bluuebunny/crossref_metadata_2025 huggingface dataset:
Deep mutational scanning of CYP2C19 reveals a substrate specificity-abundance tradeoff
Authors: Boyle Gabriel E. , Sitko Katherine , Galloway Jared G. , Haddox Hugh K. , Bianchi Aisha Haley , Dixon Ajeya , Thomson Raine E. S. , Garge Riddhiman K. , Rettie Allan E. , Rubin Alan , Geck Renee C. , Gillam Elizabeth M. J. , DeWitt William S. , Matsen Frederick A. , Fowler Douglas M.
Published: October 2023

Cytochrome P450s (CYPs) are a family of enzymes responsible for metabolizing nearly 80% of small molecule drugs. Variants in CYPs can substantially alter drug metabolism, which may result in improper dosing and severe adverse drug reactions. CYPs have low sequence conservation, making it difficult to anticipate whether variant effects measured in one CYP may extend to others based on sequence alone. Even closely related CYPs, like CYP2C9 and its closest homolog CYP2C19, have distinct phenotypic properties despite sharing 92% amino acid sequence identity. Thus, we used Variant Abundance by Massively Parallel sequencing (VAMP-seq) to measure the steady-state protein abundance, a proxy for protein stability, of 7,660 missense variants in CYP2C19 expressed in cultured human cells. Our results confirmed positions and structural features critical for CYP function and revealed how variants at positions conserved across all eukaryotic CYPs influence abundance. We jointly analyzed 4,670 variants whose abundance was measured in both CYP2C19 and CYP2C9, finding that the homologs have different variant abundances in substrate recognition sites within the hydrophobic core, and that substitutions in some regions reduced abundance in CYP2C19 but not CYP2C9. We also measured the abundance of all single and some multiple WT amino acid exchanges between CYP2C19 and CYP2C9. While most exchanges had no effect, substitutions in substrate recognition site 4 (SRS4) reduced abundance in CYP2C19. When nearby amino acids were exchanged in double and triple mutants, we found distinct interactions between the sites in CYP2C19 and CYP2C9, revealing a region that is partially responsible for the difference in thermodynamic stability between the two homologs. Since these positions are also important for determining substrate specificity, there may be an evolutionary tradeoff between stability and altered enzymatic function. Finally, we used our data to analyze 368 previously unannotated human variants, finding that 43% had decreased abundance. Thus, by comparing variant effects between two closely related and important human genes, we have uncovered regions underlying their functional differences and paved the way for a more complete understanding of one of the most versatile families of enzymes.
Introducing return of results in the Million Veteran Program: Design and pilot results of the MVP-ROAR Familial Hypercholesterolemia Study
Authors: Vassy Jason L. , Brunette Charles A. , Yi Thomas , Harrison Alicia , Cardellino Mark P. , Assimes Themistocles L. , Christensen Kurt D. , Devineni Poornima , Gaziano J. Michael , Gong Xin , Hui Qin , Knowles Joshua W. , Muralidhar Sumatra , Natarajan Pradeep , Pyarajan Saiju , Sears Mary Gavin , Shi Yunling , Sturm Amy C. , Whitbourne Stacey B. , Sun Yan V. , Danowski Morgan E. ,   the Million Veteran Program
Published: October 2023

Background

As a mega-biobank linked to a national healthcare system, the Million Veteran Program (MVP) can directly improve the health care and health outcomes of participants. Return of genetic research results at this scale presents challenges and complexities.

Methods

To determine the feasibility and outcomes of returning medically actionable genetic results to MVP participants, the program launched the MVP Return Of Actionable Results (MVP-ROAR) Study, with familial hypercholesterolemia (FH) as the exemplar actionable condition. The MVP-ROAR-FH Study consists of a completed pilot phase and an ongoing randomized clinical trial (RCT), in which MVP participants are recontacted and invited to receive clinical confirmatory gene sequencing testing and a telegenetic counseling intervention. The primary outcome of the RCT is 6-month change in low-density lipoprotein cholesterol (LDL-C) between participants receiving results at baseline and those receiving results after 6 months.

Results

Nine MVP participants suspected to have a pathogenic variant inlow-density lipoprotein receptor(LDLR) enrolled in the single-arm pilot phase of the study; one was lost to follow-up prior to confirmatory testing. Clinical sequencing confirmed the pathogenic variant for 5 of the remaining 8 participants. Six-month ΔLDL-C among enrollees after the genetic counseling intervention was −37 mg/dL (95% CI: −12 to −61;p=0.03).

