bluuebunny/crossref_metadata_2025 huggingface dataset:
Targeted mutations in IFNα2 improve its antiviral activity against various viruses
Authors: Karakoese Zehra , Le-Trilling Vu-Thuy Khanh , Schuhenn Jonas , Francois Sandra , Lu Mengji , Liu Jia , Trilling Mirko , Hoffmann Daniel , Dittmer Ulf , Sutter Kathrin
Published: September 2023

During viral infections, type I interferons (IFN) are induced and play a key role in counteracting initial viral spread. Twelve different human IFNα subtypes exist that bind the same receptor; however, they elicit unique host responses and display distinct potencies of antiviral activities. Our previous studies on HIV and HBV demonstrated that the clinically used IFNα2 is not the most effective one among the IFNα subtypes. By sequence modeling, we identified a region in helix B with mainly conserved residues at the outside facing IFNAR1, but variable residues at the inside facing the core of IFNα, potentially representing a putative tunable anchor to tune pleiotropic IFN responses. Using site-directed mutagenesis various mutations were introduced into the IFNα2b backbone targeting sites which are important for binding to IFNAR1 and IFNAR2, the putative tunable anchor, or outside these three regions. Selected mutations were based on sequence differences to high antiviral subtypes IFNα6 and IFNα14. Treatment assays against HBV and HIV identified several critical residues for the antiviral activity of IFNα mainly in the IFNAR1 binding region. Combined mutations of the IFNα2 IFNAR1/2 binding sites or the IFNAR1 binding region plus the putative tunable anchor by those of IFNα14 further augmented activation of different downstream signaling cascades providing a molecular correlate for the enhanced antiviral activity. We describe here important functional residues within IFNα subtype molecules, which enabled us to design novel and innovative drugs that may have the potential to be used in clinical trials against a variety of different viral infections.

Importance

The potency of IFNα to restrict viruses was already discovered in 1957. However, until today only IFNα2 out of the 12 distinct human IFNα subtypes has been therapeutically used against chronic viral infections. There is convincing evidence that other IFNα subtypes are far more efficient than IFNα2 against many viruses. In order to identify critical antiviral residues within the IFNα subtype sequence, we designed hybrid molecules based on the IFNα2 backbone with individual sequence motifs from the more potent subtypes IFNα6 and IFNα14. In different antiviral assays with HIV or HBV, residues binding to IFNAR1 as well as combinations of residues in the IFNAR1 binding region, the putative tunable anchor, and residues outside these regions were identified to be crucial for the antiviral activity of IFNα. Thus, we designed artificial IFNα molecules, based on the clinically approved IFNα2 backbone, but with highly improved antiviral activity against several viruses.
Slave Trade and Colonial Expansion Resulted in Strong Sex-Biased Admixture in South Africa
Authors: Schurz Haiko , Reynolds Austin W. , Meeks Gillian , Gravel Simon , Myrick Justin W. , Mendez Fernando L. , Werely Cedric J. , van Helden Paul D. , Hoal Eileen G. , Poznik G. David , Kim Minju , Uren Caitlin , Underhill Peter A. , Möller Marlo , Henn Brenna M.
Published: September 2023

The colonial-period arrival of Europeans in southern Africa is associated with strong sex-biased migration by which male settlers displaced indigenous Khoekhoe and San men. Simultaneously, the importation of South Asian, Indonesian and Eastern African slaves may have contributed female-biased migration to Cape Town and surrounding areas. We examine the spatial and temporal spread of sex-biased migration from the Cape northward into Namaqualand and the southern Kalahari using genetic data from more than 1,400 individuals. In all regions, admixture patterns were sex-biased, with evidence of a greater male contribution of European ancestry and greater female contribution of Khoe-San ancestry. While admixture among Khoe-San, European, equatorial African, and Asian groups has likely been continuous from the founding of Cape Town to present-day, we find that Khoe-San groups further north experienced a single pulse of European admixture 6-8 generations ago. European admixture was followed by additional Khoe-San gene flow, potentially reflecting an aggregation of indigenous groups due to disruption by colonial interlopers. Male migration into the northern frontier territories was not a homogenous group of expanding Afrikaners and slaves. The Nama show evidence of distinct founder effects and derive 15% of their male lineages from Asian men, a pattern absent in the ≠Khomani San. Khoe-San ancestry from the paternal line is greatly diminished in populations from Cape Town, the Cederberg Mountains and Upington, but remains more frequent in self-identified ethnically indigenous groups. Strikingly, we estimate that Khoe-San Y-chromosomes were experiencing unprecedented population growth at the time of European arrival. Our findings shed light on the patterns of admixture and the population history of South Africa as the colonial frontier expanded.
Merging Multi-OMICs with Proteome Integral Solubility Alteration Unveils Antibiotic Mode of Action
Authors: Maity Ritwik , Zhang Xuepei , Liberati Francesca Romana , Rossi Chiara Scribani , Cutruzzolà Francesca , Rinaldo Serena , Gaetani Massimiliano , Aínsa José Antonio , Sancho Javier
Published: September 2023

