bluuebunny/crossref_metadata_2025 huggingface dataset:
A critical threshold of MCM10 is required to maintain genome stability during differentiation of induced pluripotent stem cells into natural killer cells
Authors: Schmit Megan M. , Baxley Ryan M. , Wang Liangjun , Hinderlie Peter , Kaufman Marissa , Simon Emily , Raju Anjali , Miller Jeffrey S. , Bielinsky Anja-Katrin
Published: January 2024

Natural killer (NK) cell deficiency (NKD) is a rare disease in which NK cell function is reduced, leaving affected individuals susceptible to repeated viral infections and cancer. Recently, a patient with NKD was identified carrying compound heterozygous variants of
MCM10
(
minichromosome maintenance protein 10
), an essential gene required for DNA replication, that caused a significant decrease in the amount of functional MCM10. NKD in this patient presented as loss of functionally mature late-stage NK cells. To understand how MCM10 deficiency affects NK cell development, we generated
MCM10
heterozygous (

MCM10
+/−

) induced pluripotent stem cell (iPSC) lines. Analyses of these cell lines demonstrated that
MCM10
was haploinsufficient, similar to results in other human cell lines. Reduced levels of MCM10 in mutant iPSCs was associated with impaired clonogenic survival and increased genomic instability, including micronuclei formation and telomere erosion. The severity of these phenotypes correlated with the extent of MCM10 depletion. Significantly,

MCM10
+/−

iPSCs displayed defects in NK cell differentiation, exhibiting reduced yields of hematopoietic stem cells (HSCs). Although

MCM10
+/−

HSCs were able to give rise to lymphoid progenitors, these did not generate mature NK cells. The lack of mature NK cells coincided with telomere erosion, suggesting that NKD caused by these
MCM10
variants arose from the accumulation of genomic instability including degradation of chromosome ends.
Beta-cell adaptation to metabolic stresses requires prolactin receptor signaling
Authors: Lee Daniel , Kahlon Raneet , Kola-Ilesanmi Darasimi , Rahman Mahir , Huang Carol
Published: January 2024

The role of prolactin receptor (PRLR) signaling in β-cell adaptation to maternal insulin resistance of pregnancy has been well demonstrated. Using transgenic mice with an inducible β-cell-specific Prlr deletion (βPrlr-/-), we found that intact PRLR, as found in βPrlr+/+mice, were protected from developing glucose intolerance during pregnancy, and the main mechanism responsible for this PRLR-mediated effect is the up regulation of β-cell proliferation and insulin synthesis. Interestingly, studies in male mice and humans have found a link between diminished PRLR signaling and abnormal β-cell function. We aimed to determine whether PRLR has a role in regulating β-cell function outside of pregnancy, protecting β-cell against exposure to metabolic stressors.

In this study, we found that β-cell-specific PRLR reduction resulted in impaired glucose tolerance in multiparous female mice challenged with a 12-week course of high-fat diet (HFD). Unlike in pregnancy, where PRLR signaling up regulates β-cell proliferation resulting in a greater β-cell mass, we observed no difference in β-cell mass between the wild type (βPrlr+/+) and mutant (βPrlr-/-) mice. In vitro glucose-stimulated insulin secretion using isolated islets from wild type (βPrlr+/+) and mutant (βPrlr-/-) mice showed comparable insulin response, but βPrlr-/-mice showed blunted first-phase insulin release in vivo, although only when challenged with glucose orally and not intraperitoneally, suggesting an impairment of the incretin effect. In support of the observed defect in incretin action, we found a reduction in expression of both incretin hormone receptors,GiprandGlp-1r, and several of their upstream regulators, such asE2f1, Nkx6.1, Pax6, Pparγ, andTcf7l2. Islets from the mutant mice also have a lower insulin content and reduced levels of genes that regulate glucose metabolism. Together, these results suggested that PRLR signaling plays an important role in preserving β-cell function in mice exposed to metabolic stress by maintaining incretin receptor expression and insulin secretory capacity in β cells.
Sifting Through the Noise: A Computational Pipeline for Accurate Prioritization of Protein-Protein Binding Candidates in High-Throughput Protein Libraries
Authors: Mondal Arup , Singh Bhumika , Felkner Roland H. , De Falco Anna , Swapna GVT , Montelione Gaetano T. , Roth Monica J. , Perez Alberto
Published: January 2024

Identifying the interactome for a protein of interest is challenging due to the large number of possible binders. High-throughput experimental approaches narrow down possible binding partners, but often include false positives. Furthermore, they provide no information about what the binding region is (e.g. the binding epitope). We introduce a novel computational pipeline based on an AlphaFold2 (AF) Competition Assay (AF-CBA) to identify proteins that bind a target of interest from a pull-down experiment, along with the binding epitope. Our focus is on proteins that bind the Extraterminal (ET) domain of Bromo and Extraterminal domain (BET) proteins, but we also introduce nine additional systems to show transferability to other peptide-protein systems. We describe a series of limitations to the methodology based on intrinsic deficiencies to AF and AF-CBA, to help users identify scenarios where the approach will be most useful. Given the speed and accuracy of the methodology, we expect it to be generally applicable to facilitate target selection for experimental verification starting from high-throughput protein libraries.

