bluuebunny/crossref_metadata_2025 huggingface dataset:
EEG Infrastructure Within the Veterans Administration: A Survey
Authors: Lu Alisa , Chandra Krishna , Kovalev Dmitri , Savarese Edward N. , Patel Kamakshi , McCarthy David C. , Eisenschenk Stephan , Haneef Zulfi
Published: November 2024

Purpose:

EEG is a vital tool in the diagnosis and management of neurologic conditions prevalent among veterans such as seizures, epilepsy, and brain injuries. This cross-sectional study aimed to assess the state of EEG infrastructure within the Veterans Administration (VA), focusing on availability, utilization, and the potential avenues to addressing gaps in infrastructure.

Methods:

This survey was distributed to 123 VA hospitals using the Research Electronic Data Capture (REDCap) platform, gathering data on EEG equipment, staffing, and service provision from June to December 2023.

Results:

Of the 123 VA hospitals surveyed, 70 responded (56.9% response rate). Most respondents (88.6%) reported having EEG services, although only 38.7% offering continuous EEG (cEEG). Respondents reported having less EEG technologists, machines, and faculty readers than what they thought would be ideal. Significant correlations were found between the availability of resources (e.g., number of EEG machines) and service capabilities, including remote access and cEEG. The use of alternative EEG technologies such as rapid or quantitative EEG varied greatly. Interest in participating in the VA Tele-EEG program was reported by 59.4% of respondents.

Conclusions:

There is large variability in EEG infrastructure across the VA. Tele-EEG has the potential to maintain continuity of operations through challenges affecting staffing and to improve EEG service access, especially in resource-limited settings. Expanding access to quantitative, rapid, and tele-EEG services may enhance patient management and may be a potential avenue to explore as the VA continues to invest in and grow its capacity for treating neurologic conditions.
Decoding the genome of the pearl millet pathogen Sclerospora graminicola unveils the molecular strategies underlying its pathogenesis and evolution
Authors: Srivastava Rakesh K , S Chandranayaka , HS Shekar Shetty , Singh Ram Baran , Sharma Rajan , C Tara Satyavathi , Bollam Srikanth , Lachagari Vijay Reddy
Published: November 2024

Downy mildew disease, induced by the pathogenic oomycete Sclerospora graminicola, constitutes a significant global risk to pearl millet production. To understand the molecular basis of pathogenicity, we carried out sequencing and assembly of the genome of S. graminicola pathotype 1 (SG-P1) using Illumina and PacBio platforms. Comparative genomics with 21 oomycete species revealed that SG-P1 shares the closest evolutionary affinity with Phytophthora sojae. The 65,404 predicted protein-coding genes, including a substantial number of reverse transcriptase and RxLR effector proteins, demonstrate similarities to other oomycete pathogens. Additionally, the genome harbors 5,375 non-coding RNAs. Genomic analysis identified Phytophthora ramorum as the oomycete with the highest sequence similarity to SG-P1, while P. colocasiae showed the highest overall genome-wide sequence match. This comprehensive genomic resource will facilitate the development of molecular markers to track SG-P1 populations and inform the deployment of durable resistance genes in pearl millet by targeting key pathogenicity effectors.
Broad thermal tolerance and high mitochondrial genetic connectivity in the pinfish (Lagodon rhomboides)
Authors: Eaton Katherine M. , Samenuk Jacob E. , Thaxton Laurel , Chaves Victoria , Bernal Moisés A.
Published: November 2024

Pinfish (Lagodon rhomboides) are highly abundant in coastal ecosystems of the Gulf of Mexico and western Atlantic Ocean and serve as a crucial link in marine food webs. Despite their ecological relevance, little is known about this species’ susceptibility to anthropogenic climate change. Here, we characterized patterns of mitochondrial genetic divergence and examined the upper thermal tolerance of pinfish across a large portion of the species’ range. We found little evidence of population genetic differentiation among distant localities with divergent temperature regimes (e.g., Mexico and North Carolina), using two mitochondrial markers (CytBandCOI). This suggests high genetic connectivity, which implies low potential for local adaptation of populations to different thermal conditions along a latitudinal gradient. To further examine population-scale differences in thermal tolerance, we assessed the critical thermal maxima (CTmax) of pinfish from four localities: North Carolina, Florida Keys, Alabama, and Texas. We found that CTmaxwas similar across sites, with all localities showing an average CTmaxwithin a 1°C temperature range (34.5-35.5°C). This suggests that southern populations of pinfish may be more susceptible to the detrimental effects of ocean warming, as individuals in lower latitudes regularly experience temperatures within a few degrees of their CTmax. Finally, we examined the influence of varying salinity on the upper thermal limit of the pinfish and found that pinfish show no variation in CTmaxunder salinity conditions ranging from hypo-to hyper-saline (15-35 ppt). These results show that pinfish can tolerate a wide range of environmental parameters, but may rely on phenotypic plasticity rather than local adaptation to distinct conditions to cope with different environmental regimes.
Comprehensive baseline ctDNA characterization in two biomarker-selected Phase 1/2 studies using genomic and methylation profiling
Authors: Silverman Ian M. , Schonhoft Joseph D. , Herzberg Benjamin , Yablonovitch Arielle , Lagow Errin , Sethuraman Sunantha , Ulanet Danielle , Yang Julia , Kim Insil , Basciano Paul , Cecchini Michael , Lee Elizabeth , Lheureux Stephanie , Fontana Elisa , Carneiro Benedito A. , Reis-Filho Jorge S. , Yap Timothy A. , Zinda Michael , Rosen Ezra Y. , Rimkunas Victoria
Published: November 2024

