bluuebunny/crossref_metadata_2025 huggingface dataset:
Update on pain in arthritis
Authors: Bharde Sabah , Caxaria Sara , Dell’Accio Francesco , Sikandar Shafaq
Published: April 2021

Purpose of review

Osteoarthritis is a degenerative joint disease that features pain as a hallmark symptom. This review summarises progress and obstacles in our understanding of pain mechanisms in arthritis.

Recent findings

Pain phenotypes in osteoarthritis are poorly characterized in clinical studies and animal studies are largely carti-centric. Different animal models incur variable disease progression patterns and activation of distinct pain pathways, but studies reporting both structural and pain outcomes permit better translational insights. In patients, classification of osteoarthritis disease severity is only based on structural integrity of the joint, but pain outcomes do not consistently correlate with joint damage. The complexity of this relationship underlines the need for pain detection in criteria for osteoarthritis classification and patient-reported outcome measures.

Variable inflammatory and neuropathic components and spatiotemporal evolution underlie the heterogeneity of osteoarthritis pain phenotypes, which must be considered to adequately stratify patients. Revised classification of osteoarthritis at different stages encompassing both structural and pain outcomes would significantly improve detection and diagnosis at both early and late stages of disease. These are necessary advancements in the field that would also improve trial design and provide better understanding of basic mechanisms of disease progression and pain in osteoarthritis.
Staying on target: Maintaining a balanced resuscitation during damage-control resuscitation improves survival
Authors: Hynes Allyson M. , Geng Zhi , Schmulevich Daniela , Fox Erin E. , Meador Christopher L. , Scantling Dane R. , Holena Daniel N. , Abella Benjamin S. , Young Andrew J. , Holland Sara , Cacchione Pamela Z. , Wade Charles E. , Cannon Jeremy W. ,   PROMMTT Study Group
Published: April 2021

BACKGROUND

Damage-control resuscitation (DCR) improves survival in severely bleeding patients. However, deviating from balanced transfusion ratios during a resuscitation may limit this benefit. We hypothesized that maintaining a balanced resuscitation during DCR is independently associated with improved survival.

METHODS

This was a secondary analysis of the Prospective Observational Multicenter Major Trauma Transfusion (PROMMTT) study. Patients receiving >3 U of packed red blood cells (PRBCs) during any 1-hour period over the first 6 hours and surviving beyond 30 minutes were included. Linear regression assessed the effect of percent time in a high-ratio range on 24-hour survival. We identified an optimal ratio and percent of time above the target ratio threshold by Youden’s index. We compared patients with a 6-hour ratio above the target and above the percent time threshold (on-target) with all others (off-target). Kaplan-Meier analysis assessed the combined effect of blood product ratio and percent time over the target ratio on 24-hour and 30-day survival. Multivariable logistic regression identified factors independently associated with 24-hour and 30-day survival.

RESULTS

Of 1,245 PROMMTT patients, 524 met the inclusion criteria. Optimal targets were plasma/PRBC and platelet/PRBC of 0.75 (3:4) and ≥40% time spent over this threshold. For plasma/PRBC, on-target (n = 213) versus off-target (n = 311) patients were younger (median, 31 years; interquartile range, [22–50] vs. 40 [25–54]; p = 0.002) with similar injury burdens and presenting physiology. Similar patterns were observed for platelet/PRBC on-target (n = 116) and off-target (n = 408) patients. After adjusting for differences, on-target plasma/PRBC patients had significantly improved 24-hour (odds ratio, 2.25; 95% confidence interval, 1.20–4.23) and 30-day (odds ratio, 1.97; 95% confidence interval, 1.14–3.41) survival, while on-target platelet/PRBC patients did not.

CONCLUSION

Maintaining a high ratio of plasma/PRBC during DCR is independently associated with improved survival. Performance improvement efforts and prospective studies should capture time spent in a high-ratio range.

LEVEL OF EVIDENCE

Epidemiologic/prognostic study, level II; Therapeutic, level IV.
Histologic Antibody-mediated Kidney Allograft Rejection in the Absence of Donor-specific HLA Antibodies
Authors: Filippone Edward J. , Farber John L.
Published: April 2021

Histologic antibody-mediated rejection (hAMR) is defined as a kidney allograft biopsy satisfying the first 2 Banff criteria for diagnosing AMR: tissue injury and evidence of current/recent antibody interaction with the endothelium. In approximately one-half of such cases, circulating human leukocyte antigen (HLA) donor-specific antibodies (DSA) are not detectable by current methodology at the time of biopsy. Some studies indicated a better prognosis for HLA-DSA-negative cases of hAMR compared to those with detectable HLA-DSA, whereas others found equally poor survival compared to hAMR-negative cases. We reviewed the literature regarding the pathophysiology of HLA-DSA-negative hAMR. We find 3 nonmutually exclusive possibilities: (1) HLA-DSA are involved, but just not detected; (2) non-HLA-DSA (allo or autoantibodies) are pathogenically involved; and/or (3) antibody-independent NK cell activation is mediating the process through “missing-self” or other activating mechanisms. These possibilities are discussed in detail. Recommendations regarding the approach to such patients are made. Clearly, more research is necessary regarding the measurement of non-HLA antibodies, recipient/donor NK cell genotyping, and the use of antibody reduction therapy or other immunosuppression in any subset of patients with HLA-DSA-negative hAMR.
The Measurement of Everyday Cognition (ECog)
Authors: Farias Sarah T. , Weakley Alyssa , Harvey Danielle , Chandler Julie , Huss Olivia , Mungas Dan
Published: April 2021

Introduction:

The Everyday Cognition scale (ECog), a measure of everyday functioning developed in 2008, is sensitive to early detection and progression of neurodegenerative disease. The goal was to update ECog item content to ensure relevancy to contemporary older adults from diverse backgrounds.

