bluuebunny/crossref_metadata_2025 huggingface dataset:
Mucus production, host-microbiome interactions, hormone sensitivity, and innate immune responses modeled in human cervix chips
Authors: Izadifar Zohreh , Cotton Justin , Chen Siyu , Bustos Nicole A. , Horvath Viktor , Stejskalova Anna , Wu Chloe , Gulati Aakanksha , LoGrande Nina T. , Budnik Bogdan , Shahriar Sanjid , Doherty Erin R. , Xie Yixuan , To Tania , Gilpin Sarah E. , Sesay Adama M. , Goyal Girija , Ribbeck Katharina , Lebrilla Carlito , Ingber Donald E.
Published: February 2023

Modulation of mucus production by the human endo– and ecto-cervical epithelium by steroid hormones and associated interactions with commensal microbiome play a central role in the physiology and pathophysiology of the female reproductive tract. However, most of our knowledge about these interactions is based on results from animal studies orin vitromodels that fail to faithfully mimic the mucosal environment of the human cervix. Here we describe microfluidic organ-on-a-chip (Organ Chip) models of the human cervical mucosa that recreate the cervical epithelial-stromal interface with a functional epithelial barrier and produce abundant mucus that has compositional, biophysical, and hormone-responsive properties similar to the living cervix. Application of continuous fluid flow to chips lined with primary human cervical epithelial cells from a commercial source that contained a mixture of primary human ecto– and endo-cervical epithelial cells promoted preferential expression of the ecto-cervical phenotype, whereas use of periodic flow including periods of stasis induced endo-cervical specialization. When the periodic flow Cervix Chips were co-cultured with livingLactobacillus crispatusandGardnerella vaginalisbacterial communities to respectively mimic the effects of human host interactions with optimal (healthy) or non-optimal (dysbiotic) microbiome associated with an ascending infection in the female reproductive tract, significant differences in tissue innate immune responses, barrier function, cell viability and protein profile, and mucus composition were detected reminiscent of those observedin vivo. Thus, these Organ Chip models of human cervix provide a physiologically relevant experimentalin vitromodel to study cervical mucus physiology and its role in human host-microbiome interactions as well as a potential preclinical testbed for development of therapeutic interventions to enhance women’s health.
Targeting DNA2 Overcomes Metabolic Reprogramming in Multiple Myeloma
Authors: Thongon Natthakan , Ma Feiyang , Lockyer Pamela , Baran Natalia , Liu Jintan , Jackson Christopher , Rose Ashley , Wildeman Bethany , Marchesini Matteo , Marchica Valentina , Storti Paola , Giuliani Nicola , Ganan-Gomez Irene , Adema Vera , Qing Yun , Ha Min , Fonseca Rodrigo , Class Caleb , Tan Lin , Kanagal-Shamanna Rashmi , Nolasco David Berrios , Cerchione Claudio , Montalban-Bravo Guillermo , Santoni Andrea , Bueso-Ramos Carlos , Konopleva Marina , Lorenzi Philip , Garcia-Manero Guillermo , Manasanch Elisabeth , Viale Andrea , Chesi Marta , Colla Simona
Published: February 2023

DNA damage resistance is a major barrier to effective DNA-damaging therapy in multiple myeloma (MM). To discover novel mechanisms through which MM cells overcome DNA damage, we investigated how MM cells become resistant to antisense oligonucleotide (ASO) therapy targeting ILF2, a DNA damage regulator that is overexpressed in 70% of MM patients whose disease has progressed after standard therapies have failed. Here, we show that MM cells undergo an adaptive metabolic rewiring and rely on oxidative phosphorylation to restore energy balance and promote survival in response to DNA damage activation. Using a CRISPR/Cas9 screening strategy, we identified the mitochondrial DNA repair protein DNA2, whose loss of function suppresses MM cells’ ability to overcome ILF2 ASO−induced DNA damage, as being essential to counteracting oxidative DNA damage and maintaining mitochondrial respiration. Our study revealed a novel vulnerability of MM cells that have an increased demand for mitochondrial metabolism upon DNA damage activation.

STATEMENT OF SIGNIFICANCE

Metabolic reprogramming is a mechanism through which cancer cells maintain survival and become resistant to DNA-damaging therapy. Here, we show that targeting DNA2 is synthetically lethal in myeloma cells that undergo metabolic adaptation and rely on oxidative phosphorylation to maintain survival after DNA damage activation.
Air channels create a directional light signal to regulate hypocotyl phototropism
Authors: Nawkar Ganesh M. , Legris Martina , Goyal Anupama , Schmid-Siegert Emanuel , Fleury Jérémy , Mucciolo Antonio , De Bellis Damien , Schüler Andreas , Fankhauser Christian
Published: February 2023