The development of DNA damage response (DDR)-directed therapies is a major area of clinical investigation, yet to date Poly (ADP-ribose) polymerase (PARP) inhibitors remain the only approved therapy in this space. Major challenges to DDR-targeted therapies in the post-PARPi era are the context dependency of DDR alterations and the presence of pre-existing resistance in this heavily pre-treated population. To that end, we used a contemporary platform to analyze pre-treatment circulating tumor DNA (ctDNA) samples from 173 patients enrolled onto two Phase 1/2 trials harboring pathogenic variants (PVs) in DDR genes. Baseline ctDNA analysis revealed a wealth of insights, including circulating tumor fraction estimation, impact of clonal hematopoiesis, PV allelic status, homologous recombination deficiency (HRD) signatures and presence of pre-existing resistance. HRD reversions were detected in 44% of evaluable patients and included large genomic rearrangements leading to deletion of whole or partial exons. We also discovered reversion ofATMin two patients previously treated with platinum chemotherapy, which has not previously been described. This study showcases the genomic complexity of DDR-altered tumors, revealed through baseline ctDNA profiling, an understanding of which is crucial for the future clinical development of novel DDR-directed therapies and combinations.
Impact of chronic pain on numerous long COVID-like symptoms: A large-scale internet-based epidemiological study in Japan
Authors: Takaoka Saki , Saito Hanako , Kawate Morihiko , Tanaka Chisato , Wu Yihuan , Kosugi Shizuko , Yamada Takashige , Tabuchi Takahiro , Wakaizumi Kenta
Published: November 2024

Background

Individuals with chronic pain (CP) not only endure the direct burden of the pain but also experience various symptoms, including sleep disturbances and fatigue, which deteriorate their quality of life. Notably, these symptoms closely resemble those observed in ‘long COVID’, a prolonged health complication that can arise after coronavirus disease 2019 (COVID-19) infection. However, the similarities between them have not yet been explored. Therefore, this study aimed to investigate the relationship between CP and long COVID using Japanese epidemiological data.

Methods

Utilizing the Japan COVID-19 and Society Internet Survey in 2022, an Internet-based survey involving 32,000 participants, we analysed data on the presence of CP, history of COVID-19 infection, and presence of 17 long COVID-like symptoms, including gastrointestinal upset, back pain, limb/joint pain, headache, chest pain, shortness of breath, dizziness, sleep disorder, hearing disorder, taste disorder, smell disorder, memory impairment, poor concentration, hair loss, decreased libido, fatigue, and cough.

Results

Individuals with history of COVID-19 experienced a significantly greater number of long COVID-like symptoms (median: 5) compared to those with neither COVID-19 nor CP (median: 4,p< 0.001). However, individuals with CP alone and those with both COVID-19 and CP exhibited an even greater number of symptoms (median: 8 and 9, respectively). Additionally, individuals with CP exhibited greater prevalence odds for 15 of the 17 symptoms than those without CP or COVID-19 (p< 0.001).

Conclusions

Altogether, our study suggests that the long COVID-like symptoms are not specifically related to COVID-19, but CP is an independent risk factor for these symptoms.
Identification of Digital Twins to Guide Interpretable AI for Diagnosis and Prognosis in Heart Failure
Authors: Gu Feng , Meyer Andrew J. , Ježek Filip , Zhang Shuangdi , Catalan Tonimarie , Miller Alexandria , Schenk Noah , Sturgess Victoria , Uceda Domingo , Li Rui , Wittrup Emily , Hua Xinwei , Carlson Brian E. , Tang Yi-Da , Raza Farhan , Najarian Kayvan , Hummel Scott L. , Beard Daniel A.
Published: November 2024

Background

Heart failure (HF) is a highly heterogeneous and complex condition. Although patient care generates vast amounts of clinical data, robust methods to synthesize available data for individualized management are lacking.

Methods

A mechanistic computational model of cardiac and cardiovascular system mechanics was identified for each individual in a cohort of 343 patients with HF. The identifieddigital twins— comprising optimized sets of parameters and corresponding simulations of cardiovascular system function—for patients with HF in the cohort is used to inform both supervised and unsupervised approaches in identifying phenogroups and novel mechanistic drivers of cardiovascular death risk.

Findings

The integration of digital twins into AI-based analyses of patient data enhances the performance and interpretability of prognostics AI models. Prognostics AI models trained with digital twin features are more generalizable than models trained with only clinical variables, as evaluated using an independent prospective cohort. In addition, the digital twin-based approach to phenomapping and predictive AI helps address inconsistencies and inaccuracies in clinical measurements, enables imputation of missing data, and estimates functional parameters that are otherwise unmeasurable directly. This approach provides a more comprehensive and accurate representation of the patient’s disease state than raw clinical data alone.

Interpretation

The developed and validated digital twin-based AI framework has the potential to simulate patient-specific pathophysiologic parameters, thereby informing prognosis and guiding therapeutic options.Ultimately, this approach has the potential to enhance the ability to focus on the most critical aspects of a patient’s condition, leading to individualized care and management.