Antimicrobial resistance is responsible for an alarming number of deaths, estimated at 5 million per year. To combat priority pathogens, likeHelicobacter pylori, the development of novel therapies is of utmost importance. Understanding the molecular alterations induced by medications is critical for the design of multi-targeting treatments capable of eradicating the infection and mitigating its pathogenicity. However, the application of bulk omics approaches for unraveling drug molecular mechanisms of action is limited by their inability to discriminate between target-specific modifications and off-target effects. This study introduces a multi-omics method to overcome the existing limitation. For the first time, the PISA assay is utilized in bacteria in the PISA-express format to link proteome solubility with different and potentially immediate responses to drug treatment, enabling us the resolution to understand target-specific modifications and off-target effects. This study introduces a comprehensive method for understanding drug mechanisms and optimizing the development of multi-targeting antimicrobial therapies.
Vitamin D deficiency and toxicity across 2018 to 2022 in several cities of Ecuador: interrupted time series and a cross-sectional study
Authors: Zurita-Salinas Camilo , Tello Betzabé , Dueñas-Espín Iván , Zurita Jeannete , Acosta William , León Cristina Aguilera , Andrade-Muñoz Andrés , Pareja-Maldonado José
Published: September 2023

Objectives

to identify differences in mean vitamin D concentrations in samples obtained from a private laboratory in the city of Quito, and to explore their relationship with the pre-pandemic and pandemic periods spanning from 2018 to 2022.

Design

A combination of an interrupted time series design and a retrospective cross-sectional approach

Setting and participants

The study involved 9,285 participants who had their 25-hydroxyvitamin D (25(OH)D) levels tested at a well-known private laboratory in Quito, Ecuador, from 2018 to 2022.

Primary and secondary outcome measures: The 25(OH)D levels were analyzed and assessed for correlations with both age and the year in which the measurements were taken.

Results

The mean 25-hydroxyvitamin D (25(OH)D) level was 27.53 ng/mL (± 14.11). Approximately 64.58% of participants had insufficient levels, below 20 ng/mL, and 0.62% showed potential harm from excess 25(OH)D, with levels over 100 ng/mL. The analysis indicated a significant monthly increase of 0.133 units in 25(OH)D levels (p=0.006). However, the period after March 2020, compared to before, saw a non-significant decrease of 1.605 units in mean 25(OH)D levels (p=0.477).

Conclusions

The study’s findings indicate a significant prevalence of 25-hydroxyvitamin D (25(OH)D) deficiency, underscoring the necessity for preventative measures. Nevertheless, the rise in cases of vitamin D toxicity is concerning, emphasizing the importance of prudent vitamin D supplement prescriptions and public education against self-medication. For efficient resource allocation and targeting those with higher risks, it may be advantageous to concentrate vitamin D testing on specific population groups.
Control of cell fate specification and patterning by an ancestral microRNA
Authors: Aguilar-Cruz Adolfo , Flores-Sandoval Eduardo , Gutiérrez-Ramos Ximena , Lopez Omar Oltehua- , Dorantes-Acosta Ana E. , Trujillo Joshua T. , Kato Hirotaka , Ishizaki Kimitsune , Mosher Rebecca A. , Dolan Liam , Grimanelli Daniel , Haseloff Jim , Bowman John L. , Arteaga-Vazquez Mario A.
Published: September 2023