In light-limiting conditions, aerial organs of most plants reorient their growth towards the light to improve photosynthesis, through a process known as phototropism1-3. The blue light receptors phototropin control phototropic responses through light-induced protein kinase activity4. Current models posit that asymmetric activation of these sensory receptors across a unilaterally illuminated organ leads to asymmetric distribution of the growth hormone auxin ultimately leading to growth re-orientation4,5. However, the tissue properties required to generate a light gradient across the stem triggering phototropism remain unclear1. Here we show that inter-cellular air channels6,7are required for an efficient phototropic response. These channels enhance light scattering (refraction and reflection) in Arabidopsis hypocotyls thereby enhancing the light gradient across the photo-stimulated organ. We identify an embryonically expressed ABC transporter that is required to keep air in inter-cellular spaces in seedlings and for efficient phototropism. Our work suggests that this transporter shapes cell wall properties to maintain air between cells. Moreover, we establish the functional importance of inter-cellular air channels in the hypocotyl for phototropism.
A Comparison of fMRI Data-Derived and Physiological Data-Derived Methods for Physiological Noise Correction
Authors: Krentz Martin , Tutunji Rayyan , Kogias Nikos , Mahadevan Hariharan Murali , Reppmann Zala C. , Krause Florian , Hermans Erno J.
Published: February 2023

Physiological noise has been shown to have a large impact on the quality of functional MRI data, especially in areas close to fluid-filled cavities and arteries, such as the brainstem. Commonly, physiological recordings during scanning are transformed with methods such as RETROICOR and used as nuisance regressors in general linear models to remove variance associated with cardiac and respiratory cycles from the data. In contrast, modern pre-processing pipelines such as fMRIPrep, have created easy access to streamlined data-driven noise reduction methods such as aCompCor and ICA-AROMA. In combination, these methods have shown efficacy in correcting for motion, scanner as well as physiological artifacts. Given the ease of usability, it has to be questioned, whether there is any added benefit to applying logistically demanding methods such as RETROICOR. To answer this question, we applied RETROICOR, ICA-AROMA and aCompCor to a resting-state data set and compared variance explained by the respective methods and improvements in temporal signal-to-noise ratio throughout different regions of interest in the brain. In line with previous literature, RETROICOR significantly explains variance throughout the brain with peaks around areas of strong cardiac pulsations. ICA-AROMA and aCompCor largely account for the same variance. Nonetheless, RETROICOR retains unique explanatory power in individual participants. Further analysis points towards a pattern of unreliability of ICA-AROMA and aCompCor to consistently remove physiological noise across recordings, which is compensated by RETROICOR. While some of this inconsistency could be attributed to misclassifications in the noise selection models of ICA-AROMA, most is likely the consequence of secondary factors such as fMRI sequence parameters (e.g. long TR) limiting the efficiency of aCompCor and ICA-AROMA. Thus, it is advisable to additionally apply RETROICOR, especially when assuming regionally high levels of physiological noise.
Raspberry plant stress detection using hyperspectral imaging
Authors: Williams Dominic , Karley Alison , Britten Avril , McCallum Susan , Graham Julie
Published: February 2023

Monitoring plant responses to stress is an ongoing challenge for crop breeders, growers and agronomists. The measurement of below ground stress is particularly challenging as plants do not always show visible signs of stress in the above ground organs, particularly at early stages. Hyperspectral imaging is a technique that could be used to overcome this challenge if associations between plant spectral data and specific stresses can be determined. In this study, three genotypes of red raspberry plants grown under controlled conditions in a glasshouse were subjected to below ground biotic stresses (root pathogenPhytophthora rubiand root herbivoreOtiorhynchus sulcatus) or abiotic stress (soil water availability) and regularly imaged using hyperspectral cameras over this period. Significant differences were observed in plant biophysical traits (canopy height and leaf dry mass) and canopy reflectance spectrum between the three genotypes and the imposed stress treatments. The ratio of reflectance at 469nm and 523nm showed a significant genotype-by-treatment interaction driven by differential genotypic responses to thePhytophthora rubitreatment. This indicates that spectral imaging can be used to identify variable plant stress responses in raspberry plants.
Phenotypic plasticity and genetic differentiation drive troglomorphic character development in European cave loach
Authors: Behrmann-Godel Jasminca , Roch Samuel , Böhm Alexander , Jolles Jolle , Brinker Alexander
Published: February 2023

Using a cross-fostering experiment, we provide evidence for the contribution of both genetic differentiation and phenotypic plasticity to troglomorphic character development in the recently discovered cave form ofBarbatula barbatula, an evolutionarily young lineage and first cavefish described in Europe, the northernmost record. We established reproducing populations of cave- and surface-dwelling loaches to produce cave, surface, and hybrid offspring and reared the F1 fish in a common garden setting in total darkness (DD) to simulate cave conditions as well as under the natural photoperiod (DL). We observed significant differences in the occurrence and extent of typical troglomorphic target characters among the offspring groups. Regardless of rearing conditions, cave fish exhibited smaller eyes, lighter body coloration, longer barbels, and larger olfactory epithelium than seen in surface fish. Hybrids in both rearing conditions generally showed an intermediate level of these traits. Surface and hybrid DD fish differed from the DL groups, resembling the cave fish phenotype in several traits, including eye size and body pigmentation. In contrast, cave and hybrid DL fish groups resembled surface fish phenotypes. Results confirmed that troglomorphic traits arise from heritable genetic differentiation of cave from surface forms and that phenotypic plasticity contributes to the process of adaptation to novel light conditions.
Bacillus subtilisengineered for aerospace medicine: a platform for off-planet production of pharmaceutical peptides
Authors: Vallota-Eastman Alec , Bui Cynthia , Williams Philip M. , Valentine David L. , Loftus David , Rothschild Lynn
Published: February 2023

1.