Funding

National Institutes of Health and Joint Institute for Translational and Clinical Research (University of Michigan and Peking University Health Science Center)
Loss ofCFHR5function reduces the risk for age-related macular degeneration
Authors: Reeve Mary Pat , Loomis Stephanie , Nissilä Eija , Rausch Tobias , Zheng Zhili , Briotta Parolo Pietro Della , Ben-Isvy Daniel , Aho Elias , Cesetti Emilia , Okunuki Yoko , McLaughlin Helen , Mäkelä Johanna ,   FinnGen, Kurki Mitja , Talkowski Michael E. , Korbel Jan O. , Connor Kip , Meri Seppo , Daly Mark J. , Runz Heiko
Published: November 2024

Age-related macular degeneration (AMD) is a prevalent cause of vision loss in the elderly with limited therapeutic options. A single chromosomal region around the complement factor H gene (CFH) is reported to explain nearly 25% of genetic AMD risk. Here, we used association testing, statistical finemapping and conditional analyses in 12,495 AMD cases and 461,686 controls to deconvolute four majorCFHhaplotypes that convey protection from AMD. We show that beyondCFH, two of these are explained by Finn-enriched frameshift and missense variants in theCFHmodulatorCFHR5. We demonstrate through a FinnGen sample recall study thatCFHR5variant carriers exhibit dose-dependent reductions in serum levels of theCFHR5gene product FHR-5 and two functionally related proteins at the locus. Genetic reduction in FHR-5 correlates with higher preserved activities of the classical and alternative complement pathways. Our results propose therapeutic downregulation of FHR-5 as promising to prevent or treat AMD.
Presurgical ablative radiation associates with local control and immune response in pancreatic cancer
Authors: Leung Peter Q. , Elghonaimy Eslam A. , Elamir Ahmed M. , Wachsmann Megan , Zhang Song , Barrows Neha , Notgrass Hollis , Johnson Ethan , Lewis Cheryl , von Ebers Rachel , Hamilton Cassandra , Josephson Grace , Chi Zhikai , Al Mutar Salwan , Polanco Patricio M. , Sanford Nina N. , Ali Kazmi Syed M. , Porembka Matthew R. , Hsiehchen David , Yopp Adam C. , Mansour John , Beg Muhammad S. , Zeh Herbert J. , Aguilera Todd A.
Published: November 2024

Purpose

To compare outcomes and molecular characteristics of patients who had surgery after neoadjuvant chemotherapy, with and without ablative radiotherapy (SAbR) for pancreas cancer.

Experimental Design

This single-institution, tertiary care academic center cohort study included all patients diagnosed with pancreatic cancer between 2012-2023 treated with neoadjuvant chemotherapy, with or without SAbR. We compared therapeutic responses, performed cardinality matching with distance-optimized pairing, and conducted multivariable stepwise-AIC-optimized Cox modeling to identify differences between groups. We assessed molecular response using RNA sequencing to identify SAbR-induced biologic differences.

Results

Among 133 patients receiving chemotherapy and 48 chemotherapy + SAbR, RNA sequencing was available for 29 and 14 patients, respectively. Despite more advanced baseline disease, the SAbR group showed better post-treatment pathology and similar overall survival (HR = 0.97, 95% CI = 0.58–1.60,P= .9). Patient matching indicated that SAbR improved locoregional recurrence-free survival (HR = 0.24, 95% CI = 0.07–0.88,P= .009). Arterial involvement raised local failure risk with chemotherapy alone (HR = 3.37, 95% CI = 1.74–6.54,P< .001), which was significantly reduced with SAbR (HR = 0.28; 95% CI = 0.12–0.68;P= .003). Gene set enrichment analysis showed immune activation, with CD8 and NK/NKT cell signatures associated with local control, and Treg signatures associated with worse control.

Conclusion

Neoadjuvant SAbR resulted in improved pathological outcomes, enhanced local control, and maintained survival while inducing a distinct immune response. The role of neoadjuvant SAbR should be further evaluated in well powered studies to define clinical benefits.
Effects of self-rated mental and physical work demands on cognition are dependent in a cross-sectional sample of the Health and Retirement Study
Authors: Hickman Ruby C. , Wang Herong , Brandt Daniel J. , Ware Erin B. , Bakulski Kelly M.
Published: November 2024

Objective

This study assessed whether self-rated physical and mental work demands were associated with cognition among older working adults and whether their effects were dependent.

Methods

Our cross-sectional sample consisted of 6,377 working older adults uisng the Health and Retirement Study in 2004. Self-rated work demands were summarized from four questions about frequency of mental or physical demands in the respondent’s current job. Cognition was assessed using a subset of the Telephone Interview for Cognitive Status. We used multivariable linear regression to test for associations and additive interaction between physical and mental work demands and cognition, adjusted for age, sex, race, education, and practice effect.

Results

Independently, higher physical work demands were associated(P<0.001)with poorer cognition and higher mental work demands were associated (P<0.001) with better cognition. The effect of one work demand measure became more negative as level of the other increased (B for interaction = -0.23, 95% CI: -0.43, -0.03). A one-point increase in mental work demands was associated with 0.79 (95% CI: 0.51, 1.08) points higher cognition score when physical work demands were lowest, but was not associated with cognition when physical work demands were highest (0.11, 95% CI: -0.26, 0.48). The highest predicted cognition score was for the highest mental and lowest physical work demands. Results were robust to additional adjustment for health and behavior covariates.