The formation of an organized body requires the establishment and maintenance of cells with structural and functional distinctive characteristics. A central question in developmental biology is how changes in the regulation of genes drive cell specification and patterning1. microRNAs (miRNAs) are small non-coding RNAs that regulate development through mRNA cleavage and/or translational repression2. In plants, miRNAs regulate key aspects including growth, development, stem cell maintenance, vegetative phase change, leaf morphogenesis, floral organ formation and flowering time3. Biogenesis of plant miRNAs depends on the activity of DICER-LIKE 1 (DCL1), an RNase type III endonuclease that processes double stranded RNA to give rise to mature miRNAs4. The genomes of today’s flora contain at least one bona fide copy ofDCL15,6. UsingMarchantia polymorpha-a model bryophyte that allows comparative approaches to infer characteristics of the ancestral land plant-, we demonstrate that MpDCL1ais required for the biogenesis of miRNAs and uncovered a central role for miR166/Homeodomain Zipper Class III-regulated auxin synthesis in the specification of cell identity, patterning, meristem function, laminar expansion and the development of the body in the last common ancestor of extant land plants.
Structural basis for the allosteric regulation and dynamic assembly of DNMT3B
Authors: Lu Jiuwei , Fang Jian , Zhu Hongtao , Liang Kimberly Lu , Khudaverdyan Nelli , Song Jikui
Published: September 2023

Oligomerization of DNMT3B, a mammaliande novoDNA methyltransferase, critically regulates its chromatin targeting and DNA methylation activities. However, how the N-terminal PWWP and ADD domains interplay with the C-terminal methyltransferase (MTase) domain in regulating the dynamic assembly of DNMT3B remains unclear. Here, we report the cryo-EM structure of DNMT3B under various oligomerization states. The ADD domain of DNMT3B interacts with the MTase domain to form an autoinhibitory conformation, resembling the previously observed DNMT3A autoinhibition. Our combined structural and biochemical study further identifies a role for the PWWP domain and its associated ICF mutation in the allosteric regulation of DNMT3B tetramer, and a differential functional impact on DNMT3B by potential ADD-H3K4me0 and PWWP-H3K36me3 bindings. In addition, our comparative structural analysis reveals a coupling between DNMT3B oligomerization and folding of its substrate-binding sites. Together, this study provides mechanistic insights into the allosteric regulation and dynamic assembly of DNMT3B.
O-GlcNAcylation of YTHDF2 antagonizes ERK-dependent phosphorylation and inhibits lung carcinoma
Authors: Li Jie , Zhou Wen , Zhang Jianzhi , Ma Li , Lv Zhuan , Geng Yiqun , Chen Xing , Li Jing
Published: September 2023

The intracellular O-linked N-acetylglucosamine (O-GlcNAc) glycosylation mediates many signal transduction events and regulates tumorigenesis. Previously the RNA N6-methyladenosine (m6A) reader, YTH (YT521-B homology) domain 2 (YTHDF2), has been shown to be O-GlcNAcylated on Ser-263 during Hepatitis B virus (HBV) infection and promote HBV-related hepatocellular carcinoma. Herein we mapped YTHDF2 O-GlcNAcylation at Thr-49 via electron-transfer dissociation mass spectrometry under unperturbed conditions. We show that YTHDF2 Thr-49 O-GlcNAcylation antagonizes Extracellular-signal regulated kinase (ERK)-dependent phosphorylation at Ser-39 and promotes YTHDF2 degradation. The downstream signaling pathway of YTHDF2 in lung carcinoma are thus upregulated, which leads to the downregulation of c-Myc. We further used mouse xenograft models to show that YTHDF2-T49A mutants increased lung cancer mass and size. Our work reveals a key role of YTHDF2 O-GlcNAcylation in tumorigenesis and suggests that O-GlcNAcylation exerts distinct functions under different biological stress.
Potential Structural Biomarkers in 3D Images Validated by the First Functional Biomarker for Early Age-Related Macular Degeneration - ALSTAR2 Baseline
Authors: Fasih-Ahmad Sohaib , Wang Ziyuan , Mishra Zubin , Vatanatham Charles , Clark Mark E , Swain Thomas A. , Curcio Christine A. , Owsley Cynthia , Sadda SriniVas R , Hu Zhihong Jewel
Published: September 2023

Purpose

While intermediate and late age-Related Macular Degeneration (AMD) have been widely investigated, rare studies were focused on the pathophysiologic mechanism of early AMD. Delayed rod-mediated dark adaptation (RMDA) is the first functional biomarker for incident early AMD. The status of outer retinal bands on optical coherence tomography (OCT) may be potential imaging biomarkers and the purpose is to investigate the hypothesis that the integrity of interdigitation zone (IZ) may provide insight into the health of photoreceptors and retinal pigment epithelium (RPE) in early AMD.

