bluuebunny/crossref_metadata_2025 huggingface dataset:
BRCA mutational status shapes the stromal microenvironment of pancreatic cancer linking CLU+ CAF expression with HSF1 signaling
Authors: Shaashua Lee , Pevsner-Fischer Meirav , Friedman Gil , Levi-Galibov Oshrat , Nandakumar Subhiksha , Nevo Reinat , Brown Lauren E. , Zhang Wenhan , Stein Yaniv , Kim Han Sang , Bojmar Linda , Jarnagin William R. , Lecomte Nicolas , Stok Roni , Bishara Hend , Hamodi Rawand , Levy-Lahad Ephrat , Golan Talia , Porco John A. , Iacobuzio-Donahue Christine A. , Schultz Nikolaus , Lyden David , Tuveson David A. , Kelsen David , Scherz-Shouval Ruth
Published: August 2021

Cancer-associated fibroblasts (CAFs) give rise to desmoplastic stroma, which supports tumor progression and metastasis, and comprises up to 90% of the tumor mass in pancreatic cancer. Recent work by us and others has shown that CAFs are transcriptionally rewired by adjacent cancer cells to form heterogeneous subtypes. Whether this rewiring is differentially affected by different driver mutations in cancer cells is largely unknown. Here we address this question by dissecting and comparing the stromal landscape of BRCA-mutated and BRCA Wild-type (WT) pancreatic ductal adenocarcinoma (PDAC). We comprehensively analyze PDAC samples from a cohort of 42 patients by laser-capture microdissection, RNA-sequencing and multiplexed immunofluorescence, revealing different CAF subtype compositions in germline BRCA-mutated vs. BRCA-WT tumors. In particular, we detect an increase in a subset of Clusterin (CLU)-positive CAFs in BRCA-mutated tumors. We further unravel a network of stress responses upregulated in BRCA-mutated tumors. Using cancer organoids and cell co-cultures, we show that the transcriptional shift of pancreatic stellate cells into CLU+ CAFs is mediated through activation of heat-shock factor 1 (HSF1), the transcriptional regulator of Clu. Our findings unravel a new dimension of stromal heterogeneity, influenced by germline mutations in cancer cells, with direct translational implications for clinical research.

Significance

BRCA1/2 mutations initiate some of the deadliest cancers, yet the fibroblastic microenvironment of BRCA-mutated cancers remains uncharted. Our work addresses a major unsolved question – to what extent is the tumor microenvironment determined by cancer mutations? We find that BRCA mutations in the cancer cells affect the composition of CAFs in PDAC. These findings have direct implications for diagnosis and for efforts to exploit CAFs for therapy.
A novel ion conducting route besides the central pore in an inherited mutant of G-protein-gated inwardly rectifying K+ channel
Authors: Chen I-Shan , Eldstrom Jodene , Fedida David , Kubo Yoshihiro
Published: August 2021

G-protein-gated inwardly rectifying K+ (GIRK; Kir3.x) channels play important physiological roles in various organs. Some of the disease-associated mutations of GIRK channels are known to induce loss of K+ selectivity but their structural changes remain unclear. In this study, we investigated the mechanisms underlying the abnormal ion selectivity of inherited GIRK mutants. By the two-electrode voltage-clamp analysis of GIRK mutants heterologously expressed in Xenopus oocytes, we observed that Kir3.2 G156S permeates Li+ better than Rb+, while T154del or L173R of Kir3.2 and T158A of Kir3.4 permeate Rb+ better than Li+, suggesting a unique conformational change in the G156S mutant. Applications of blockers of the selectivity filter (SF) pathway, Ba2+ or Tertiapin-Q (TPN-Q), remarkably increased the Li+-selectivity of Kir3.2 G156S but did not alter those of the other mutants. In single-channel recordings of Kir3.2 G156S expressed in mouse fibroblasts, two types of events were observed, one attributable to a TPN-Q sensitive K+ current and the second a TPN-Q resistant Li+ current. The results show that a novel Li+ permeable and blocker-resistant pathway exists in G156S in addition to the SF pathway. Mutations in the pore helix (PH), S148F and T151A, also induced high Li+ permeation. Our results demonstrate that the mechanism underlying the loss of K+ selectivity of Kir3.2 G156S involves formation of a novel ion permeation pathway besides the SF pathway, which allows permeation of various species of cations.
Fetal Electrocardiogram Extraction from the Mother’s Abdominal Signal Using the Ensemble Kalman Filter
Authors: Sarafan Sadaf , Le Tai , Lau Michael P.H. , Hameed Afshan , Ghirmai Tadesse , Cao Hung
Published: August 2021

Fetal electrocardiogram (fECG) assessment is essential throughout pregnancy to monitor the wellbeing and development of the fetus, and to possibly diagnose potential congenital heart defects. Due to the high noise incorporated in the abdominal ECG (aECG) signals, the extraction of fECG has been challenging. And it is even a lot more difficult for fECG extraction if only one channel of aECG is provided, i.e. in a compact patch device. In this paper, we propose a novel algorithm based on the Ensemble Kalman Filter (EnKF) for non-invasive fECG extraction from a single-channel aECG signal. To assess the performance of the proposed algorithm, we used our own clinical data, obtained from a pilot study with 10 subjects each of 20 min recording, and data from the PhysioNet 2013 Challenge bank with labeled QRS complex annotations. The proposed methodology shows the average positive predictive value (PPV) of 97.59%, sensitivity (SE) of 96.91%, and F1-score of 97.25% from the PhysioNet 2013 Challenge bank. Our results also indicate that the proposed algorithm is reliable and effective, and it outperforms the recently proposed Extended Kalman Filter (EKF) based algorithm.
Implications of critical nodes-dependent unidirectional cross-talk between Plasmodium and Human SUMO pathway proteins in Plasmodium infection
Authors: Mishra Ram Kumar , Singh Jai Shankar , T K Sajeev , Panigrahi Rajlaxmi , Cherry Pearl , Panchakshari Nimisha Abhay , Shukla Vaibhav Kumar , kumar Ashutosh
Published: August 2021