Table of Contents
Full resolution HLA and KIR genes annotation for human genome assemblies
Authors: Zhou Ying , Song Li , Li Heng
Published: January 2024

The HLA (Human Leukocyte Antigen) genes and the KIR (Killer cell Immunoglobulin-like Receptor) genes are critical to immune responses and are associated with many immune-related diseases. Located in highly polymorphic regions, they are hard to be studied with traditional short-read alignment-based methods. Although modern long-read assemblers can often assemble these genes, using existing tools to annotate HLA and KIR genes in these assemblies remains a non-trivial task. Here, we describe Immuannot, a new computation tool to annotate the gene structures of HLA and KIR genes and to type the allele of each gene. Applying Immuannot to 56 regional and 212 whole-genome assemblies from previous studies, we annotated 9,931 HLA and KIR genes and found that almost half of these genes, 4,068, had novel sequences compared to the current Immuno Polymorphism Database (IPD). These novel gene sequences were represented by 2,664 distinct alleles, some of which contained non-synonymous variations resulting in 92 novel protein sequences. We demonstrated the complex haplotype structures at the two loci and reported the linkage between HLA/KIR haplotypes and gene alleles. We anticipate that Immuannot will speed up the discovery of new HLA/KIR alleles and enable the association of HLA/KIR haplotype structures with clinical outcomes in the future.
Development and optimization of a diluted whole blood ELISpot assay to test immune function
Authors: Ungaro Ricardo F. , Xu Julie , Kucaba Tamara A. , Rao Mahil , Brakenridge Scott C. , Efron Philip A. , Gould Robert W. , Hotchkiss Richard S. , Mazer Monty B. , McGonagill Patrick W. , Moldawer Lyle L. , Remy Kenneth E. , Turnbull Isaiah R. , Caldwell Charles C. , Badovinac Vladimir P. , Griffith Thomas S.
Published: January 2024

Background

Sepsis remains a leading cause of death worldwide with no proven immunomodulatory therapies. Stratifying Patient Immune Endotypes in Sepsis (‘SPIES’) is a prospective, multicenter observational study testing the utility of ELISpot as a functional bioassay specifically measuring cytokine-producing cells after stimulation to identify the immunosuppressed endotype, predict clinical outcomes in septic patients, and test potential immune stimulants for clinical development. Most ELISpot protocols call for the isolation of PBMC prior to their inclusion in the assay. In contrast, we developed a diluted whole blood (DWB) ELISpot protocol that has been validated across multiple laboratories.

Methods

Heparinized whole blood was collected from healthy donors and septic patients and tested under different stimulation conditions to evaluate the impact of blood dilution, stimulant concentration, blood storage, and length of stimulation onex vivoIFNγ and TNFα production as measured by ELISpot.

Results

We demonstrate a dynamic range of whole blood dilutions that give a robustex vivocytokine response to stimuli. Additionally, a wide range of stimulant concentrations can be utilized to induce cytokine production. Further modifications demonstrate anticoagulated whole blood can be stored up to 24 hours at room temperature without losing significant functionality. Finally, we showex vivostimulation can be as brief as 4 hours allowing for a substantial decrease in processing time.

Conclusions

The data demonstrate the feasibility of using ELISpot to measure the functional capacity of cells within DWB under a variety of stimulation conditions to inform clinicians on the extent of immune dysregulation in septic patients.
The lifetime accumulation of multimorbidity and its influence on dementia risk: a UK Biobank Study
Authors: Patel R. , Mackay C.E. , Griffanti L. , Gillis G. , Ebmeier K.P. , Suri S.
Published: January 2024

The number of people living with dementia worldwide is projected to reach 150 million by 2050, making prevention a crucial priority for health services1. The co-occurrence of two or more chronic health conditions, termed multimorbidity, occurs in up to 80% of dementia patients2, raising the potential of multimorbidity as an important risk factor for dementia. However, precise understanding of which specific conditions, as well as their age of onset, drive the link between multimorbidity and dementia is unclear. We defined the patterns of accumulation of 46 chronic conditions over their lifetime in 282,712 individuals from the UK Biobank. By grouping individuals based on their life-history of chronic illness, we show here that risk of incident dementia can be stratified by both the type and timing of their accumulated chronic conditions. We identified several distinct clusters of multimorbidity, and their associated risks varied in an age-specific manner. Compared to low multimorbidity, cardiometabolic and neurovascular conditions acquired before 55 years were most strongly associated with dementia. Acquisition of mental health and neurovascular conditions between the ages of 55 and 70 was associated with an over two-fold increase in dementia risk compared to low multimorbidity. The age-dependent role of multimorbidity in predicting dementia risk could be used for early stratification of individuals into high and low risk groups and inform targeted prevention strategies based on a person’s prior history of chronic disease.
ChronicToxoplasma gondiiinfection curtails the cytotoxic potential of acute T cell responses to West Nile virus in the brain
Authors: Uhrlaub Jennifer L. , McGovern Kathryn E. , Merritt Emily F. , Kuhns Michael S. , Koshy Anita A. , Nikolich Janko Ž.
Published: January 2024

