bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterizing spatial variations of PAH emission in the reflection nebula NGC 1333
Authors: Knight C , Peeters E , Wolfire M , Stock D J
Published: November 2021

Infrared emission features at 3.3, 6.2, 7.7, 8.6, and 11.2 µm, attributed to polycyclic aromatic hydrocarbons (PAHs), show variations in relative intensity, shape, and peak position. These variations depend on the physical conditions of the photodissociation region (PDR) in which strong PAH emission arises but their relationship has yet to be fully quantified. We aim to better calibrate the response of PAH species to their environment using observations with matching apertures and spatial resolution. We present observations from the Field-Imaging Far-Infrared Line Spectrometer onboard the Stratospheric Observatory for Infrared Astronomy of the gas cooling lines [O i] 63, 146 µm and [C ii] 158 µm in the reflection nebula NGC 1333 and use archival dust continuum observations from the Photodetector Array Camera and Spectrometer (PACS) onboard Herschel. We employ PDR modelling to derive the physical conditions and compare these with the characteristics of the PAH emission as observed with the Infrared Spectrometer onboard Spitzer. We find distinct spatial characteristics for the various PAH spectral components. We conclude that the ionic bands (6.2, 7.7, 8.6, and 11.0) and the 7–9 µm emission are due to multiple PAH subpopulations and that the plateaus are distinct from the features perched on top. The 6–9 µm PAH emission exhibits a significant change in behaviour between the irradiated PDR and diffuse outskirts, confirming these bands arise from multiple PAH subpopulations with different underlying molecular properties. We find multiple promising relationships between PAH ratios and the far-ultraviolet radiation field strength but no clear correlations with the PAH ionization parameter.
Modelling cosmic masers in C-type shock waves – the coexistence of Class I CH3OH and 1720 MHz OH masers
Authors: Nesterenok A V
Published: November 2021

The collisional pumping of CH3OH and OH masers in non-dissociative C-type shock waves is studied. The chemical processes responsible for the evolution of molecule abundances in the shock wave are considered in detail. The large velocity gradient approximation is used to model radiative transfer in molecular lines. We present calculations of the optical depth in maser transitions of CH3OH and OH for a grid of C-type shock models that vary in cosmic ray ionization rate, gas density, and shock speed. We show that pre-shock gas densities nH, tot = 2 × 104–2 × 105 cm−3 are optimal for the pumping of methanol maser transitions. A complete collisional dissociation of methanol at the shock front takes place for shock speeds us ≳ 25 km s−1. At high pre-shock gas density nH, tot = 2 × 106 cm−3, the collisional dissociation of methanol takes place at shock speeds just above the threshold speed us ≈ 15–17.5 km s−1, corresponding to sputtering of icy mantles of dust grains. We show that the methanol maser transition E 4−1 → 30 at 36.2 GHz has an optical depth |τ| higher than that of the transition A+ 70 → 61 at 44.1 GHz at high cosmic ray ionization rate $\zeta _\mathrm{H_2} \gtrsim 10^{-15}$ s−1 and pre-shock gas density nH, tot = 2 × 104 cm−3. These results can be applied to the interpretation of observational data on methanol masers near supernova remnants and in molecular clouds of the Central Molecular Zone. At the same time, a necessary condition for the operation of 1720 MHz OH masers is a high ionization rate of molecular gas, $\zeta _\mathrm{H_2} \gtrsim 10^{-15}$ s−1. We find that physical conditions conducive to the operation of both hydroxyl and methanol masers are cosmic ray ionization rate $\zeta _\mathrm{H_2} \approx 10^{-15}$–3 × 10−15 s−1 and a narrow range of shock speeds 15 ≲ us ≲ 20 km s−1. The simultaneous observations of OH and CH3OH masers may provide restrictions on the physical parameters of the interstellar medium in the vicinity of supernova remnants.
Cosmological constraints from H ii starburst galaxy, quasar angular size, and other measurements
Authors: Cao Shulei , Ryan Joseph , Ratra Bharat
Published: November 2021

We compare the constraints from two (2019 and 2021) compilations of H ii starburst galaxy (H iiG) data and test the model independence of quasar (QSO) angular size data using six spatially flat and non-flat cosmological models. We find that the new 2021 compilation of H iiG data generally provides tighter constraints and prefers lower values of cosmological parameters than those from the 2019 H iiG data. QSO data by themselves give relatively model-independent constraints on the characteristic linear size, lm, of the QSOs within the sample. We also use Hubble parameter [H(z)], baryon acoustic oscillation (BAO), Pantheon Type Ia supernova (SN Ia) apparent magnitude (SN-Pantheon), and DES-3 yr binned SN Ia apparent magnitude (SN-DES) measurements to perform joint analyses with H iiG and QSO angular size data, since their constraints are not mutually inconsistent within the six cosmological models we study. A joint analysis of H(z), BAO, SN-Pantheon, SN-DES, QSO, and the newest compilation of H iiG data provides almost model-independent summary estimates of the Hubble constant, $H_0=69.7\pm 1.2\ \rm {km\,s^{-1}\,Mpc^{-1}}$, the non-relativistic matter density parameter, $\Omega _{\rm m_0}=0.293\pm 0.021$, and lm = 10.93 ± 0.25 pc.
Redshift space three-point correlation function of IGM at z < 0.48
Authors: Maitra Soumak , Srianand Raghunathan , Gaikwad Prakash , Khandai Nishikanta
Published: November 2021