Biologics, such as pharmaceutical peptides, have notoriously short shelf lives, insufficient for long-duration space flight missions to the Moon or Mars. To enable the sustainable presence of humans on the Moon or Mars, we must develop methods for on-site production of pharmaceutical peptides in space, a concept we callAstropharmacy. Here, we present proof-of-concept for the first step needed: a low-mass system for pharmaceutical production designed to be stable in space. To demonstrate feasibility, we engineered strains of the space-hardy spore-forming bacterium,Bacillus subtilis, to secrete two pharmaceutical peptides important for astronaut health: teriparatide (an anabolic agent for combating osteoporosis) and filgrastim (an effective countermeasure for radiation-induced neutropenia). We found that the secretion peptides from thewalMandyoqHgenes ofB. subtilis168 worked well for secreting teriparatide and filgrastim, respectively. In consideration of the TRISH challenge to produce a dose equivalent in 24 hours, dried spores of our engineered strains were used to produce 1 dose equivalent of teriparatide from a 2 mL culture and 1 dose equivalent of filgrastim from 52 mL of culture in 24 hours. Further optimization of strain growth conditions, expression conditions, and promoter sequences should allow higher production rates to be achieved. These strains provide the template for future optimization efforts and address the first step in theAstropharmacy, capable of on-site production, purification, and processing of biopharmaceutical compounds in platforms amenable for use in space.
Mass Spectrometry Reveals that Oxysterols are Secreted from Non-Alcoholic Fatty Liver Disease Induced Organoids
Authors: Kømurcu Kristina Sæterdal , Wilhelmsen Ingrid , Thorne James L , Karl Krauss Stefan Johannes , Haakon Wilson Steven Ray , Aizenshtadt Aleksandra , Røberg-Larsen Hanne
Published: February 2023

Oxysterols are potential biomarkers for liver metabolism that are altered under disease conditions such as non-alcoholic fatty liver disease (NAFLD). We here apply sterolomics to organoids used for disease modeling of NAFLD. Using liquid chromatography-mass spectrometry with on-line sample clean-up and enrichment, we establish that liver organoids produce and secrete oxysterols. We find elevated levels of 26-hydroxycholesterol, an LXR agonist and the first oxysterol in the acidic bile acid synthesis, in medium from steatotic liver organoids compared to untreated organoids. Other upregulated sterols in medium from steatotic liver organoids are dihydroxycholesterols, such as 7α,26–dihydroxycholesterol, and 7α,25-dihydroxycholesterol. Through 26-hydroxycholesterol exposure to human stem cell-derived hepatic stellate cells, we observe a trend of expressional downregulation of the pro-inflammatory cytokine CCL2, suggesting a protective role of 26-hydroxycholesterol during early-phased NAFLD disease development. Our findings support the possibility of oxysterols serving as NAFLD indicators, demonstrating the usefulness of combining organoids and mass spectrometry for disease modeling and biomarker studies.

Graphical abstract
Real-time monitoring of cell surface protein arrival with split luciferases
Authors: Fischer Alexandra A.M. , Baaske Julia , Römer Winfried , Weber Wilfried , Thuenauer Roland
Published: February 2023

Each cell in a multicellular organism permanently adjusts the concentration of its cell surface proteins. In particular, epithelial cells tightly control the number of carriers, transporters and cell adhesion proteins at their plasma membrane. However, the sensitively measuring the cell surface concentration of a particular protein of interest in live cells and in real time represents a considerable challenge.

Here, we introduce a novel approach based on split luciferases, which uses one luciferase fragment as tag on the protein of interest and the second fragment as supplement to the extracellular medium. Once the protein of interest arrives at the cell surface, the luciferase fragments complement and generate luminescence. We compared the performance of split Gaussia luciferase and split Nanoluciferase by using a system to synchronize biosynthetic trafficking with conditional aggregation domains. The best results were achieved with split Nanoluciferase, for which luminescence increased more than 6000-fold upon recombination. Furthermore, we showed that our approach can separately detect and quantify the arrival of membrane proteins at the apical and basolateral plasma membrane in single polarized epithelial cells by detecting the luminescence signals with a microscope, thus opening novel avenues for characterizing the variations in trafficking in individual epithelial cells.