Methods

We establish the structure-function relationship between ellipsoid zone (EZ) integrity and RMDA, and IZ integrity and RMDA in a large-scale OCT dataset from eyes with normal aging (n=237), early AMD (n=138), and intermediate AMD (n=101) by utilizing a novel deep-learning-derived algorithm with manual correction when needed to segment the EZ and IZ on OCT B-scans (57,596 B-scans), and utilizing the AdaptDx device to measure RMDA.

Results

Our data demonstrates that slower RMDA is associated with less preserved EZ (r = -0.334; p<0.001) and IZ area (r = -0.591; p<0.001), and decreased IZ thickness (r = -0.434; p<0.001). These associations are not apparent when considering normal eyes alone.

Conclusions

The association with IZ area and RMDA in large-scale data is biologically plausible because retinoid availability and transfer at the interface attributed to IZ is rate-limiting for RMDA. This study supports the hypothesis that the IZ integrity provides insight into the health of photoreceptors and RPE in early AMD and is a potential new imaging biomarker.
Incidence of Acute Watery Diarrhea among Internally Displaced People in Burhakaba Camps, Bay Region, Somalia
Authors: Jayte Mohamed , Dahir Maryan
Published: September 2023

Background

Acute watery diarrhea (AWD) is a major public health issue among internally displaced persons (IDPs) in Somalia due to inadequate water, sanitation and hygiene (WASH) infrastructure and services, in crowded camps. This study aimed to determine the incidence and associated factors of AWD in IDP camps in Burhakaba, Bay region.

Methods

A cross-sectional survey was conducted among 318 IDPs across 6 camps in Burhakaba town. Structured interviews collected data on demographics 7-day episodes of AWD, water sources, latrine access, hygiene practices, and food consumption. AWD incidence was calculated and bivariate analysis identified associated factors.

Results

The overall AWD incidence was 16.7%. Children under 5 had the highest incidence, at 9.8% among under 1 year and 8.9% among 1-5 years. Use of open wells (p=0.026), lack of latrines (p=0.017), poor hand-washing practices (p=0.002), and reduced food intake (p<0.001) were significantly associated with higher AWD risk.

Conclusions

Targeted intervention to improve water quality, sanitation coverage, hygiene practices, and food security are urgently needed to reduce the high AWD burden among IDPs in Burhakaba.
Exploring the relationship between food environment and preferences among school children in a low socio-economic community in Sri Lanka: A GIS based assessment
Authors: Senevirathne Chamil , Katulanda Prasad , de Silva Padmal , Prashadika Dilini , Senarathne Lalith
Published: September 2023

Food environment in school neighborhood plays a crucial role in manipulating food choices of school children. This study investigated the relationship between food environment in neighborhood and dietary practices of government school students in a low socio-economic setting, Sri Lanka. This cross-sectional study surveyed the neighborhood food environment of selected schools (n=30) in Monaragala District, Sri Lanka, using Geographical Information System (GIS) data, and collected dietary information from a representative sample of school children (n=603). Chi-square and spearman correlation tests were performed using SPSS version 23.0 to estimate the associations between food environment and BMI of students, while ArcGIS 10.4.1 was used to analyze GIS data of the study.