Ly α forest decomposed into Voigt profile components allows us to study clustering properties of the intergalactic-medium and its dependence on various physical quantities. Here, we report the first detections of probability excess of low-z (i.e z < 0.48) Ly α absorber triplets over redshift-space scale of r∥ ≤ 8 pMpc (Mpc in physical units) with maximum amplitude of $8.76^{+1.96}_{-1.65}$ at a longitudinal separation of 1–2 pMpc. We measure non-zero three-point correlation ($\zeta = 4.76^{+1.98}_{-1.67}$) only at this scale with reduced three-point correlation Q = $0.95^{+0.39}_{-0.38}$. The measured ζ shows an increasing trend with increasing minimum H i column density (NH i) threshold while Q does not show any NH i dependence. About 88 per cent of the triplets contributing to ζ (at z ≤ 0.2) have nearby galaxies (whose distribution is known to be complete for ∼0.1L* at z < 0.1 and for ∼L* at z ∼ 0.25 within 20 arcsec to the quasar sightlines) within velocity separation of 500 km s−1 and median impact parameter of 405 pkpc. The measured impact parameters are consistent with majority of the identified triplets not originating from individual galaxies but tracing the underlying galaxy distribution. Frequency of occurrence of Broad-Ly α absorbers (b > 40 km s−1) in triplets (∼85 per cent) is factor ∼3 higher than that found among the full sample (∼32 per cent). Using four different cosmological simulations, we quantify the effect of peculiar velocities and feedback and show that most of the observed trends are broadly reproduced. However, ζ at small scales (r∥ < 1 pMpc) and its b-dependence found in simulations are inconsistent with observations. This could either be related to the failure of these simulations to reproduce the observed b and NH i distributions for NH i > 1014 cm−2 self-consistently or to the wide spread of signal-to-noise ratio in the observed data.
Demographic and Clinical Correlates of High-lethality Suicide Attempts: A Retrospective Study in Psychiatric Inpatients
Authors: Berardelli Isabella , Innamorati Marco , Sarubbi Salvatore , Rogante Elena , Erbuto Denise , Lester David , Pompili Maurizio
Published: November 2021

Assessment of the lethality of suicide attempts is a neglected topic in the literature in this area. Based on the hypothesis that suicide attempters who choose a highly lethal method differ from those who use less lethal methods, we analyzed the characteristics of suicide attempters who used different suicide methods to determine demographic and clinical risk factors for the lethality of suicide methods. For this purpose, we used the Risk-Rescue Rating Scale to assess the lethality of the suicide method in a consecutive sample of 107 psychiatric inpatients with a recent suicide attempt (in 6 mo before hospitalization). The results demonstrated that patients who used a highly lethal method were younger and more frequently single. A novel finding of this study was that earlier age of onset of psychiatric symptoms and a higher number of previous hospitalizations were associated with the use of more lethal methods. In conclusion, patients who used more lethal methods differed from those who used less lethal methods. Identification of these differences may be necessary to implement specific suicide prevention strategies in patients with psychiatric conditions.
Another Step Toward Implementing Mental Health Parity
Authors: Plakun Eric M.
Published: November 2021

This column describes a recent $14.3 million settlement in a case brought against United Behavioral Health by the Department of Labor and New York State Attorney General Letitia James. United Behavioral Health agreed to stop 2 practices that were in violation of the Mental Health Parity and Addiction Equity Act. One of the practices involved systematic underpayment of nonphysician therapists and the other involved systematic use of targeted utilization review to end behavioral treatment after 20 sessions in a year.
A Patient With Electroconvulsive Therapy–resistant Major Depressive Disorder With a Full Response to Heated Yoga: A Case Report
Authors: Sakurai Hitoshi , Norton Richard J. , Fisher Lauren B. , Nagaswami Megha V. , Streeter Chris C. , Meyer Ashley K. , Dean Taquesha , Fava Maurizio , Mischoulon David , Nyer Maren B.
Published: November 2021

Depression remains difficult to treat as a result of less than optimal efficacy and troublesome side effects of antidepressants. The authors present the case of a patient with treatment-resistant depression with melancholic features who had previously been unresponsive to electroconvulsive therapy (ECT) plus an antidepressant regimen but whose condition fully remitted with the addition of a standardized form of heated hatha yoga (HY; Bikram yoga) practiced in a room heated to 105°F. The patient was a 28-year-old woman who underwent 8 weeks of HY as part of a randomized controlled trial of HY for depression while continuing her antidepressant treatment. The patient was asked to attend a minimum of 2 weekly, 90-minute HY classes. After 8 weeks (12 classes in total), the patient no longer met the criteria for a major depressive episode with melancholic features, per Mini-International Neuropsychiatric Interview (MINI) criteria. Her depressive symptoms had improved dramatically, with Inventory of Depressive Symptomatology, Clinician-Rated (IDS-C30), and Hamilton Depression Rating Scale (HAM-D28) scores decreasing from 28 at baseline to 3, and from 28 at baseline to 4, respectively, indicating remission. This patient’s ECT-resistant depression remitted with the addition of HY to her antidepressant regimen. Because of her youth and athleticism, this patient was likely well suited to this rigorous form of yoga. Further research is needed to explore HY as a potential intervention for treatment-resistant depression.
Subtypes of Major Depressive Disorder Based on Pharmacological Responsiveness
Authors: Preskorn Sheldon H.
Published: November 2021