Conclusions

While underscoring the importance of analytic validity and clinical confirmation of research results, the pilot phase of the MVP-ROAR-FH Study demonstrates the feasibility of a protocol to return genetic results to MVP participants and their providers. The ongoing RCT will contribute to understanding of how such a program might improve patient health care and outcomes.
A model of marmoset monkey vocal turn-taking
Authors: Grijseels Dori M. , Fairbank Daniella A. , Miller Cory T.
Published: October 2023

Vocal turn-taking has been described in a diversity of species. Yet a model that captures the various processes underlying this social behavior across species has not been developed. To this end, here we recorded a large and diverse dataset of marmoset monkey vocal behavior in social contexts comprising one, two and three callers and developed a model to determine the keystone factors that affect the dynamics of these natural communicative interactions. While a coupled oscillator model failed to account for turn-taking in marmosets, our model alternatively revealed four key factors that encapsulate much of patterns evident in the behavior, ranging from internal processes, such as the state of the individual, to social context driven suppression of calling. In addition, we show that the same key factors apply to the meerkat, a carnivorous species, in a multicaller setting. These findings indicate that vocal turn-taking is affected by a broader suite of mechanisms than previously considered and that our model provides a predictive framework with which to further explicate this natural behavior in marmosets and for direct comparisons with the analogous behavior in other species.
Immunomodulators and risk for breakthrough infection after third COVID-19 mRNA vaccine among patients with rheumatoid arthritis: A cohort study
Authors: Schiff Abigail E. , Wang Xiaosong , Patel Naomi J. , Kawano Yumeko , Kowalski Emily N. , Cook Claire E. , Vanni Kathleen M.M. , Qian Grace , Bade Katarina J. , Saavedra Alene A. , Srivatsan Shruthi , Williams Zachary K. , Venkat Rathnam K. , Wallace Zachary S. , Sparks Jeffrey A.
Published: October 2023

Objectives

To investigate COVID-19 breakthrough infection after third mRNA vaccine dose among patients with RA by immunomodulator drug class, and we hypothesized that CD20 inhibitors (CD20i) would have higher risk for breakthrough COVID-19 vs. TNF inhibitors (TNFi).

Methods

We performed a retrospective cohort study investigating breakthrough COVID-19 among RA patients at Mass General Brigham in Boston, MA, USA. Patients were followed from the date of 3rd vaccine dose until breakthrough COVID-19, death, or end of follow-up (18/Jan/2023). Covariates included demographics, lifestyle, comorbidities, and prior COVID-19. We used Cox proportional hazards models to estimate breakthrough COVID-19 risk by immunomodulator drug class. We used propensity score (PS) overlap-weighting to compare users of CD20i vs. TNFi.

Results

We analyzed 5781 patients with RA that received 3 mRNA vaccine doses (78.8% female, mean age 64.2 years). During mean follow-up of 12.8 months, 1173 (20.2%) had breakthrough COVID_19. Use of CD20i (adjusted HR 1.74, 95%CI 1.30-2.33) and glucocorticoid monotherapy (adjusted HR 1.47, 95%CI 1.09-1.98) were each associated with breakthrough COVID-19 compared to TNFi use. In the PS overlap-weighted analysis, CD20i users also had higher breakthrough COVID-19 risk than TNFi users (HR 1.62, 95%CI 1.02-2.56). A sensitivity analysis excluding patients with cancer or interstitial lung disease yielded similar findings.

Conclusions

We identified CD20i and glucocorticoid monotherapy as risk factors for breakthrough COVID-19 among patients with RA after a 3rd vaccine dose. This contemporary study highlights the real-world impact of blunted immune responses in these subgroups and the need for effective risk mitigation strategies.

What is already known about this topic

Patients with RA are at increased risk for COVID-19 breakthrough infection after two vaccine doses so a third dose is recommended to complete the initial series.

Some immunomodulator medications, particularly CD20 inhibitors, can impact vaccine immunogenicity and waning.

What this study adds

CD20 inhibitor use was associated with increased risk of COVID-19 breakthrough infection in people with RA who received 3 vaccine doses compared to TNF inhibitor use.

Glucocorticoid monotherapy was also associated with increased risk of COVID-19 breakthrough infection.

How this study might affect research, practice or policy

Patients with RA who are using CD20 inhibitors or glucocorticoid monotherapy should be prioritized for risk mitigation strategies after the initial vaccine series of 3 mRNA doses.

The impact of additional vaccine doses, timing of medication dosing, and other protective measures will need further study.
Pilot study of the FoxP3+ T lymphocyte count and its relationship with the Gensini score in patients with coronary heart disease and type 2 diabetes mellitus from a South American cohort
Authors: Estévez Gómez María Juliana , Acevedo Peña Diego Andrey , Castillo Goyeneche Silvia Fernanda , Arias Anderson Felipe , Dulcey Sarmiento Luis Andres , Gomez Jaime , Hernandez Carlos , Theran Leon Juan Sebastián , Caltagirone Raimondo , Blanco Edgar , Ciliberti María
Published: October 2023

INTRODUCTION

One of the pathogenic links between type 2 diabetes mellitus (T2DM) and coronary heart disease (CHD) is low-intensity chronic inflammation, which is limited by FoxP3+ regulatory T cells.

MATERIALS AND METHODS

A comparative, observational, single-center, single-stage study was carried out. The severity of atherosclerosis was assessed by calculating the Gensini score based on selective coronary angiography. The absolute and relative content of CD4+CD25 high FoxP3+ and CD4+CD25 low FoxP3+ T cells in the blood was evaluated by flow cytometry.

RESULTS

57 patients with chronic ischemic heart disease were examined. Patients with a combination of CHF and T2DM are characterized by an increase in the relative and absolute content of FoxP3+CD25 lymphocytes in the peripheral blood and an increase in the intranuclear content of FoxP3 in them, which is more pronounced in patients with disease moderate. atherosclerosis (Gensini score 17 to 45 points).

