ciliary-related pathologies, including congenital heart disease, hydrocephalus, and blindness. However, the role of autism genes at the cilium has not been systematically investigated. Here we demonstrate that autism proteins spanning disparate functional annotations converge in expression, localization, and function at cilia, and that patients with pathogenic variants in these genes have cilia-related co-occurring conditions and biomarkers of disrupted ciliary function. This degree of convergence among genes spanning diverse functional annotations strongly suggests that cilia are relevant to autism, as well as to commonly co-occurring conditions, and that this organelle should be explored further for therapeutic potential.

One-Sentence Summary

Autism genes of diverse functional annotations converge at cilia, deepening our understanding of underlying autism biology and co-occurring conditions.
GET3B interacts with the thylakoidal ALB3 and ALB4 insertases and is involved in the initial stages of chloroplast biogenesis
Authors: Bodensohn Uwe , Dünschede Beatrix , Kuhlmann Chiara , Kumari Khushbu , Ladig Roman , Grefen Christopher , Schleiff Enrico , Fernandez Donna , Schünemann Danja
Published: December 2024

Protein targeting and insertion into membranes are essential for cellular organization and organelle function. The Guided Entry of Tail-anchored (GET) pathway facilitates the post-translational targeting and insertion of tail-anchored (TA) membrane proteins.Arabidopsis thalianahas four GET3 homologues, includingAtGET3B andAtGET3D localized to chloroplasts. These photosynthetic organelles possess complex membrane systems, and the mechanisms underlying their protein targeting and membrane biogenesis are not fully understood. This study conducted a comprehensive proteomic analysis ofget3bmutant plastids, which displayed significant alterations. Fluorometric based complex assembly as well as CO2assimilation analyses confirmed that disruption of GET3B function displayed a significant impact on photosystem II assembly as well as carbon fixation, respectively, indicating a functional role in chloroplast biogenesis. Additionally, genetic interactions were found between GET3B and the two component STIC system, which cooperates with the cpSRP pathway and is involved in the co-translational sorting of thylakoid proteins. Further, physical interactions were observed between GET3B and the C-terminus of ALB3 and ALB4in vitroand the full length proteinsin vivo, indicating a role of GET3B in protein targeting and membrane integration within chloroplasts. These findings enhance our understanding of GET3B’s involvement in stromal protein targeting and thylakoidal biogenesis.
The impact of organisational resilience and government communication on the well-being of tourism SME operators
Authors: Natoli Riccardo , Nguyen Van K. , Gamage Ancy , Pyke Joanne , de Lacy Terry , Nguyen Thu-Huong , Drake Colin
Published: December 2024

Purpose

Drawing on crisis management theory and complexity theory, the purpose of this study is to examine the impact of a prolonged COVID-19 induced lockdown on tourism small and medium enterprise (SME) operators’ well-being.

Design/methodology/approach

A mixed methods approach was used, with survey data from 226 SME tourism operators located in Victoria (Australia) and 33 interviews with a cross-representative selection of tourism stakeholders.

Findings

The findings of this study show that planned resilience, adaptive resilience, government communication (i.e. Roadmap to Recovery announcement) and revenue status are positively linked to well-being.

Research limitations/implications

The cross-sectional nature of this study is not able to provide evidence of a temporal relationship between exposure and outcome, as both are examined at the same time. This study is restricted to one Australian State and may have limited generalisability.

Practical implications

The findings identify strategies to improve tourism SMEs resilience and their operator well-being. Programs designed to meet the needs of tourism SME owners and enhance access to well-being services, while training for SME tourism operators should focus on improving the diversification potential of the business.

Originality/value

To the best of the authors’ knowledge, this is among the first studies applying crisis management and complexity theories as theoretical lenses to explore the joint effect of organisational resilience and government communication on SME tourism operators’ well-being. The inclusion of communication on SME well-being is an area hitherto unexplored in the tourism literature.
Grand Challengers: the exemplars of Follett and Barnard
Authors: S. O’Connor Ellen
Published: December 2024

Purpose

This study aims to present a new contribution from recognized historical sources that gives proven knowledge on how to develop individuals to meet Grand Challenges.

Design/methodology/approach

Textual analysis and interpretive synthesis of little-known biographical and autobiographical data on Mary Parker Follett and Chester Barnard showing a method for meeting Grand Challenges.

Findings

Follett and Barnard developed a method of self-development for making significant societal contributions.

Research limitations/implications

The major limitation is a claim that there is sufficient empirical evidence to document a strictly internal process of Follett’s and Barnard’s.

Practical implications

A method that is teachable and replicable.

Social implications

A method that could scale to a curriculum enabling better and faster development of Grand Challengers.