Methods:

Participants included 44 culturally diverse older adults (18 with normal cognition, 11 with mild cognitive impairment) and their study partners. Item understandability and relevance was evaluated using iterative interviewing methods that were analyzed using standard qualitative methods. On the basis of this information, items were modified, deleted, or developed as needed.

Results:

Of the 39 original items, 19 were revised, 3 new items were added (primarily to cover contemporary activities such as the use of technology), and 1 was deleted. The revised version (ECog-II) includes 41 items.

Discussion:

To ensure strong psychometric properties, and to facilitate harmonization of previously collected data, we preserved well over half of the items. Future work will validate the revised ECog by measuring associations with neuropsychological performance, external measures of disease, and other functional measures. Overall, the revised ECog will continue to be a useful tool for measuring cognitively relevant everyday abilities in clinical settings and intervention clinical trials.
Increasing Sample Diversity in Psychiatric Genetics – Introducing a new Cohort of Patients with Schizophrenia and Controls from Vietnam – Results from a Pilot Study
Authors: Nguyen VT , Braun A , Kraft J , Ta TMT , Panagiotaropoulou GM , Nguyen VP , Nguyen TH , Trubetskoy V , Le CT , Le TTH , Pham XT , Heuser-Collier I , Lam NH , Böge K , Hahne IM , Bajbouj M , Zierhut MM , Hahn E , Ripke S
Published: April 2021

Objectives

Genome-Wide Association Studies (GWAS) of Schizophrenia (SCZ) have provided new biological insights; however, most cohorts are of European ancestry. As a result, derived polygenic risk scores (PRS) show decreased predictive power when applied to populations of different ancestries. We aimed to assess the feasibility of a large-scale data collection in Hanoi, Vietnam, contribute to international efforts to diversify ancestry in SCZ genetic research and examine the transferability of SCZ-PRS to individuals of Vietnamese Kinh ancestry.

Methods

In a pilot study, 368 individuals (including 190 SCZ cases) were recruited at the Hanoi Medical University’s associated psychiatric hospitals and outpatient facilities. Data collection included sociodemographic data, baseline clinical data, clinical interviews assessing symptom severity and genome-wide SNP genotyping. SCZ-PRS were generated using different training data sets: i) European, ii) East-Asian and iii) trans-ancestry GWAS summary statistics from the latest SCZ GWAS meta-analysis.

Results

SCZ-PRS significantly predicted case status in Vietnamese individuals using mixed-ancestry (R2 liability=4.9%, p=6.83*10−8), East-Asian (R2 liability=4.5%, p=2.73*10−7) and European (R2 liability=3.8%, p = 1.79*10−6) discovery samples.

Discussion

Our results corroborate previous findings of reduced PRS predictive power across populations, highlighting the importance of ancestral diversity in GWA studies.
Mathematical modeling suggests pre-existing immunity to SARS-CoV-2
Authors: Carlsson Marcus , Hatem Gad , Söderberg-Nauclér Cecilia
Published: April 2021

Mathematical models have largely failed to predict the unfolding of the COVID-19 pandemic. We revisit several variants of the SEIR-model and investigate various adjustments to the model in order to achieve output consistent with measured data in Manaus, India and Stockholm. In particular, Stockholm is interesting due to the almost constant NPI’s, which substantially simplifies the mathematical modeling. Analyzing mobility data for Stockholm, we argue that neither behavioral changes, age and activity stratification nor NPI’s alone are sufficient to explain the observed pandemic progression. We find that the most plausible hypothesis is that a large portion of the population, between 40 to 60 percent, have some protection against infection with the original variant of SARS-CoV-2.
Effects of B.1.1.7 and B.1.351 on COVID-19 dynamics. A campus reopening study
Authors: Linka Kevin , Peirlinck Mathias , Schäfer Amelie , Tikenogullari Oguz Ziya , Goriely Alain , Kuhl Ellen
Published: April 2021