Synopsis

We present here a novel method to determine the arrival of a membrane protein of interest at the cell surface in real time and with sufficient sensitivity to achieve single-cell resolution. This allows measuring detailed kinetics of plasma membrane trafficking and thus to detect also minor changes in protein sorting and intracellular trafficking. Furthermore, the single-cell sensitivity of the method will enable to systematically characterize variations in trafficking between neighboring cells within a multicellular organism.
Arsenic is a potent co-mutagen of ultraviolet light
Authors: Speer Rachel M. , Nandi Shuvro P. , Cooper Karen L. , Zhou Xixi , Yu Hui , Guo Yan , Hudson Laurie G. , Alexandrov Ludmil B. , Liu Ke Jian
Published: February 2023

Environmental co-exposures are widespread and are major contributors to carcinogenic mechanisms. Two well-established environmental agents causing skin cancer are ultraviolet radiation (UVR) and arsenic. Arsenic is a known co-carcinogen that enhances UVR’s carcinogenicity. However, the mechanisms of arsenic co-carcinogenesis are not well understood. In this study, we utilized primary human keratinocytes and a hairless mouse model to investigate the carcinogenic and mutagenic properties of co-exposure to arsenic and UVR.In vitroandin vivoexposures revealed that, on its own, arsenic is neither mutagenic nor carcinogenic. However, in combination with UVR, arsenic exposure has a synergistic effect leading to an accelerated mouse skin carcinogenesis as well as to more than 2-fold enrichment of UVR mutational burden. Notably, mutational signature ID13, previously found only in UVR-associated human skin cancers, was observed exclusively in mouse skin tumors and cell lines jointly exposed to arsenic and UVR. This signature was not observed in any model system exposed purely to arsenic or purely to UVR, making ID13 the first co-exposure signature to be reported using controlled experimental conditions. Analysis of existing genomics data from basal cell carcinomas and melanomas revealed that only a subset of human skin cancers harbor ID13 and, consistent with our experimental observations, these cancers exhibited an elevated UVR mutagenesis. Our results provide the first report of a unique mutational signature caused by a co-exposure to two environmental carcinogens and the first comprehensive evidence that arsenic is a potent co-mutagen and co-carcinogen of UVR. Importantly, our findings suggest that a large proportion of human skin cancers are not formed purely due to UVR exposure but rather due to a co-exposure of UVR and other co-mutagens such as arsenic.
The contributions of DNA accessibility and transcription factor occupancy to enhancer activity during cellular differentiation
Authors: Long Trevor , Bhattacharyya Tapas , Repele Andrea , Naylor Madison , Nooti Sunil , Krueger Shawn , Manu
Published: February 2023

The upregulation of gene expression by enhancers depends upon the interplay between the binding of sequence-specific transcription factors (TFs) and DNA accessibility. DNA accessibility is thought to limit the ability of TFs to bind to their sites, while TFs can increase accessibility to recruit additional factors that upregulate gene expression. Given this interplay, the causative regulatory events underlying the modulation of gene expression during cellular differentiation remain unknown for the vast majority of genes. We investigated the binding-site resolution dynamics of DNA accessibility and the expression dynamics of the enhancers of an important neutrophil gene,Cebpa, during macrophage-neutrophil differentiation. Reporter genes were integrated in a site-specific manner in PUER cells, which are progenitors that can be differentiated into neutrophils or macrophagesin vitroby activating the pan-leukocyte TF PU.1. Time series data show that two enhancers upregulate reporter expression during the first 48 hours of neutrophil differentiation. Surprisingly, there is little or no increase in the total accessibility, measured by ATAC-Seq, of the enhancers during the same time period. Conversely, total accessibility peaks 96 hrs after PU.1 activation—consistent with its role as a pioneer—but the enhancers do not upregulate gene expression. Combining deeply sequenced ATAC-Seq data with a new bias-correction method allowed the profiling of acces-sibility at single-nucleotide resolution and revealed protected regions in the enhancers that match all previously characterized TF binding sites and ChIP-Seq data. Although the accessibility of most positions does not change during early differentiation, that of positions neighboring TF binding sites, an indicator of TF occupancy, did in-crease significantly. The localized accessibility changes are limited to nucleotides neighboring C/EBP-family TF binding sites, showing that the upregulation of enhancer activity during early differentiation is driven by C/EBP-family TF binding. These results show that increasing the total accessibility of enhancers is not sufficient for upregulating their activity and other events such as TF binding are necessary for upregulation. Also, TF binding can cause upregulation without a perceptible increase in total accessibility. Finally, this study demonstrates the feasibility of comprehensively mapping individual TF binding sites as footprints using high coverage ATAC-Seq and inferring the sequence of events in gene regulation by combining with time-series gene expression data.
Machine learning investigation of gene expression datasets revealsTP53mutant-like AML with wild typeTP53and poor prognosis
Authors: Lee Yoonkyu , Baughn Linda B. , Myers Chad L. , Sachs Zohar
Published: February 2023

Acute myeloid leukemia (AML) withTP53mutations (TP53Mut) has poor clinical outcomes with 1-year survival rates of less than 10%. We investigated whether this AML subtype harbors a distinct gene expression profiling (GEP), what this GEP reveals aboutTP53MutAML pathophysiology, and whether this GEP is prognostic inTP53wild type (TP53WT) AML.

