bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

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

AbstractObjectiveThis study assessed whether self-rated physical and mental work demands were associated with cognition among older working adults and whether their effects were dependent.MethodsOur 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.ResultsIndependently, 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.ConclusionsThe 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 pointsWhat is already known on this topicMental 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 addsWe 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 policyThis 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

AbstractWhile 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

ABSTRACTMetabolic 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

AbstractCDKL5 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

AbstractThe 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

AbstractThe 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

AbstractT 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

SummaryOLM 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

AbstractThe 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

AbstractIt 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

AbstractOilfield 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.ImportanceIt 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.