CONCLUSIONS

This was the first Latin American study that managed to show the relationship between an increase in the content of low FoxP3+CD25 lymphocytes in the peripheral blood with atherosclerosis in patients with a combination of coronary artery disease and DM2.
Hibernating ribosomes tether to mitochondria as an adaptive response to cellular stress during glucose depletion
Authors: Gemin Olivier , Gluc Maciej , Purdy Michael , Rosa Higor , Niemann Moritz , Peskova Yelena , Mattei Simone , Jomaa Ahmad
Published: October 2023

Cell survival under nutrient-deprived conditions relies on cells’ ability to adapt their organelles and to rewire their metabolic pathways. In the fission yeastSchizosaccharomyces pombe, nutrient depletion is an unfavorable condition for protein synthesis and triggers a response characterized by mitochondrial fragmentation and the sequestration of cytosolic ribosomes on mitochondria. The molecular mechanism underlying ribosomal sequestration remains elusive. In this study, we performed time-lapsein situcryo-electron tomography and cryo-electron microscopy complemented by biochemical experiments to elucidate the molecular details of this adaptive response. Our analysis indicate that upon glucose depletion protein synthesis is halted, causing ribosomes to enter an inactive state characterized by a conformational change that obstructs the peptidyl transferase center. Ourin situexperiments reveal the presence of oligomeric arrays of hibernating ribosomes tethered to the mitochondrial surface. Surprisingly, ribosomes bind to the outer mitochondrial membraneviathe small ribosomal subunit, an interaction facilitated by the ribosomal protein RACK1-orthologue Cpc2. Our experiments show that ribosome tethering is important for cell survival under glucose depletion conditions. This study broadens our understanding of the cellular adaptations triggered by nutrient scarcity and the underlying molecular mechanisms that regulate cell quiescence.
PAX6 protein in neuromasts of the lateral line system of salamanders (Eurycea)
Authors: Dobbins Brittany A. , Tovar Ruben U. , Oddo Braden J. , Devitt Thomas J. , Hillis David M. , García Dana M.
Published: October 2023

PAX6 is well known as a transcription factor that drives eye development in animals as widely divergent as flies and mammals. In addition to its localization in eyes, PAX6 expression has been reported in the central nervous system, the pancreas, testes, Merkel cells, nasal epithelium, and developing cells of the inner ear. Here we show that PAX6 is also found in the mechanosensory neuromasts of the lateral line system in paedomorphic salamanders of the genusEurycea. Using immunohistochemistry and confocal microscopy, we found that PAX6 is extranuclear, and antibody labeling is most intense in the apical appendages of the hair cells of the neuromast. This extranuclear localization raises the possibility of an as yet undescribed function for PAX6 as a cytoskeleton-associated protein.
The hepcidin-ferroportin axis influences mitochondrial function, proliferation, and migration in pulmonary artery endothelial and smooth muscle cells
Authors: Issitt Theo , Toe Quezia K , Pedersen Sofia L , Shackshaft Thomas , Ghazaly Maziah Mohd , West Laura , Arnold Nadine D , Mahomed Abdul , Kagugube George W , Ramakrishnan Latha , Lawrie Allan , Wort S John , Quinlan Gregory J
Published: October 2023

Rationale

Elevated circulating hepcidin levels have been reported in patients with pulmonary artery hypertension (PAH). Hepcidin has been shown to promote proliferation of human pulmonary artery smooth muscle cells (PASMCs) in vitro, suggesting a potential role in PAH pathogenesis. However, the role of human pulmonary artery endothelial cells (PAECs) as either a source of hepcidin, or the effect of hepcidin on PAECfunction has not previously been described.

Objective

To define the role of the hepcidin-ferroportin axis on the phenotype of pulmonary artery endothelial cells

Methods and results

PAECs treated with hepcidin, or IL-6 were investigated for both ferroportin and hepcidin release and regulation with immunofluorescence, mRNA levels and cellular release assays. Effects of hepcidin on PASMC and PAEC mitochondrial function was investigated using immunofluorescence and seahorse assay. Migration and proliferation of PASMC treated with conditioned media from hPAEC treated with hepcidin was investigated using the Xcelligence system and other tools.

PAECs express ferroportin; hepcidin treatment of PAECs results in mitochondrial iron accumulation and intracellular hepcidin biosynthesis and release. Conditioned media from hepcidin treated PAECs causes PASMCs to down regulate ferroportin expression whilst promoting migration and proliferation. Inhibition of hepcidin in PAEC conditioned media limits these responses. PASMC cellular and mitochondrial iron retention are associated with migratory and proliferative responses.