The timing and sequence of safe campus reopening has remained the most controversial topic in higher education since the outbreak of the COVID-19 pandemic. By the end of March 2020, almost all colleges and universities in the United States had transitioned to an all online education and many institutions have not yet fully reopened to date. For a residential campus like Stanford University, the major challenge of reopening is to estimate the number of incoming infectious students at the first day of class. Here we learn the number of incoming infectious students using Bayesian inference and perform a series of retrospective and projective simulations to quantify the risk of campus reopening. We create a physics-based probabilistic model to infer the local reproduction dynamics for each state and adopt a network SEIR model to simulate the return of all undergraduates, broken down by their year of enrollment and state of origin. From these returning student populations, we predict the outbreak dynamics throughout the spring, summer, fall, and winter quarters using the inferred reproduction dynamics of Santa Clara County. We compare three different scenarios: the true outbreak dynamics under the wild-type SARS-CoV-2, and the hypothetical outbreak dynamics under the new COVID-19 variants B.1.1.7 and B.1.351 with 56% and 50% increased transmissibility. Our study reveals that even small changes in transmissibility can have an enormous impact on the overall case numbers. With no additional countermeasures, during the most affected quarter, the fall of 2020, there would have been 203 cases under base-line reproduction, compared to 4727 and 4256 cases for the B.1.1.7 and B.1.351 variants. Our results suggest that population mixing presents an increased risk for local outbreaks, especially with new and more infectious variants emerging across the globe. Tight outbreak control through mandatory quarantine and test-trace-isolate strategies will be critical in successfully managing these local outbreak dynamics.
Approximate Reciprocal Relationship Between Two Cause-Specific Hazard Ratios in COVID-19 Data With Mutually Exclusive Events
Authors: Cetin Sirin , Ulgen Ayse , Sivgin Hakan , Li Wentian
Published: April 2021

COVID-19 survival data presents a special situation where not only the time-to-event period is short, but also the two events or outcome types, death and release from hospital, are mutually exclusive, leading to two cause-specific hazard ratios (csHRd and csHRr). The eventual mortality/release outcome can also be analyzed by logistic regression to obtain odds-ratio (OR). We have the following three empirical observations concerning csHRd, csHRr and OR: (1) The magnitude of OR is an upper limit of the csHRd: | log(OR) | ≥ | log(csHRd)|. This relationship between OR and HR might be understood from the definition of the two quantities; (2) csHRd and csHRr point in opposite directions: log(csHRd)· log(csHRr) < 0; This relation is a direct consequence of the nature of the two events; and (3) there is a tendency for a reciprocal relation between csHRd and csHRr: csHRd ∼ 1/csHRr. Though an approximate reciprocal trend between the two hazard ratios is in indication that the same factor causing faster death also lead to slow recovery by a similar mechanism, and vice versa, a quantitative relation between csHRd and csHRr in this context is not obvious. These resutls may help future analyses of COVID-19 data, in particular if the deceased samples are lacking.
A Pan-Cancer Census of Dominant Tumor Immune Archetypes
Authors: Combes Alexis J. , Samad Bushra , Tsui Jessica , Chew Nayvin W. , Yan Peter , Reeder Gabriella C. , Kushnoor Divyashree , Shen Alan , Davidson Brittany , Barczac Andrea J. , Adkisson Michael , Edwards Austin , Naser Mohammad , Barry Kevin C. , Courau Tristan , Hammoudi Taymour , Arguëllo Rafael J , Rao Arjun Arkal , Olshen Adam B. ,   The Immunoprofiler consortium, Cai Cathy , Zhan Jenny , Davis Katelyn C. , Kelley Robin K. , Chapman Jocelyn S. , Attreya Chloe E. , Patel Amar , Daud Adil I. , Ha Patrick , Diaz Aaron A. , Kratz Johannes R. , Collisson Eric A. , Fragiadakis Gabriela K , Erle David J. , Boissonnas Alexandre , Asthana Saurabh , Chan Vincent , Krummel Matthew F.
Published: April 2021

Cancers display significant heterogeneity with respect to tissue of origin, driver mutations and other features of the surrounding tissue. It is likely that persistent tumors differentially engage inherent patterns–here ‘Archetypes’–of the immune system, to both benefit from a tumor immune microenvironment (TIME) and to disengage tumor-targeting. To discover dominant immune system archetypes, the Immunoprofiler Initiative (IPI) processed 364 individual tumors across 12 cancer types using standardized protocols. Computational clustering of flow cytometry and transcriptomic data obtained from cell sub compartments uncovered archetypes that exist across indications. These Immune composition-based archetypes differentiate tumors based upon unique immune and tumor gene-expression patterns. Archetypes discovered this way also tie closely to well-established classifications of tumor biology. The IPI resource provides a template for understanding cancer immunity as a collection of dominant patterns of immune infiltration and provides a rational path forward to learn how to modulate these patterns to improve therapy.
Discovery of an unusual high number ofde novomutations in sperm of older men using duplex sequencing
Authors: Salazar Renato , Arbeithuber Barbara , Ivankovic Maja , Heinzl Monika , Moura Sofia , Hartl Ingrid , Mair Theresa , Lahnsteiner Angelika , Ebner Thomas , Shebl Omar , Pröll Johannes , Tiemann-Boege Irene
Published: April 2021

De novomutations (DNMs) are an important player in heritable diseases and evolution. Of particular interest are highly recurrent DNMs associated with congenital disorders that have been described as selfish mutations expanding in the male germline, thus becoming more frequent with age. Here, we have adapted duplex sequencing (DS), an ultra-deep sequencing method that renders sequence information on both DNA strands; thus, one mutation can be reliably called in millions of sequenced bases. With DS, we examined ∼4.5 kb of theFGFR3coding region in sperm DNA from older and younger donors. We identified sites with variant frequencies of 10−4to 10−5, with an overall mutation frequency of the region of ∼6×10−7. Some of the substitutions were re-current and were found at a higher variant frequency in older donors than in younger ones, or exclusively, in older donors. Also, older donors harbored more mutations associated with congenital disorders. Other mutations were present in both age groups suggesting that these might result from a different mechanism (e.g., post-zygotic mosaicism). We also observed that independent of age, the frequency and deleteriousness of the mutational spectra was more similar to COSMIC than to gnomAD variants. Our approach is an important strategy to identify mutations that could be associated with a gain-of-function of the receptor tyrosine kinase activity, with unexplored consequences in a society with delayed fatherhood.
Quantitative imaging ofCaenorhabditis elegansdauer larvae during cryptobiotic transition using optical diffraction tomography
Authors: Kim Kyoohyun , Gade Vamshidhar R. , Kurzchalia Teymuras V. , Guck Jochen
Published: April 2021