We applied a supervised machine-learning approach to assess whether a uniqueTP53MutGEP could be detected. Using the BEAT-AML dataset, we randomly divided the samples into training and testing datasets, while the TCGA dataset was reserved as a validation dataset. We trained a ridge regression machine learning model to classifyTP53MutandTP53WTcases. This model was highly accurate in distinguishingTP53MutversusTP53WTcases in both the test and validation data sets. Additionally, we noted a cohort ofTP53WTsamples with high ridge regression scores and poor overall survival, suggesting share clinical and GEP features withTP53MutAML. We defined theseTP53WTsamples asTP53mutant-like (TP53Mut-like) AMLs. We trained a second ridge regression model to specifically detectTP53Mut-like samples in the BEAT AML dataset and found that TCGA data also harborsTP53Mut-like samples. TheTP53Mut-like samples in the TCGA also have a worse OS rate thanTP53WTcases. Using drug sensitivity data from 122 small molecules in the BEAT AML dataset, we foundTP53Mut-like AMLs have distinct drug sensitivity patterns compared toTP53WT. Finally, we identified a 25 gene signature that can identifyTP53Mut-like cases. This signature could be used clinically to identify this novel subset of poor-prognosis AML.
Membrane buckling and the determination of Gaussian curvature modulus
Authors: Wang Mei-Ting , Ma Rui , Wu Chen-Xu
Published: February 2023

Biological membranes are able to exhibit various morphology due to the fluidity of the lipid molecules within the monolayers. The shape transformation of membranes has been well described by the classical Helfrich theory, which consists only a few phenomenological parameters, including the mean and the Gaussian curvature modulus. Though various methods have been proposed to measure the mean curvature modulus, determination of the Gaussian curvature modulus remains difficult both in experiments and in simulation. In this paper we study the buckling process of a rectangular membrane and a circular membrane subject to compressive stresses and under different boundary conditions. We find that the buckling of a rectangular membrane takes place continuously, while the buckling of a circular membrane can be discontinous depending on the boundary conditions. Furthermore, our results show that the stress-strain relationship of a buckled circular membrane can be used to effectively determine the Gaussian curvature modulus.
Identifying High Priority Ethical Challenges for Precision Emergency Medicine - A Nominal Group Study
Authors: Rose Christian , Shearer Emily , Woller Isabela , Foster Ashley , Ashenburg Nicholas , Kim Ireh L. , Newberry Jennifer
Published: February 2023

OBJECTIVE

Precision medicine is a rapidly progressing avenue to providing the right care to the right patient at the right time and spans all medical fields and specialties. However, given its reliance on computation and timely, accurate information, actualizing precision medicine within the emergency department and its “anyone, anywhere, anytime” approach presents unique challenges which could exacerbate disparities rather than improve care.

METHODS

We performed a qualitative, nominal group technique study of emergency physicians with prior knowledge of precision medicine concepts to identify high priority ethical concerns facing the implementation of precision medicine in the emergency department.

RESULTS

Twelve emergency physicians identified 91 ethical concerns which were organized into a framework with three major themes: values, privacy, and justice. The framework identified the need to address these themes across three time points of the precision medicine process: acquisition of data, actualization in the care setting, and after effects of its use.

CONCLUSIONS

Precision medicine may help to improve the quality of care provided in the emergency department, but significant hurdles exist. Our framework helps to identify high-yield ethical concerns that could serve as focus areas for future research and policy in order to guide the effective implementation of precision medicine in the emergency department.
Multilevel determinants of Covid-19 vaccine hesitancy and undervaccination among marginalized populations in the United States: A scoping review
Authors: Newman Peter A. , Nyoni Thabani , Allan Kate , Fantus Sophia , Dinh Duy , Tepjan Suchon , Reid Luke , Guta Adrian
Published: February 2023

Background

Amid persistent disparities in Covid-19 vaccination, we conducted a scoping review to identify multilevel determinants of Covid-19 vaccine hesitancy (VH) and undervaccination among marginalized populations in the U.S.

Methods

We utilized the scoping review methodology developed by the Joanna Briggs Institute and report all findings according to PRISMA-ScR guidelines. We developed a search string and explored 7 databases to identify peer-reviewed articles published from January 1, 2020–October 31, 2021, the initial period of U.S. Covid-19 vaccine avails.comability. We combine frequency analysis and narrative synthesis to describe factors influencing Covid-19 vaccination among marginalized populations.

Results

The search captured 2,496 non-duplicated records, which were scoped to 50 peer-reviewed articles: 11 (22%) focused on African American/Black people, 9 (18%) people with disabilities, 4 (8%) justice-involved people, and 2 (4%) each on Latinx, people living with HIV/AIDS, people who use drugs, and LGBTQ+ people. Forty-four articles identified structural factors, 36 social/community, 27 individual, and 40 vaccine-specific factors. Structural factors comprised medical mistrust (of healthcare systems, government public health) and access barriers due to unemployment, unstable housing, lack of transportation, no/low paid sick days, low internet/digital technology access, and lack of culturally and linguistically appropriate information. Social/community factors including trust in a personal healthcare provider (HCP), altruism, family influence, and social proofing mitigated VH. At the individual level, low perceived Covid-19 threat and negative vaccine attitudes were associated with VH.