Toxoplasma gondii (T. gondii), a common brain-tropic parasite, chronically infects the central nervous system (CNS) of up to a third of the world’s population. Constant immune surveillance interrupts cyst reactivation within the CNS and dramatically alters the immune landscape of the brain. West Nile virus (WNV) is a mosquito-borne infection with a clinical spectrum ranging from asymptomatic to mild flu-like symptoms to severe neuroinvasive disease. In a cohort of WNV infected people, we discovered a positive correlation between WNV disease severity andT. gondiiseropositivity. In a mouse model pairing chronicT. gondiiwith acute WNV infection, we found an increased susceptibility of mice to WNV, with reduced granzyme B expression in WNV-specific T cells and increased regulatory T cell (Treg) numbers in the brain, but not the periphery. This demonstrates that theT. gondii-infected tissue microenvironment impairs immune defense against other brain infections by blunting local T cell responses.
A highly sensitive XNA-based RT-qPCR assay for the identification of ALK, RET, and ROS1 fusions in lung cancer
Authors: Lee Bongyong , Chern Andrew , Fu Andrew Y. , Zhang Aiguo , Sha Michael Y.
Published: January 2024

In lung cancer, the progression of tumors is often fueled by genetic alterations leading to the expression of oncogenic tyrosine kinases. Specifically, chimeric tyrosine kinases involving ALK, RET, and ROS1 are observed in approximately 5-7%, 1-2%, and 1-2% of NSCLS patients, respectively. The presence of these ALK, RET, and ROS1 fusion genes determines the response to tyrosine kinase inhibitors. Consequently, accurate detection of these gene fusions is crucial in the realm of precision medicine. To address this need, we have developed a multiplexed RT-qPCR assay based on xenonucleic acids (XNA) molecular clamping technology for detecting lung cancer fusions. This assay is designed to quantitatively detect thirteen ALK, seven ROS1, and seven RET gene fusions in FFPE samples. The sensitivity of the assay was established at a limit of detection of 50 copies of the synthetic template. Our assay successfully identified all fusion transcripts using 50 ng of RNA from both reference FFPE samples and cell lines. Following this validation, we tested a total of 77 lung cancer patient FFPE samples, demonstrating the effectiveness of our XNA-based fusion gene assay with clinical samples. Notably, this assay is adaptable to highly degraded RNA samples with low input amounts. Our next phase involves expanding the testing to include a broader range of clinical samples as well as cell-free RNAs to further validate its applicability and reliability.
Comparison of Bayesian approaches for developing prediction models in rare disease: application to the identification of patients with Maturity-Onset Diabetes of the Young
Authors: Cardoso Pedro , McDonald Timothy J. , Patel Kashyap A. , Pearson Ewan R. , Hattersley Andrew T. , Shields Beverley M. , McKinley Trevelyan J.
Published: January 2024

Background

Clinical prediction models can help identify high-risk patients and facilitate timely interventions. However, developing such models for rare diseases presents challenges due to the scarcity of affected patients for developing and calibrating models. Methods that pool information from multiple sources can help with these challenges.

Methods

We compared three approaches for developing clinical prediction models for population-screening based on an example of discriminating a rare form of diabetes (Maturity-Onset Diabetes of the Young - MODY) in insulin-treated patients from the more common Type 1 diabetes (T1D). Two datasets were used: a case-control dataset (278 T1D, 177 MODY) and a population-representative dataset (1418 patients, 96 MODY tested with biomarker testing, 7 MODY positive). To build a population-level prediction model, we compared three methods for recalibrating models developed in case-control data. These were prevalence adjustment (“offset”), shrinkage recalibration in the population-level dataset (“recalibration”), and a refitting of the model to the population-level dataset (“re-estimation”). We then developed a Bayesian hierarchical mixture model combining shrinkage recalibration with additional informative biomarker information only available in the population-representative dataset. We developed prior information from the literature and other data sources to deal with missing biomarker and outcome information and to ensure the clinical validity of predictions for certain biomarker combinations.

Results

The offset, re-estimation, and recalibration methods showed good calibration in the population-representative dataset. The offset and recalibration methods displayed the lowest predictive uncertainty due to borrowing information from the fitted case-control model. We demonstrate the potential of a mixture model for incorporating informative biomarkers, which significantly enhanced the model’s predictive accuracy, reduced uncertainty, and showed higher stability in all ranges of predictive outcome probabilities.

Conclusion

We have compared several approaches that could be used to develop prediction models for rare diseases. Our findings highlight the recalibration mixture model as the optimal strategy if a population-level dataset is available. This approach offers the flexibility to incorporate additional predictors and informed prior probabilities, contributing to enhanced prediction accuracy for rare diseases. It also allows predictions without these additional tests, providing additional information on whether a patient should undergo further biomarker testing before genetic testing.
Anemia, hemoglobin concentration and cognitive function in the Longitudinal Ageing Study in India-Harmonized Diagnostic Assessment of Dementia (LASI-DAD) and the Health and Retirement Study
Authors: Winchester Laura M. , Newby Danielle , Ghose Upamanyu , Hu Peifeng , Green Hunter , Chien Sandy , Ranson Janice , Faul Jessica , Llewellyn David , Lee Jinkook , Bauermeister Sarah , Nevado-Holgado Alejo
Published: January 2024

Background

In India, anemia is widely researched in children and women of reproductive age, however, studies in older populations are lacking. Given the adverse effect of anemia on cognitive function and dementia this older population group warrants further study. The Longitudinal Ageing Study in India – Harmonized Diagnostic Assessment of Dementia (LASI-DAD) dataset contains detailed measures to allow a better understanding of anaemia as a potential risk factor for dementia.