Majority of students (35.5%) were 15 years old and approximately 51% were females. Mean BMI of study participants was 18.14 (± 3.28). More than 90% of outlets within close proximity sold unhealthy foods. Consumption of confectionaries was 72.3% of students whereas healthy foods choices was ranged from 5% to 12%. A positive correlation between consuming unhealthy food and distance to the outlets from the school was observed (p<0.05). Risk of consuming low nutrition food found to be doubled (OR = 2.47, 95% CI: 1.52-3.89) among students studied in schools where larger proportion of energy dense food sold in closer proximity. In conclusion, density and the proximity of the outlets that sold food in low nutrients in school neighborhood environment were positively associated with choosing unhealthy food items by students.
Cancer diagnostic service use in people with HIV in South Africa: a cross-sectional study
Authors: Olago Victor , Nimako Gideon , Bartels Lina , Bohlius Julia , Dhokotera Tafadzwa , Egger Matthias , Singh Elvira , Sengayi-Muchengeti Mazvita
Published: September 2023

Objective

The objective of this study was to map place of cancer diagnosis in relation to Human Immunodeficiency Virus (HIV) care centre among people with HIV (PWH) within South Africa (SA) using national laboratory database.

Design

We linked HIV and cancer laboratory data from 2004-2014 using supervised machine-learning algorithms. We performed a cross-sectional analysis comparing province where individuals accessed their HIV care versus where they had their cancer diagnosis.

Setting

We used laboratory test records related to HIV diagnostics and care, such as CD4 cell counts and percentages, rapid tests, qualitative Polymerase Chain Reaction (PCR), antibody and antigen tests for HIV data that was documented as HIV positive and laboratory diagnosed cancer records from SA.

Study population

Our study population consisted of HIV records from the National Health Laboratory Service (NHLS) that linked to cancer record at the National Cancer Registry (NCR) between 2004-2014.

Primary and secondary outcomes

We linked HIV records from NHLS to cancer records at NCR in order to study the inherent characteristics of the population with both HIV and cancer.

Results

The study population was 68,284 individuals with cancer and documented HIV related laboratory test. The median age at cancer diagnosis was 40 [IQR, 33-48] years for the study population with most cancers in PWH diagnosed in females 70.9% [n=46,313]. Of all the PWH and cancer, 25% (n=16,364 p < 0.001) sought treatment outside their province of residence with 60.7% (n=10,235) travelling to Gauteng. KZN had 46.6% (n=4,107) of its PWH getting cancer diagnosis in Gauteng. Western Cape had 95% (n=6,200) of PWH getting cancer diagnosis within the province.

Conclusions

Our results showed health systems inequalities across provinces in South Africa with respect to cancer diagnosis. KZN for example had nearly half of the PWH getting cancer diagnosis outside the province while Western Cape is able to offer cancer diagnostic services to most of the PWH in the province. Gauteng is getting over burdened with referral for cancer diagnosis from other provinces. More effort is required to ensure equitable access to cancer diagnostic services within the country.

Article Summary

Strengths and limitations of this study

We mapped the facilities of cancer diagnosis versus HIV care facilities for the PWH seeking cancer diagnosis in South Africa.

We compared PWH who sought treatment in their province of residence versus those who sought treatment outside their province of residence.

We used HIV care facility’s addresses as a proxy for place of residence for PWH.

We did not account for movement due to other reasons such as migration for better jobs and education.
Loss of cholesterol in Junctional Epidermolysis Bullosa skin identifies a key role for Laminin-332 in actomyosin mediated cholesterol transport
Authors: Jones Eleri. M. , Camera Emanuela. , Parzymies Piotr. , Marsh Supatra.T. , O’Shaughnessy Ryan.F. , Aumailley Monique. , McGrath John. A. , O’Toole Edel.A. , Caley Matthew.
Published: September 2023

Individuals with Junctional Epidermolysis Bullosa (JEB), a rare genetic skin disease characterised by loss of function mutations in the Laminin332 (Lam332), do not survive beyond their first birthday. Here we report that loss of Lam332 leads to absence of cholesterol lipid from the epidermisin vitroandin vivo. Stable knockdown of Lam332 chains (LAMA3, LAMB3 and LAMC2) was established using shRNA and were used to develop 3D skin equivalents. Changes in lipid synthesis were assessed by western blot analysis and immunohistochemistry. Findings were confirmed in an inducible mouse model of Lamα3 (Lama3flox/flox/K14CreERT) and in anonymized, archival human tissue: JEB skin and normal age-matched controls. Further lipid analysis was explored using lipidomics in 3D skin equivalents and mouse tissue. Cholesterol biosynthesis genes were increased with loss of Lam332in vitro, however a decrease in nile red lipid staining was observed in Lamα3 mouse (n = 6) and in JEB patient skin (n = 7). Further changes to the epidermal lipid profile with loss of Lam332 was confirmed with lipidomic analysis of Lamα3 mouse epidermis and Lam332 skin equivalents. Cholesterol transport within Lam332 KD keratinocytes was revealed to be disrupted, which in keratinocytes is dependent on the actomyosin network, which was reversed with recombinant human Lam332. In conclusion these findings suggest a role for Lam332 in lipid metabolism in the skin and a broader role in epidermal homeostasis and barrier formation. Restoration of cholesterol transport in JEB patients offers the potential to improve the skin barrier and survival.
Reconfiguration of brain-wide neural activity after early life adversity
Authors: Uselman Taylor W. , Jacobs Russell E. , Bearer Elaine L
Published: September 2023