Discussion

This review indicates the importance of identifying and disaggregating structural factors underlying Covid-19 undervaccination among marginalized populations, both cross-cutting and population-specific—including multiple logistical and economic barriers in access, and systemic mistrust of healthcare systems and government public health—from individual and social/community factors, including trust in personal HCPs/clinics as reliable sources of vaccine information, altruistic motivations, and family influence, to effectively address individual decisional conflict underlying VH as well as broader determinants of undervaccination.
Design of logistics Indicators for Monitoring the Covid-19 Vaccination Process in Colombia
Authors: Velasco Nubia , Herrera Andrea , Trujillo-Diaz Johanna , Amaya Ciro-Alberto , González-Uribe Catalina , Hernandez Estefania
Published: February 2023

The vaccine supply chain (VSC) integrates all the activities from production to dispensing. It is characterized by its complexity and low responsiveness, highlighting the importance of defining key performance indicators (KPIs). The design science research methodology was used to develop 38 KPIs, which were grouped into humanitarian and technological dimensions. The former includes demographic, epidemiological, and vaccination indicators, while the latter is classified into five groups according to the echelons of the supply chain. Public and private health organizations and research groups validated the indicators. They were calculated and recorded daily to monitor the logistics progress of the National Vaccination Plan against covid-19 in Colombia. These tailored KPIs, made it possible to evaluate and compare the results of the execution and effectiveness of public policies, and to redefine the strategies, showing that the logistics point of view helps identify the impact of good practices and transfer them promptly.
Influence of HIV-1 genomic RNA on the formation of Gag biomolecular condensates
Authors: Monette Anne , Niu Meijuan , Maldonado Rebecca Kaddis , Chang Jordan , Lambert Gregory S. , Flanagan John M. , Cochrane Alan , Parent Leslie J. , Mouland Andrew J.
Published: February 2023

Biomolecular condensates (BMCs) play an important role in the replication of a growing number of viruses, but many important mechanistic details remain to be elucidated. Previously, we demonstrated that pan-retroviral nucleocapsid (NC) and the HIV-1 pr55Gag(Gag) proteins phase separate into condensates, and that HIV-1 protease (PR)-mediated maturation of Gag and Gag-Pol precursor proteins yield self-assembling BMCs having HIV-1 core architecture. Using biochemical and imaging techniques, we aimed to further characterize the phase separation of HIV-1 Gag by determining which of its intrinsically disordered regions (IDRs) influence the formation of BMCs and how the HIV-1 viral genomic RNA (gRNA) could influence BMC abundance and size. We found that mutations in the Gag matrix (MA) domain or the NC zinc finger motifs altered condensate number and size in a salt-dependent manner. Gag BMCs were also bimodally influenced by the gRNA, with a condensate-promoting regime at lower protein concentrations and a gel dissolution at higher protein concentrations. Interestingly, incubation of Gag with CD4+T cell nuclear lysates led to the formation of larger BMCs as compared to much smaller ones observed in the presence of cytoplasmic lysates. These findings suggests that the composition and properties of Gag-containing BMCs may be altered by differential association of host factors in nuclear and cytosolic compartments during virus assembly. This study significantly advances our understanding of HIV-1 Gag BMC formation and provides a foundation for future therapeutic targeting of virion assembly.
Energy Coupling and Stoichiometry of Zn2+/H+Antiport by the Cation Diffusion Facilitator YiiP
Authors: Hussein Adel , Fan Shujie , Lopez-Redondo Maria , Kenney Ian , Zhang Xihui , Beckstein Oliver , Stokes David L.
Published: February 2023

YiiP is a prokaryotic Zn2+/H+antiporter that serves as a model for the Cation Diffusion Facilitator (CDF) superfamily, members of which are generally responsible for homeostasis of transition metal ions. Previous studies of YiiP as well as related CDF transporters have established a homodimeric architecture and the presence of three distinct Zn2+binding sites named A, B, and C. In this study, we use cryo-EM, microscale thermophoresis and molecular dynamics simulations to address the structural and functional roles of individual sites as well as the interplay between Zn2+binding and protonation. Structural studies indicate that site C in the cytoplasmic domain is primarily responsible for stabilizing the dimer and that site B at the cytoplasmic membrane surface controls the structural transition from an inward facing conformation to an occluded conformation. Binding data show that intramembrane site A, which is directly responsible for transport, has a dramatic pH dependence consistent with coupling to the proton motive force. A comprehensive thermodynamic model encompassing Zn2+binding and protonation states of individual residues indicates a transport stoichiometry of 1 Zn2+to 2-3 H+depending on the external pH. This stoichiometry would be favorable in a physiological context, allowing the cell to use the proton gradient as well as the membrane potential to drive the export of Zn2+.
The CTCF-H3K27me3 axis supports melanoma cell migration by repressing cholesterol biosynthesis
Authors: Kaczmarczyk Lukasz Stanislaw , Levi Nehora , Salmon-Divon Mali , Gerlitz Gabi
Published: February 2023