The endoparasitic pathogen, Plasmodium falciparum (Pf), modulates protein-protein interactions to employ post-translational modifications like SUMOylation in order to establish successful infections. The interaction between E1 and E2 (Ubc9) enzymes governs species specificity in the Plasmodium SUMOylation pathway. Here, we demonstrate that a unidirectional cross-species interaction exists between Pf-SUMO and Human-E2, whereas Hs-SUMO1 failed to interact with Pf-E2. Biochemical and biophysical analysis revealed that surface-accessible Aspartates of Pf-SUMO determine the efficacy and specificity of SUMO-Ubc9 interactions. Furthermore, we demonstrate that critical residues of the Pf-Ubc9 N-terminal are responsible for the lack of interaction between Hs-SUMO1 and Pf-Ubc9. Mutating these residues to corresponding Hs-Ubc9 residues restore electrostatic, π-π, and hydrophobic interactions and allows efficient cross-species interactions. We suggest that the critical changes acquired on the surfaces of Plasmodium SUMO and Ubc9 proteins as nodes can help Plasmodium exploit the host SUMOylation machinery. Thus, Pf-SUMO interactions can be targeted for developing antimalarials.
Comparative phylogenomic patterns in the Baja California avifauna, their conservation implications, and the stages in lineage divergence
Authors: Vázquez-Miranda Hernán , Zink Robert M. , Pinto Brendan J.
Published: August 2021

Comparative phylogeography explores the historical congruence of co-distributed species to understand the factors that led to their current genetic and phenotypic structures. Even species that span the same biogeographic barrier can exhibit different phylogeographic structures owing to differences in effective population sizes, marker bias, and dispersal abilities. The Baja California peninsula and adjacent desert regions include several biogeographic barriers that have left phylogeographic patterns in some but not all species. We found that mitochondrial DNA, single nuclear genes, and genome-wide SNP data sets show largely concordant phylogeographic patterns for four bird species along the Baja California peninsula and adjacent mainland: cactus wren, Gila woodpecker, California gnatcatcher, and LeConte’s thrasher. The cactus wren and LeConte’s thrasher show a concordant historical division at or near the Vizcaíno Desert in north-central Baja California, the Gila woodpecker appears to be at an intermediate stage of divergence, and the California gnatcatcher lacks notable phylogeographic structure. None of these four species are classified taxonomically in a way that captures their evolutionary history with the exception of the LeConte’s thrasher. We also present mtDNA data on small samples of ten other species that span the Vizcaíno Desert, with five showing no apparent division, and five species from the Sierra de la Laguna, all of which appear differentiated. Reasons for contrasting phylogeographic patterns should be explored further with genomic data to test the extent of concordant phylogeographic patterns. The evolutionary division at the Vizcaíno desert is well known in other vertebrate species, and our study further corroborates the extent, profound effect and importance of this biogeographic boundary. The areas north and south of the Vizcaíno Desert, which contains considerable diversity, should be recognized as historically significant areas for conservation.
In the Line of Fire: Debris Throwing by Wild Octopuses
Authors: Godfrey-Smith Peter , Scheel David , Chancellor Stephanie , Linquist Stefan , Lawrence Matthew
Published: August 2021

Wild octopuses at an Australian site frequently propel shells, silt, and algae through the water by releasing these materials from their arms while creating a forceful jet from the siphon held under the arm web. These “throws” occur in several contexts, including interactions with conspecifics, and material thrown in conspecific contexts frequently hits other octopuses. Some throws appear to be targeted on other individuals and play a social role, as suggested by several kinds of evidence. Such throws were significantly more vigorous and more often used silt, rather than shells or algae, and high vigor throws were significantly more often accompanied by uniform or dark body patterns. Some throws were directed differently from beneath the arms and such throws were significantly more likely to hit other octopuses. Throws targeted at other individuals in the same population, as these appear to be, are the least common form of nonhuman throwing.
Breeding displacement in gray wolves(Canis lupus): Three males usurp breeding position and pup rearing from a neighboring pack in Yellowstone National Park
Authors: SunderRaj Jeremy D. , Rabe Jack W. , Cassidy Kira A. , McIntyre Rick , Stahler Daniel R. , Smith Douglas W.
Published: August 2021