Upon starvation or overcrowding, the nematodeCaenorhabditis elegansenters diapause by forming a dauer larva. This larva can further transit into an anhydrobiotic state and survive harsh desiccation. We previously identified the genetic and biochemical pathways essential for survival — but without an accompanying physical model, the mechanistic understanding of this amazing phenomenon will remain inadequate. Neither microscopic investigation of structural changes upon entry into anhydrobiosis nor the most basic quantitative characterization of material properties of living desiccated larvae, however, have been feasible, due to lack of appropriate techniques. Here, we employed optical diffraction tomography (ODT) to quantitatively assess the internal mass density distribution of living larvae in the reproductive and diapause stages. More importantly, ODT allowed for the first time physical analysis of desiccated dauer larvae: their mass density was significantly increased in the anhydrobiotic state. We also applied ODT on different mutants that are sensitive to desiccation. Remarkably, one of them displayed structural abnormalities in the anhydrobiotic stage that could not be observed either by conventional light or electron microscopy. Our advance opens a door to quantitatively assessing fine differences in material properties and structure necessary to fully understanding an organism on the verge of life and death.
Quantifying chromosomal instability from intratumoral karyotype diversity using agent-based modeling and Bayesian inference
Authors: Lynch A.R. , Arp N.L. , Zhou A.S. , Weaver B.A. , Burkard M.E.
Published: April 2021

Chromosomal instability (CIN) — persistent chromosome gain or loss through abnormal karyokinesis — is a hallmark of cancer that drives aneuploidy. Intrinsic chromosome mis-segregation rates, a measure of CIN, can inform prognosis and are a likely biomarker for response to anti-microtubule agents. However, existing methodologies to measure this rate are labor intensive, indirect, and confounded by karyotype selection reducing observable diversity. We developed a framework to simulate and measure CIN, accounting for karyotype selection, and recapitulated karyotype-level clonality in simulated populations. We leveraged approximate Bayesian computation using phylogenetic topology and diversity to infer mis-segregation rates and karyotype selection from single-cell DNA sequencing data. Experimental validation of this approach revealed extensive chromosome mis-segregation rates caused by the chemotherapy paclitaxel (17.5±0.14/division). Extending this approach to clinical samples revealed the inferred rates fell within direct observations of cancer cell lines. This work provides the necessary framework to quantify CIN in human tumors and develop it as a predictive biomarker.
PEAR: a flexible fluorescent reporter for the identification and enrichment of successfully prime edited cells
Authors: Simon Dorottya A. , Tálas András , Kulcsár Péter I. , Welker Ervin
Published: April 2021

Prime editing is a recently developed gene engineering tool that allows the introduction of short insertions, deletions or substitutions into the genome. However, the efficiency of prime editing, generally reaching around 10-30% editing, has not resembled its versatility. Here, Prime Editor Activity Reporter (PEAR), a sensitive fluorescent tool is introduced for the identification of single cells with prime editing activity. Possessing no background fluorescence, PEAR specifically reports on prime editing events in individual cells. By design, it ensures unrestricted flexibility for sequence variations in the full length of the target sequence. The application of PEAR as an enrichment marker of prime editing can increase the edited population by up to 70% and alleviate the burden of the otherwise time and labour consuming process of cloning of the correctly edited cells, therefore considerably improving the applicability of prime editing in fundamental research and biotechnological uses.
Loss ofMafbandMafdistorts myeloid cell ratios and disrupts fetal mouse testis vascularization and organogenesis
Authors: Li Shu-Yun , Gu Xiaowei , Heinrich Anna , Hurley Emily G. , Capel Blanche , DeFalco Tony
Published: April 2021

Testis differentiation is initiated whenSryin pre-Sertoli cells directs the gonad toward a male-specific fate. Sertoli cells are essential for testis development, but cell types within the interstitial compartment, such as immune and endothelial cells, are also critical for organ formation. Our previous work implicated macrophages in fetal testis morphogenesis, but little is known about genes underlying immune cell development during organogenesis. Here we examine the role of the immune-associated genesMafbandMafin mouse fetal gonad development, and we demonstrate that deletion of these genes leads to aberrant hematopoiesis manifested by supernumerary gonadal monocytes.Mafb;Mafdouble knockout embryos underwent initial gonadal sex determination normally, but exhibited testicular hypervascularization, testis cord formation defects, Leydig cell deficit, and a reduced number of germ cells. In general,MafbandMafalone were dispensable for gonad development; however, when both genes were deleted, we observed significant defects in testicular morphogenesis, indicating thatMafbandMafwork redundantly during testis differentiation. These results demonstrate previously unappreciated roles forMafbandMafin immune and vascular development and highlight the importance of interstitial cells in gonadal differentiation.