Major depressive disorder (MDD) is a descriptive, syndromic diagnosis which will likely be discovered to be more than a single disorder when understood from a pathobiological or pathoetiological perspective. To date, attempts to divide this disorder into more homogenous phenotypes on the basis of signs and symptoms have not yielded more information on the pathobiological or pathoetiological factors that can cause a major depressive episode. This column proposes a new way of dividing MDD into 3 subtypes based on responsiveness to pharmacological treatments that are pharmacologically quite different from each other: type 1, which is responsive to treatment with biogenic amine antidepressants; type 2, which is not responsive to treatment with biogenic amine antidepressants but is responsive to antidepressants that work on the glutamine neurotransmitter system via the N-methyl-D-aspartate receptor; and type 3, which is not responsive to either of these 2 types of antidepressants. The goal of this formulation is to develop biologically meaningful subtypes that can be further studied to understand the pathobiology underlying these 3 types of MDD with the goal of developing newer treatments and earlier ways of diagnosing these conditions.
Long-term evolution of quantitative traits in theDrosophila melanogasterspecies subgroup
Authors: Yassin Amir , Gidaszewski Nelly , Debat Vincent , David Jean R.
Published: November 2021

Quantitative genetics aims at untangling the genetic and environmental effects on phenotypic variation. Trait heritability, which summarizes the relative importance of genetic effects, is estimated at the intraspecific level, but theory predicts that heritability could influence long-term evolution of quantitative traits. The phylogenetic signal concept bears resemblance to heritability and it has often been called species-level heritability. Under certain conditions, such as trait neutrality or contribution to phylogenesis, within-species heritability and between-species phylogenetic signal should be correlated. Here, we investigate the potential relationship between these two concepts by examining the evolution of multiple morphological traits for which heritability has been estimated inDrosophila melanogaster. Specifically, we analysed 42 morphological traits in both sexes on a phylogeny inferred from 22 nuclear genes for nine species of themelanogastersubgroup. We used Pagel’s λ as a measurement of phylogenetic signal because it is the least influenced by the number of analysed taxa. Pigmentation traits showed the strongest concordance with the phylogeny, but no correlation was found between phylogenetic signal and heritability estimates mined from the literature. We obtained data for multiple climatic variables inferred from the geographical distribution of each species. Phylogenetic regression of quantitative traits on climatic variables showed a significantly positive correlation with heritability. Convergent selection, the response to which depends on the trait heritability, may have led to the null association between phylogenetic signal and heritability for morphological traits inDrosophila. We discuss the possible causes of discrepancy between both statistics and caution against their confusion in evolutionary biology.
Expression and novel alternative purification of the recombinant nucleocapsid (N) protein of SARS-CoV-2 in Escherichia coli for the serodiagnosis of COVID-19
Authors: Rosales Jose David , Quintero William , Cruz Jhon , Perdomo Balbino , Quintero Militza , Bastidas Marcos , Lugo Jose Domingo , Rodriguez Keila Rivas , Freites-Perez Juan Carlos , Castillo Annie
Published: November 2021

The SARS-CoV-2 coronavirus causes severe acute respiratory syndrome and has caused a global pandemic by causing the COVID-19 disease. To monitor and control it, diagnostic methods such as molecular and serological tests are necessary. The serological approach uses SARS-CoV-2 antigens to detect the antibodies present in patients using quantitative techniques such as enzyme-linked immunosorbent assay (ELISA) or qualitative rapid tests such as lateral flow chromatography (RDT’s). The main antigens used are the spike protein (S) and the nucleocapsid protein (N). Both proteins are obtained in different expression systems, in eukaryotic cells, their production is expensive, so in this work we chose a simpler and cheaper system such as prokaryotic to express and purify the N protein. Thereore, the nucleotide sequence had to being optimized to be expressed in Escherichia coli. The protein N is sensitive to E.coli proteases and also has the ability to self-proteolyze under native conditions, degrading into different fragments. However, under denaturing conditions, using urea and at pH 5.3 it is stable and efficiently purified using metal exchange chromatography (IMAC). In our purification strategy, we surprisingly found that by not using a sonicator, a homogeneous and time-stable preparation of the recombinant antigen is obtained. An approximate yield of 200 mg / L was obtained. It was then tested with healthy sera and sera from COVID-19 convalescent patients in Wester-blot tests that were able to recognize it. Our work provides a novel strategy to produce the SARS-CoV-2 protein N so that it can be used as an input in the development and innovation of serological tests in the diagnosis of COVID-19.
Anin vivodrug repurposing screen and transcriptional analyses reveals the serotonin pathway and GSK3 as major therapeutic targets for NGLY1 deficiency
Authors: Hope Kevin A. , Berman Alexys R. , Peterson Randall T. , Chow Clement Y.
Published: November 2021