Gray Wolves(Canis lupus)are territorial, group living carnivores that live in packs typically consisting of a dominant breeding pair and their offspring. Breeding tenures are relatively short and competitive, with vacancies usually occurring following a breeder’s death, and are often filled by unrelated immigrants or by relatives of the previous breeder. The frequency and conditions of active breeder displacements are poorly understood. Position changes in the dominance hierarchy are common yet rarely documented in detail. We describe a turnover in male breeding position in a wolf pack by males from a neighboring pack in mid-summer 2016 in Yellowstone National Park. Over the course of two months, three males from the Mollie’s pack displaced the breeding male of the neighboring Wapiti Lake pack, joined the pack’s two adult females, and subsequently raised the previous male’s four approximately three-month old pups. In the four years following the displacement (2017 to 2020), at least one of the intruding males has successfully bred with the dominant female and most years with a subordinate female (who was one of the pups at the time of displacement). The pack reared pups to adulthood each year. Male breeding displacements are likely influenced by male-male competition and female mate choice. These changes are the result of individuals competing to improve breeding position and may lead to increased pack stability and greater reproductive success. We report in detail on the behavior of a closely observed breeding displacement and we discuss the adaptive benefits of the change.
RRNPP_detector: a tool to detect RRNPP quorum sensing systems in chromosomes, plasmids and phages of gram-positive bacteria
Authors: Bernard Charles , Li Yanyan , Bapteste Eric , Lopez Philippe
Published: August 2021

Gram-positive bacteria (e.g. Firmicutes) and their mobile genetic elements (plasmids, bacteriophages) encode peptide-based quorum sensing systems (QSSs) that regulate behavioral transitions in a density-dependent manner. In their simplest form, termed “RRNPP”, these QSSs are composed of two adjacent genes: a communication propeptide and its cognate intracellular receptor. Despite the prime importance of RRNPP QSSs in the regulation of key biological pathways such as virulence, sporulation or biofilm formation in bacteria, conjugation in plasmids or lysogeny in temperate bacteriophages, no tools exist to predict their presence in target genomes/mobilomes. Here, we introduce RRNPP_detector, a software to predict RRNPP QSSs in chromosomes, plasmids and bacteriophages of gram-positive bacteria, available at https://github.com/TeamAIRE/RRNPP_detector. RRNPP_detector does not rely on homology searches but on a signature of multiple criteria, which are common between distinct families of experimentally-validated RRNPP QSSs. Because this signature is generic while specific to the canonical mechanism of RRNPP quorum sensing, it enables the discovery of novel RRNPP QSSs and thus of novel “languages” of biocommunication. Applying RRNPP_detector against complete genomes of viruses and Firmicutes available on the NCBI, we report a potential 7.5-fold expansion of RRNPP QSS diversity, alternative secretion-modes for certain candidate QSS propeptides, ‘bilingual’ bacteriophages and plasmids, as well as predicted chromosomal and plasmidic Biosynthetic-Gene-Clusters regulated by QSSs.
Spatial and Temporal Consistency of Brain Networks for different Multi-Echo fMRI Combination Methods
Authors: Pilmeyer J. , Hadjigeorgiou G. , Lamerichs R. , Breeuwer M. , Aldenkamp A.P. , Zinger S.
Published: August 2021

The application of multi-echo functional magnetic resonance imaging (fMRI) studies has considerably increased in the last decade due to its superior BOLD sensitivity compared to single-echo fMRI. Various methods have been developed that combine the fMRI time-series derived at different echo times to improve the data quality. Here we evaluated three multi-echo combination schemes, i.e. ‘optimal combination’ (T2*-weighted), temporal Signal-to-Noise Ratio (tSNR) weighted, and temporal Contrast-to-Noise Ratio (tCNR) weighted combination. For the first time, the effect of these multi-echo combinations on functional resting-state networks was assessed in the temporal and spatial domain, and compared to networks derived from the second echo (35 ms) functional images. Sixteen healthy volunteers were scanned during a 5 minutes resting-state fMRI session. After obtaining the networks, several temporal and spatial metrics were calculated for their time-series and spatial maps. Our results showed that, compared to the second echo network time-series, the Pearson correlation and root mean square error were the most consistent for the optimal combination time-series and the least with those derived from tSNR-weighted combination. The frequency analysis further suggested that the time-series from the tSNR-weighted combination method reduced hardware- and physiological-related artifacts as reflected by the reduced power for the associated frequencies in almost all networks. Moreover, the spatial stability and extent of the networks significantly increased after multi-echo combination, primarily for the optimal combination, followed by the tSNR-weighted combination. The performance of the tCNR-weighted combination lacked robustness and instead varied remarkedly between resting-state networks in both the temporal and spatial domain. The results highlight the benefits of multi-echo sequences on resting-state networks as well as the importance of adjusting the choice of multi-echo combination method to the research question and domain of interest.
Sharks, Lies, and Videotape: A content analysis of 32 years of Shark Week documentaries
Authors: Whitenack Lisa B. , Mickley Brady L. , Saltzman Julia , Kajiura Stephen M. , Macdonald Catherine C. , Shiffman David S.
Published: August 2021