Conclusions

The associations of self-rated mental and physical work demands on cognition are dependent. Future studies should strongly consider examining interactions to capture the range of work demand effects.

Key points

What is already known on this topic

Mental work demands may help to preserve cognition in older adults, both while working and after retirement. However, the relationship of physical work demands and its interaction with mental work demands on cognition is less clear.

What this study adds

We found that the associations of mental and physical work demands on cognition are dependent. There was a statistically significant interaction between mental and physical work demands, with the beneficial effect of mental work demands attenuating with increasing levels of physical work demands.

How this study might affect research, practice or policy

This study suggested the interactive impact of mental and physical work demands on cognition. Future studies examining work demands need to consider interaction between mental and physical work demands. More generally, this means that the traditional view of mentally stimulating work as protective of cognition may not apply for workers who also have physically demanding jobs. The effects that our jobs have on our cognitive health is complex, and ever more important as we live and work longer.
Gastroesophageal Malignancies Are Associated with Poorer Outcomes in Young Patients Seen in California Comprehensive Cancer Centers
Authors: Azizi Armon , Mahadevan Aditya , Chiao Elaine , Senthil Maheswari , Dayyani Farshid
Published: November 2024

While the overall incidence of adenocarcinomas of the stomach and esophagus (GEA) has been declining in the United States, there has been an increase in cases among those under 50. Clinical and demographic data on GEA in young patients, especially in the United States, is limited. A retrospective cohort study was performed using the TrinetX database to investigate the association between patient demographics, geography, and clinical outcomes in patients with GEA between academic centers in California and a national, multi-institutional cohort. Young patients in both cohorts were more likely to be female, Hispanic, and have metastatic disease at the time of diagnosis. In California, young patients with GEA had significantly worse overall survival compared to older patients (HR 0.69, p = 0.002) whereas nationally, young patients did significantly better than old patients (HR 1.4, p < 0.0001). These disparate survival outcomes among the young UC cohort raises significant concerns and warrants further investigation.
NLRP1 is activated by palmitic acid and induced in human metabolic dysfunction-associated steatohepatitis
Authors: Pinilla Miriam , Campos Baños Eulalia , Martínez-Sánchez María Antonia , Sánchez-Villalobos María , Oliva-Bolarín Alba , Rico-Chazarra Sara , Ruiz-Alcaraz Antonio José , Martínez Carlos Manuel , Mika Adriana , Frutos María Dolores , Ramos-Molina Bruno , Núñez-Sánchez María Ángeles , Pérez-Oliva Ana Belén
Published: November 2024

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent cause of liver disease worldwide. This progressive condition ranges from simple steatosis to a more advanced stage, known as metabolic dysfunction-associated steatohepatitis (MASH), which is characterized by inflammation, hepatocellular ballooning, and hepatic steatosis. Several studies have demonstrated the involvement of inflammasomes in MASH development. Recently, the NLRP1 inflammasome has gained attention as an important sensor in various human inflammatory conditions, though its role in metabolic diseases like MASLD remains unclear. In this study, we identified significantly higher mRNA and protein levels of NLRP1 in liver samples from patients with MASH compared to those with normal or steatotic livers. Furthermore,NLRP1mRNA levels correlated with hepatic palmitic acid (PA) levels. We also showed that NLRP1 inflammasome expression is mediated by PA in both human HepG2 cells and human liver organoids. Importantly, we found that NLRP1 was activated by PA, but not by other saturated fatty acids like myristic acid, and that PA-induced NLRP1 activation was inhibited by oleic acid. These findings uncover a previously unknown role of the hepatic NLRP1 inflammasome in the human liver. However, further research is needed to fully understand the complex interactions between NLRP1, inflammation, and metabolic processes in the development of MASLD.
Excitatory Cortical Neurons from CDKL5 Deficiency Disorder Patient-Derived Organoids Show Early Hyperexcitability Not Identified in Neurogenin2 Induced Neurons
Authors: Glass Madison R. , Whye Dosh , Anderson Nickesha C. , Wood Delaney , Makhortova Nina R. , Polanco Taryn , Kim Kristina H. , Donovan Kathleen E. , Vaccaro Lorenzo , Jain Ashish , Cacchiarelli Davide , Sun Liang , Olson Heather , Buttermore Elizabeth D. , Sahin Mustafa
Published: November 2024

CDKL5 deficiency disorder (CDD) is a rare developmental and epileptic encephalopathy resulting from variants in cyclin-dependent kinase-like 5 (CDKL5) that lead to impaired kinase activity or loss of function. CDD is one of the most common genetic etiologies identified in epilepsy cohorts. To study how CDKL5 variants impact human neuronal activity, gene expression and morphology, CDD patient-derived induced pluripotent stem cells and their isogenic controls were differentiated into excitatory neurons using either an NGN2 induction protocol or a guided cortical organoid differentiation. Patient-derived neurons from both differentiation paradigms had decreased phosphorylated EB2, a known molecular target of CDKL5. Induced neurons showed no detectable differences between cases and isogenic controls in network activity using a multielectrode array, or in MAP2+ neurite length, and only two genes were differentially expressed. However, patient-derived neurons from the organoid differentiation showed increased synchrony and weighted mean firing rate on the multielectrode array within the first month of network maturation. CDD patient-derived cortical neurons had lower expression of CDKL5 and HS3ST1, which may change the extracellular matrix around the synapse and contribute to hyperexcitability. Similar to the induced neurons, there were no differences in neurite length across or within patient-control cell lines. Induced neurons have poor cortical specification while the organoid derived neurons expressed cortical markers, suggesting that the changes in neuronal excitability and gene expression are specific to cortical excitatory neurons. Examining molecular mechanisms of early hyperexcitability in cortical neurons is a promising avenue for identification of CDD therapeutics.