Summary statement

Deletion ofMafbandMafgenes leads to supernumerary monocytes in fetal mouse gonads, resulting in vascular, morphogenetic, and differentiation defects during testicular organogenesis.
Maintaining grass coverage increases methane uptake in Amazonian pasture soils
Authors: de Souza Leandro Fonseca , Alvarez Dasiel Obregon , Domeignoz-Horta Luiz A. , Gomes Fabio Vitorino , de Souza Almeida Cassio , Merloti Luis Fernando , Mendes Lucas William , Andreote Fernando Dini , Bohannan Brendan J. M. , Rodrigues Jorge M. , Nüsslein Klaus , Tsai Siu Mui
Published: April 2021

Cattle ranching is the largest driver of deforestation in the Brazilian Amazon. The rainforest- to-pasture conversion affects the methane cycle in upland soils, changing it from sink to source of atmospheric methane. However, it remains unknown if management practices could reduce the impact of land-use on methane cycling. In this work, we evaluated how pasture management can regulate the soil methane cycle either by maintaining continuous grass coverage on pasture soils, or by liming the soil to amend acidity. Methane fluxes from forest and pasture soils were evaluated in moisture-controlled greenhouse experiments with and without grass cover (Urochloa brizanthacv. Marandu) or liming. In parallel, we assessed changes in the soil microbial community structure of both bare pasture soil as well as rhizosphere soil through high throughput sequencing of the 16S rRNA gene, and quantified the methane cycling microbiota by their respective marker genes related to methane generation (mcrA) or oxidation (pmoA). The experiments used soils from eastern and western Amazonia, and concurrent field studies allowed us to confirm greenhouse data. The presence of a grass cover not only increased methane uptake by up to 35% in pasture soils, but also reduced the abundance of the methane-producing community. In the grass rhizosphere this reduction was up to 10-fold. Methane-producing archaea belonged to the generaMethanosarcina sp.,Methanocella sp.,Methanobacterium sp., and Rice Cluster I. Further, we showed that liming compromised the capacity of forest and pasture soils to be a sink for methane, and instead converted formerly methane-consuming forest soils to become methane sources in only 40-80 days. Our results demonstrate that pasture management that maintains grass coverage can mitigate soil methane emissions, if compared to a bare pasture soil.
The Lack of Nrf2 Causes Hepatocyte Dedifferentiation and Reduced Albumin Production in an Experimental Extrahepatic Cholestasis Model
Authors: Wang Guo-Ying , Garcia Veronica , Lee Joonyong , Yanum Jennifer , Jiang Huaizhou , Dai Guoli
Published: April 2021

The transcription factor Nrf2 modulates the initiation and progression of a number of diseases including liver disorders. The aim of this study was to evaluate whether Nrf2 mediates hepatic adaptive responses to cholestasis. Wild-type and Nrf2-null mice were subjected to bile duct ligation (BDL) or a sham operation. Various assessments were performed at different days after surgery. Significant genotype-dependent changes in liver size, biliary ductular reaction, hepatocyte proliferation, and fibrotic response were not observed. However, as cholestasis progressed to Day 15 post-BDL, hepatocytes in the wild-type mice exhibited a tendency to dedifferentiate, indicated by the very weak expression of hepatic progenitor markers: CD133 and fibroblast growth factor-inducible 14 (Fn14). During the same period, Nrf2 deficiency augmented this tendency, manifested by higher CD133 expression, earlier, stronger, and continuous induction of Fn14 expression, and markedly reduced albumin production. Remarkably, as cholestasis advanced to the late stage (40 days after BDL), hepatocytes in the wild-type mice exhibited a Fn14+ phenotype and strikingly upregulated the expression of deleted in malignant brain tumor 1 (DMBT1), a protein essential for epithelial differentiation during development. In contrast, at this stage, hepatocytes in the Nrf2-null mice entirely inhibited the upregulation of DMBT1 expression, displayed a strong CD133+/Fn14+ phenotype indicative of severe dedifferentiation, and persistently reduced albumin production. Collectively, our studies revealed that Nrf2 maintains hepatocytes in the differentiated state potentially via the increased activity of the Nrf2/DMBT1 pathway during cholestasis. These findings enable us to gain novel insight into how hepatocytes respond to cholestasis.

New and Noteworthy

We found that, when hepatocytes are exposed to cholestasis, they exhibit a tendency of dedifferentiation. In this case, Nrf2 is highly activated to markedly up-regulate the expression of epithelial differentiation gene DMBT1, which potentially prevent hepatocytes from dedifferentiation. Our findings revealed a plastic property of hepatocytes in response to cholestasis and demonstrated a novel Nrf2/DMBT1 pathway likely controlling this property of hepatocytes.
The parallel origins of vertebrate venoms
Authors: Barua Agneesh , Koludarov Ivan , Mikheyev Alexander S.
Published: April 2021