Early life adversity (ELA) predisposes individuals to both physical and mental disorders lifelong. How ELA affects brain function leading to this vulnerability is under intense investigation. Research has begun to shed light on ELA effects on localized brain regions within defined circuits. However, investigations into brain-wide neural activity that includes multiple localized regions, determines relationships of activity between regions and identifies shifts of activity in response to experiential conditions is necessary. Here, we performed longitudinal manganese-enhanced magnetic resonance imaging (MEMRI) to image the brain in normally reared or ELA-exposed adults. Images were captured in the freely moving home cage condition, and short- and long-term after naturalistic threat. Images were analyzed with new computational methods, including automated segmentation and fractional activation or difference volumes. We found that neural activity was increased after ELA compared to normal rearing in multiple brain regions, some of which are involved in defensive and/or reward circuitry. Widely distributed patterns of neural activity, “brain states”, and their dynamics after threat were altered with ELA. Upon acute threat, ELA-mice retained heightened neural activity within many of these regions, and new hyperactive responses emerged in monoaminergic centers of the mid- and hindbrain. Nine days after acute threat, heightened neural activity remained within locus coeruleus and increased within posterior amygdala, ventral hippocampus, and dorso- and ventromedial hypothalamus, while reduced activity emerged within medial prefrontal cortical regions (prelimbic, infralimbic, anterior cingulate). These results reveal that functional imbalances arise between multiple brain-systems which are dependent upon context and cumulative experiences after ELA.

Significance Statement

Early life adversity (ELA) is a crucial determinant of adult health. Yet, the neurobiological basis for this association remains elusive. Neural activity differs within localized brain regions in rodents who experienced ELA, yet how this localized activity contributes to overall brain states has hitherto been unknown. Here we used longitudinal manganese-enhanced MRI to reveal brain-wide activities altered by ELA compared to normal rearing. Advanced computational analyses unveiled widespread reconfiguration of segment-wise neural activity throughout the brain across a series of conditions: freely moving, experiencing threat or its aftermath. These brain state dynamics were unique to ELA. Reconfiguration of brain states after ELA, shown here for the first time, may underlie predisposition to mental and physical disorders after childhood adversity.
Harnessing axonal transport to map reward circuitry: Differing brain-wide projections from medial forebrain domains
Authors: Bearer E. L. , Medina C. S. , Uselman T. W. , Jacobs R. E.
Published: September 2023