Method

2,758 respondents from the LASI-DAD cohort, aged 60 or older, had a complete blood count measured from venous blood as well as cognitive function tests including episodic memory, executive function and verbal fluency. Linear regression was used to test the associations between blood measures (including anemia and hemoglobin concentration (g/dL)) with 11 cognitive domains. All models were adjusted for age and gender with the full model containing adjustments for rural location, years of education, smoking, region, BMI and population weights.

Results from LASI-DAD were validated using the USA-based Health and Retirement Study (HRS) cohort (n=5720) to replicate associations between blood cell measures and global cognition.

Results

In LASI-DAD, we showed an association between anemia and poor memory (p=0.0054). We found a positive association between hemoglobin concentration and ten cognitive domains tested (β=0.041-0.071, p<0.05). The strongest association with hemoglobin was identified for memory-based tests (immediate episodic, delayed episodic and broad domain memory, β=0.061-0.071, p<0.005). Positive associations were also shown between the general cognitive score and the other red blood count tests including mean corpuscular hemoglobin concentration (MCHC, β=0.06, p=0.0001) and red cell distribution width (RDW, β =-0.11, p<0.0001). In the HRS cohort, positive associations were replicated between general cognitive score and other blood count tests (Red Blood Cell, MCHC and RDW, p<0.05).

Conclusion

We have established in a large South Asian population that low hemoglobin and anaemia are associated with low cognitive function, therefore indicating that anaemia could be an important modifiable risk factor. We have validated this result in an external cohort demonstrating both the variability of this risk factor cross-nationally and its generalizable association with cognitive outcomes.
Evidence-based recommendations for gene-specific ACMG/AMP variant classification from the ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel
Authors: Parsons Michael T. , de la Hoya Miguel , Richardson Marcy E. , Tudini Emma , Anderson Michael , Berkofsky-Fessler Windy , Caputo Sandrine M. , Chan Raymond C. , Cline Melissa C. , Feng Bing-Jian , Fortuno Cristina , Gomez-Garcia Encarna , Hadler Johanna , Hiraki Susan , Holdren Megan , Houdayer Claude , Hruska Kathleen , James Paul , Karam Rachid , Leong Huei San , Martins Alexandra , Mensenkamp Arjen R. , Monteiro Alvaro N. , Nathan Vaishnavi , O’Connor Robert , Pedersen Inge Sokilde , Pesaran Tina , Radice Paolo , Schmidt Gunnar , Southey Melissa , Tavtigian Sean , Thompson Bryony A. , Toland Amanda E. , Turnbull Clare , Vogel Maartje J. , Weyandt Jamie , Wiggins George A.R. , Zec Lauren , Couch Fergus J. , Walker Logan C. , Vreeswijk Maaike P. G. , Goldgar David E. , Spurdle Amanda B.
Published: January 2024

The ENIGMA research consortium (https://enigmaconsortium.org/) develops and applies methods to determine clinical significance of variants in Hereditary Breast and Ovarian Cancer genes. An ENIGMABRCA1/2classification sub-group, originally formed in 2016 as a ClinGen external expert panel, evolved into a ClinGen internal Variant Curation Expert Panel (VCEP) to align with Federal Drug Administration recognized processes for ClinVar contributions.

The VCEP reviewed American College of Medical Genetics/Association of Molecular Pathology (ACMG/AMP) classification criteria for relevance to interpretingBRCA1andBRCA2variants. Statistical methods were used to calibrate evidence strength for different data types. Pilot specifications were tested on 40 variants, and documentation revised for clarity and ease-of-use.

The original criterion descriptions for 13 evidence codes were considered non-applicable or overlapping with other criteria. Scenario of use was extended or re-purposed for eight codes. Extensive analysis and/or data review informed specification descriptions and weights for all codes. Specifications were applied to pilot variants with pre-existing ClinVar classification as follows: 13 Uncertain Significance or Conflicting, 14 Pathogenic and/or Likely Pathogenic, and 13 Benign and/or Likely Benign. Review resolved classification for 11/13 Uncertain Significance or Conflicting variants, and retained or improved confidence in classification for the remaining variants.

Alignment of pre-existing ENIGMA research classification processes with ACMG/AMP classification guidelines highlighted several gaps in both the research processes and the baseline ACMG/AMP criteria. Calibration of evidence types was key to justify utility and strength of different evidence types for gene-specific application. The gene-specific criteria demonstrated value for improving ACMG/AMP-aligned classification ofBRCA1andBRCA2variants.
Evoked oscillatory cortical activity during acute pain: Probing brain in pain by transcranial magnetic stimulation combined with electroencephalogram
Authors: De Martino Enrico , Casali Adenauer , Casarotto Silvia , Hassan Gabriel , Nascimento Couto Bruno Andry , Rosanova Mario , Graven-Nielsen Thomas , de Andrade Daniel Ciampi
Published: January 2024