NGLY1 deficiency, a rare disease with no effective treatment, is caused by autosomal recessive, loss-of-function mutations in theN-glycanase 1 (NGLY1)gene and is characterized by global developmental delay, hypotonia, alacrima, and seizures. We used an adultDrosophilamodel of NGLY1 deficiency to conduct anin vivo,unbiased, small molecule, repurposing screen of FDA-approved drugs to identify therapeutic compounds. Seventeen molecules rescued lethality in a patient-specific NGLY1 deficiency model, including multiple serotonin and dopamine modulators. ExclusivedNGLY1expression in serotonin and dopamine neurons, in an otherwisedNGLY1-null fly, was sufficient to rescue lethality. Further, genetic modifier and transcriptomic data supports the importance of serotonin signaling in NGLY1 deficiency. Connectivity Map analysis identified glycogen synthase kinase 3 (GSK3) inhibition as a potential therapeutic mechanism for NGLY1 deficiency, which we experimentally validated with TWS119 and lithium. Strikingly, GSK3 inhibitors and a serotonin modulator rescued size defects indNGLY1deficient larvae upon proteasome inhibition, suggesting that these compounds act through NRF1, a transcription factor that regulates proteasome expression. This study reveals the importance of the serotonin pathway in NGLY1 deficiency, and serotonin modulators or GSK3 inhibitors may be effective therapeutics for this rare disease.
An individualized causal framework for learning intercellular communication networks that define microenvironments of individual tumors
Authors: Chen Xueer , Chen Lujia , Kürten Cornelius H.L. , Jabbari Fattaneh , Vujanovic Lazar , Ding Ying , Lu Binfeng , Lu Kevin , Kulkarni Aditi , Tabib Tracy , Lafyatis Robert , Cooper Gregory , Ferris Robert , Lu Xinghua
Published: November 2021

Cells within a tumor microenvironment (TME) dynamically communicate and influence each other’s cellular states through an intercellular communication network (ICN). In cancers, intercellular communications underlie immune evasion mechanisms of individual tumors. We developed an individualized causal analysis framework for discovering tumor-specific ICNs. Using head and neck squamous cell carcinoma (HNSCC) tumors as a testbed, we first mined single-cell RNA-sequencing data to discover gene expression modules (GEMs) that reflect the states of transcriptomic processes within tumor and stromal single cells. By deconvoluting bulk transcriptomes of HNSCC tumors profiled by The Cancer Genome Atlas (TCGA), we estimated the activation states of these transcriptomic processes in individual tumors. Finally, we applied individualized causal network learning to discover an ICN within each tumor. Our results show that cellular states of cells in TMEs are coordinated through ICNs that enable multi-way communications among epithelial, fibroblast, endothelial, and immune cells. Further analyses of individual ICNs revealed structural patterns that were shared across subsets of tumors, leading to the discovery of 4 different subtypes of networks that underlie disparate TMEs of HNSCC. Patients with distinct TMEs exhibited significantly different clinical outcomes. Our results show that the capability of estimating individual ICNs reveals heterogeneity of ICNs and sheds light on the importance of intercellular communication in impacting disease development and progression.
Glypican-1 drives unconventional secretion of Fibroblast Growth Factor 2
Authors: Sparn Carola , Dimou Eleni , Meyer Annalena , Saleppico Roberto , Wegehingel Sabine , Gerstner Matthias , Klaus Severina , Ewers Helge , Nickel Walter
Published: November 2021

Fibroblast Growth Factor 2 (FGF2) is a tumor cell survival factor that is transported into the extracellular space by an unconventional secretory mechanism. Cell surface heparan sulfate proteoglycans are known to play an essential role in this process. Unexpectedly, we found that among the diverse sub-classes consisting of syndecans, perlecans, glypicans and others, Glypican-1 (GPC1) is both the principle and rate-limiting factor that drives unconventional secretion of FGF2. By contrast, we demonstrate GPC1 to be dispensable for FGF2 signaling into cells. We provide first insights into the structural basis for GPC1-dependent FGF2 secretion, identifying disaccharides with N-linked sulfate groups to be enriched in the heparan sulfate chains of GPC1 to which FGF2 binds with high affinity. Our findings have broad implications for the role of GPC1 as a key molecule in tumor progression.
Spontaneous DNA synapsis by forming noncanonical intermolecular structures
Authors: Severov V.V. , Tsvetkov V.B. , Barinov N.A. , Babenko V.V. , Klinov D.V. , Pozmogova G.E.
Published: November 2021

We report the spontaneous formation of DNA–DNA junctions in solution in the absence of proteins visualised using atomic force microscopy. The synapsis position fits with potential G-quadruplex (G4) sites. In contrast to the Holliday structure, these conjugates have affinity for G4 antibodies. Molecular modelling was used to elucidate the possible G4/IM-synaptic complex structures. Our results indicate a new role of the intermolecular noncanonical structures in chromatin architecture and genomic rearrangement.
G6b-B regulates an essential step in megakaryocyte maturation
Authors: Becker Isabelle C. , Nagy Zoltan , Manukjan Georgi , Haffner-Luntzer Melanie , Englert Maximilian , Heib Tobias , Vögtle Timo , Gross Carina , Bharti Richa , Dietrich Sascha , Mott Kristina , Heck Johannes , Jeschke Anke , Schinke Thorsten , Schlegel Nicolas , Heckel Tobias , Stegner David , Pleines Irina , Ignatius Anita , Schulze Harald , Nieswandt Bernhard
Published: November 2021