Despite evidence of their importance to marine ecosystems, at least 25% of all chondrichthyan species are estimated or assessed as threatened with extinction. In addition to the logistical difficulties of effectively conserving wide-ranging marine species, shark conservation is believed to have been hindered in the past by public perceptions of sharks as dangerous to humans. Shark Week is a high-profile, international programming event that has potentially enormous influence on public perceptions of sharks, shark research, shark researchers, and shark conservation. However, Shark Week has received regular criticism for poor factual accuracy, fearmongering, bias, and inaccurate representations of science and scientists. This research analyzes the content and titles of Shark Week episodes across its entire 32 years of programming to determine if there are trends in species covered, research techniques featured, expert identity, conservation messaging, type of programming, and portrayal of sharks. We analyzed titles from 272 episodes (100%) of Shark Week programming and the content of all available (201; 73.9%) episodes. Our data demonstrate that the majority of episodes are not focused on shark bites, although such shows are common and many Shark Week programs frame sharks around fear, risk, and adrenaline. While anecdotal descriptions of disproportionate attention to particular charismatic species (e.g. great whites, bull sharks, and tiger sharks) are accurate and supported by data, 79 shark species have been featured briefly at least once. Shark Week’s depictions of research and of scientists are biased towards a small set of (typically visual and expensive) research methodologies and (mostly white, mostly male) scientists, including presentation of many white male non-scientists as experts. While sharks are more often portrayed negatively than positively, limited conservation messaging does appear in 53% of episodes analyzed. Results suggest that as a whole, while Shark Week is likely contributing to the collective perception of sharks as monsters, even relatively small alterations to programming decisions could substantially improve the presentation of sharks and shark science and conservation issues.
Integration of RT-LAMP and Microfluidic Technology for Detection of SARS-CoV-2 in Wastewater as an Advanced Point-of-care Platform
Authors: Donia Ahmed , Shahid Muhammad Furqan , Hassan Sammer-ul , Shahid Ramla , Ahmad Aftab , Javed Aneela , Nawaz Muhammad , Yaqub Tahir , Bokhari Habib
Published: August 2021

Development of lab-on-a-chip (LOC) system based on integration of reverse transcription loop-mediated isothermal amplification (RT-LAMP) and microfluidic technology is expected to speed up SARS-CoV-2 diagnostics allowing early intervention. In the current work, reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) and RT-LAMP assays were performed on extracted RNA of 7 wastewater samples from COVID-19 hotspots. RT□LAMP assay was also performed on wastewater samples without RNA extraction. Current detection of SARS-CoV-2 is mainly by RT-qPCR of ORF (ORF1ab) and N genes so we targeted both to find the best surrogate marker for SARS-CoV-2 detection. We also performed RT-LAMP with/without RNA extraction inside microfluidic device to target both genes. Positivity rates of RT-qPCR and RT-LAMP performed on extracted RNA were 100.0% (7/7) and 85.7% (6/7), respectively. RT-qPCR results revealed that all 7 wastewater samples were positive for N gene (Ct range 37-39), and negative for ORF1ab, suggesting that N gene could be used as a surrogate marker for detection of SARS-CoV-2. RT-LAMP of N and ORF (ORF1a) genes performed on wastewater samples without RNA extraction indicated that all 7 samples remains pink (negative). The color remains pink in all microchannels except microchannels which subjected to RT-LAMP for targeting N region after RNA extraction (yellow color) in 6 out of 7 samples. This study shows that SARS-CoV-2 was successfully detected from wastewater samples using RT-LAMP in microfluidic chips.
Ubiquitin modulates 26S proteasome conformational dynamics and promotes substrate degradation
Authors: Jonsson Erik , Htet Zaw Min , Bard Jared A.M. , Dong Ken C. , Martin Andreas
Published: August 2021

The 26S proteasome is the major ATP-dependent protease in eukaryotic cells, where it catalyzes the degradation of thousands of proteins for general homeostasis and the control of vital processes. It specifically recognizes appropriate substrates through attached ubiquitin chains and uses its ATPase motor for mechanical unfolding and translocation into a proteolytic chamber. Here, we used single-molecule Förster Resonance Energy Transfer (FRET) measurements to provide unprecedented insights into the mechanisms of selective substrate engagement, ATP-dependent degradation, and the regulation of these processes by ubiquitin chains. Our assays revealed the proteasome conformational dynamics and allowed monitoring individual substrates as they progress through the central channel during degradation. We found that rapid transitions between engagement- and processing-competent conformations of the proteasome control substrate access to the ATPase motor. Ubiquitin-chain binding functions as an allosteric regulator to slow these transitions, stabilize the engagement-competent state, and facilitate degradation initiation. The global conformational transitions cease upon substrate engagement, and except for apparent motor slips when encountering stably folded domains, the proteasome remains in processing-competent states for substrate translocation and unfolding, which is further accelerated by ubiquitin chains. Our studies revealed the dependence of ATP-dependent substrate degradation on the conformational dynamics of the proteasome and its allosteric regulation by ubiquitin chains, which ensure substrate selectivity and prioritization in a crowded cellular environment.
Unraveling Fe(II)-oxidizing mechanisms in a facultative Fe(II) oxidizer Sideroxydans lithotrophicus ES-1 via culturing, transcriptomics, and RT-qPCR
Authors: Zhou Nanqing , Keffer Jessica L. , Polson Shawn W. , Chan Clara S.
Published: August 2021