Temporal dynamics of local cortical rhythms during acute pain remain largely unknown. The current study used a novel approach based on transcranial magnetic stimulation combined with electroencephalogram (TMS-EEG) to investigate evoked-oscillatory cortical activity during acute pain. Motor (M1) and dorsolateral prefrontal cortex (DLPFC) were probed by TMS, respectively, to record oscillatory power (event-related spectral perturbation and relative spectral power) and phase synchronization (inter-trial coherence) by 63 EEG channels during experimentally induced acute heat pain in 24 healthy participants. TMS-EEG was recorded before, during, and after noxious heat (Acute Pain condition) and non-noxious warm (Control condition), delivered in a randomized sequence. The main frequency bands (α, β1, and β2) of TMS-evoked potentials after M1 and DLPFC stimulation were recorded close to the TMS coil and remotely. Cold and heat pain thresholds were measured before TMS-EEG. Over M1, Acute pain decreased α-band oscillatory power locally and α-band phase synchronization remotely in parietal-occipital clusters compared with non-noxious warm (all P<0.05). The remote (parietal-occipital) decrease in α-band phase synchronization during Acute Pain correlated with the cold (P=0.001) and heat pain thresholds (P=0.023) and to local (M1) α-band oscillatory power decrease (P=0.024). Over DLPFC, Acute Pain only decreased β1-band power locally compared with non-noxious warm (P=0.015). Thus, evoked-oscillatory cortical activity to M1 stimulation is reduced by acute pain in central and parietal-occipital regions and correlated with pain sensitivity, in contrast to DLPFC, which had only local effects. This finding expands the significance of α and β band oscillations and may have relevance for pain therapies.
“Embryonic piRNAs target horizontally transferred vertebrate transposons in assassin bugs”
Authors: Brito Tarcísio Fontenele , Cardoso Maira Arruda , Atinbayeva Nazerke , Brito Ingrid Alexandre de Abreu , da Costa Lucas Amaro , Iovino Nicola , Pane Attilio
Published: January 2024

Piwi proteins and the associated Piwi-interacting RNAs (piRNAs) coordinate a surveillance system that protects the animal genome from DNA damage induced by transposable element (TE) mobilization. While the pathway has been described in detail in the fruit flyDrosophila melanogaster,much less is known in more basal insects. Here, we investigated the adaptation of the piRNA pathway to horizontally transferred transposons (HTTs) in the assassin bugRhodnius prolixus, a primary vector of Chagas disease.Rhodniusacquired specific classes of HTTs by feeding on bats, opossums and squirrel monkeys. By analyzing the temporal dynamics of piRNA cluster expression and piRNA production during critical stages ofRhodniusdevelopment, we show that peak levels of ∼28 nt long piRNAs correlate with reduced HTT and resident TE expression primarily during embryogenesis. Strikingly, while resident TEs piRNAs seem to engage in a typical ping-pong amplification mechanism, sense and antisense HTT piRNAs instead overlap by ∼20 nt or do not display ping-pong signatures. These features are explained at least in part by the low number of HTT copies inserted into the piRNA clusters and might point to a non-canonical mechanism of biogenesis. Our data reveal that the piRNA, but not the siRNA pathway, responded to HTTs that were recently transferred from vertebrate tetrapods to a hematophagous insect of medical relevance.
Extracellular matrix signals promotes actin-dependent mitochondrial elongation and activity
Authors: Gatti Priya , Mukherjee Pritha , Talukdar Priyanka Dey , Freppel Wesley , Kanou Joseph , Chatel-Chaix Laurent , Chatterji Urmi , Germain Marc
Published: January 2024

Mitochondria are crucial metabolic organelles that are regulated by both intracellular and extracellular cues. The extracellular matrix (ECM) is a key component of the cellular environment that controls cellular behavior and metabolic activity. Here, we determined how ECM signalling regulates mitochondrial structure and activity. To distinguish mitochondrial regulation from the general survival cues generated by the ECM, we used breast cancer-derived spheres (mammospheres) because of their ability to grow in suspension culture in the absence of ECM. Using this system, we demonstrate that the association of mammospheres with the ECM results in dramatic mitochondrial elongation, along with enhanced mitochondrial respiration and ATP production. This remodeling occurs independently of DRP1 activity, but relies on integrin signaling and actin polymerization. Therefore, our findings demonstrate that ECM-driven actin polymerization plays a crucial role in remodeling mitochondrial networks to promote OXPHOS, which represents a vital step for migrating cells to enhance cellular adhesion and facilitate cell growth.
Transcriptomic Profile of Lin-Sca1+c-kit (LSK) cells in db/db mice with long-standing diabetes
Authors: Mahajan Neha , Luo Qianyi , Abhyankar Surabhi , Bhatwadekar Ashay D.
Published: January 2024

The Lin-Sca1+c-Kit+(LSK) fraction comprises multipotent hematopoietic stem cells (HSCs), vital to tissue homeostasis and vascular repair. While HSC homeostasis is impaired in diabetes, it is not known how chronic (>6 months) type 2 diabetes (T2D) alters the HSC transcriptome. Herein, we assessed the transcriptomic signature of HSCs in db/db mice employing mRNA and miRNA sequencing. We uncovered 2076 mRNAs and 35 miRNAs differentially expressed in db/db mice, including two novel miRNAs previously unreported in T2D. Further analysis of these transcripts showed a molecular shift with an increase in the pro-inflammatory cytokines and a decrease in anti-inflammatory cytokine expression. Also, pathway mapping unveiled inflammation and angiogenesis as one of the top pathways. These effects were reflected in bone marrow mobilopathy, retinal microglial inflammation, and neurovascular deficits in db/db mice. In conclusion, our study highlights that chronic diabetes alters HSCs’ at the transcriptomic level, thus potentially contributing to overall homeostasis and neurovascular deficits of diabetes, such as diabetic retinopathy.