Graphical Abstract
Systemic genome-epigenome analysis captures the lineage specificity and functional significance forMYBassociated super-enhancer in gastrointestinal adenocarcinoma
Authors: Li Fuyuan , Wang Shangzi , Chen Lian , Jiang Ning , Chen Xingdong , Li Jin
Published: November 2024

The gastrointestinal adenocarcinoma is a major cancer type for the digestive system, ranking as the top cause of cancer-related deaths worldwide. In contrast to the large body of studies on the protein-coding regions’ mutations, the knowledge about the landscape of its non-coding regulatory elements is still insufficient. Combining the analysis of active enhancers profile and genomic structural variation, we discovered and validated a lineage-specific super-enhancer forMYBin gastrointestinal adenocarcinoma. This super-enhancer is constituted by a predominant enhancer e4 and multiple facilitator enhancers, whose transcriptional activity is controlled by the direct binding of HNF4A and MYB itself. Suppression of the super-enhancer downregulated the expression ofMYB, inhibited the downstream Notch signaling and prevented the development of gastrointestinal adenocarcinomain vitroandin vivo. Our study revealed a non-coding variation-based mechanism to affectMYBexpression in a lineage-specific manner, which provided an inspiring insight into the carcinogenic mechanism and therapeutic strategies for gastrointestinal adenocarcinoma.
Penalized reduced rank regression for multi-outcome survival data supports a common metabolic risk score for age-related diseases
Authors: Sluiskes Marije H. , Putter Hein , Beekman Marian , Goeman Jelle J. , Rodríguez-Girondo Mar
Published: November 2024

The increasing availability of multi-outcome data in health research presents new opportunities for understanding complex health processes, such as ageing. Ageing is a multifaceted process, encompassing both lifespan and healthspan, as well as the onset of age-related diseases. To model this complexity, we propose the penalized reduced rank regression model for multi-outcome survival data (penalized survRRR), which identifies shared latent factors driving multiple outcomes. The model imposes a rank constraint on the coefficient matrix to capture underlying mechanisms of ageing, while accommodating high-dimensional and correlated predictors and outcomes by introducing penalization. We discuss the statistical properties of this doubly-regularized approach and show how the optimal number of ranks can be estimated from the data. We apply a lasso-penalized reduced rank regression model to 78,553 participants of the UK Biobank, using over 200 metabolic variables as predictors and the onset of seven age-related diseases and mortality as the outcomes of interest. Our results indicate that a rank 1 model provides the best fit to the data, resulting in a single metabolite-based score of age-related disease susceptibility. This highlights the potential of the penalized survRRR model to provide new insights into the nature of the relationship between metabolomics and age-related diseases.
Single molecule imaging of transcription dynamics, RNA localization and fate in T cells
Authors: Lattanzio M. Valeria , Šoštarić Nikolina , Kanagasabesan Nandhini , Popović Branka , Bradarić Antonia , Wardak Leyma , Guislain Aurélie , Savakis Philipp , Tutucci Evelina , Wolkers Monika C.
Published: November 2024

T cells are critical effector cells against infections and malignancies. To achieve this, they produce pro-inflammatory cytokines, including IFN-γ and TNF. Cytokine production is a tightly regulated process. The relative contribution of transcriptional and post-transcriptional regulation to mRNA expression is, however, unknown. We therefore implemented single-molecule FISH for primary human T cells (T-cell smFISH) to simultaneously quantify nascent RNA, mature mRNA levels and its localization with single-cell resolution. T-cell smFISH uncovered heterogeneous cytokine mRNA levels, with high cytokine producers displaying dualIFNG/TNFRNA transcription activity. Throughout activation, nuclear cytokine mRNAs accumulated, whereas cytoplasmic cytokine mRNA was degraded through translation-dependent decay. Lastly, T-cell smFISH uncovered cytokine-specific regulation by the RNA-binding protein HuR. Thus, T-cell smFISH provides novel insights in the intricate (post)-transcriptional processes in T cells.
Hippocampal OLM interneurons regulate CA1 place cell plasticity and remapping
Authors: Udakis Matt , Claydon Matthew , Zhu Heng Wei , Mellor Jack R
Published: November 2024

OLM interneurons selectively target inhibition to the distal dendrites of CA1 pyramidal cells in the hippocampus but the role of this unique morphology in controlling place cell physiology remains a mystery. Here we show that OLM activity prevents associative synaptic plasticity at Schaffer collateral synapses on CA1 pyramidal cells by inhibiting dendritic Ca2+signalling initiated by entorhinal synaptic inputs. Furthermore, we find that OLM activity is reduced in novel environments suggesting that reducing OLM activity and thereby enhancing excitatory synaptic plasticity is important for the formation of new place cell representations. Supporting this, we show that selectively increasing OLM activity in novel environments enhances place cell stability and reduces remapping of newly formed place cells whilst increasing OLM activity in familiar environments led only to a transient silencing of place cells. Our results therefore demonstrate a critical role for distal dendrite targeting interneurons in regulating plasticity of neuronal representations.
Regulation ofbicoidmRNA throughout oogenesis and early embryogenesis impacts protein gradient formation
Authors: Athilingam T. , Wilby E.L. , Bensidoun P. , Trullo A. , Verbrugghe M. , Lagha M. , Saunders T.E. , Weil T.T.
Published: November 2024