Sideroxydans lithotrophicus ES-1 grows autotrophically either by Fe(II) oxidation or thiosulfate oxidation, in contrast to most other neutrophilic Fe(II)-oxidizing bacteria (FeOB) isolates. This provides a unique opportunity to explore the physiology of a facultative FeOB and constrain the genes specific to Fe(II) oxidation. We compared the growth of S. lithotrophicus ES-1 on Fe(II), thiosulfate, and both substrates together. While initial growth rates were similar, thiosulfate-grown cultures had higher yield with or without Fe(II) present, which may give ES-1 an advantage over obligate FeOB. To investigate the Fe(II) and S oxidation pathways, we conducted transcriptomics experiments, validated with RT-qPCR. We explored the long-term gene expression response at different growth phases (over days-week) and expression changes during a short-term switch from thiosulfate to Fe(II) (90 min). The dsr and sox sulfur oxidation genes were upregulated in thiosulfate cultures. The Fe(II) oxidase gene cyc2 was among the top expressed genes during both Fe(II) and thiosulfate oxidation, and addition of Fe(II) to thiosulfate-grown cells caused an increase in cyc2 expression. These results support the role of Cyc2 as the Fe(II) oxidase and suggest that ES-1 maintains readiness to oxidize Fe(II) even in the absence of Fe(II). We used gene expression profiles to further constrain the ES-1 Fe(II) oxidation pathway. Notably, among the most highly upregulated genes during Fe(II) oxidation were genes for alternative complex III, reverse electron transport and carbon fixation. This implies a direct connection between Fe(II) oxidation and carbon fixation, suggesting that CO2 is an important electron sink for Fe(II) oxidation.

Importance

Neutrophilic FeOB are increasingly observed in various environments, but knowledge of their ecophysiology and Fe(II) oxidation mechanisms is still relatively limited. Sideroxydans are widely observed in aquifers, wetlands, and sediments, and genome analysis suggests metabolic flexibility contributes to their success. The type strain ES-1 is unusual amongst neutrophilic FeOB isolates as it can grow on either Fe(II) or a non-Fe(II) substrate, thiosulfate. Almost all our knowledge of neutrophilic Fe(II) oxidation pathways comes from genome analyses, with some work on metatranscriptomes. This study used culture-based experiments to test the genes specific to Fe(II) oxidation in a facultative FeOB and refine our model of the Fe(II) oxidation pathway. We gained insight into how facultative FeOB like ES-1 connect Fe, S, and C biogeochemical cycling in the environment, and suggest a multi-gene indicator would improve understanding of Fe(II) oxidation activity in environments with facultative FeOB.
Heterogeneity of the Cancer Cell Line Metabolic Landscape
Authors: Shorthouse David , Bradley Jenna , Critchlow Susan E. , Bendtsen Claus , Hall Benjamin A
Published: August 2021

The unravelling of the complexity of cellular metabolism is in its infancy. Cancer-associated genetic alterations may result in changes to cellular metabolism that aid in understanding phenotypic changes, reveal detectable metabolic signatures, or elucidate vulnerabilities to particular drugs. To understand cancer-associated metabolic transformation we performed untargeted metabolite analysis of 173 different cancer cell lines from 11 different tissues under constant conditions for 1099 different species using liquid chromatography-mass spectrometry (LC-MS). We correlate known cancer-associated mutations and gene expression programs with metabolic signatures, generating novel associations of known metabolic pathways with known cancer drivers. We show that metabolic activity correlates with drug sensitivity and use metabolic activity to predict drug response and synergy. Finally, we study the metabolic heterogeneity of cancer mutations across tissues, and find that genes exhibit a range of context specific, and more general metabolic control.
An early Shh-H2O2 feedback loop controls the progression of the regenerative program during adult zebrafish fin regeneration
Authors: Thauvin Marion , de Sousa Rodolphe Matias , Alves Marine , Volovitch Michel , Vriz Sophie , Rampon Christine
Published: August 2021

Reactive oxygen species (ROS), originally classified as toxic molecules, have attracted increasing interest given their actions in cell signaling. Among these molecules, Hydrogen peroxide (H2O2) is the major ROS produced by cells and acts as a second messenger to modify redox-sensitive proteins or lipids. After amputation, tight spatiotemporal regulation of ROS is required first for wound healing and later to initiate the regenerative program. However, the mechanisms carrying out this sustained ROS production and their integration with signaling pathways are still poorly understood. We focused on the early dialog between H2O2 and Sonic Hedgehog (Shh) during fin regeneration. We demonstrate that H2O2 controls Shh expression and that Shh in turn regulates the H2O2 level via a canonical pathway. Moreover, this tightly controlled feedback loop changes during the successive phases of the regenerative program. Dysregulation of the Hedgehog pathway has been implicated in several developmental syndromes, diabetes and cancer. These data support the existence of a very early feedback loop between Shh and H2O2 that might be more generally involved in various physiological or pathological processes. These new findings pave the way to improve regenerative processes, particularly in vertebrates.
Comparative Molecular Genomic Analyses of a Spontaneous Rhesus Macaque Model of Mismatch Repair-Deficient Colorectal Cancer
Authors: Lermi Nejla Ozirmak , Gray Stanton B. , Bowen Charles M. , Reyes-Uribe Laura , Dray Beth K. , Deng Nan , Harris R. Alan , Raveendran Muthuswamy , Benavides Fernando , Hodo Carolyn L. , Taggart Melissa W. , Maresso Karen Colbert , Sinha Krishna M. , Rogers Jeffrey , Vilar Eduardo
Published: August 2021