Highlights

Bone marrow mobilopathy with long-standing diabetes

Switch in LSK transcriptomic profile towards inflammation and angiogenesis

Discovered 35 miRNAs, including two novel miRNAs, miR-3968 and miR-1971

LSK dysfunction reflected in inflammation and neurovascular deficits of the retina
Cell surface morphology mimicking nano-bio platform for immune cell stimulation
Authors: Varghese Beena , González-Navarro José Alfredo , Guerra Valentino Libero Pio , Faizulina Margarita , Artemieva Daria , Chum Tomáš , Ramakrishna Tejaswini Rama Bangalore , Cebecauer Marek , Kovaříček Petr
Published: January 2024

Studying the complex realm of cellular communication and interactions by fluorescence microscopy requires sample fixation on a transparent substrate. To activate T cells, which are pivotal in controlling the immune system, it is important to present the activating antigen in a spatial arrangement similar to the nature of the antigen-presenting cell, including the presence of ligands on microvilli. Similar arrangement is predicted for some other immune cells. In this work, immune cell-stimulating platform based on nanoparticle-ligand conjugates have been developed using a scalable, affordable, and broadly applicable technology, which can be readily deployed without the need for state-of-the-art nanofabrication instruments. The validation of surface biofunctionalization was performed by combination of fluorescence and atomic force microscopy techniques. We demonstrate that the targeted system serves as a biomimetic scaffold on which immune cells make primary contact with the microvilli-mimicking substrate and exhibit stimulus-specific activation.
Balancing safety and efficiency in human decision making
Authors: Mahajan Pranav , Tong Shuangyi , Lee Sang Wan , Seymour Ben
Published: January 2024

The safety-efficiency dilemma describes the problem of maintaining safety during efficient exploration and is a special case of the exploration-exploitation dilemma in the face of potential dangers. Conventional exploration-exploitation solutions collapse punishment and reward into a single feedback signal, whereby early losses can be overcome by later gains. However, the brain has a separate system for Pavlovian fear learning, suggesting a possible computational advantage to maintaining a specific fear memory during exploratory decision-making. In a series of simulations, we show this promotes safe but efficient learning and is optimised by arbitrating Pavlovian avoidance of instrumental decision-making according to uncertainty. We provide a basic test of this model in a simple human approach-withdrawal experiment, and show that this flexible avoidance model captures choice and reaction times. These results show that the Pavlovian fear system has a more sophisticated role in decision-making than previously thought, by shaping flexible exploratory behaviour in a computationally precise manner.
Structural flexibility of Toscana virus nucleoprotein in the presence of a single-chain camelid antibody
Authors: Papageorgiou Nicolas , Baklouti Amal , Lichière Julie , Desmyter Aline , Canard Bruno , Coutard Bruno , Ferron François
Published: January 2024

Phenuiviridae nucleoprotein is the main structural and functional component of the viral cycle, protecting the viral RNA and mediating the essential replication/transcription processes. The nucleoprotein (N) binds the RNA using its globular core and polymerizes through the N-terminus, which is presented as a highly flexible arm, as demonstrated in this article. The nucleoprotein exists in an `open' or a `closed' conformation. In the case of the closed conformation the flexible N-terminal arm folds over the RNA-binding cleft, preventing RNA adsorption. In the open conformation the arm is extended in such a way that both RNA adsorption and N polymerization are possible. In this article, single-crystal X-ray diffraction and small-angle X-ray scattering were used to study the N protein of Toscana virus complexed with a single-chain camelid antibody (VHH) and it is shown that in the presence of the antibody the nucleoprotein is unable to achieve a functional assembly to form a ribonucleoprotein complex.
Femininity penalties and rewards: obstacles and opportunities for Chinese female entrepreneurs in gender-segregated industries
Authors: LI Lulu
Published: January 2024

Purpose

This study aims to answer two questions: (a) what obstacles and opportunities do Chinese female entrepreneurs face when doing business? And (b) how do they negotiate their entrepreneurial careers and gender identities in different gender-segregated markets?

Design/methodology/approach

This study uses qualitative research methods of participant observation and in-depth interviews with 41 female entrepreneurs in China and the theoretical lenses of gender role theory and doing gender in entrepreneurship.

Findings

The study findings reveal that Chinese female entrepreneurs face different obstacles and opportunities in gender-segregated industries. Their experiences vary in industries that are mainly occupied by males and females. On the one hand, women in female-dominated industries may be supported by a feminine working environment that is coherent with their domestic roles. However, they may also be questioned on the cultural impurity implied in some industries, which harms their class-based feminine virtue. On the other hand, women in male-dominated industries may be challenged and marginalized due to their gender. However, some find ways to turn the disadvantaged feminine characters into favourable conditions and break out of the stereotypical gender constraints in doing business.