Neurons project long axons that contact other distant neurons. Projections can be mapped by hijacking endogenous membrane trafficking machinery by introducing tracers. To witness functional connections in living animals, we developed a tracer detectible by magnetic resonance imaging (MRI), Mn(II). Mn(II) relies on kinesin-1 and amyloid-precursor protein to travel out axons. Within 24h, projection fields of cortical neurons can be mapped brain-wide with this technology. MnCl2was stereotactically injected either into anterior cingulate area (ACA) or into infralimbic/prelimbic (IL/PL) of medial forebrain (n=10-12). Projections were imaged, first bymanganese-enhancedMRI(MEMRI) live, and then after fixation by microscopy. MR images were collected at 100µm isotropic resolution (∼5 neurons) in 3D at four time points: before and at successive time points after injections. Images were preprocessed by masking non-brain tissue, followed by intensity scaling and spatial alignment. Actual injection locations, measured from post-injection MR images, were found to be 0.06, 0.49 and 0.84mm apart between cohorts, in R-L, A-P, and D-V directions respectively. Mn(II) enhancements arrived in hindbrains by 24h in both cohorts, while co-injected rhodamine dextran was not detectible beyond immediate subcortical projections. Data-driven unbiased voxel-wise statistical maps after ACA injections revealed significant progression of Mn(II) distally into deeper brain regions: globus pallidus, dorsal striatum, amygdala, hypothalamus, substantia nigra, dorsal raphe and locus coeruleus. Accumulation was quantified as a fraction of total volume of each segment containing significantly enhanced voxels (fractional accumulation volumes), and results visualized in column graphs. Unpaired t-tests between groups of brain-wide voxel-wise intensity profiling by either region of interest (ROI) measurements or statistical parametric mapping highlighted distinct differences in distal accumulation between injection sites, with ACA projecting to periaqueductal gray and IL/PL to basolateral amygdala (p<0.001 FDR). Mn(II) distal accumulations differed dramatically between injection groups in subdomains of the hypothalamus, with ACA targeting dorsal medial, periventricular region and mammillary body nuclei, while IL/PL went to anterior hypothalamic areas and lateral hypothalamic nuclei. Given that these hypothalamic subsegments communicate activity in the central nervous system to the body, these observations describing distinct forebrain projection fields will undoubtedly lead to newer insights in mind-body relationships.
Reduced expression of fMRI subsequent memory effects with increasing severity across the Alzheimer’s disease risk spectrum
Authors: Soch Joram , Richter Anni , Kizilirmak Jasmin M. , Schütze Hartmut , Altenstein Slawek , Dechent Peter , Fliessbach Klaus , Glanz Wenzel , Herrera Ana Lucia , Hetzer Stefan , Incesoy Enise I. , Kilimann Ingo , Kimmich Okka , Lammerding Dominik , Laske Christoph , Lohse Andrea , Lüsebrink Falk , Munk Matthias H. , Peters Oliver , Preis Lukas , Priller Josef , Rostamzadeh Ayda , Roy-Kluth Nina , Scheffler Klaus , Schneider Anja , Spottke Annika , Spruth Eike Jakob , Teipel Stefan , Wiltfang Jens , Jessen Frank , Düzel Emrah , Schott Björn H.
Published: September 2023

In functional magnetic resonance imaging (fMRI) studies, episodic memory is commonly investigated with the subsequent memory paradigm in which brain activity is recorded during encoding and analyzed as a function of subsequent remembering and forgetting. Impaired episodic memory is common in individuals with or at risk for Alzheimer’s disease (AD), but only few studies have reported subsequent memory effects in AD or its risk states like mild cognitive impairment (MCI). One reason for this might be that subsequent memory responses may be blunted in AD or MCI and thus less likely to manifest in fMRI signal differences. Here, we used Bayesian model selection of single-subject fMRI general linear models (GLMs) for a visual novelty and memory encoding experiment to compare the model performance of categorical and parametric subsequent memory models as well as memory-invariant models in a clinical cohort (N = 468) comprising healthy controls (HC) as well as individuals with subjective cognitive decline (SCD), MCI, and AD, plus healthy relatives of AD patients (AD-rel). We could replicate the previously reported superiority of parametric subsequent memory models over categorical models (Soch et al., 2021a) in the HC and also in the SCD and AD-rel groups. However, memory-invariant models outperformed any model assuming subsequent memory effects in the MCI and AD groups. In the AD group, we additionally found substantially lower model preference for models assuming novelty compared to models not differentiating between novel and familiar stimuli. Our results suggest that voxel-wise memory-related fMRI activity patterns in AD and also MCI should be interpreted with caution and point to the need for additional or alternative approaches to investigate memory function.
Atf3 controls transitioning in female mitochondrial cardiomyopathy as identified by single-cell transcriptomics
Authors: Qaqorh Tasneem , Takahashi Yusuke , Otani Kentaro , Yazawa Issei , Nishida Yuya , Fujihara Yoshitaka , Honda Mizuki , Oki Shinya , Ohkawa Yasuyuki , Thorburn David R. , Frazier Ann E. , Takeda Atsuhito , Ikeda Yoshihiko , Sakaguchi Heima , Watanabe Takuya , Fukushima Norihide , Tsukamoto Yasumasa , Makita Naomasa , Yamaguchi Osamu , Murayama Kei , Ohtake Akira , Okazaki Yasushi , Inoue Hijiri , Matsuoka Ken , Yamazaki Satoru , Takashima Seiji , Shintani Yasunori
Published: September 2023