Colorectal cancer (CRC) remains the third most common cancer in the US with 15% of cases displaying Microsatellite Instability (MSI) secondary to Lynch Syndrome (LS) or somatic hypermethylation of the MLH1 promoter. A cohort of rhesus macaques from our institution developed spontaneous mismatch repair deficient (MMRd) CRC with a notable fraction harboring a pathogenic germline mutation in MLH1 (c.1029C<G, p.Tyr343Ter). Our study incorporated a detailed molecular characterization of rhesus CRC for cross-comparison with human MMRd CRC. We performed PCR-based MSI testing, transcriptomic analysis, and reduced-representation bisulfite sequencing (RRBS) of rhesus CRC (n=41 samples) using next-generation sequencing (NGS). Systems biology pipelines were used for gene set enrichment analysis (GSEA) for pathway discovery, consensus molecular subtyping (CMS), and somatic mutation profiling. Overall, the majority of rhesus tumors displayed high levels of MSI (MSI-high) and differential gene expression profiles that were consistent with known deregulated pathways in human CRC. DNA methylation analysis exposed differentially methylated patterns among MSI-H, MSI-L (MSI-low)/MSS (MS-stable) and LS tumors with MLH1 predominantly inactivated among sporadic MSI-H CRCs. The findings from this study support the use of rhesus macaques as the preferred animal model to study carcinogenesis, develop immunotherapies and vaccines, and implement chemoprevention approaches pertinent to sporadic MSI-H and LS CRC in humans.
Connectomic features underlying diverse synaptic connection strengths and subcellular computation
Authors: Liu Tony X. , Davoudian Pasha A. , Lizbinski Kristyn M. , Jeanne James M.
Published: August 2021

Connectomes generated from electron microscopy images of neural tissue unveil the complex morphology of every neuron and the locations of every synapse interconnecting them. These wiring diagrams may also enable inference of synaptic and neuronal biophysics, such as the functional weights of synaptic connections, but this requires integration with physiological data to properly parameterize. Working with a stereotyped olfactory network in theDrosophilabrain, we make direct comparisons of the anatomy and physiology of diverse neurons and synapses with subcellular and subthreshold resolution. We find that synapse density and location jointly predict the amplitude of the somatic postsynaptic potential evoked by a single presynaptic spike. Biophysical models fit to data predict that electrical compartmentalization allows axon and dendrite arbors to balance independent and interacting computations. These findings begin to fill the gap between connectivity maps and activity maps, which should enable new hypotheses about how network structure constrains network function.
Effects of Hydroxychloroquine and Azithromycin on iPSC-derived Cardiomyocytes: Considerations for the Treatment of COVID-19 Patients
Authors: Li Wener , Luo Xiaojing , Poetsch Mareike S. , Oertel Reinhard , Nichani Kapil , Schneider Martin , Strano Anna , Hasse Marcel , Steiner Robert-Patrick , Cyganek Lukas , Hettwer Karina , Uhlig Steffen , Simon Kirsten , Guan Kaomei , Schubert Mario
Published: August 2021

Despite known adverse effects of hydroxychloroquine (HCQ) and azithromycin (AZM) on cardiac function, HCQ and AZM have been used as combination therapy in the treatment of COVID-19 patients. Recent clinical data indicate higher complication rates with HCQ/AZM combination treatment in comparison to monotherapy. Here, we used human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) to systematically investigate the effects of HCQ and AZM individually and in combination. The clinically observed QT prolongation caused by treatment with HCQ could be recapitulated in iPSC-CMs based on prolonged field potential duration (FPDc). Interestingly, HCQ-induced FPDc prolongation was strongly enhanced by combined treatment with AZM, although AZM alone slightly shortened FPDc in iPSC-CMs. Furthermore, combined treatment with AZM and HCQ leads to higher cardiotoxicity, more severe structural disarrangement, and more pronounced contractile and electrophysiological dysfunctions, compared to respective mono-treatments. First mechanistic insights underlying the synergistic effects of AZM and HCQ on iPSC-CM functionality are provided based on increased Cx43- and Nav1.5-protein levels. Taken together, our results highlight that combined treatment with HCQ and AZM strongly enhances the adverse effects on cardiomyocytes, providing mechanistic evidence for the high mortality in patients receiving HCQ/AZM combination treatment.
Pandemic, epidemic, endemic: B cell repertoire analysis reveals unique anti-viral responses to SARS-CoV-2, Ebola and Respiratory Syncytial Virus
Authors: Stewart Alexander , Sinclair Emma , Ng Joseph , O’Hare Joselli Silvia , Page Audrey , Serangeli Ilaria , Margreitter Christian , Kasar Nora , Longman Katherine , Frampas Cecile , Costa Catia , Lewis Holly , Wu Bryan , Kipling David , Openshaw Peter , Chu Christopher , Baillie J Kenneth , Scott Janet T , Semple Malcolm G , Bailey Melanie , Fraternali Franca , Dunn-Walters Deborah
Published: August 2021

Immunoglobulin gene heterogeneity reflects the diversity and focus of the humoral immune response towards different infections, enabling inference of B cell development processes. Detailed compositional and lineage analysis of long read IGH repertoire sequencing, combining examples of pandemic, epidemic and endemic viral infections with control and vaccination samples, demonstrates general responses including increased use of IGHV4-39 in both EBOV and COVID-19 infection cohorts. We also show unique characteristics absent in RSV infection or yellow fever vaccine samples: EBOV survivors show unprecedented high levels of class switching events while COVID-19 repertoires from acute disease appear underdeveloped. Despite the high levels of clonal expansion in COVID-19 IgG1 repertoires there is a striking lack of evidence of germinal centre mutation and selection. Given the differences in COVID-19 morbidity and mortality with age, it is also pertinent that we find significant differences in repertoire characteristics between young and old patients. Our data supports the hypothesis that a primary viral challenge can result in a strong but immature humoral response where failures in selection of the repertoire risks off-target effects.
Template design based on molecular and crystal structure similarity to regulate conformational polymorphism nucleation: the case of α,ω-alkanedicarboxylic acids
Authors: Lin Jiawei , Shi Peng , Wang Ying , Wang Lingyu , Ma Yiming , Liu Fei , Wu Songgu , Gong Junbo
Published: August 2021