The transcription factor Bicoid (Bcd) establishes patterning in the earlyDrosophilablastocyst through its graded concentration along the anterior-posterior (AP) axis.bcdmRNA is maternally deposited during oogenesis, yet precisely when and wherebcdmRNA is translated remains an open problem. Here, we take advantage of the SunTag reporter system to quantitatively examine the spatiotemporal profile ofbcdmRNA translationin vivo. We demonstrate that Processing body (P body) localisation in the oocyte suppresses prematurebcdmRNA translation. Upon egg laying,bcdmRNA disassociates from P bodies and translation is observed exclusively in the anterior pole of the embryo. Accompanying nuclear migration to the embryo cortex at nuclear cycle (n.c.) 9,bcdmRNA relocates to the apical domain of the nuclear environment and translation continues near the embryo surface. In n.c. 14,bcdmRNA localises to newly formed P bodies and further translation is not detected. We use these observations to build a modified source-diffusion-degradation model of Bcd gradient formation that leads to an exponential gradient by n.c. 12 and is consistent with other experimental measurements of Bcd dynamics. Consequently, we see that the spatiotemporal dynamics ofbcdmRNA translation are highly regulated throughout oogenesis and early embryo development.
Expression divergence in response to sex-biased selection
Authors: Grieshop Karl , Liu Michelle J. , Frost Ryan S. , Lindsay Matthew P. , Bayoumi Malak , Brengdahl Martin I. , Molnar Ruxandra I. , Agrawal Aneil F.
Published: November 2024

It remains debated whether greater degrees of sexual dimorphism would evolve if not for intersexual genetic constraints. Here we used experimental evolution to partially break the intersexual genetic constraint inDrosophila melanogasterto test for the presence of sexually antagonistic genetic variation and characterize the evolution of sexual dimorphism in gene expression. In six replicate populations of 1000 flies, a dominant marker (DsRed) on Chromosome 2 was used to force a “Red” pool of genetically variable chromosomes through exclusive father-to-son inheritance, while a complimentary pool of “NonRed” chromosomes was inherited primarily from mothers to daughters. After 100 generations, males carrying aRedchromosome copy exhibited greater mating success than males with onlyNonRedchromosomes, consistent with the accumulation of male-benefit/female-detriment sexually antagonistic alleles in theRedpool relative toNonRed. Differentially expressed genes between flies with and withoutRedchromosomes had on average higher intersexual genetic correlations (rMF), as expected if such correlations represent a constraint to sex-specific adaptation under normal inheritance. If conflict hinders the evolution of further dimorphism, the transcriptomes of male-selectedRedchromosomes were predicted to evolve to be “masculinized” relative to female-selectedNonRedchromosomes. Consistent with this, splicing patterns inRedmales (but notRedfemales) were masculinized relative toNonRedmales. Contrastingly, gene expression levels were largely feminized inRedflies of both sexes compared toNonRed. We discuss alternative forms of intralocus sexual conflict that may explain these patterns.
Simulating Offshore Oilfield Conditions: Insights into Microbiologically Influenced Corrosion from a Dual Anaerobic Biofilm Reactor
Authors: Jones Liam , Salta Maria , Skovhus Torben Lund , Thomas Kathryn , Illson Timothy , Wharton Julian , Webb Jeremy
Published: November 2024

Oilfield systems are a multifaceted ecological niche which consistently experience microbiologically influenced corrosion. However, simulating environmental conditions of an offshore system within the laboratory is notoriously difficult. A novel dual anaerobic biofilm reactor protocol allowed a complex mixed-species marine biofilm to be studied. Interestingly, electroactive corrosive bacteria and fermentative electroactive bacteria growth was supported within the biofilm microenvironment. Critically, the biotic condition exhibited pits with a greater average area which is characteristic of microbiologically influenced corrosion. This research seeks to bridge the gap between experimental and real-world scenarios, ultimately enhancing the reliability of biofilm management strategies in the industry.

Importance

It is becoming more widely understood that any investigation of microbiologically influenced corrosion requires a multidisciplinary focus on multiple lines of evidence. While there are numerous standards available to guide specific types of testing, there are none that focus on integrating biofilm testing. By developing a novel dual anaerobic reactor model to study biofilms, insights into the different abiotic and biotic corrosion mechanisms under relevant environmental conditions can be gained. Using multiple lines of evidence to gain a holistic understanding, more sustainable prevention and mitigation strategies can be designed. To our knowledge, this is the first time all these metrics have been combined in one unified approach. The overall aim for this paper is to explore recent advances in biofilm testing and corrosion research, to provide recommendations for future standards being drafted. However, it is important to note that this article itself is not intending to serve as a standard.
Patterns of crossover distribution inDrosophila mauritiananecessitate a re-thinking of the centromere effect on crossing over
Authors: Hawley R. Scott , Price Andrew , Li Hua , Jagannathan Madhav , Staber Cynthia , Hughes Stacie E. , Williams Stefanie , Perera Anoja , Egidy Rhonda R. , Lawlor Amanda , Miller Danny E. , Blumenstiel Justin P.
Published: November 2024