CTCF is a key factor in three-dimensional chromatin folding and transcriptional control that was found to affect cancer cell migration by a mechanism that is still poorly understood. To identify this mechanism, we used mouse melanoma cells with a partial loss of function (pLoF) of CTCF. We found that CTCF pLoF inhibits cell migration rate while leading to an increase in the expression of multiple enzymes in the cholesterol biosynthesis pathway along with an elevation in the cellular cholesterol levels. Inhibition of cholesterol synthesis in CTCF pLoF cells restored the cellular migration rate, suggesting that CTCF supports cell migration by suppressing cholesterol synthesis. Detailed analysis of the promoter ofHmgcs1, an early enzyme in the cholesterol synthesis pathway, revealed that CTCF enables PRC2 recruitment to the promoter and deposition of H3K27me3 to prevent SREBP2 binding and activation of transcription. By this mechanism CTCF fine-tunes cholesterol levels to support cell migration. Notably, genome wide association studies suggest a link between CTCF and cholesterol-associated diseases, thus CTCF emerges as a new regulator of cholesterol biosynthesis.
Effect of tuft-IL-25-ILC2 pathway on mouse small intestine stimulated byTrichinella spiralisES antigen
Authors: Jie Bai , Ling HE , Jureti Napisha
Published: February 2023

Objective

To explore the regulatory effect ofTrichinella spiralisES antigen on the intestinal immune function, we observed the immune response of mouse small intestine to this antigen by quantifying the changes in the related cytokines of Tuft-IL-25-ILC2 pathway.

Methods

A total of 30 BALB/c female mice were randomly divided into three groups: control group,Trichinellaexcretion-secretion (ES) antigen stimulation group, and IL-25 blocking group. The mice in the control group were injected intraperitoneally with PBS; those in the ES antigen stimulation group were injected intraperitoneally with ES antigen once per day for 7 consecutive days; and those in the IL-25 blocking group were injected intraperitoneally, first with anti-mouse IL-25 monoclonal antibody and 3 days later with ES antigen. Alcian blue-nuclear fast red staining was employed to observe the changes in the number of small intestinal goblet cells. The number of Tuft cells was determined by immunofluorescence chemical analysis, and the expression levels of IL-25, IL-13, IL-25R, Pou2f3, and RORα mRNA were quantified by RT-PCR.

Key results

The results of Alcian blue-nuclear fast red staining showed that, compared with the control group, the number of goblet cells in the small intestinal tissue of mice in the ES antigen stimulation group increased, and the difference was statistically significant (P<0.05). Compared with the ES antigen stimulation group, the number of goblet cells in the small intestinal tissue of the mice in the IL-25 blocking group was slightly decreased (P<0.05). Immunofluorescence analysis showed that, compared with the control group, the number of Tuft cells in the ES antigen-stimulated group increased (P<0.05), while in the IL-25 blocking group, the number of Tuft cells was decreased compared with that in the ES antigen stimulation group (P<0.05). RT-PCR analysis showed that, compared with the control group, the mRNA expression levels of IL-25, IL-13, IL- 25R, RORαand Pou2f3 in the small intestine of mice in the ES antigen stimulation group were increased (P<0.05); compared with the ES antigen stimulation group, the IL-25, IL-13, IL-25R, RORαand Pou2f3 mRNA expressions in the tissues of the mice in the IL-25 blocking group were decreased, and the difference was statistically significant (P<0.05).

Conclusion

The small intestinal mucosa of mice stimulated byTrichinellaES antigen may possess an immune function via the Tuft-IL-25-ILC2 pathway.
Assessing GIS education and GIS workforce in Saudi Arabia
Authors: Alrwais Omer
Published: February 2023

Purpose

The geographic information systems (GIS) sector is witnessing significant growth in recent times at the global level and in the Kingdom of Saudi Arabia at the same pace. In this research, the authors aim to measure the GIS market employability in the Kingdom of Saudi Arabia, the required skills of those seeking GIS employees, existing knowledge and abilities of graduates of relevant academic programs and gaps, if any, between the graduates and the labor market requirements in terms of GIS. Research on GIS education and GIS employability from an information system perspective is scarce; thus, this study is needed.

Design/methodology/approach

In this study, a questionnaire was distributed manually and electronically to a specific group of GIS students, teachers and employees. The questionnaire was prepared in Arabic and English language. It was distributed manually to the attendees of the 12th GIS Symposium, organized by Imam Abdulrahman Bin Faisal University at Dammam city, Saudi Arabia in April of 2018. The event is a yearly one that gathers local GIS community and outside speakers and guests. An electronic version of the questionnaire was also available and distributed via personal contacts. Responses were received until the end of 2019.

Findings

The results of 107 respondents indicates good GIS foundation (for example in topology, geospatial data processing and cartography); however, programming and business skills (namely cost benefit analysis, organizational perspective and business understanding) are lacking from Saudi GIS graduates. About 67% of respondents acknowledge directly that it is difficult to find locally qualified GIS graduates. Moreover, 55% of respondents classify GIS job candidates as underqualified. This research identifies under qualification in business competencies and computer programming skills for GIS students and workers in Saudi Arabia. This research did not find a statistically significant different response between GIS teachers and GIS employees/employers; however, students’ response was significantly different from these two groups.

Originality/value

Research on GIS education and GIS employability from an Information System perspective is scarce; thus, this study is needed. Moreover, research about this topic in Saudi Arabia and the Arabian Gulf is almost nonexistent.
The performance of business groups during institutional transition and economic downturn in a developing country
Authors: Bhutta Aamir Inam , Sultan Jahanzaib , Sheikh Muhammad Fayyaz , Sajid Muhammad , Mushtaq Rizwan
Published: February 2023

Purpose

Pakistan has experienced financial liberalization with rapid ups and downs in economic growth due to domestic issues during the last 2 decades. Motivated by inconclusive and conflicting time-driven findings about the performance of the business groups, this study examines the performance of business groups in Pakistan for a relatively long period from 2003 to 2018.