Originality/value

This study contributes to the literature on gender and entrepreneurship in general. More specifically, it contributes to the study of doing gender in gender-segregated markets, and it also illustrates women’s gendered opportunities and constraints in Chinese society that are affected by the long-lasting traditional gender norms.
Forging an entrepreneur – gendered ideas and ideals
Authors: Roos Annie , Pettersson Katarina
Published: January 2024

Purpose

The purpose of this study is to investigate the gendered ideas and ideals attached to an imagined ideal Entrepreneur in a post-industrial rural community in Sweden. While research has not yet clearly explained how the ideal entrepreneur is constructed, the result, i.e. the gendered representations of entrepreneurs, is well-researched. Previous results indicate a prevalent portrayal of entrepreneurship as a predominantly masculine construct characterised by qualities such as self-made success, confidence and assertiveness.

Design/methodology/approach

Ethnographic fieldwork was conducted in a community that is attempting to re-brand itself through garden tourism. Through inductive reasoning, this study analyses the gendered ideas and ideals regarding the community’s imagined ideal Entrepreneur who is to help the community solve its problems.

Findings

This study finds that the community forges the Entrepreneur into an imagined masculine ideal as holy, a saviour and a god and is replacing its historical masculine ironmaster with a masculine Entrepreneur. This study develops forging as a metaphor for the construction of the masculine ideal Entrepreneur, giving the community, rather than the entrepreneur himself, a voice as constructors. From social constructionism, this study emphasises how gendered ideas and ideals are shaped not only by the individual realities but more so in the reciprocal process by the realities of others.

Originality/value

The metaphor of forging adds an innovative theoretical dimension to the feminist constructionist approach and suggests focusing on how the “maleness” of entrepreneurship is produced and reproduced in the local. Previously, light has been shed on how male entrepreneurs perform their identities collectively; the focus of this study is on the social construction of this envisioned Entrepreneur within a rural community. The development of forging thus contributes as a way of analysing entrepreneurship in place. The choice of an ethnographic study allowed the authors to be a part of the real-life world of community members, providing rich data to explore entrepreneurship and gender.
Learning from Habermas and Machiavelli: a thought experiment in supply chain management
Authors: Bille Amanda
Published: January 2024

Purpose

The purpose of this paper is to show the benefits of bridging the gap between supply chain management (SCM) and political philosophy to challenge the underlying assumptions about SCM concepts and open doors to novel theory building.

Design/methodology/approach

A thought experiment is conducted to illustrate how the two philosophers Niccolò Machiavelli and Jürgen Habermas would tackle sustainability issues in coffee supply chains from a research perspective. The thought experiment is carried out using data from 30 semi-structured interviews with actors from the coffee industry. Supplementing the thought experiment with empirical insights allows for a deeper understanding of supply chain dynamics and how these are impacted by the application of the philosophical viewpoints.

Findings

The research stresses the importance of SCM scholars being aware of the underlying assumptions of their research, as these have a remarkable impact on theory building. A combination of empirical insights and philosophical understandings makes it possible to reflect on the underlying concepts of SCM, providing suggestions for reimagining SCM.

Originality/value

The contribution of the research is twofold. First, the paper presents an original view on SCM, as the thought experiment is introduced as an approach to better understand SCM concepts. By challenging the underlying assumptions with political philosophy, researchers will be better equipped to address grand challenges in the twenty-first century. Second, this is exemplified by the case study of the coffee supply chain, which provides the reader with insight into the dynamics of supply chains with prevalent power differences.
Network of public equity funds and investment performance in South Korea
Authors: Kim Yongwon , Song Inwook , Park Young Kyu
Published: January 2024

Using overlapped portfolio data on public equity funds in Korea, the authors construct several types of fund-stock weighted bipartite networks and measure fund network centrality. The authors also examine the relationship between network centrality and fund investment performance. The authors' results are three-fold. First, the authors find that the fund centrality of the network in which funds and stocks are connected based on the most active investing behavior positively affects the fund performance. Second, the funds with a high centrality level based on the same network generate higher returns by holding stocks with high value uncertainty. Third, the authors find that fund centrality is not associated with herd behavior. Based on these results, the authors argue that fund centrality is a proxy of information advantage and skill of fund managers. The authors' paper shows that network analysis could be a new way to identify funds with better performance and measure the skill and information advantage to construct an optimal portfolio.
Unraveling the impact of COVID-19 pandemic on foreign direct investment and its determinants: empirical insights from SAARC countries
Authors: Firdos Rizwan , Subhan Mohammad , Mansuri Babu Bakhsh , Alharthi Majed
Published: January 2024

Purpose

This paper aims to unravel the impact of post-pandemic COVID-19 on foreign direct investment (FDI) and its determinants in the South Asian Association for Regional Cooperation (SAARC) Countries.

Design/methodology/approach

The study utilized four macroeconomic variables includes growth domestic product growth rate (GDPG), inflation rate (IR), exchange rate (ER), and unemployment rate (UR) to assess their impact on post-pandemic FDI, along with two variables control of corruption (CC) and political stability (PS) to measure the influence of good governance. Random effects, fixed effects, cluster random effects, cluster fixed effects and generalized method of moments (GMM) models were applied to a balanced panel dataset comprising eight SAARC countries over the period 2010–2021. To identify the random trend component in each variable, three renowned unit root tests (Levin, Lin and Chu LLC, Im-Pesaran-Shin IPS and Augmented Dickey-Fuller ADF) were used, and co-integration associations between variables were verified through the Pedroni and Kao approaches. Data analysis was performed using STATA 17 software.