Evolution can occur with surprising predictability when organisms face similar ecological challenges. How and why traits arise repeatedly remains a central question in evolutionary biology, but the complexity of most traits makes it challenging to answer. Reptiles and mammals independently evolved oral venoms consisting of proteinaceous cocktails that allow mapping between genotype and phenotype. Although biochemically similar toxins can occur as major venom components across many taxa, whether these toxins evolved via convergent or parallel processes remains unknown. Most notable among them are kallikrein-like serine proteases that form the core of most vertebrate oral venoms. We used a combination of comparative genomics and phylogenetics to investigate whether serine protease recruitment into the venom occurred independently or in parallel in mammalian and reptilian lineages. Using syntenic relationships between genes flanking known toxins, we traced the origin of kallikreins to a single locus containing one or more nearby paralogous kallikrein-like clusters. Independently, phylogenetic analysis of vertebrate serine proteases revealed that kallikrein-like toxins in mammals and reptiles are homologous. Given the shared regulatory and genetic machinery, these findings suggest a unified model underlying vertebrate venom evolution. Namely, the common tetrapod ancestor possessed salivary genes that were biochemically suitable for envenomation. We term such genes ‘toxipotent’ – in the case of salivary kallikreins they already had potent vasodilatory activity that was weaponized by venomous lineages. Furthermore, the ubiquitous distribution of kallikreins across vertebrates suggests that the evolution of envenomation may be more common than previously recognized, blurring the line between venomous and non-venomous animals.
THC modifies the impact of heroin delivered by vapor inhalation in rats
Authors: Gutierrez Arnold , Nguyen Jacques D. , Creehan Kevin M. , Javadi-Paydar Mehrak , Grant Yanabel , Taffe Michael A.
Published: April 2021

Opioids are effective medications, but they have several key limitations including the development of tolerance, establishment of dependence, diversion for non-medical use and the development of addiction. Therefore, any drugs which act in an additive or synergistic fashion with opioids to address medical applications have the potential to reduce opioid-related harms. This study was conducted to determine if heroin and Δ9-tetrahydrocannabinol (THC) interact in an additive or independent manner to alter nociception, body temperature and spontaneous locomotor activity when inhaled or injected.

Groups of male and female rats implanted with radiotelemetry transmitters were exposed to vapor for assessment of effects on temperature and activity. Heroin (50 mg/mL in the propylene glycol; PG) inhalation increased temperature and activity whereas THC (50 mg/mL) inhalation decreased temperature and activity. Effects of combined inhalation were in opposition, and additional experiments found the same outcome for the injection of heroin (0.5 mg/kg, s.c.) and THC (10 mg/kg, i.p.) alone and in combination. In contrast, the co-administration of Heroin and THC by either inhalation or injection produced additive effects on thermal nociception assessed with a warm water tail-withdrawal assay in male and female Sprague-Dawley and Wistar rats.

The conclusion of this study is that additive effects of THC with heroin on a medical endpoint such as analgesia may not generalize to other behavioral or physiological effects, which may be a positive outcome for unwanted side effects.
Integrated spatial genomics in tissues reveals invariant and cell type dependent nuclear architecture
Authors: Takei Yodai , Zheng Shiwei , Yun Jina , Shah Sheel , Pierson Nico , White Jonathan , Schindler Simone , Tischbirek Carsten , Yuan Guo-Cheng , Cai Long
Published: April 2021

Nuclear architecture in tissues can arise from cell-type specific organization of nuclear bodies, chromatin states and chromosome structures. However, the lack of genome-wide measurements to interrelate such modalities within single cells limits our overall understanding of nuclear architecture. Here, we demonstrate integrated spatial genomics in the mouse brain cortex, imaging thousands of genomic loci along with RNAs and subnuclear markers simultaneously in individual cells. We revealed chromatin fixed points, combined with cell-type specific organization of nuclear bodies, arrange the interchromosomal organization and radial positioning of chromosomes in diverse cell types. At the sub-megabase level, we uncovered a collection of single-cell chromosome domain structures, including those for the active and inactive X chromosomes. These results advance our understanding of single-cell nuclear architecture in complex tissues.
Testing the Tea Bag Index as a potential indicator for assessing litter decomposition in aquatic ecosystems
Authors: Mori Taiki , Ono Kenji , Sakai Yoshimi
Published: April 2021

The Tea Bag Index (TBI) approach is a standardized method for assessing litter decomposition in terrestrial ecosystems. This method allows determination of the stabilized portion of the hydrolysable fraction during the decomposition process, and derivation of a decomposition constant (k) using single measurements of the mass-loss ratios of green and rooibos teas. Although this method is being applied to aquatic systems, it has not been validated in these environments, where initial leaching tends to be higher than in terrestrial ecosystems. Here, we first validated a critical assumption of the TBI method that green tea decomposition plateaus during the standard incubation period of 90 days, and then tested the accuracy of a TBI-based asymptote model using a second model obtained from fitting actual decomposition data. Validation data were obtained by incubating tea bags in water samples taken from a stream, a pond, and the ocean in Kumamoto, Japan. We found that green tea decomposition did not plateau during the 90-day period, contradicting a key assumption of the TBI method. Moreover, the TBI-based asymptote models disagreed with actual decomposition data. Subtracting the leachable fraction from the initial tea mass improved the TBI-based model, but discrepancies with the actual decomposition data remained. Thus, we conclude that the TBI approach, which was developed for a terrestrial environment, is not appropriate for aquatic ecosystems. However, the use of tea bags as a standard material in assessments of aquatic litter decomposition remains beneficial.
Generation of a Sleeping Beauty transposon-based cellular system for rapid and sensitive identification of SARS-CoV-2 host dependency and restriction factors
Authors: Widera Marek , Wilhelm Alexander , Toptan Tuna , Raffel Johanna M. , Kowarz Eric , Roesmann Fabian , Siemund Anna Lena , Luciano Vanessa , Külp Marius , Reis Jennifer , Bracharz Silvia , Pallas Christiane , Ciesek Sandra , Marschalek Rolf
Published: April 2021