Conclusions

The Hepcidin-ferroportin axis is present and operational in PAECs. Modulation of this axis shows distinct differences in responses seen between PAECS and PASMCs. Stimulation of this axis in PAECS with hepcidin may well institute proliferative and migratory responses in PASMCs of relevance to pathogenesis of PAH offering a potential therapeutic target.
Quantifying weak interactions in ferroelectric and paraelectric phases of phenazine and chloroanilic acid co-crystal using experimental and theoretical electron densities
Authors: Anil Kumar G. N. , Hathwar Venkatesha R.
Published: October 2023

The co-crystal of phenazine and chloroanilic acid is known to display paraelectric properties at room temperature. It shows a paraelectric to ferroelectric phase transition at 253 K and has an incommensurately modulated ferroelectric phase below 137 K. High-resolution synchrotron X-ray data were collected at 160 K to model the experimental electron-density distributions, and derived topological properties from the electron density were used to quantify the weak interactions responsible for the origin of the ferroelectric phase. The structure and non-covalent interactions are analysed using Hirshfeld surfaces and energy frameworks. The topological properties, energies, atomic charges and molecular electrostatic potential surfaces are determined from the experimental data, further supported by theoretical calculations. The results from the ferroelectric phase are compared with the paraelectric phase. Although the structural descriptions indicate neutral phenazine and chloroanilic acid molecules in the ferroelectric phase, the topological properties of the electron density indicate a considerable amount of proton transfer in the O—H...O hydrogen bond. Indeed, the displaced H atom in the O—H...O hydrogen bond suggests a mixed covalent/polar nature of chemical bonding. Subtle changes in the chemical bonding and proton-transfer pathways could be detected from the high-resolution electron-density studies.
1-Methyl-3-(naphthalen-2-yl)cyclopentadiene
Authors: Michailidis Melina , Bonitatibus Jr Peter J.
Published: October 2023

The title compound, C16H14, an asymmetric naphthyl-/methyl-substituted cyclopentadiene was synthesized and one isomer of five accessible through sigmatropic rearrangement was isolated and characterized by 1H NMR and X-ray diffraction. The crystal packing features an intermolecular C—H...π interaction.
Al0.88Cu0.94Fe0.18
Authors: Liu Yibo , Liu Huizi , Wen Bin , Fan Changzeng
Published: October 2023

The intermetallic phase with composition Al0.88Cu0.94Fe0.18 was synthesized by high-temperature sintering of a mixture with initial chemical composition Al78Cu48Fe13. Al0.88Cu0.94Fe0.18 adopts the CsCl structure type in space-group Pm\overline{3}m. The structure analysis revealed that one site is co-occupied by Al and Cu with a ratio of 0.88 (5):0.12 (5) and the other is co-occupied by Fe and Cu with a ratio of 0.2 (4):0.8 (4). The Al/Cu...Fe/Cu separation is 2.5465 (13) Å.
How do you manage? An auto-ethnographic inquiry into contemporary maternal labor
Authors: Baliç İlkay
Published: October 2023

Purpose

This article tackles the intersection of mothering and labor through the author's own experience as a feminist mother/manager from Istanbul, Turkey. It aims to revisit the first years of motherhood, exploring the struggle to invent a peculiar maternal subjectivity in opposition and negotiation with the patriarchal institution of motherhood, the new definition of maternal labor in a highly digital, neoliberal context and the issue of marital fairness in a dual-income heterosexual marriage.

Design/methodology/approach

The article presents an autoethnographic, retrospective and introspective inquiry into the first seven years of the author's mothering experience in order to offer an in-depth exploration of the various aspects of contemporary maternal labor.

Findings

The article shows how maternal labor has shifted in nature and expanded in scope in a contemporary non-Western context. It investigates the dissolution of the spatial, temporal and sensorial boundaries between the managerial labor dedicated to the workplace, and to the family. Highlighting the similarities of the two forms of labor, the article manifests the materiality, tangibility and visibility of maternal labor.

Research limitations/implications

Further intersectional studies shall be beneficial to redefine maternal labor in different contexts.

Practical implications

Departing and diverting from the terms “invisible labor” and “mental load”, the article suggests a shift in terminology to stress the multifaceted medley of managerial tasks mothers undertake today.

Originality/value

The article provides an original take on maternal labor through the first-hand experience of a middle-class, professional mother from Istanbul, Turkey.
A review on social segregation research: insights from bibliometric analysis
Authors: Zeini Nahed T. , Okasha Ahmed E. , Soliman Amal S.
Published: October 2023

Purpose

Using bibliometrics, this study aims to explore the intellectual structure of social segregation research, key contributors, thematic areas and hotspot topics.

Design/methodology/approach

A bibliometric analysis was performed for more than 15,000 research papers listed in one of the famous, rich and widely used scientific databases: Web of Science (WoS). This review approach was used to identify social research hotspots on segregation, intellectual structure, borders and development trends. VOSviewer and Gephi software were employed for mapping and analysis.

Findings

The study indicates a marked increase in segregation research, particularly from a spatial/urban perspective. The study reveals the interrelationship between segregation and many other social concepts, such as social equality, cohesion, integration and inclusion. In conclusion, addressing the ramifications resulting from the multiple forms of segregation will help in implementing social policies and evaluating their impact on achieving inclusive social development in general and the 2030 agenda of Sustainable Development Goals (SDGs) in specific.

Research limitations/implications

This study remains limited to the precision and thoroughness of the bibliographic data gained from WoS.

Originality/value

This study is valuable for readers to gain rich insights into the state of research on social segregation. It also provides ideas for future research that prospective authors and interested research and academic institutions can investigate.
The short and long‐term prognostic influences of liver grafts with high bilirubin levels at the time of organ recovery
Authors: Akabane Miho , Bekki Yuki , Imaoka Yuki , Inaba Yosuke , Kwong Allison J. , Esquivel Carlos O. , Melcher Marc L , Sasaki Kazunari
Published: October 2023

Background

Donors with hyperbilirubinemia are often not utilized for liver transplantation (LT) due to concerns about potential liver dysfunction and graft survival. The potential to mitigate organ shortages using such donors remains unclear.