G6b-B is a megakaryocyte lineage-specific immunoreceptor tyrosine-based inhibition motif (ITIM)-containing receptor, essential for platelet homeostasis. Mice with a genomic deletion of the entireMpig6blocus develop severe macrothrombocytopenia and myelofibrosis, which is reflected in humans with null-mutations inMPIG6B. The current model proposes that megakaryocytes lacking G6b-B develop normally, while proplatelet release is hampered, but the underlying molecular mechanism remains unclear. Here, we report on a spontaneous recessive single nucleotide mutation in C57BL/6 mice, localized within the intronic region of theMpig6blocus that abolishes G6b-B expression and reproduces macrothrombocytopenia, myelofibrosis and osteosclerosis. As the mutation is based on a single nucleotide exchange,Mpig6bmutmice represent an ideal model to study the role of G6b-B. Megakaryocytes from these mice were smaller in size, displayed a less developed demarcation membrane system and reduced expression of receptors. RNA sequencing revealed a striking global reduction in the level of megakaryocyte-specific transcripts, in conjunction with decreased protein levels of the transcription factor GATA-1, and impaired thrombopoietin signaling. The reduced number of mature MKs in the bone marrow was corroborated on a newly developedMpig6bnull mouse strain. Our findings highlight an unexpected essential role of G6b-B in the early differentiation within the megakaryocytic lineage.
Disruption of Mitochondrial Quality Control Genes Promotes Caspase-Resistant Cell Survival Following Apoptotic Stimuli
Authors: Kushnareva Yulia , Moraes Vivian , Suess Julian , Peters Bjoern , Newmeyer Donald D. , Kuwana Tomomi
Published: November 2021

In cells undergoing cell-intrinsic apoptosis, mitochondrial outer membrane permeabilization (MOMP) typically marks an irreversible step in the cell death process. However, in some cases a subpopulation of the treated cells can exhibit a sublethal response, termed “minority MOMP”. In this phenomenon, the affected cells survive, despite a low level of caspase activation and a subsequent limited activation of the endonuclease CAD (DFFB). Consequently, these cells can experience DNA damage, increasing the probability of oncogenesis. To discover genes affecting MOMP response in individual cells, we conducted an imaging-based phenotypic siRNA screen. We identified multiple candidate genes whose downregulation increased the heterogeneity of MOMP within single cells. Among these were genes related to mitochondrial dynamics and mitophagy, which participate in the mitochondrial quality control (MQC) system. To test the hypothesis that functional MQC is important for reducing the frequency of minority MOMP, we developed an assay to measure the clonogenic survival of caspase-engaged cells. We found that cells deficient in various MQC genes were indeed prone to aberrant post-MOMP survival. Our data highlight the important role of proteins involved in mitochondrial dynamics and mitophagy in preventing apoptotic dysregulation and oncogenesis.
Merlin Tumor Suppressor Function is Regulated by PIP2-Mediated Dimerization
Authors: Hennigan Robert F. , Thomson Craig S. , Stachowski Kye , Nassar Nicolas , Ratner Nancy
Published: November 2021

Neurofibromatosis Type 2 is an inherited disease characterized by Schwann cell tumors of cranial and peripheral nerves. TheNF2gene encodes Merlin, a member of the ERM family consisting of an N-terminal FERM domain, a central α-helical region and a C-terminal domain that binds to the FERM domain. Changes in the intermolecular FERM-CTD interaction allow Merlin to transition between an open, FERM accessible conformation and a closed, FERM-inaccessible conformation, modulating Merlin activity. These conformational transitions are regulated by both phosphorylation and phosphoinositide binding. Merlin has been shown to dimerize, but the regulation and function Merlin dimerization is not clear. We used a nanobody based binding assay and found that Merlin dimerizes via a FERM-FERM interaction, orientated with each C-terminus in close proximity. Dimerization. Patient derived and structural mutants show that dimerization controls interactions with specific binding partners, including HIPPO pathway components, and correlates with tumor suppressor activity. We demonstrate that dimerization occurs after a PIP2 mediated transition from a closed to open conformation monomers that are then able dimerize. This process requires the first 18 amino acids of the FERM domain and is inhibited by phosphorylation at serine 518. The discovery that active, open conformation Merlin is a dimer represents a new paradigm for Merlin function with implications for the development of therapies designed to compensate for Merlin loss.
Leukocyte proliferation mediates disease pathogenesis in theNdufs4(KO) mouse model of Leigh syndrome
Authors: Stokes Julia C , Bornstein Rebecca L , James Katerina , Park Kyung Yeon , Spencer Kira , Vo Katie , Snell John C , Johnson Brittany M , Morgan Philip G , Sedensky Margaret M , Baertsch Nathan , Johnson Simon C
Published: November 2021

Symmetric, progressive, necrotizing lesions in the brainstem are a defining feature of Leigh syndrome (LS). A mechanistic understanding of the pathogenesis of these lesions has been elusive. Here, we report that leukocyte proliferation is causally involved in the pathogenesis of Leigh syndrome. Directly depleting leukocytes with a colony-stimulating factor 1 receptor (CSF1R) inhibitor dramatically attenuates disease, including complete prevention of CNS lesion formation and substantial extension of survival. Leukocyte depletion rescues a range of symptoms including hyperlactemia, seizures, respiratory function, and neurologic symptoms. These data provide a mechanistic explanation for the beneficial effects of mTOR inhibition. More importantly, these findings dramatically alter our understanding of the pathogenesis of LS, demonstrating that immune involvement directly drives disease. These findings have significant implication for the mechanisms of disease resulting from mitochondrial dysfunction, and may lead to novel therapeutic strategies.

