bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pan-cancer Analysis of Homologous Recombination Deficiency in Cell Lines
Authors: Dodson Anne E. , Shenker Sol , Sullivan Pamela , Middleton Chris , McGuire Michael , Chipumuro Edmond , Mishina Yuji , Tobin Erica , Cadzow Louise , Wylie Andrew A. , Sangurdekar Dipen 
Published: May 2024

ABSTRACTHomologous Recombination Deficiency (HRD) drives genomic instability in multiple cancer types and renders tumors vulnerable to certain DNA damaging agents such as PARP inhibitors. Thus, HRD is emerging as an attractive biomarker in oncology. A variety of in silico methods are available for predicting HRD; however, few of these methods have been applied to cell lines in a comprehensive manner. Here we utilized two of these methods, “CHORD” and “HRDsum” scores, to predict HRD for 1,332 cancer cell lines and 84 non-cancerous cell lines. Cell lines with biallelic mutations inBRCA1orBRCA2, which encode key components of the homologous recombination pathway, showed the strongest HRD predictions, validating the two methods in cell lines. A small subset ofBRCA1/2-wildtype cell lines were also classified as HRD, several of which showed evidence of epigeneticBRCA1silencing. Similar to HRD in patient samples, HRD in cell lines was associated with p53 loss, was mutually exclusive with microsatellite instability and occurred most frequently in breast and ovarian cancer types. In addition to validating previously identified associations with HRD, we leveraged cell line-specific datasets to gain new insights into HRD and its relation to various genetic dependency and drug sensitivity profiles. We found that in cell lines, HRD was associated with sensitivity to PARP inhibition in breast cancer, but not at a pan-cancer level. By generating large-scale, pan-cancer datasets on HRD predictions in cell lines, we aim to facilitate efforts to improve our understanding of HRD and its utility as a biomarker.SIGNIFICANCE STATEMENTHomologous Recombination Deficiency (HRD) is common in cancer and can be exploited therapeutically, as it sensitizes cells to DNA damaging agents. Here we scored over 1,300 cancer cell lines for HRD using two different bioinformatic approaches, thereby enabling large-scale analyses that provide insight into the etiology and features of HRD.
The Hidden Potential of PDE4 Inhibitor Rolipram: A Multifaceted Examination of its Inhibition of MMP2/9 Reveals Therapeutic Implications
Authors: Bagchi Arka , Roy Analabha , Halder Anindya , Biswas Arunima 
Published: May 2024

ABSTRACTA PDE4 inhibitor, Rolipram, was previously found to down-regulate (in a manner dependent on cAMP-PKA) MMP2 and MMP9 levels, important markers of epithelial-to-mesenchymal transition in human breast cancer cell lines. However, zymographic studies revealed that rolipram could also alter the enzymatic activities of these MMPs, even in the presence of the PKA inhibitor H89. This calls for more detailed investigations of the inhibitory mechanism of rolipram on MMP2 and MMP9. The prediction of ligand-based targets through online reverse screening indicated that proteases are likely targets of rolipram. Computational molecular docking also demonstrated significant binding affinities of rolipram for both MMP2 and MMP9 proteins. Concurrently, a well-known inhibitor of MMPs, SB3CT, was utilized as a positive control for this study. The best models of the docked complexes were used as initial conditions for molecular dynamics (MD) simulations to explore their dynamic behavior and stability. In particular, both the MMP2-rolipram and MMP9-rolipram complexes were found to be stable and compact for the duration of the simulation (300 ns). Several stable hydrogen bonds were also detected between the proteins and rolipram.In vitroexperiments using primary cells from patients with breast cancer also showed that rolipram could alter the enzymatic activities of MMP2 and MMP9, independent of the cAMP-PKA signaling pathway. These observations indicate the ability of rolipram to control breast cancer by regressing the functions of MMP2 and MMP9, thus having ‘off-targets’ other than PDE4 to have direct control over proteins that are involved in the advancement of metastasis.
A novel expression domain ofextradenticleunderlies the evolutionary developmental origin of the chelicerate patella
Authors: Klementz Benjamin C. , Brenneis Georg , Hinne Isaac A. , Laumer Ethan M. , Neu Sophie M. , Hareid Grace M. , Gainett Guilherme , Setton Emily V.W. , Simian Catalina , Vrech David E. , Joyce Isabella , Barnett Austen A. , Patel Nipam H. , Harvey Mark S. , Peretti Alfredo V. , Gulia-Nuss Monika , Sharma Prashant P. 
Published: May 2024