Design/methodology/approach

The study uses 3,821 firm-year observations from non-financial firms listed on the Pakistan Stock Exchange (PSX). For the estimation, pooled ordinary least squares (OLS) with industry- and year fixed effects and two-step system generalized methods of moments (GMM) are used.

Findings

The study finds that group-affiliated firms outperform independent firms in accounting performance, while underperform in market performance. The outperformance is mainly driven by medium-sized business groups, while underperformance is driven by small and large business groups. Further, the study documents that the underperformance in terms of market performance of firms affiliated with small and large groups is greater before the economic downturn, while outperformance in terms of the accounting measure of firms affiliated with medium-sized groups is greater during the economic downturn. These findings support our time-driven concerns. Overall, the authors' findings are consistent with institutional and transaction cost theories.

Practical implications

Business groups are important channels to reduce market inefficiencies. Business groups may enhance the affiliated firms' resources and resistance capacity through active utilization of the internal capital market, specifically when market conditions are not ideal for affiliates. However, effective utilization of internal capital markets depends on group size. Therefore, investors should deliberate on the size of business groups and diversification within business groups.

Originality/value

The authors extend the literature by providing fresh evidence related to the performance of business groups in the Pakistani context while accounting for the role of the size of business groups.
Panacea or poison? Exploring the paradoxical problematizations of loneliness, technology and youth in Norwegian and UK policymaking
Authors: Jentoft Elian Eve , Haldar Marit
Published: February 2023

Purpose

Loneliness’ impact on health and wellbeing has emerged as a public health issue in several countries. Young people are increasingly understood as a ‘risk group’ and intervention target for loneliness-reduction. This research paper aims to present a discourse analysis of policies and political speech about young people and loneliness.

Design/methodology/approach

Using discourse analysis inspired by Carol Bacchi’s “What is the Problem Represented to Be” (WPR) approach, this cross-cultural analysis studies loneliness policy in the United Kingdom (UK) and Norway. In doing so, the authors ask: What is the problem of loneliness among young people represented to be in UK and Norwegian welfare policy?

Findings

The findings indicate paradoxical problematizations of the role technology plays among lonely young people, who, in this context, are divided in two categories: able normative and disabled youth. We reveal fundamental differences in beliefs about the impact of technology on these groups, and corresponding differences in the proposed solutions. The problem of young peoples’ loneliness is represented as uncertainty about potential harms of digital connectedness and reduced face-to-face interactions. In contrast, the problem of loneliness among disabled youth is represented as impeded access to social realms, with technology serving a benign role as equalizer.

Originality/value

Little research has examined this new policy field. The article contributes to filling this gap and encourages policymakers to consider how political discourses on loneliness may lead them to overlook digital interventions young people could find beneficial.
A bibliometric analysis of political connections literature
Authors: Ahmed Fatma , Hussainey Khaled
Published: February 2023

Purpose

This paper aims to present a catalogue of the influential aspects resulting from a bibliometric meta-analysis of political connection literature.

Design/methodology/approach

This study undertakes a bibliometric meta-analysis review of political connections literature, covering 138 research papers from 2000 to 2020 using the visualization of similarities viewer program.

Findings

The authors identify six research groups: the value of political connections; political connections and finance; political connections in banks; political connections and debt; management and political connections; and political connections and governance. This study discusses each stream through a cartographic analysis, including co-authorship, countries and time networks.

Originality/value

This study makes an important and novel contribution to political connection literature. So far, to the best of the authors’ knowledge, it is the only bibliometric study on political connections. This study is the first to use network analysis and community detection to understand social clustering and to identify main research steams in political connection literature.
Sustainable apparel: a perspective from Bangladesh’s young consumers
Authors: Su Jin , Iqbal Md Arif , Haque Farhan , Akter Maeen Md Khairul
Published: February 2023

Purpose

This study aims to understand Bangladeshi young consumers’ perceptions of sustainable apparel. Specifically, through the lens of the theory of reasoned action (TRA), this study investigates the impacts of man–nature orientation (MNO) and social influences on Bangladeshi young consumers’ intention to purchase sustainable apparel.

Design/methodology/approach

Empirical survey-based research was conducted, and data were collected from 387 Bangladeshi college students.

Findings

The findings of the study show that MNO significantly influences Bangladeshi young consumers’ attitudes toward purchasing sustainable apparel, which, together with social influences, impacts young Bangladeshi consumers’ intention of making efforts to purchase sustainable apparel.

Originality/value

This study incorporates the specific cultural value – MNO with the traditional TRA model to understand young Bangladeshi consumers’ sustainable apparel purchase intention. The results of this study demonstrate the applicability of the TRA framework in understanding young consumers’ sustainable apparel consumer behavior in the context of Bangladesh, which is a developing country with a collectivistic culture. This study provides insights into how apparel brands and retailers should design their sustainability strategies in developing countries such as Bangladesh.