One-Sentence Summary

Pharmacologic targeting of leukocytes prevents CNS lesions, neurological disease, and metabolic dysfunction in theNdufs4(KO) mouse model of Leigh syndrome.
Three-dimensional Cancer Cell Migration Directed by Dual Mechanochemical Guidance
Authors: Esfahani Pedram , Levine Herbert , Mukherjee Mrinmoy , Sun Bo
Published: November 2021

Directed cell migration guided by external cues plays a central role in many physiological and pathophysiological processes. The microenvironment of cells often simultaneously contains various cues and the motility response of cells to multiplexed guidance is poorly understood. Here we combine experiments and mathematical models to study the three-dimensional migration of breast cancer cells in the presence of both contact guidance and a chemoattractant gradient. We find that the chemotaxis of cells is complicated by the presence of contact guidance as the microstructure of extracellular matrix (ECM) vary spatially. In the presence of dual guidance, the impact of ECM alignment is determined externally by the coherence of ECM fibers, and internally by cell mechanosensing Rho/Rock pathways. When contact guidance is parallel to the chemical gradient, coherent ECM fibers significantly increase the efficiency of chemotaxis. When contact guidance is perpendicular to the chemical gradient, cells exploit the ECM disorder to locate paths for chemotaxis. Our results underscores the importance of fully characterizing the cancer cell microenvironment in order to better understand invasion and metastasis.
Integration of the Salmonella Typhimurium methylome and transcriptome reveals DNA methylation and transcriptional regulation are largely decoupled under virulence-related conditions
Authors: Bourgeois Jeffrey S. , Anderson Caroline E. , Wang Liuyang , Modliszewski Jennifer L. , Chen Wei , Schott Benjamin H. , Devos Nicolas , Ko Dennis C.
Published: November 2021

Despite being in a golden age of bacterial epigenomics, little work has systematically examined the plasticity and functional impacts of the bacterial DNA methylome. Here, we leveraged SMRT sequencing to examine the m6A DNA methylome of two Salmonella enterica ser. Typhimurium strains: 14028s and a ΔmetJ mutant with derepressed methionine metabolism, grown in Luria Broth or a media that simulates the intracellular environment. We find that the methylome is remarkably static—over 95% of adenosine bases retain their methylation status across conditions. Integration of methylation with transcriptomic data revealed limited correlation between changes in methylation and gene expression. Further, examining the transcriptome in ΔyhdJ bacteria, lacking the m6A methylase with the most dynamic methylation pattern in our dataset, revealed little evidence of YhdJ-mediated gene regulation. Curiously, despite G(m6A)TC motifs being particularly resistant to change across conditions, incorporating dam mutants into our analyses revealed two examples where changes in methylation and transcription may be linked across conditions. This includes the novel finding that the ΔmetJ motility defect may be partially driven by hypermethylation of the chemotaxis gene tsr. Together, these data redefine the S. Typhimurium epigenome as a highly stable system that has rare, but important, roles in transcriptional regulation. Incorporating these lessons into future studies will be critical as we progress through the epigenomic era.

Importance

While recent breakthroughs have enabled intense study of bacterial DNA modifications, limitations in current work have potentiated a surprisingly untested narrative that DNA methylation is a common mechanism of the bacterial response to environmental conditions. Essentially, whether epigenetic regulation of bacterial transcription is a common, generalizable phenomenon is a critical unanswered question that we address here. We find that most DNA methylation is static in Salmonella enterica serovar Typhimurium, even when the bacteria are grown under dramatically different conditions that cause broad changes in the transcriptome. Further, even when the methylation of individual bases change, these changes generally do not correlate with changes in gene expression. Finally, we demonstrate methods by which data can be stratified in order to identify coupled changes in methylation and gene expression.
Strategic synthon approach in obtaining cocrystals and cocrystal polymorphs of a high-Z′ system deferiprone – an anti-thalassemia drug
Authors: Rajendrakumar Satyasree , Surampudi Venkata Sai Durga Anuja , Balasubramanian Sridhar
Published: November 2021