Template design on polymorph control, especially conformational polymorphs, is still in its infancy and the result of polymorph control is often accidental. A method of regulating the crystallization of conformational polymorphs based on the crystal structure similarity of templates and the target crystal form has been developed. Crystal structure similarity was considered to be able to introduce lattice matching (geometric term) with chemical interactions to regulate conformational polymorph nucleation. The method was successfully applied to induce the crystallization of DA7-II [HOOC–(CH2)n−2–COOH (diacids), named DAn, wheren= 7, 9, 15, 17 and II represents the metastable polymorph] on the surface of DA15-II. An analogous two-dimensional plane – the (002) face of both DA15-II and DA7-II – was firstly predicted as the epitaxially attached face with similar lattice parameters and the strongest adsorption energy. The powder DA15-II template with the preferred orientation face in (002) presented much stronger inducing DA7-II ability than the template with other preferred orientation faces. The epitaxial growth of DA7-II on DA15-II through an identical (002) face was clearly observed and verified by the single-crystal inducing experiments. The molecular dynamics simulation results demonstrated that the strong interactions occurred between DA7 molecules and the (002) face of DA15-II. This method has been verified and further applied to the crystallization of DA7-II on the surface of DA17-II and DA9-II on the surface of DA15-II. This study developed a strategy based on structure similarity to regulate the conformational polymorph and verified the significant role of lattice matching and chemical effects on the design and preparation of templates.
Geometrical prediction of cleavage planes in crystal structures
Authors: Vaknin Uriel , Sherman Dov , Gorfman Semën
Published: August 2021

Cleavage is the ability of single crystals to split easily along specifically oriented planes. This phenomenon is of great interest for materials' scientists. Acquiring the data regarding cleavage is essential for the understanding of brittle fracture, plasticity and strength, as well as for the prevention of catastrophic device failures. Unfortunately, theoretical calculations of cleavage energy are demanding and often unsuitable for high-throughput searches of cleavage planes in arbitrary crystal structures. A simplified geometrical approach (GALOCS= gaps locations in crystal structures) is suggested for predicting the most promising cleavage planes.GALOCSenumerates all the possible reticular lattice planes and calculates the plane-average electron density as a function of the position of the planes in the unit cell. The assessment of the cleavage ability of the planes is based on the width and depth of planar gaps in crystal structures, which appear when observing the planes lengthwise. The method is demonstrated on two-dimensional graphene and three-dimensional silicon, quartz and LiNbO3structures. A summary of planar gaps in a few more inorganic crystal structures is also presented.
The influence of online and offline brand trust on consumer buying intention
Authors: Nosi Costanza , Pucci Tommaso , Melanthiou Yioula , Zanni Lorenzo
Published: August 2021

Purpose

The study tests a model that considers online brand trust in different nonbrand-owned touchpoints as a multifactorial construct constituted by: social network influencers, bloggers, online retail platforms and brand-related user generated content. Furthermore, it examines the influences that offline and online brand trust exert on consumer buying intention.

Design/methodology/approach

A convenience sample of 3,335 total individuals participated in the survey. Structural equation modelling was used to test the hypotheses.

Findings

Online brand trust is significantly influenced by trust in all investigated nonbrand-owned touchpoints. Both offline and online brand trust positively influence buying intention.

Research limitations/implications

Whereas brand trust is considered a multidimensional construct that includes both cognitive and affective aspects, in addition to individuals' personality traits, the present study only investigated the rational dimension of the brand trust paradigm. Moreover, this study examined the influence of brand trust on consumers' buying intention and not overt behavior. In addition, even though the extant literature suggests that the relation between trust and behavioral outcomes may vary across cultures, no test of the possible influences that culture exerted on brand trust and BInt was run. Finally, given the convenience sampling method used in this research, statistically significant surveys would provide a more solid basis for the investigated phenomenon, and they would enable an appropriate generalization of the findings.

Practical implications

To build brand trust and favour buying intention, marketers should monitor and influence the online touchpoints that are partially under or totally out of their control, and reconceive and manage physical stores.

Originality/value

This paper contributes to the stream of literature on online brand trust by proving that it is a multifactorial construct resulting from trust in different non-proprietary online entities and pointing out the prevalent role that physical stores play in shaping consumer buying intention. It also indicates that a trust transfer effect takes place between different online information sources and offline outlets.
Female entrepreneurship in emerging markets: challenges of running a business in turbulent contexts and times
Authors: Kogut Clarice Secches , Mejri Kais
Published: August 2021

Purpose

The present study seeks to investigate female entrepreneurship in turbulent times (COVID-19) and contexts (emerging markets).

Design/methodology/approach

An in-depth, multiple-firm (five SMEs), cross-country (2 countries – Brazil and Tunisia), cross-region (Latin America and the MENA region) case study based on a mixed embeddedness perspective.