Findings

The major findings revealed that the variables have an order of integration at the first difference I (1). Nonetheless, this situation suggests the possibility of a long-term link between the series. And the main results of the findings show that the coefficients of GDPG, CC and PS are positive and significant in the long run, showing that these variables boosted FDI inflows in the SAARC region as they are significantly positively linked to FDI inflows. Similarly, the coefficients of UR, IR, ER and COVID-19 are negative and significant.

Practical implications

By identifying the specific impacts of the post-pandemic FDI and its determinants, governments and policymakers can formulate targeted policies and measures to mitigate the adverse effects and enhance investment attractiveness. Additionally, investors can gain a deeper understanding of the risk factors and adapt their strategies accordingly, ensuring resilience and sustainable growth. Finally, this paper adds value to the literature on the post-pandemic impact on FDI inflows in the SAARC region.

Originality/value

This paper is the first attempt to trace the impact of COVID-19 on Foreign Direct Investment and its determinants in the SAARC Countries. Most of the previous studies were analytical in nature and, if empirical, excluded some countries due to the unviability of the data set. This study includes all the SAARC member countries, and all variables' data are completely available. There is still a lack of empirical studies related to the SAARC region; this study attempts to fill the gap.
Measuring novice auditor orientation and its impact on judgment
Authors: van Beest Ferdy , Pinsker Robert
Published: January 2024

Purpose

The purpose of this study is to construct and test a new measure of auditor orientation using two audit quality-related tasks.

Design/methodology/approach

The sample consists of 66 Dutch and US graduate auditing students. Participants complete two tasks: one involving a lease classification and another, supplemental experiment involving a contingent liability judgment. The purpose is to construct a new measure for rules-based/ principles-based orientation. Rigorous, psychometric testing confirms that parts of tolerance for ambiguity (TOA) and need for cognition (NFC), together, form a new construct the authors identify as auditor orientation. The authors next conduct a main and supplemental experiment with novice auditor participants from both the USA and the Netherlands.

Findings

The authors begin with rigorous, psychometric testing using participants from the USA and the Netherlands. The resulting 10-item scale combines parts of TOA and NFC to reflect auditor orientation. The common themes across scale items are high (low) adaptability to complexity and a substance-over-form (form-over-substance) preference for principles-oriented (PO) (rules-oriented [RO]) auditors. Conducting two experiments, results from two distinct tasks confirm our research question; novice auditors classified as RO (PO) are more (less) likely to recommend a more aggressive/client-favorable disclosure judgment.

Originality/value

Auditor orientation (i.e. rules or principles) has a significant impact on the application of rules-based or principles-based standards. How the standards are applied, therefore, influences auditor decision-making and thus audit quality. However, there is a paucity of auditor orientation research to date, including a validated measure. The study contributes a new measure for future research in the related accounting standards and audit quality literatures, while also identifying a potentially important construct in auditor training.
Medicare, Medicaid, and dual enrollment for adults with intellectual and developmental disabilities
Authors: Rubenstein Eric , Tewolde Salina , Levine A. Alex , Droscha Lillian , Meyer Rachel Midori , Michals Amy , Skotko Brian
Published: January 2024

Objective

Given high rates of un‐ and underemployment among disabled people, adults with intellectual and developmental disabilities rely on Medicaid, Medicare, or both to pay for healthcare. Many disabled adults are Medicare eligible before the age of 65 but little is known as to why some receive Medicare services while others do not. We described the duration of Medicare enrollment for adults with intellectual and developmental disabilities in 2019 and then compared demographics by enrollment type (Medicare‐only, Medicaid‐only, dual‐enrolled). Additionally, we examined the percent in each enrollment type by state, and differences in enrollment type for those with Down syndrome.

Data Sources and Study Setting

2019 Medicare and Medicaid claims data for all adults (≥18 years) in the US with claim codes for intellectual disability, Down syndrome, or autism at any time between 2011 and 2019.

Study Design

Administrative claims cohort.

Data Collection and Abstraction Methods

Data were from the Transformed Medicaid Statistical Information System Analytic Files and Medicare Beneficiary Summary files.

Principle Findings

In 2019, Medicare insured 582,868 adults with identified intellectual disability, autism, or Down syndrome. Of 582,868 Medicare beneficiaries, 149,172 were Medicare only and 433,396 were dual‐enrolled. Most Medicare enrollees were enrolled as child dependents (61.5%) Medicaid‐only enrollees (N = 819,256) were less likely to be white non‐Hispanic (58.5% white non‐Hispanic vs. 72.9% white non‐Hispanic in dual‐enrolled), more likely to be Hispanic (19.6% Hispanic vs. 9.2% Hispanic in dual‐enrolled) and were younger (mean 34.2 years vs. 50.5 years dual‐enrolled).

Conclusion

There is heterogeneity in public insurance enrollment which is associated with state and disability type. Action is needed to ensure all are insured in the program that works for their healthcare needs.