Methods

This study analyzed adult deceased donor data from the United Network for Organ Sharing database (2002–2022). Hyperbilirubinemia was categorized as high total bilirubin (3.0–5.0 mg/dL) and very high bilirubin (≥5.0 mg/dL) in brain‐dead donors. We assessed the impact of donor hyperbilirubinemia on 3‐month and 3‐year graft survival, comparing these outcomes to donors after circulatory death (DCD).

Results

Of 138 622 donors, 3452 (2.5%) had high bilirubin and 1999 (1.4%) had very high bilirubin levels. Utilization rates for normal, high, and very high bilirubin groups were 73.5%, 56.4%, and 29.2%, respectively. No significant differences were found in 3‐month and 3‐year graft survival between groups. Donors with high bilirubin had superior 3‐year graft survival compared to DCD (hazard ratio .83, p = .02). Factors associated with inferior short‐term graft survival included recipient medical condition in intensive care unit (ICU) and longer cold ischemic time; factors associated with inferior long‐term graft survival included older donor age, recipient medical condition in ICU, older recipient age, and longer cold ischemic time. Donors with ≥10% macrosteatosis in the very high bilirubin group were also associated with worse 3‐year graft survival (p = .04).

Discussion

The study suggests that despite many grafts with hyperbilirubinemia being non‐utilized, acceptable post‐LT outcomes can be achieved using donors with hyperbilirubinemia. Careful selection may increase utilization and expand the donor pool without negatively affecting graft outcome.
Hospital admissions among people with diabetes: A systematic review
Authors: Feleke Berhanu Elfu , Sacre Julian , Tomic Dunya , Huynh Quan , Shaw Jonathan E. , Magliano Dianna J.
Published: October 2023

Objective

To describe the reasons for hospital admission among people with diabetes.

Methods

We searched Emcare, Embase, Medline and Google Scholar databases for population‐based studies describing the causes of hospitalisation among people with diabetes. We included articles published in English from 1980 to 2022. For each study, we determined the most frequent reasons for admission. Studies were assessed for quality using the Newcastle Ottawa quality assessment tool.

Results

6920 research articles were retrieved from the search of all sources. After screening the titles and abstracts of these, we reviewed the full text of 135 papers and finally included data from 42 studies. Admissions among the total diabetes were reported in 25 papers: 5 articles reported type 1 diabetes alone, 10 articles reported type 2 diabetes alone and the remaining 2 articles reported type 1 and type 2 diabetes separately. Among the 25 total and type 2 diabetes studies that reported the distribution of hospitalisations in broad categories, cardiovascular diseases (CVD) were the leading cause of admission in 19/25 (76%) of studies. Among the 19 studies that reported CVD admissions by subcategories, ischaemic or coronary heart disease was the leading subtype of CVD in 58% of studies. The other common causes of admissions were infections, renal disorders, endocrine, nutritional, metabolic and immunity disorders. In people with type 1 diabetes, acute diabetes complications were the leading cause of admission.

Conclusion

CVD are the leading cause of hospital admission for people with diabetes, with ischaemic or coronary heart disease as the predominant subtype.
Dissection of cellular disruptions in autism spectrum disorder comorbidities
Authors: Griffin Aoife , Chen Mei , Tiwari Vijay K.
Published: October 2023

Up to 80% of children with autism spectrum disorder have at least one other neuropsychiatric comorbidity. The causes of such disorders are highly genetic, yet many studies fail to take analysis further than risk gene discovery to see cellular and mechanistic changes occurring. Therefore, the goal of this study was to unveil novel gene expression signatures involved in important neurodevelopmental processes that, when disrupted, lead to each of the autism comorbidities of interest. We achieved this by analysing a single‐nuclei RNA sequencing dataset with prefrontal cortex samples from autism spectrum disorder plus comorbidities for differentially expressed genes. The highest number of alterations was seen in excitatory neurons, which also showed differential population and cell–cell interactions across disorders and an increase in expression of genes involved in neurodevelopmental pathways. Interestingly, the group without comorbidities displayed an increase in neuron–neuron interactions yet a decrease in population number, suggesting a major rewiring of neuronal connections. Further analysis of the topmost significant genes from this cell type in developing prefrontal cortex datasets revealed interesting expression trajectories corresponding to important time points during corticogenesis. This further identified four novel candidate genes that show a potential link to developmental pathways that may contribute to autism and its comorbidities when dysregulated. The study provides a better understanding of co‐occurring conditions at a transcriptomic and cell‐type level and thereby aid future research in providing earlier diagnosis, care and intervention.
Structural and functional analysis of two SHMT8 variants associated with soybean cyst nematode resistance
Authors: Korasick David A. , Owuocha Luckio F. , Kandoth Pramod K. , Tanner John J. , Mitchum Melissa G. , Beamer Lesa J.
Published: October 2023