Compounds with more than one molecule in the crystallographic asymmetric unit (Z′ > 1) display a noticeably stronger propensity to form cocrystals. Deferiprone is an anti-thalassemia drug known to exhibit polymorphic behaviour. Previously, three polymorphs were reported out of which one of them exhibited Z′ > 1. In the present manuscript, a fourth polymorph of deferiprone was identified and it also possessed Z′ > 1. All the four polymorphs showed similar hydrogen bonding features and differed in crystal packing. The ability of deferiprone to crystallize as Z′ > 1 prompted us to investigate the hydrogen bonding and synthon variation upon cocrystallization of deferiprone with hydroxyl-group-containing coformers such as catechol, hydroquinone, phloroglucinol, resorcinol and pyrogallol. Crystallization attempts along with PXRD analysis aided in obtaining 11 new cocrystal structures which involve different stoichiometric cocrystals and some polymorphs. Synthon analysis, crystal packing as well as thermal behaviour were assessed and compared. The presence of multiple phases in each cocrystal system in its respective bulk powders was identified and quantified using PXRD and Rietveld analysis. Homosynthons were observed in three co-crystal systems, while a heterosynthon was observed in five systems. The combination of both homo- and heterosynthon was observed in three cocrystal systems. The phase transformation events were observed in most of the systems. In nine co-crystal systems, the melting points were observed intermediate between those of the API and the coformers.
Work stress related cardiovascular diseases among construction professionals
Authors: Kamardeen Imriyas
Published: November 2021

Purpose

Cardiovascular diseases (CVDs) are responsible for one-third of global deaths. Work stress is a major risk factor for CVDs in the workforce. Construction professionals endure excessive work stress, yet their vulnerability to CVDs remains underexplored. The study investigated the prevalence of CVDs among construction professionals and its relationships to job stressors, stress coping methods and socio-demographics.

Design/methodology/approach

An online survey was conducted among construction professionals in Australia wherein data related to job stressor experiences, stress management methods adopted, and incidents of CVDs were collected. Structural path analysis was conducted to discover associations.

Findings

Junior level professionals reported higher incidents of angina and heart muscle weakening than others. Statistically significant positive associations were discovered between the reported CVDs, and job stressors such as excessive workload, unpredictable work hours, lack of support, discrimination and work–life conflict and negative stress coping methods such as consuming alcohol and/or drugs, emotional eating and aggression. However, no evidence was found to support the claim that demographic factors such as age and gender were also risk factors for CVDs.

Originality/value

The workers' compensation system provides financial protection to injured employees. It extends similar protection for work-related illnesses; however, it is more difficult to prove work-related causes for illnesses. The study provides scientific evidence to support the recognition of CVDs among construction professionals as work-related diseases, mediated by work stress.
Electronic service quality (e-SQ) measurement: a cross-functional review
Authors: Nandankar Sunil , Sachan Amit , Mukherjee Arindam , Adhikari Arnab
Published: November 2021

Purpose

Although comprehensive work has been conducted in several scholarly journals in electronic service quality (e-SQ) measurement, there has been no cross-functional review of these studies. The majority of the review studies focus on e-SQ assessment in the field of electronic retail. This paper explores and synthesizes e-SQ evaluation work across the various functional domains in the last two decades and maps critical methodological challenges. It further classifies the dimensions used by researchers in six broad categories for better comprehension.

Design/methodology/approach

To analyze and appreciate past e-SQ measurement research, a content assessment of the 50 most relevant research papers from various functional domains drawn from prestigious repositories was undertaken.

Findings

The results indicate shortcomings noticed in methodological issues in the e-SQ measurement research like research approaches, data analysis procedures, sampling methods, generation and purification of items, validity and reliability assessment, and dimensionality analysis. It further reveals that though e-SQ is multi-dimensional and context-specific, dimensions like content/information quality, website design, ease of use/usability, efficiency, security/and privacy, responsiveness, reliability, customer service, trust and fulfillment have been consistently cited in the reviewed studies across the various functional domains.

Originality/value

An assessment of 50 publications over the past 2 decades identifies key areas of concern in the existing research on e-SQ measurement in various functional domains for scholars and professionals. This study also provides a unique categorization of e-SQ dimensions used in various functional domains and has the potential to guide future research.
The impact of task description linguistic style on task performance: a text mining of crowdsourcing contests
Authors: Yang Keng , Qi Hanying , Huang Qian
Published: November 2021

Purpose

Existing studies on the relationship between task description and task performance are insufficient, with many studies considering description length rather than content to measure quality or only evaluating a single aspect of task performance. To address this gap, this study analyzes the linguistic styles of task descriptions from 2,545 tasks on the Taskcn.com crowdsourcing platform.

Design/methodology/approach

An empirical analysis was completed for task description language styles and task performance. The paper used text mining tool Simplified Chinese Linguistic Inquiry and Word Count to extract eight linguistic styles, namely readability, self-distancing, cognitive complexity, causality, tentative language, humanizing personal details, normative information and language intensity. And it tests the relationship between the eight language styles and task performance.

Findings

The study found that more cognitive complexity markers, tentative language, humanized details and normative information increase the quantity of submissions for a task. In addition, more humanized details and normative information in a task description improves the quality of task. Conversely, the inclusion of more causal relationships in a task description reduces the quantity of submissions. Poorer readability of the task description, less self-estrangement and higher language intensity reduces the quality of the task.

Originality/value

This study first reveals the importance of the linguistic styles used in task descriptions and provides a reference for how to attract more task solvers and achieve higher quality task performance by improving task descriptions. The research also enriches existing knowledge on the impact of linguistic styles and the applications of text mining.
Are school leaders culturally intelligent? Validation of the cultural intelligence (CQ) scale in the UAE
Authors: Al Dhaheri Ali
Published: November 2021

Purpose

The purpose of this paper is to report results of testing and validation of the cultural intelligence (CQ) Scale in a new location, the culturally diverse United Arab Emirates (UAE) and in a new sector: public and private school leaders.