AbstractNeofunctionalization of duplicated gene copies is thought to be an important process underlying the origin of evolutionary novelty and provides an elegant mechanism for the origin of new phenotypic traits. One putative case where a new gene copy has been linked to a novel morphological trait is the origin of the arachnid patella, a taxonomically restricted leg segment. In spiders, the origin of this segment has been linked to the origin of the paralogdachshund-2, suggesting that a new gene facilitated the expression of a new trait. However, various arachnid groups that possess patellae do not have a copy ofdachshund-2, disfavoring the direct link between gene origin and trait origin. We investigated the developmental genetic basis for patellar patterning in the harvestmanPhalangium opilio, which lacksdachshund-2. Here, we show that the harvestman patella is established by a novel expression domain of the transcription factorextradenticle. Leveraging this definition of patellar identity, we surveyed targeted groups across chelicerate phylogeny to assess when this trait evolved. We show that a patellar homolog is present in Pycnogonida (sea spiders) and various arachnid orders, suggesting a single origin of the patella in the ancestor of Chelicerata. A potential loss of the patella is observed in Ixodida. Our results suggest that the modification of an ancient gene, rather than the neofunctionalization of a new gene copy, underlies the origin of the patella. Broadly, this work underscores the value of comparative data and broad taxonomic sampling when testing hypotheses in evolutionary developmental biology.
Age-Related KLHL22 Expression in Human MSCs and Regenerative Implications
Authors: Utley James , Briggs Daniel 
Published: May 2024

AbstractAging in human bone marrow-derived mesenchymal stromal cells (hMSCs) affects their regenerative capabilities and therapeutic efficacy, which are critical for successful cell-based regeneration therapies. In this study, we aimed to identify genetic markers of aging in hMSCs to better understand the impact of donor age on cell function. We conducted analysis on data from genome-wide microarray analysis on early-passage hMSCs isolated from the bone marrow of 61 donors aged between 17 and 84 years found in the GSE39540 public dataset. One such gene, identified asKLHL22 (ENSG00000099910), showed a significant negative correlation with age (p=0.032), with a regression slope of −0.0089 indicating decreased expression in older donors. TheR2R2 value of 0.243 suggests that approximately 24.3% of the expression variability of this gene can be explained by age. These findings are consistent with the known decline in tissue maintenance and regeneration capabilities in aging hMSCs and may reflect broader aging processes impacting cell-based therapies. Our results provide insight into the molecular basis of aging in hMSCs and highlight the potential of using gene expression profiles as markers to select more potent hMSCs for therapeutic applications. This gene signature could serve as a foundation for developing strategies to rejuvenate aged hMSCs, enhancing the efficacy of regenerative therapies.
Recruitment of CTCF to the SIRT1 promoter after Oxidative Stress mediates Cardioprotective Transcription
Authors: Wagner Tobias , Priyanka Priyanka , Micheletti Rudi , Friedman Meyer J. , Nair Sreejith J. , Gamliel Amir , Taylor Havilah , Song Xiaoyuan , Cho Miook , Oh Soohwan , Li Wenbo , Han Jeehae , Ohgi Kenneth A. , Abrass Madeline , D’Antonio-Chronowska Agnieszka , D’Antonio Matteo , Hazuda Helen , Duggirala Ravindranath , Blangero John , Ding Sheng , Guzmann Carlos , Frazer Kelly A. , Aggarwal Aneel K. , Zemljic-Harpf Alice E. , Rosenfeld Michael G. , Suh Yousin 
Published: May 2024

ABSTRACTBecause most DNA-binding transcription factors (dbTFs), including the architectural regulator CTCF, bind RNA and exhibit di-/multimerization, a central conundrum is whether these distinct properties are regulated post-transcriptionally to modulate transcriptional programs. Here, investigating stress-dependent activation ofSIRT1,encoding an evolutionarily-conserved protein deacetylase, we show that induced phosphorylation of CTCF acts as a rheostat to permit CTCF occupancy of low-affinity promoter DNA sites to precisely the levels necessary. This CTCF recruitment to the SIRT1 promoter is eliciting a cardioprotective cardiomyocyte transcriptional activation program and provides resilience against the stress of the beating heartin vivo. Mice harboring a mutation in the conserved low-affinity CTCF promoter binding site exhibit an altered, cardiomyocyte-specific transcriptional program and a systolic heart failure phenotype. This transcriptional role for CTCF reveals that a covalent dbTF modification regulating signal-dependent transcription serves as a previously unsuspected component of the oxidative stress response.
Molecular basis of the biogenesis of a protein organelle for ethanolamine utilization
Authors: Yang Mengru , Adegbite Oluwatobi , Chang Ping , Zhu Xiaojun , Li Yan , Dykes Gregory F. , Chen Yu , Savage Natasha , Hinton Jay C. D. , Lian Lu-Yun , Liu Lu-Ning 
Published: May 2024