Two amino acid variants in soybean serine hydroxymethyltransferase 8 (SHMT8) are associated with resistance to the soybean cyst nematode (SCN), a devastating agricultural pathogen with worldwide economic impacts on soybean production. SHMT8 is a cytoplasmic enzyme that catalyzes the pyridoxal 5‐phosphate‐dependent conversion of serine and tetrahydrofolate (THF) to glycine and 5,10‐methylenetetrahydrofolate. A previous study of the P130R/N358Y double variant of SHMT8, identified in the SCN‐resistant soybean cultivar (cv.) Forrest, showed profound impairment of folate binding affinity and reduced THF‐dependent enzyme activity, relative to the highly active SHMT8 in cv. Essex, which is susceptible to SCN. Given the importance of SCN‐resistance in soybean agriculture, we report here the biochemical and structural characterization of the P130R and N358Y single variants to elucidate their individual effects on soybean SHMT8. We find that both single variants have reduced THF‐dependent catalytic activity relative to Essex SHMT8 (10‐ to 50‐fold decrease in kcat/Km) but are significantly more active than the P130R/N368Y double variant. The kinetic data also show that the single variants lack THF‐substrate inhibition as found in Essex SHMT8, an observation with implications for regulation of the folate cycle. Five crystal structures of the P130R and N358Y variants in complex with various ligands (resolutions from 1.49 to 2.30 Å) reveal distinct structural impacts of the mutations and provide new insights into allosterism. Our results support the notion that the P130R/N358Y double variant in Forrest SHMT8 produces unique and unexpected effects on the enzyme, which cannot be easily predicted from the behavior of the individual variants.
PEASANTS, BRIGANDS, AND THE CHRONOPOLITICS OF THE NEW LEVIATHAN IN THE MEZZOGIORNO
Authors: ESPOSITO FERNANDO
Published: October 2023

The image of a backward, archaic South whose barbarian population had remained at a low tier of civilization was a child of Italian unification. Not unlike the Orientalist East, the South that meridionalist discourse brought forth was a “chronotopos”—that is, a time‐space that had supposedly remained in the past. The war against brigandage in the Mezzogiorno demonstrates the workings of the “politics of historicism.” This article first sheds some light on the grande brigantaggio and on the descriptions of the South that it generated among both contemporaries and later historians, such as Eric Hobsbawm. With the help of Pierre Clastres's and James C. Scott's political anthropology, it then attempts to uncover the structure beneath the “denial of coevalness.” It argues that the dichotomy between the “backward” and the “modern” was based on the political distinction between friend and enemy, which, in the age of historicism, was temporalized; that is, the temporal dichotomy of the savage and the civilized can be understood as the historicist variant of those “asymmetric counterconcepts” that have always served the state and its representatives to demarcate the corpus politicum from other political entities, to justify the state, and to praise the advantages of being governed. In conclusion, the article addresses the close interweaving of state and history, progress and civilization, in the historicist worldview and argues that it was this nexus of state and history that drove the mechanics of time‐power.
Platform Oligopoly with Endogenous Homing: Implications for Mergers and Free Entry*
Authors: Adachi Takanori , Sato Susumu , Tremblay Mark J.
Published: October 2023

Consumer multi‐homing is critical for competition policy regarding digital platforms. To assess the role of multi‐homing, we embed endogenous homing into a model of oligopolistic competition between two‐sided platforms and apply it to mergers and free entry. We find that the required merger‐specific cost reduction is larger if consumers benefit more from multi‐homing and that the equilibrium level of platform entry can be insufficient in the presence of consumer multi‐homing. These results contrast the belief that multi‐homing mitigates the need for stricter policy. We also show that reductions to sellers' benefit from multi‐homing reduces entry (is an effective entry barrier).
A randomized controlled trial assessing denture adhesive efficacy on denture retention across 13 hours
Authors: Klukowska Malgorzata , Grender Julie , Gossweiler Ana
Published: October 2023

Purpose

To compare the effects of two denture adhesive formulations on the bite force required to dislodge a maxillary denture in adult participants during a 13‐h test period.

Materials and Methods

Twenty‐two participants with a fair‐to‐poor fitting maxillary denture opposed by natural dentition or a stable mandibular denture were enrolled in this single‐center, randomized, double‐blind, two‐treatment, 4‐period crossover study. Participants were randomly assigned a product usage sequence so that each participant used each product twice during the 4‐day test period. The test product was a denture cream adhesive formulated with an optimized calcium/zinc partial salt of polyvinyl methyl ether/maleic acid (Fixodent Ultra technology); the control product was a cream adhesive formulated with a calcium/zinc partial salt of polyvinyl methyl ether/maleic acid (Fixodent Original technology). On each study day, bite force at dislodgement was measured with a gnathodynamometer at baseline, representing the “no adhesive” score. Then, after standardized product application to the participant's existing maxillary denture by site staff, bite force measurements were retaken at 1, 3, 5, 7, 9, 11, and 13 h. The change from baseline and the 13‐h area under the bite‐force–change‐from‐baseline curve were analyzed via an analysis of variance.

Results

Twenty‐one participants completed all test periods; one additional participant completed three test periods so 22 participants were included in the analysis. There were 15 females and 7 males with a mean age of 70 years. The mean 13‐h area under the bite‐force–change‐from‐baseline curve was 8% greater (p = 0.010) for the test adhesive (114.3 lb) than for the control adhesive (105.9 lb). Both adhesives showed a statistically significant increase in bite force (p < 0.001) at each time point compared to no adhesive.