Originality/value

A new contribution, from historically recognized sources, which responds to a leadership crisis in general and particularly where Grand Challenges are concerned.
Distinct effects of consumer innovativeness on willingness to pay a green premium when framing social norms information
Authors: Shao Changpeng
Published: December 2024

Purpose

This study aims to explore the dynamic interplay between consumer innovativeness and willingness to pay a green premium (WPGP), moderated by the information frames of social norms. Using a cybernetic framework, we examine how consumer traits and the presentation of social norms (including descriptive and injunctive norms) influence green consumption.

Design/methodology/approach

This study conducts a between-subjects survey experiment and collects a sample from 535 Chinese consumers to examine the hypothesis.

Findings

Our findings reveal that different dimensions of consumer innovativeness – hedonic, social, functional and cognitive – affect WPGP in varied ways. Importantly, the effect of functionally motivated consumer innovativeness (fMCI) is significantly moderated by how social norms are framed. We also find that negatively framed norms about the number of people do not consume green products and consequences of not engaging in green behaviours are generally more effective than positively framed norms in influencing WPGP, though the effect is slight.

Originality/value

The study employs a comprehensive experimental design with a Chinese sample to test these relationships, contributing novel insights into the marketing strategies and policy formulations necessary to enhance green consumption. By integrating theories of normative social behaviour and bounded rationality, our research not only deepens the understanding of consumer behaviour in environmental contexts but also offers practical implications for fostering more sustainable consumption patterns.
Historical Bird Atlas and Contemporary Citizen Science Data Reveal Long‐Term Changes in Geographic Range of Kenyan Birds
Authors: Nussbaumer Raphaël , Nussbaumer Améline , Guchu Samuel , Hatfield Richard Stratton , M. Kanga Erustus , Kung'u Gladys Nyakeru , Kuria Anthony , Miller Eliot , Ndang'ang'a Paul Kariuki , Njoroge Peter , Ogada Darcy , Shema Sidney , Jackson Colin
Published: December 2024

Aim

Historical bird atlases provide comprehensive datasets for investigating long‐term changes in species' distribution. In the context of accelerating biodiversity loss, these datasets can lend critical insights into the state of bird distributions across broad spatio‐temporal scales and provide much‐needed information for impactful conservation. In Africa, the potential of atlas data to understand changes in avian populations remains largely untapped.

Location

This study mapped changes in national distribution patterns of 1088 bird species found in Kenya.

Methods

Tapping into one of the earliest atlas databases, this study compared Kenyan bird atlas data collected between 1970 and 1984 with recent citizen science data sourced from the Kenya Bird Map project and eBird to determine changes in ranges across 50 years. We produced maps displaying, for every 27 × 27 km square of the country, whether a species appeared, was present throughout both periods, or disappeared. We account for the change in data collection effort between the two periods by quantifying the confidence of the change for each square.

Results

The maps produced for each species are publicly accessible through an interactive website: https://kenyabirdtrends.co.ke/. We found that related species tended to experience similar changes in their distribution ranges. The ranges of Palearctic migrants and scavengers declined drastically, while introduced birds experienced a significant range increase over the past 50 years.

Main Conclusions

This study demonstrates the potential of integrating recent citizen science data with historical atlas data to draw out the changes in range for all species at national level. The range contraction of Palearctic migrants and scavengers echoed corresponding drops in abundance at local, regional and global scales. These findings lend additional weight to the need for an increased conservation focus on migratory and scavenging birds in Kenya.
Efficacy of endoscopic radiofrequency ablation for proton pump inhibitor‐dependent gastroesophageal reflux disease: Multicenter prospective cohort study
Authors: Jiang Yuanxi , Dong Zhiyu , Chen Ying , Sun Huihui , Wang Junwen , Wang Zhenxiang , Meng Qianqian , Lin Han , Zhang Qingwei , Chen Shengliang , Ge Zhizheng , Wang Luowei , Xu Shuchang
Published: December 2024

Objectives

To evaluate the effects of endoscopic radiofrequency ablation (RFA) on proton pump inhibitor (PPI)‐dependent gastroesophageal reflux disease (GERD) in a Chinese population, and to explore the factors associated with favorable efficacy.

Methods

A multicenter, single‐armed prospective cohort study was conducted. PPI‐dependent GERD patients were enrolled and underwent RFA. The primary outcome was improvement of GERD health‐related quality of life (GERD‐HRQL). Secondary outcomes were symptom improvement, satisfaction, PPI use, and the indicators of 24‐h pH‐impedance monitoring. A nomogram to predict complete remission was constructed.