Design/methodology/approach

This study surveys 167 school leaders from public and private schools in the UAE using the 20-item version of the CQ Scale, which uses a seven-point Likert response scale of strongly agree to strongly disagree. An examination of the dimensionality of the 20 items was conducted using both principal components analysis and confirmatory factor analysis. Demographics were also gathered.

Findings

Results from testing and validation of the scale indicated a high level of CQ among school leaders in the Emirate of Abu Dhabi. An examination of the dimensionality of the 20 items showed them to fall into the same structure of four sub-components as conceptually conceived: knowledge, strategy, motivation and behaviour. The mean scores for the four components of CQ in this study indicate high CQ amongst Abu Dhabi school leaders, although the knowledge dimension measured slightly lower. The results confirm previous research that found CQ to be higher in culturally diverse settings, which, according to socio-demographic details gathered in the study applies to the UAE.

Originality/value

This is the first known study to test the Cultural Intelligence Scale in UAE schools. It answers the call from the CQ Scale developers to validate the scale in diverse contexts.
High-speed railways and local economic performance: evidence from China’s prefecture-level cities
Authors: Li Chao , Zhao Zhao , Li Han
Published: November 2021

Purpose

The purpose of this paper is to identify the causal effect of high-speed railways (HSRs) and investigate the affecting channels; the second purpose is to examine how HSRs change the distribution of economic activity across cities and sectors.

Design/methodology/approach

A difference-in-difference strategy is implemented to estimate the impact of recently built HSRs on local economic performance in China, exploiting the geography and time variations in HSR operations.

Findings

Using panel data from China’s City Statistical Yearbook 2001–2019, the authors find that HSRs lead to a significant increase in cities’ gross domestic product (GDP) and GDP per capita, but the authors do not find any significant change in GDP growth. This conclusion still holds true after the authors address the endogeneity problems. A mechanism analysis shows that HSRs improve local economic performance mainly by increasing fixed asset investment. The authors also find that the HSR investment is a policy that favors metropolitan areas due to the larger increase in the GDP for larger cities and with HSRs, the industrial and service sectors will further agglomerate in larger cities.

Originality/value

The authors contribute to the literature in several ways. First, this paper improves the estimation strategy in identifying the HSR impact on the local economic performance. Second, this paper investigates the affecting channels of HSRs. This paper proves that HSRs in China promote the cities’ economic performance mainly by increasing the fixed asset investment. Third, this study provides evidence for the new economic geography models pioneered by Krugman (1991).
Improving school performance and student academic orientation: the role of safety-oriented knowledge management and diversity
Authors: Birasnav M. , Gantasala Prabhakar Venugopal , Gantasala Swapna Bhargavi
Published: November 2021

Purpose

The purpose of this study is to examine the influence of the implementation of safety-oriented knowledge management (KM) processes and student diversity acceptance in schools and the interaction effect of safety-oriented KM processes and student diversity acceptance over school performance and student academic orientation.

Design/methodology/approach

Responses of 977 American schools available in the database of the National Center for Education Statistics were analyzed using hierarchical regression analyses.

Findings

Results show that implementation of safety-oriented KM processes and diversity acceptance in schools have varying effects on school performance and student academic orientation. The impact of knowledge acquisition from parents on the academic achievement of students is positive and stronger in schools that are low in student diversity acceptance than schools that are high in student diversity acceptance.

Originality/value

This study adds value to the KM literature by exploring how KM processes are executed in American schools to improve their performance and students’ academic orientation and how diversity among students alters the strength of the relationships.
Immune activity in Merkel cell carcinoma
Authors: Nakamura Motoki , Morita Akimichi
Published: November 2021

Merkel cell carcinoma (MCC) is widely known as a highly malignant skin cancer. The pathogenesis of MCC, however, remains mysterious due to the extremely small number of cases and its prevalence in the elderly. Despite its high‐grade malignancy, spontaneous regression occurs with some frequency. The immune activity of the tumor underlies this peculiar behavior. In recent years, immune checkpoint blockade therapies, including the anti‐programmed death ligand 1 antibody, have provided successful results. These therapies, however, are ineffective in approximately half the patients with advanced MCC and few treatments are available for those patients. In this review, we summarize the increasing body of evidence relating to the immune activity of MCC and immunological biomarkers. The interesting and sometimes peculiar behavior of MCC, such as their spontaneous regression, is largely due to their high immunosensitivity. Understanding the tumor immunokinetics of MCC should provide critical insight for understanding cancer immunotherapy. Here, we introduce a new classification for MCC according to its immune activity. Combined application of programmed death ligand 1 (a prognostic factor and predictor of the efficacy of immune checkpoint inhibitors in various cancers) with glucose‐6‐phosphate dehydrogenase (a new promising biomarker for MCC) may enable classification of MCC based on its immune status. Whether the new classification can be used to predict the efficacy of immune checkpoint blockade therapies remains to be evaluated in future studies, but the classification may facilitate future treatment selection.