Conclusions

The optimized calcium/zinc partial salt of polyvinyl methyl ether/maleic acid test adhesive provided superior maxillary denture retention relative to that of the control adhesive across 13 h. Both adhesives increased bite force at dislodgement compared to no adhesive.
“For the planet. For home”: Generating planetary responsibility in the climate fiction of Los Angeles
Authors: Gilson Edwin
Published: October 2023

This article argues that three prominent recent works of Los Angeles climate fiction—Maria Amparo Escandon's L.A. Weather (2021), Alexandra Kleeman's Something New Under the Sun (2021) and Paul Beatty's The Sellout (2016)—generate a sense of planetary responsibility. Despite their regional settings, these novels possess a planetary consciousness, illuminating the local‐global connectivity of climate change and the Anthropocene. As one of the biggest greenhouse gas emitting cities in the world, L.A. drives climate injustice, with its gargantuan energy consumption having an adverse impact on populations both within and far beyond its own borders. This article explains how literature, and climate fiction particularly, can highlight this inequality at micro and macro scales, and encourage collective opposition to it. I argue that the novels of Escandon, Kleeman and Beatty conjure the impression of responsibility identified by Kristian Shaw and Sara Upstone in their overview of post‐postmodern fiction, while also exhibiting the ‘planetarity’ discussed by Amy Elias and Christian Moraru: a term to describe the global worldview of contemporary culture. In applying these concepts to the novels examined here, I ultimately contend that Los Angeles climate fiction demystifies the spatial and political dimensions of the Anthropocene, generating planetary responsibility and addressing local and global injustice.
Effects of Increased Transparency on Political Divides and MP Behavior: Evidence from Televised Question Hours in the Finnish Parliament
Authors: Nieminen Jeremias , Simola Salla , Tukiainen Janne
Published: October 2023

We study the effects of increasing the transparency of parliamentary speeches on polarization and other types of MP behavior. We utilize the 1989 introduction of TV broadcasting to the Finnish government's parliamentary question hours held on the first Thursday of every month. By contrast, the question hours held on other Thursdays of the month were not televised until 2007, allowing us to use a difference‐in‐differences design. We find a positive effect on government–opposition divides, but no evidence that the TV broadcasting of question hours would affect left–right polarization, differences between individual parties, or within‐party group differences. We also observe an increase in attendance and a negative effect on the number of speeches, but no effects on topics discussed, speech length or interruptions. Our results suggest there is no trade‐off between increased transparency and left–right polarization. However, the presence of TV cameras can fuel other political divides and increase politicians’ effort.
Raloxifene increases the risk of gastroesophageal reflux disease, Barrett's esophagus, and esophageal stricture in postmenopausal women with osteoporosis
Authors: Liu Benjamin D. , Udemba Sharon C. , Saleh Sherif , Hill Hannah , Song Gengqing , Fass Ronnie
Published: October 2023

Background and Aims

Estrogen‐based therapies may increase the risk of gastroesophageal reflux (GERD) and its complications. We aimed to determine the effect of raloxifene on the development of GERD, Barrett's esophagus, and esophageal stricture in postmenopausal women with osteoporosis.

Methods

This was a population‐based, propensity‐matched cohort study using the TriNetX platform. Patients 50 years and older with a diagnosis of “menopause” and “osteoporosis” were included in this study. Odds ratios (OR) and 95% confidence intervals (CI) were calculated for new GERD, esophageal stricture and Barrett's esophagus after raloxifene exposure. The control cohort consisted of patients who did not start any hormonal replacement therapy. We conducted a multivariable logistic regression analysis to evaluate the effect of confounding variables and also addressed common confounding medications with 1:1 propensity score‐matching. Internal validity was confirmed by comparing to negative controls (lisinopril, atorvastatin) and positive controls (metformin, ibuprofen, aspirin).

Results

Five thousand four hundred and seventy two postmenopausal women with osteoporosis were on raloxifene of which 1908 (34.86%) developed GERD, compared to 296,067 postmenopausal who were not on raloxifene of which 90,643 (30.62%) developed GERD (OR 1.2; 95% CI 1.10–1.31, p < 0.0001). This persisted after adjusting for common medications known to affect GERD. Raloxifene was identified as a risk factor for GERD in a multivariate analysis, controlling for factors including age, obesity, smoking, and alcohol use (OR 1.51, 95% Wald CI 1.47–1.53). Raloxifene was associated with esophageal stricture (OR 1.60; 95% Wald CI 1.51–1.69) and Barrett's esophagus (OR 1.50; 95% Wald CI 1.37–1.63) in multivariate analysis. These associations persisted using sensitivity analyses.

Conclusion

Raloxifene increases the risk of GERD, esophageal stricture and Barrett's esophagus in postmenopausal women with osteoporosis. Further studies are needed to confirm our findings.
A sensory signature of unaffected biological parents predicts the risk of autism in their offspring
Authors: Chen Chenyi , Cheng Yawei , Wu Chien‐Te , Chiang Chung‐Hsin , Wong Ching‐Ching , Huang Chih‐Mao , Martínez Róger Marcelo , Tzeng Ovid J. L. , Fan Yang‐Teng
Published: October 2023

Aim

Despite the emphasis on sensory dysfunction phenotypes in the revised diagnostic criteria for autism spectrum disorder (ASD), there has been limited research, particularly in the field of neurobiology, investigating the concordance in sensory features between individuals with ASD and their genetic relatives. Therefore, our objective was to examine whether neurobehavioral sensory patterns could serve as endophenotypic markers for ASD.