We present a SNP-based crossover map forDrosophila mauritiana. Using females derived by crossing two different strains ofD.mauritiana, we analyzed crossing over on all five major chromosome arms. Analysis of 105 male progeny allowed us to identify 327 crossover chromatids bearing single, double, or triple crossover events, representing 398 separate crossover events. We mapped these crossover sites along these five chromosome arms using a genome sequence map that includes the euchromatin-heterochromatin boundary. Confirming previous studies, we show that the overall crossover frequency inD.mauritianais higher than is seen inD.melanogaster. Much of the increase in exchange frequency inD.mauritianais due to a greatly diminished centromere effect. Using larval neuroblast metaphases fromD.mauritiana–D.melanogasterhybrids we show that the lengths of the pericentromeric heterochromatin do not differ substantially between the two species, and thus cannot explain the observed differences in crossover distribution. Using a new and robust maximum likelihood estimation tool for obtaining Weinstein tetrad distributions, we observed an increase in bivalents with two or more crossovers when compared toD.melanogaster. This increase in crossing over along the arms ofD.mauritianalikely reflects an expansion of the crossover-available euchromatin caused by the reduction in the centromere effect. The pattern of crossing over inD.mauritianaconflicts with the commonly accepted view of centromeres as polar suppressors of exchange (whose intensity is buffered by sequence non-specific heterochromatin) and demonstrates the importance of expanding such studies into other species of Drosophila.

Article Summary

In meiosis, homolog segregation is usually ensured by crossovers. The number and distribution of crossovers is in part regulated by cis-acting factors such as the cis- acting centromere effect, a polar suppression of exchange emanating from the vicinity of the centromere. We use SNP-based crossover mapping to show that inDrosophila mauritiana, the centromere effect is greatly reduced on four of the five major chromosome arms. We conclude that the centromere effect differs betweenDrosophila mauritianaandDrosophila melanogasterand that the ability to attenuate the centromere effect is not a general property of heterochromatin.
Inter-individual gene expression variability implies stable regulation of brain-biased genes across organs
Authors: Bucao Christabel F. , Aletti Consolée , Moretti Sébastien , Thompson Andrew W. , Racicot Brett L. , Wilson Catherine A. , Bobe Julien , Braasch Ingo , Guiguen Yann , Postlethwait John H. , Robinson-Rechavi Marc
Published: November 2024

Phenotypic variation among individuals plays a key role in evolution, since variation provides the material on which natural selection can act. One important link between genetic and phenotypic variation is gene expression. As for other phenotypes, the range of accessible expression variation is limited and biased by different evolutionary and developmental constraints. Gene expression variability broadly refers to the tendency of a gene to vary in expression (i.e., between individuals or cells) due to stochastic fluctuations or differences in genetic, epigenetic, or environmental factors, separately from the differences between e.g. organs. Variability due to biomolecular stochasticity (transcriptional ‘noise’) and cell-to-cell heterogeneity has been well-studied in isogenic populations of unicellular organisms such as bacteria and yeasts. However, for more complex organisms with multiple cells, tissues, and organs sharing the same genetic background, the interplay between inter-individual expression variability, gene and organ function, and gene regulation remains an open question. In this study, we used highly multiplexed 3’-end Bulk RNA Barcoding and sequencing (BRB-seq) to generate transcriptome profiles spanning at least nine organs in outbred individuals of three ray-finned fish species: zebrafish, Northern pike, and spotted gar. For each condition, we measured expression variation per gene independent of mean expression level. We observed that lowly variable genes are enriched in cellular housekeeping functions whereas highly variable genes are enriched in stimulus-response functions. Furthermore, genes with highly variable expression between individuals evolve under weaker purifying selection at the coding sequence level, indicating that intra-species gene expression variability predicts inter-species protein sequence divergence. Genes that are broadly expressed across organs tend to be both highly expressed and lowly variable between individuals, whereas organ-biased genes are typically highly variable within their top organ of expression. For genes with organ-biased expression profiles, we inferred differences in selective pressure on gene regulation depending on their top organ. We found that genes with peak expression in the brain have low inter-individual expression variability across non-nervous organs, suggesting stabilizing selection on regulatory evolution of brain-biased genes. Conversely, liver-biased genes have highly variable expression across organs, implying weaker regulatory constraints. These patterns show that gene regulatory mechanisms evolved differently based on constraints on the primary organ.
Genotype-immunophenotype relationships inNPM1-mutant AML clonal evolution uncovered by single cell multiomic analysis
Authors: Drucker Morgan , Lee Darren , Zhang Xuan , Kain Bailee , Bowman Michael , Nicolet Deedra , Wang Zhe , Stone Richard M. , Mrózek Krzysztof , Carroll Andrew J. , Starczynowski Daniel T. , Levine Ross L. , Byrd John C. , Eisfeld Ann-Kathrin , Salomonis Nathan , Grimes H. Leighton , Bowman Robert L. , Miles Linde A.
Published: November 2024