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the causative agent of the acute respiratory disease COVID-19, which has become a global concern due to its rapid spread. The common methods to monitor and quantitate SARS-CoV-2 infectivity in cell culture are so far time-consuming and labor-intensive. Using the Sleeping Beauty transposase system, we generated a robust and versatile reporter cell system that allows SARS-CoV-2 infection experiments compatible for high-throughput and live cell imaging. The reporter cell is based on lung derived A549 cells, which show a profound interferon response and convenient cell culture characteristics. ACE2 and TMPRSS2 were introduced for constitutive expression in A549 cells. Subclones with varying levels of ACE2/TMPRSS2 were screened for optimal SARS-CoV2 susceptibility. Furthermore, extensive evaluation demonstrated that SARS-CoV-2 infected reporter cells were distinguishable from mock-infected cells and already showed approximately 12 h post infection a clear signal to noise ratio in terms of cell roughness, fluorescence and a profound visible cytopathic effect. Moreover, due to the high transfection efficiency and proliferation capacity, Sleeping Beauty transposase-based overexpression cell lines with a second inducible fluorescence reporter cassette (eGFP) can be generated in a very short time, enabling the investigation of host and restriction factors in a doxycycline-inducible manner. Thus, the novel reporter cell line allows rapid and sensitive detection of SARS-CoV-2 infection and the screening for host factors essential for viral replication.

Highlights

- Sleeping Beauty transposon-based cellular system was used to generate a highly susceptible cell line for monitoring SARS-CoV-2 infection

- The versatile reporter cell line A549-AT is suitable for rapid and sensitive high-throughput assays

- Additional gene specific expression cassettes allow the identification of SARS-CoV-2 host dependency and restriction factors
Women CEOs and firm performance in the construction industry: evidence from Spain
Authors: Hernández-Nicolás Carmen María , Martín-Ugedo Juan Francisco , Minguez-Vera Antonio
Published: April 2021

Purpose

The construction industry has traditionally been a male-dominated economic sector. Barely 10% of managers are women. On the other hand, this sector is considered an engine of the economy. For these reasons, it is important to examine the influence of women CEOs on financial variables of firms in the construction industry.

Design/methodology/approach

The empirical study is carried out using a sample from the Iberian Balance Sheet Analysis System record (“Sistema de Análisis de Balances Ibérico”, SABI). The sample includes 8,492 Spanish companies from the construction sector. The methodology employed is a three-stage least squares (3SLS) analysis. This methodology controls for the endogeneity of explanatory variables. It is employed in accordance with the peculiar characteristics of the sample, which includes data for only one year.

Findings

The results show that firms with a woman CEO have a lower level of debt, whatever the terms of the maturity of the debt are. In contrast to most previous evidence, firms managed by women are found to be less profitable.

Originality/value

The paper gives evidence of the influence of the CEO's gender on the performance (return and risk) of a firm. It provides original empirical evidence for the male-dominated construction sector. An extensive search identified no literature in which the researchers had focused on the construction industry.
Thermal comfort practices for precast concrete building construction projects: towards BIM and IOT integration
Authors: Ismail Zul-Atfi Bin
Published: April 2021

Purpose

Improper evaluation and information mismanagement concerning thermal comfort appears to negatively affect occupants' satisfaction and building energy consumption in precast concrete (PC) building contexts. Predictive models are particularly problematic in PC building construction projects where natural ventilation levels do not coincide with occupants' thermal comfort and thermal sensation specifications.

Design/methodology/approach

A systematic literature review is undertaken to explore the viability and benefits of a new ICT-based approach for meeting social and environmental objectives.

Findings

Sophisticated thermal comfort system solutions are essential for optimising thermal comfort and saving energy in PC building construction projects.

Originality/value

It is imperative that designers and manufacturers are kept up-to-date with the possibilities and potentials associated with new and nascent technologies so that building projects can meet key sustainability criteria.
Adaptive mechanisms in a continuing landscape: assessing biocultural diversity as a form of resilience
Authors: Palazzo Elisa , Bardsley Douglas K.
Published: April 2021

Purpose

This paper investigates the adaptive capacity expressed by an agricultural region in response to changing conditions as a mean to address the future of cultural landscapes in a time of extreme uncertainty. Through the conceptual framework of biocultural diversity, the work assesses regimes shifts and persistence as a dialectic between natural and anthropogenic components of the landscape.

Design/methodology/approach

Specifically, the mechanisms of progressive landscape adaptation are explored by using an integrated method to align manifestations of biological and cultural diversity. Through a multidimensional approach applied to spatial analysis, the study determines a relationship between the footprint of past and modern landscape regimes and contemporary rural management practices in McLaren Vale, South Australia.

Findings

The biological and cultural diversity patterns along riparian corridors, or “biocultural corridors” are indicators of past and current adaptive capacity, which are able to convey novel trajectories of sustainable management in the landscape system.