Results

In total, 66 patients were included. The GERD‐HRQL score was significantly reduced at the 3 month (mean difference, 14.7 [12.6–16.9]), 6 month (mean difference, 15.9 [13.8–18.1]), 12 month (mean difference, 16.7 [14.4–18.9]), 24 month (mean difference, 18.4 [16.2–20.1]), 36 month (mean difference, 18.2 [16.3–20.4]), and 48 month follow‐up (mean difference, 16.1 [14.2–18.3]), all P < 0.001. The esophageal and extra‐esophageal symptom scores were all significantly decreased. The proportion of satisfaction and no PPI use were significantly higher. With regard to the indicators of 24‐h pH‐impedance monitoring, acid exposure time (AET), and DeMeester score, but not lower esophageal sphincter (LES) pressure, decreased significantly at the 12 month follow‐up. A nomogram based on age, body mass index (BMI), baseline AET, and LES pressure was then constructed and showed good discrimination in the prediction of complete remission following RFA.

Conclusions

This study demonstrated that RFA improved life quality as well as symptoms in PPI‐dependent GERD patients in a Chinese population. Younger age, higher BMI, lower baseline AET, and higher baseline LES pressure indicate favorable efficacy of RFA.
Usefulness of a novel 11F digital single‐operator cholangioscopy through a colonoscope in a patient with surgically altered anatomy
Authors: Mie Takafumi , Takeda Tsuyoshi , Sasaki Takashi
Published: December 2024

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Cu(In, Ga)(Se, S)2 thin‐film technology: Aspects of historical development, current status, and future prospects
Authors: Dalibor Thomas , Reichel Rene , Wu Chung Hsien , Borowski Peter , Peng Shou , Chen Jie
Published: December 2024

Copper indium gallium selenide (CIGS)‐based solar cells are a type of thin‐film photovoltaic technology used to convert sunlight into electricity. They are one of the most promising thin‐film technologies with high efficiency and low‐cost potential. CIGS is a direct band gap material with a high absorption coefficient, around 2 µm thickness can absorb most of the light which can reduce the usage of material. CIGS solar cells have a better temperature coefficient, meaning their efficiency decreases less in high‐temperature environments compared to other solar technologies. Furthermore, CIGS solar cells also have excellent low‐light performance due to their broad absorption spectrum. This allows them to generate electricity even in partially shaded or cloudy conditions, which can be common in urban environments with tall buildings or trees casting shadows. Thus, CIGS solar cells are also a good option to be used for building‐integrated PV (BIPV) systems. The latest cell efficiency record was reached in 2023 with 23.6%. Ongoing research aims to increase efficiency, durability, and cost‐effectiveness, making the CIGS thin‐film technology a mainstream option for solar energy generation.
Trade‐in program options in a retailer‐led supply chain
Authors: Zhao Wenyu , Xia Yulan , Zhang Lu , Fan Xiaojun
Published: December 2024

Firms offer trade‐in programs that consumers trade an old product and receive trade‐in rebate when buying a new one. To study whether the manufacturer or the retailer should introduce a trade‐in program, we build a Stackelberg game that consists of one manufacturer and one retailer by considering old and new consumers in a retailer‐led supply chain. We find that when the production cost of a product is high under no trade‐in program, old consumers do not purchase the product. When the retailer provides the trade‐in program, there are “lose–win” situation for the manufacturer and retailer. However, when the manufacturer provides the trade‐in program, there are “win–win” situation for the manufacturer and retailer. Then, we find that the manufacturer (retailer) can benefit more from providing trade‐in program by themselves than that provided by the other one.
Barbatula nuda: an economically valuable freshwater fish that accepts phytoplankton as first food
Authors: Li Jiao , Luo Xiaonian , Wu Chen , Duan Youjian , Wei Yong
Published: December 2024

Barbatula nuda is considered a promising emerging species to diversify small cold‐water fish aquaculture worldwide due to its rapid growth and delicious flesh. However, limited information on larval development and nutrition is available. In this study, 7‐day feeding experiments were performed to evaluate three different initial diets (zooplankton, phytoplankton, and artificial microdiet) in the zoo group, algae group, and AD group on growth, development, and digestion of larvae B. nuda. The results showed that there was no significant difference in survival rate among the three groups (p > 0.05). The algae group exhibited the highest feed intake success rate and body weight (p < 0.05), the best intestinal development with the protruded intestinal mucosa, and visible intestinal microvillus. Pepsase and trypsin enzyme activities in the algae group larvae were significantly higher than those in the other two groups (p < 0.05). Transcriptome data showed that the mechanistic target of rapamycin pathway of B. nuda fed with phytoplankton was activated, and the metabolisms of carbohydrate were significantly more active than those in the other two groups. As omnivorous fish, B. nuda could accept zooplankton, phytoplankton, and microdiet as initial diets with its survival unaffected, but B. nuda fed with phytoplankton exhibited better growth status and digestive tract development and higher digestive enzyme activities than those fed with other two diets. Therefore, phytoplankton was a suitable initial diet for B. nuda. Our findings provide guidance for the artificial breeding of B. nuda and a theoretical basis for research on fish initial diet.