Acute myeloid leukemia (AML) is a multi-clonal disease, existing as a milieu of clones with unique but related genotypes as initiating clones acquire subsequent mutations. However, bulk sequencing cannot fully capture AML clonal architecture or the clonal evolution that occurs as patients undergo therapy. To interrogate clonal evolution, we performed simultaneous single cell molecular profiling and immunophenotyping on 43 samples from 32NPM1-mutant AML patients at different stages of disease. Here we show that diagnosis and relapsed AML samples display similar clonal architecture patterns, but signaling mutations can drive increased clonal diversity specifically at relapse. We uncovered unique genotype-immunophenotype relationships regardless of disease state, suggesting leukemic lineage trajectories can be hard-wired by the mutations present. Analysis of longitudinal samples from patients on therapy identified dynamic clonal, transcriptomic, and immunophenotypic changes. Our studies provide resolved understanding of leukemic clonal evolution and the relationships between genotype and cell state in leukemia biology.
gen3DNet: An R Package for Generating 3D Network Models
Authors: Morrison Paul , Tang Tina , Lu Charles , Mollah Shamim
Published: November 2024

Motivation

Networks are ubiquitous to organize and represent data in the real world such as the biomedical networks, social networks, etc. Due to the attractive property of networks which can explicitly capture the rich relationships among data samples, there is an increasing demand to transform linkage-free data to graph-structure data for efficient downstream analyses. Existing works typically focus on representing a single data object like gene expression profile in a homogeneous 2D network, which fail to deal with situations where two different data objects are involved to create a 3D heterogeneous network.

Results

In this paper, we introduce an R package, gen3DNet (a generic version of the iPhDNet), for generating 3D network models from two correlated objects with shared common factors. Specifically, gen3DNet builds the relationships between samples and shared factors using the non-negative matrix factorization, where three clustering techniques are evaluated to determine the number of functional modules. In addition, it builds the relationships between samples from the two distinct data objects based on a partial least squares regression model. Usage of the package is illustrated through a real-world application.

GitHub URLSource code is available athttps://github.com/mollahlab/gen3DNet
Vaccine-induced and hybrid immunity against SARS-CoV-2 variants of concern in two cohorts in Queensland, Australia (2021-2022)
Authors: Parry Rhys H. , Shang Yingjun , Sng Julian D.J. , McMillan Christopher L. D. , Modhiran Naphak , Amarilla Alberto A. , Isaacs Ariel , Liang Benjamin , Muller David A. , Rawle Daniel , Suhrbier Andreas , Anderson Stevie , Kelly Samuel , Watterson Daniel , Burr Lucy D. , Khromykh Alexander A.
Published: November 2024

The spike glycoprotein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the main target for vaccine development, as antibodies generated against the spike protein are the most immunodominant and neutralizing against the virus. However, variants of concern (VOC), often containing multiple mutations within neutralizing epitopes, confer immune evasion of the response generated by current SARS-CoV-2 vaccines. To assess the immunogenicity and virus-neutralisation ability of antibodies induced by individual or combination of Vaxzevria (AstraZeneca: AZ) and Comirnaty (Pfizer: PZ) vaccines and of a hybrid immunity induced in people who were also infected with SARS-CoV-2, longitudinal sera samples of participants recruited through the David Serisier Research biobank (Mater Research Hospital) or at the University of Queensland were collected. ELISA with a panel of purified Spike proteins from ancestral, alpha, delta and omicron BA.1 and BA.2 VOCs showed significantly (by ∼2 to 6-fold) reduced IgG antibody titres against Spike proteins from Omicron BA.1 and BA.2 compared to ancestral strain regardless of the number of vaccinations or presence of infection. Neutralisation assays showed reduced activity against delta and omicron BA.1, BA.5 and BA.5 VOCs. However, the differences were in general less pronounced than in the ELISA assay and some were not statistically significant, particularly after four (two AZ and two PZ) vaccinations. We also generated by circular polymerase extension reaction an attenuated SARS-CoV-2 strain with deletion of all accessory genes, ORF 3, 6, 7 and 8, based on the ancestral (QLD02) virus backbone (QLD02Δ3678) and validated it in virus-neutralization assays with our panel of sera samples. We showed the attenuation of the QLD02Δ3678virus in Vero E6 and human Caco2 cells. We demonstrated that neutralization assays with the wild-type QLD02 virus and QLD02Δ3678virus were concordant, providing a safe platform for neutralisation assays in BSL2/PC2 settings.
Grading assistance for a handwritten thermodynamics exam using artificial intelligence: An exploratory study
Authors: Kortemeyer Gerd , Nöhl Julian , Onishchuk Daria
Published: November 2024

[This paper is part of the Focused Collection in Artificial Intelligence Tools in Physics Teaching and Physics Education Research.] Using a high-stakes thermodynamics exam as the sample (252 students, four multipart problems), we investigate the viability of four workflows for AI-assisted grading of handwritten student solutions. We find that the greatest challenge lies in converting handwritten answers into a machine-readable format. The granularity of grading criteria also influences grading performance: employing a fine-grained rubric for entire problems often leads to errors and grading failures, as the model appears to be unable to keep track of scores for more than a handful of rubric items, while grading problems in parts is more reliable but tends to miss nuances. We also found that grading hand-drawn graphics, such as process diagrams, is less reliable than mathematical derivations due to the difficulty in differentiating essential details from extraneous information. Although the system is precise in identifying exams that meet passing criteria, exams with failing grades still require human grading. We conclude with recommendations to overcome some of the encountered challenges.

Published by the American Physical Society
2024