AbstractMany pathogenic bacteria use proteinaceous ethanolamine-utilization microcompartments (Eut BMCs) to facilitate the catabolism of ethanolamine, an abundant nutrient in the mammalian gut. The ability to metabolize ethanolamine gives pathogens a competitive edge over commensal microbiota which can drive virulence in the inflamed gut. Despite their critical functions, the molecular mechanisms underlying the synthesis of Eut BMCs in bacterial cells remain elusive. Here, we report a systematic study for dissecting the molecular basis underlying Eut BMC assembly inSalmonella. We determined the functions of individual building proteins in the structure and function of Eut BMCs and demonstrated that EutQ plays an essential role in both cargo encapsulation and Eut BMC formation through specific association with the shell and cargo enzymes. Furthermore, our data reveal that Eut proteins can self-assemble to form cargo and shell aggregates independentlyin vivo, and that the biogenesis of Eut BMCs follows a unique “Shell-first” pathway. Cargo enzymes exhibit dynamic liquid-like organization within the Eut BMC. These discoveries provide mechanistic insights into the structure and assembly of the Eut BMC, which serves as a paradigm for membrane-less organelles. It opens up new possibilities for therapeutic interventions for infectious diseases.
Harnessing homeostatically active RhoC at cell junctions preserves human endothelial barrier function during inflammation
Authors: Colás-Algora Natalia , Muñoz-Pinillos Pablo , Barroso Susana , Cacho-Navas Cristina , Caballero Álvaro , Cerro-Tello Gema , de Rivas Gema , González-Fernández Martín , Jiménez-Alfaro Ignacio , Fresno Manuel , Ribas Catalina , Paradela Alberto , López-Collazo Eduardo , Fernández José Jesús , Millán Jaime 
Published: May 2024

ABSTRACTRho GTPases are molecular targets of bacterial toxins that modulate their enzymatic activity. RhoA, RhoB and RhoC are almost identical and play critical roles in generating actomyosin-mediated contractile forces that cause endothelial hyperpermeability during inflammation. Searching for new treatments to modulate endothelial integrity, we demonstrate that the specific and simultaneous activation of these three Rho GTPases with a chimeric recombinant toxin does not induce cell contraction but enhances homeostatic endothelial barrier function, increases reticular adherens junctions and preserves the microvascular endothelium in response to pathological inflammatory challengesin vitroandin vivo. This pro-barrier effect is specifically mediated by RhoC, whose activity is increased by cell confluence. The uniqueness of RhoC relies on an arginine 188 within its hypervariable region that determines its junctional localization, high homeostatic activity, and barrier-protective function. Quantitative proteomics revealed that RhoC regulates the expression of myosin light chain proteins and junction-stabilizing actomyosin. Thus, harnessing the activity of RhoC represents a potential therapy for strengthening endothelial barriers during pathological inflammation.
Long-term imaging of three-dimensional hyphal development using the ePetri dish
Authors: Zhang Oumeng , Dahlquist Nic , Leete Zachary , Xu Michael , Schneider Dean , Yang Changhuei 
Published: May 2024

AbstractImaging three-dimensional microbial development and behavior over extended periods is crucial for advancing microbiological studies. Here, we introduce an upgraded ePetri dish system specifically designed for extended microbial culturing and 3D imaging, addressing the limitations of existing methods. Our approach includes a sealed growth chamber to enable long-term culturing, and a multi-step reconstruction algorithm that integrates 3D deconvolution, image filtering, ridge, and skeleton detection for detailed visualization of the hyphal network. The system effectively monitored the development of Aspergillus brasiliensis hyphae over a seven-day period, demonstrating the growth medium’s stability within the chamber. The system’s 3D imaging capability was validated in a volume of 5.5 mm × 4 mm × 0.5 mm, revealing a radial growth pattern of fungal hyphae. Additionally, we show that the system can identify potential filter failures that are undetectable with 2D imaging. With these capabilities, the upgraded ePetri dish represents a significant advancement in long-term 3D microbial imaging, promising new insights into microbial development and behavior across various microbiological research areas.
Structural and Dynamical Analyses of Apo and Cap-binding eIF4E: Anin silicoStudy
Authors: Hasegawa Karin , Burzachiello Justin , Connolly Liam , Kementzidis Georgios , Niu Ziyuan , Papadopoulos Evangelos , Aktas Bertal Huseyin , Deng Yuefan 
Published: May 2024