Findings

The study highlights how challenges and uncertainties are managed, what inspires female entrepreneurs and what frightens them. We capture these entrepreneurs' insecurities, self-doubts and creative survival strategies. Our findings reinforce the need for self-efficacy and resilience, as well as the importance of a support network and the ability to “reboot” whenever needed. Despite persistent patriarchal norms and cultures, the women surveyed did not see themselves as female entrepreneurs but as successful entrepreneurs, akin to their male counterparts.

Research limitations/implications

Academically, the study contributes to the fields of entrepreneurship, female entrepreneurship and crisis management with empirical evidence in new contexts (LATAM and MENA regions) and times (collected during a crisis). The results also contribute in a practical way to female entrepreneurs, policy makers and global agencies.

Originality/value

The study's originality arises from a qualitative cross-country comparison of findings from internationally minded companies from under-researched developing countries and regions at an especially interesting and turbulent time: the pandemic of 2020.
Coping with the crisis: the effects of psychological capital and coping behaviors on perceived stress
Authors: Maykrantz Sherry A. , Nobiling Brandye D. , Oxarart Richard A. , Langlinais Luke A. , Houghton Jeffery D.
Published: August 2021

Purpose

The COVID-19 pandemic has dramatically altered the daily lives of millions of people around the world, substantially increasing anxiety and stress levels for many. Psychological capital (PsyCap), a multidimensional construct that includes hope, optimism, resilience and self-efficacy, may serve as a resource for helping people more effectively cope with uncertainty resulting in lower levels of perceived stress. The authors hypothesize a negative relationship between PsyCap and perceived stress that is partially and differentially mediated by adaptive and maladaptive coping styles. The authors further hypothesize that work context (home vs workplace) will moderate the relationships between coping styles and perceived stress.

Design/methodology/approach

After receiving Institutional Review Board approval, data were collected during the first week of May 2020 using an online survey. The hypothesized model was tested using structural equation modeling (SEM) techniques, specifically Mplus 8. The authors validated their initial findings using PROCESS Model 14 with 5,000 boot-strapped samples and a 95% confidence interval.

Findings

The authors’ results show that adaptive and maladaptive coping styles differentially mediate the effects of PsyCap on perceived stress with the indirect effects of PsyCap on perceived stress through maladaptive coping being stronger than the indirect effects through adaptive coping. The authors found support for the relationships in our hypothesized model.

Practical implications

The authors’ findings suggest that health interventions aimed at increasing PsyCap may be an effective means of reducing maladaptive coping and perceived stress. Future research should continue to explore PsyCap as a potential means of shaping positive health behaviors.

Originality/value

This study makes a unique contribution to the literature by explaining how PsyCap operates through coping to affect perceptions of stress in the context of the COVID-19 pandemic.
Fraudulent financial reporting: an application of fraud diamond to Toshiba’s accounting scandal
Authors: Demetriades Polydoros , Owusu-Agyei Samuel
Published: August 2021

Purpose

The purpose of this paper is to examine Toshiba’s fraudulent financial reporting in relation to the fraud diamond (pressure, opportunity, rationalisation and capability).

Design/methodology/approach

A quantitative empirical research, analysing secondary data from Toshiba’s published annual reports before restatement, from 2008–2014 has been used. A simultaneous equations approach was used to test the hypothesis. Excel software was used to analyse secondary data and to carry out correlation analysis and descriptive statistics analysis.

Findings

This study uncovers evidence that pressure proxied by return on assets (ROA), the opportunity proxied by ineffective monitoring (BDOUT), rationalisation proxied by audit opinion (AO) and capability proxied by board member changes (BCHANGE) had moderate to strong relationship to financial statement fraud (FSF) (proxied by Beneish M-score model). However, ROA has a negative and significant effect on Toshiba’s FSF. BDOUT, AO and BCHANGE have positive and significant effect on Toshiba’s FSF. Furthermore, there is no multicollinearity problem within the four variables. Overall, this study has statistically proven that all dimensions of fraud diamond are required for the explanation of Toshiba’s accounting scandal.

Originality/value

Although a few studies discuss the four dimensions (fraud diamond), none, to our surprise, exists which explain the circumstances led Toshiba’s high-level executives to commit fraud. This study is the first thorough investigation of Toshiba’s accounting scandal that uses all four dimensions to explain Toshiba’s FSF.
Assessing organizational culture in public mental healthcare service organizations
Authors: Prodromou Maria , Papageorgiou George
Published: August 2021

Purpose

The purpose of this paper is to investigate aspects of organizational culture among the nursing staff of public mental health services organizations in Cyprus. Specifically, highlights are provided of possible differences on the attitudes of nurses regarding actual and desired aspects of organizational culture with respect to demographic characteristics such as gender, years of service and experience.

Design/methodology/approach

A descriptive explanatory type survey study was conducted in all public mental health services organizations of Cyprus. Specifically, a questionnaire was given to a representative sample of the nursing population, and data were collected and analyzed. The survey questionnaire was based on the organizational culture profile (OCP) methodology. Statistical analysis was carried out using correlational analysis, t-tests and analysis of variance (ANOVA).

Findings

Results showed that there are significant discrepancies between the actual organizational culture and what is desired by staff members of public mental health services organizations in Cyprus. Further, significant differences are identified between actual and desired organizational culture moderated by the type of work, which is determined by the workplace.

Originality/value

Even though, organizational culture is a major research topic little has been done in the context of public mental healthcare organizations. Further, for the case of Cyprus, it is the first time that such a study is carried out. The results presented in this paper may provide the foundation for measures to be taken for improving the existing operation of public mental healthcare organizations.