Originality/value

Understanding the positive feedback loops between nature and human interactions as represented by their interrelationships in the landscape can inform planning decisions for sustainable agricultural development and enable effective regional long-term trajectories of resilience.
Integrating maternal and child health data into the Iraqi Kurdistan health information system
Authors: Alsilefanee Haveen H. , Qadir Sivar A. , Salih Shahla O. , Alhanabadi Luma H. , Emberti Gialloreti Leonardo , Moramarco Stefania
Published: April 2021

Purpose

The purpose of this study is to present the workflow on the integration of Maternal and Child Health Care Services (MCHCS) into the electronic Health Information System of the Iraqi Kurdistan (KRG-HIS).

Design/methodology/approach

As part of the cooperation between the University of Rome Tor Vergata-Italy and the Iraqi Kurdistan Ministry of Health, six PhD positions were granted for Iraqi students to create a local team of experts with the aim of supporting the scaling-up of the KRG-HIS. After specific training, the team then trained the staff members of the health centers, met health authorities and analyzed the local scenario to ensure that the KRG-HIS could be better tailored to regional needs. In 2019, the integration of MCHCS into the KRG-HIS was one of the main areas of research.

Findings

Health data collection was mostly paper-based, which made vital statistics and evaluation of outcomes difficult to measure. More than 15,000 paper-files from the Duhok Obstetrics and Gynaecology Hospital were retrieved from storage. Then data entered in the KRG-HIS. Theoretical and practical training sessions were conducted for local staff members, with 183 health operators already having been trained. Daily supervision of the online system and field visits were ensured.

Originality/value

There is a need to support health authorities in improving data collection on MCHCS, ensuring the future self-sufficiency of the HIS. Key to the process is the creation of a specialized team of local experts with the objective of “training the trainers”.
The relationship between managerial attributes and firm risk-taking
Authors: Salehi Mahdi , Arianpoor Arash , Naghshbandi Nader
Published: April 2021

Purpose

The main objective of the paper is to examine the relationship between managerial attributes (e.g. managerial entrenchment, managerial myopia and managerial overconfidence) and firm risk-taking on the Tehran Stock Exchange (TSE).

Design/methodology/approach

The study’s sample comprises 150 companies listed on the TSE from 2011 to 2017. Risk-taking is calculated as the standard deviation (SD) of stock return. Explanatory factor analysis was performed to calculate the weight of each of the five variables managerial ownership, board independence, chief executive officer (CEO) tenure, board compensation and CEO duality as a proxy for managerial entrenchment. The study by Anderson and Hsiao (1982) was also used to calculate managerial myopia, and the study by Schrand and Zechman (2012) was used to calculate managerial overconfidence.

Findings

The results indicate that the effect of managerial entrenchment and managerial myopia on risk-taking of listed firms on the TSE is positive and significant, implying that an increase in CEO entrenchment is likely to give rise to risk-taking. The authors conjecture that this finding could be due to the investment projects impairing the firm performance in the long run. Furthermore, the effect of managerial overconfidence on listed firms' risk-taking on the TSE is significantly negative. Since overconfidence is one of the traits of narcissism and corporate managers tend to be encouraged and admired, it is implied that they tend to make efficient and low-risk investments that ultimately reduce the firm risk-taking.

Originality/value

Several theoretical studies show that managerial behavior is a determining factor in the economy. One of the reasons which justify the originality of this study is the context and institutional environment. Undoubtedly, managerial behavior (e.g. managerial entrenchment, managerial myopia and managerial overconfidence) is expected to have some significant variations in developing countries compared to prevailing in developed countries, particularly in the Iranian stock market the economic sanctions. Furthermore, due to the direct impact of individuals' psychological and behavioral characteristics on their decisions and the effect of companies' risk-taking on increasing and decreasing shareholders and companies' wealth, this research is essential. Given the function of designed behavioral criteria for assessing risk-taking behaviors, the relationship between managerial attributes and firms' risk-taking is still unclear and investigated in this study.
The effect of intellectual capital on fraud in financial statements
Authors: Lotfi Afsaneh , Salehi Mahdi , Lari Dashtbayaz Mahmoud
Published: April 2021

Purpose

The purpose of this present study is to assess the impact of intellectual capital (IC) on fraud in listed firms' financial statements on the Tehran Stock Exchange (TSE). In other words, this paper seeks to figure out whether IC and its components, namely, the efficiency of human capital (HC), structural capital (SC), relational capital (RC) and customer capital (CC).

Design/methodology/approach

The logistic regression model is used for analyzing the material of this study. Research hypotheses are also examined using a sample of 187 listed firms on the TSE during 2011–2018 by employing the logistic regression pattern based on synthetic data technique. Moreover, some robustness checks are also used to ensure the correctness of the obtained results.

Findings

The findings show a negative and significant relationship between IC and its components, including the efficiency of HC, SC, RC and CC, and fraud in financial statements. This means that by investing in the IC and its components, the amount of fraud in business firms' financial statements decreases.

Originality/value

Since few studies are carried out by existing literature, this paper is among the pioneer efforts assessing IC's potential impact on fraud commitment. The findings apply to policymakers to improve the clarity of the business atmosphere of Iran.