AbstractMolecular dynamics (MD) simulations were utilized to investigate the dynamic behavior of eukaryotic translation initiation factor 4E (eIF4E) in its apo (ligand-free) and Cap-bound (complexed with mRNA Cap) forms. Specifically, we focused on the rearrangement of critical eIF4E residues, including W102, E103, W56, and key charged residues within the alpha helix, such as lysine and arginine. Three independent 1µsMD simulations were performed for four eIF4E structures based on an available Capbound eIF4E crystal structure (PDB: 4TPW) to sample protein conformations and explore metastable states. Metastable states were successfully sampled within the 1µstrajectories for all four structures; however, 2D-root-mean-square deviation (RMSD) and free-energy landscape (FEL) analyses indicate that additional trajectory data may be needed to fully explore the conformational space. Notably, the clearest state transitions were observed in the Cap-A simulations. Our data suggests that previously reported allosteric site eIF4E inhibitor 4EGI-1 stabilized the7mGTP-eIF4E interaction by binding to a site dorsal from the eIF4G binding site, facilitating stable protein states even after ligand removal and promoting cleaner state transitions in simulations. Root-mean-square fluctuation (RMSF) and distance analyses aligned consistently with experimental results, affirming the validity of our MD simulation system. Observations on apo and Cap eIF4E structures revealed structural changes in one of the alpha helices (i.e.,H3), particularly the transition from alpha helix to loop upon Cap binding. This transition was also observed during the cap to apo transition, where residues E105-R109 underwent structural rearrangements from loop to alpha helix. These findings support the strategy of designing agents targeting critical Cap-binding residues (W56, W102, E103) and H3 lysine residues (K106, K108) to disrupt the7mGTP-eIF4E interaction, potentially informing future drug design efforts targeting this oncogenic protein. Future work will focus on studying the apo to Cap transition using available eIF4E apo structures, such as PDB entry 2GPQ, to deepen our understanding of eIF4E’s metastable states during Cap binding.
Unilateral and Bilateral Theta Burst Stimulation for Treatment-Resistant Depression: Follow up on a Naturalistic Observation Study
Authors: Elnazali Mariam , Veerakumar Ashan , Blair Mervin , Pearce Emily L. , Kim Noah , Sebastian Sreya , Santo Jonathan B. , Rybak Iouri E. , Burhan Amer M. 
Published: May 2024

AbstractObjectivesTheta burst stimulation (TBS) is a novel and faster modality of transcranial magnetic stimulation, which is showing promise as a treatment-resistant depression (TRD) treatment. Though TBS can be applied unilaterally or bilaterally, few studies have compared the effectiveness of both approaches in a naturalistic clinical sample. In this retrospective chart review, we aimed to: (1) replicate previous bilateral sequential TBS effectiveness in a larger cohort of patients at a single centre, (2) present treatment outcome data between unilateral and bilateral TBS approaches, (3) investigate baseline factors associated with our observed outcomes, and (4) examine the sustainability of response, with follow-up data up to 6 months from patients.MethodsWe included 161 patients who received TBS (unilateral: n = 64 (40%), 45.55 ± 14.25 years old, 55% females; bilateral: n = 97 (60%), 47.67 ± 15.11 years old, 58% females).ResultsFirstly, we observed 47% response and 34% remission in the bilateral group, replicating findings from a smaller naturalistic study from our group; patients receiving unilateral TBS displayed 36% response and 26% remission, with no significant differences found between unilateral and bilateral TBS in remission and response rates. Secondly, bilaterally stimulated patients needed fewer treatments than those stimulated unilaterally (27 vs 29 on average respectively,t[159] = 3.31,p= .001), and had significantly lower anxiety symptoms post treatment (GAD-7) relative to patients receiving unilateral stimulation,F(1,148) = 3.95,p=0.049. Thirdly, no baseline factors were found to predict treatment outcomes. Lastly, after six months, 69% of patients who met the response criteria did not require additional treatment or a change in medication.ConclusionsOur findings support the efficacy and tolerability of TBS in TRD and indicate that bilateral TBS may have a superior anxiolytic effect and offer a slightly faster time to response.
Research involvement of medical students in a medical school of India: exploring knowledge, attitude, practices, and perceived barriers
Authors: Jha Abhinav , Shah Manas Ratan , Goyal Ritik , Dhamnetiya Deepak , Bharatwal Apoorv Amitabh , Jha Ravi Prakash , Renjhen Prachi 
Published: May 2024