Methods

We combined questionnaire‐ and lab‐based sensory evaluations with sensory fMRI measures to examine the patterns of sensory responsivity in 30 clinically diagnosed with ASD, 26 matched controls (CON), and 48 biological parents for both groups (27 parents of individuals with ASD [P‐ASD] and 21 for individuals with CON [P‐CON]).

Results

The ASD and P‐ASD groups had higher sensory responsivity and rated sensory stimuli as more unpleasant than the CON and P‐CON groups, respectively. They also exhibited greater hemodynamic responses within the sensory cortices. Overlapping activations were observed within these sensory cortices in the ASD and P‐ASD groups. Using a machine learning approach with robust prediction models across cohorts, we demonstrated that the sensory profile of biological parents accurately predicted the likelihood of their offspring having ASD, achieving a prediction accuracy of 71.4%.

Conclusions

These findings provide support for the hereditary basis of sensory alterations in ASD and suggest a potential avenue to improve ASD diagnosis by utilizing the sensory signature of biological parents, especially in families with a high risk of ASD. This approach holds promising prospects for early detection, even before the birth of the offspring.
An optimized procedure for Luminex‐based human platelet antigen‐specific antibody screening and identification (PakLx assay) with a cost‐effective approach and improved sensitivity
Authors: Bertrand Gerald , Griffon Julien , Renac Virginie
Published: October 2023

Background and Objectives

Detection of anti‐platelet antibodies is required for the diagnosis of foetal/neonatal alloimmune thrombocytopaenia. The most commonly used methods for anti‐platelet antibody detection are the monoclonal antibody‐specific immobilization of platelet antigens (MAIPA) and the Luminex bead assay (PakLx). However, for economic reasons, the use of the PakLx assay is limited.

Materials and Methods

In the present study, we evaluated the performance of an optimized protocol based on a half‐volume of PakLx reagents. We compared two alternative procedures: one with a half‐volume of all components including patient samples, and another based on a half‐volume of reagents but a standard volume of patient sample.

Results

Our results obtained with a panel of 67 samples demonstrate improved sensitivity when using a standard sample volume.

Conclusion

In the event of an inconclusive result with this optimized protocol (e.g., incomplete panel of positive Luminex beads), we recommend testing the sample with an alternative protocol (e.g., MAIPA or the original PakLx protocol).
Effects of duty cycle and nitrogen flow rate on the mechanical properties of (V,Mo)N coatings deposited by high-power pulsed magnetron sputtering
Authors: Feng Yiqun , Chung Tsai-Fu , Hsiao Chien-Nan , Huang Jia-Hong
Published: October 2023

(V,Mo)N is theoretically predicted to have high hardness and fracture toughness and is a promising material for the application on protective hard coatings. However, the toughness enhancement of (V,Mo)N coatings deposited by dc-unbalanced magnetron sputtering (dc-UBMS) was not as remarkable as expected. The issue could be due to insufficient energy delivery to the plasma species in the deposition process such that nitrogen and metal atoms were not fully reacted and led to the degradation of coating quality. Since high-power pulsed magnetron sputtering (HPPMS) can provide high peak power density, the method was selected to deposit (V,Mo)N coatings in this research. The objective of this study was to investigate the effects of duty cycle and nitrogen flow rate on the microstructure and mechanical properties of (V,Mo)N coatings deposited on Si substrates by HPPMS. Four sets of (V,Mo)N coatings were deposited by HPPMS at different durations with two duty cycles, 5% and 3%, and two nitrogen flow rates, 6.0 and 12.0 SCCM. The results showed that the N/metal ratio was mainly affected by the nitrogen flow rate, ranging from 0.70 to 0.96 with increasing nitrogen flow rate. The lattice parameter of the samples linearly increased with the N/metal ratio. The x-ray diffraction (XRD) patterns revealed that all samples tended to approach (200)-preferred orientation with increasing deposition duration. The glancing incident XRD patterns indicated that the samples deposited at 6 SCCM nitrogen flow rate and 3% duty cycle have multiphases. Transmission electron microscopy analysis confirmed that phase separation from (V,Mo)N to (V-rich,Mo)N and (V,Mo-rich)N occurred in those samples. The hardness of the (V,Mo)N coatings decreased with increasing N/metal ratio, which may be related to the N-vacancy hardening effect. The sample deposited at 6 SCCM nitrogen flow rate and 3% duty cycle for 36 h showed the highest hardness of 28.4 GPa, which was possibly associated with the phase separation, and hence plastic deformation became difficult. The fracture toughness (Gc) of the (V,Mo)N coatings was evaluated using the internal energy-induced cracking method. The resultant Gc of the (V,Mo)N coatings, ranging from 36.1 to 43.7 J/m2, was higher than that of the coatings deposited by dc-UBMS in our previous study. The toughness enhancement could be caused by a higher fraction of Mo–N bonding due to the adequate reaction energy provided by the HPPMS process.