AbstractIntroductionResearch in the medical discipline significantly impacts society by improving the general well-being of the population, through improvements in diagnostic and treatment modalities. However, of 579 Indian medical colleges, 332 (57.3%) did not publish a single paper from the year 2005 to 2014," indicating a limited contribution from medical fraternity In order to probe in to the cause of this a study was conducted to assess the knowledge, attitude, practices (KAP) and perceived barriers to research among students of a medical school in Delhi, India.MethodsA cross-sectional study was conducted among medical students and the data on academic-cum-demographic information, assessment of knowledge, attitude, practices and barriers to research was collected using a pre-tested, semi-structured questionnaire. Chi-square test was used to check the association of various factors with the KAP of research. A p-value less than 0.05 was considered significant.ResultsA total of 402 (N) subjects were enrolled in the study. Majority were male (79.6%) and from clinical professional years (57%). Majority (266, 66.2%) of the subjects had adequate knowledge. Of the study subjects (61,15%) having inadequate knowledge of research, sixty percent were from pre- and para-clinical years, while around 70 % of those having good knowledge were from clinical professional years. However, only 16.9% of the participants had participated in a research project, and only 4.72% had authored a publication. Sixty one percent of study subjects having a positive attitude towards research, were from pre- and para-clinical years. Among the study subjects having a positive attitude towards research, over 60% were from pre- and para-clinical years. The barriers for conducting research were mostly; lack of funds/laboratory equipment/infrastructure (85.1%), lack of exposure to opportunities for research in the medical (MBBS) curriculum (83.8%), and lack of time (83.3%). There was a statistically significant association between knowledge and attitude towards research with a professional year of study.ConclusionsThe study revealed that while most of the students had a positive attitude towards research as well as an adequate knowledge of research, there was a poor level of participation in research. These challenges can be overcome by incorporating research as a part of the medical school curriculum from early years on, setting aside separate time for research, and establishing student research societies that can actively promote research.
Survival among cancer patients after a coalmine fire: Analysis of registry data in regional Victoria, Australia
Authors: Lane Tyler J , Yu Pei , Gao Caroline , Smith Catherine L , Loi Sherene , Kinsman Natasha , Ikin Jill , Guo Yuming , Sim Malcolm R. , Abramson Michael J. 
Published: May 2024

AbstractBackgroundAir pollution is associated with poorer survival among cancer patients. However, much of the evidence is from studies of ambient air pollution rather than acute exposures like from fires. In this study, we examined the effect of a 2014 coalmine fire in regional Australia, which shrouded nearby communities in smoke for six weeks.MethodsWe analysed Victorian Cancer Registry data on new cancers diagnosed between January 2009 and February 2014, the start of the coalmine fire, and survival up to August 2019. Tumours were grouped by location and subtypes for breast and lung cancers. The exposure group was based on residence at diagnosis: Morwell (most exposure), the rest of Latrobe Valley (less exposure), and the rest of Victoria excluding Melbourne (little to no exposure). Those who were diagnosed in Morwell or the Latrobe Valley but died before the fire were classified as unexposed. Months of survival post-fire were compared using Cox proportional hazards frailty and discrete survival models.ResultsIn Morwell 488 total cancers were diagnosed, 1738 in the rest of the Latrobe Valley, while 42,738 were unexposed. There was no detectable overall effect. However, there were significant reductions in survival among cancers of female reproductive organs in Morwell and breast in the rest of Latrobe Valley.ConclusionThere were no overall changes in cancer survival and isolated increases in two subtypes, although not consistent across exposure sites. Reduced survival from female reproductive cancers were plausibly related to smoke exposure, though numbers were small and there is a high likelihood this was a chance finding. Otherwise, we found little evidence that medium-duration exposure to smoke from the Hazelwood coalmine fire shortened survival among cancer patients. However, owing to limited statistical power, we could not rule out an effect of smoke on cancer survival.