Oxidative phosphorylation defects results in mitochondrial diseases, with cardiac involvement markedly impacting prognosis. However, the mechanisms underlying the transition from compensation to dysfunction in response to metabolic deficiency remain unclear, impeding the development of effective treatments. Here, we employed single-nucleus RNA sequencing (snRNA-seq) on hearts from mitochondrial cardiomyopathy (MCM) mice with cardiac-specificNdufs6knockdown (FS6KD). Pseudotime trajectory analysis of cardiomyocytes from early stage of female FS6KD hearts revealed dynamic cellular state transitioning from compensation to severe compromise, coincided with transient upregulation of a critical transcription factor,activating transcription factor 3(Atf3). Genetic ablation or adeno-associated virus-mediatedAtf3knockdown in FS6KD mice effectively delayed cardiomyopathy progression in a female-specific manner. Notably, human MCM snRNA-seq revealed a similar transition, including the dynamic expression ofATF3. In conclusion, our findings highlight a fate-determining role of Atf3 in female MCM progression, providing a promising therapeutic candidate for the currently intractable disease.
Design and performance of the high-resolution stress and texture neutron diffractometer HETU
Authors: Wang Baihua , Zhong Shengyi , Lin Hao , Li Jian , Yang Zhaolong , Goukassov Arsen , Zhang Hongxia , Sun Guang-ai
Published: September 2023

The high-resolution stress and texture neutron diffractometer HETU at the China Mianyang Research Reactor is dedicated to measuring and analysing the residual stress and texture of engineering materials. The instrument can provide a high instrument resolution and a high neutron flux at the sample position. This article presents the HETU neutron optics design based on Monte Carlo simulation and the first assessment of its experimental performance. The technical parameters of the monochromators, slit system, radial collimators and detector were determined. A double-focusing silicon monochromator with (311) and (400) planes and a highly oriented pyrolytic graphite (HOPG) monochromator with (002) and (004) planes were selected to provide either high instrument resolution or high neutron flux modes. The highest instrument resolution of Δd/d = 1.65 × 10−3 is obtained when using Si(400), while the highest neutron flux at the sample position is 3.0 × 107 n s−1 cm−2 at the wavelength of 2.37 Å reflected by HOPG(004). The HETU diffractometer started operation in early 2022.
TERSE/PROLIX (TRPX) – a new algorithm for fast and lossless compression and decompression of diffraction and cryo-EM data
Authors: Matinyan Senik , Abrahams Jan Pieter
Published: September 2023

High-throughput data collection in crystallography poses significant challenges in handling massive amounts of data. Here, TERSE/PROLIX (or TRPX for short) is presented, a novel lossless compression algorithm specifically designed for diffraction data. The algorithm is compared with established lossless compression algorithms implemented in gzip, bzip2, CBF (crystallographic binary file), Zstandard(zstd), LZ4 and HDF5 with gzip, LZF and bitshuffle+LZ4 filters, in terms of compression efficiency and speed, using continuous-rotation electron diffraction data of an inorganic compound and raw cryo-EM data. The results show that TRPX significantly outperforms all these algorithms in terms of speed and compression rate. It was 60 times faster than bzip2 (which achieved a similar compression rate), and more than 3 times faster than LZ4, which was the runner-up in terms of speed, but had a much worse compression rate. TRPX files are byte-order independent and upon compilation the algorithm occupies very little memory. It can therefore be readily implemented in hardware. By providing a tailored solution for diffraction and raw cryo-EM data, TRPX facilitates more efficient data analysis and interpretation while mitigating storage and transmission concerns. The C++20 compression/decompression code, custom TIFF library and an ImageJ/Fiji Java plugin for reading TRPX files are open-sourced on GitHub under the permissive MIT license.
Modeling antecedents of safety compliance of construction workers in Australia: a perspective of trait activation theory
Authors: Yan Diya , Zhao Xianbo , Kalutara Pushpitha , Jiang Zhou
Published: September 2023

Purpose

Construction workers’ safety compliance is attracting considerable critical attention as it plays a decisive role in improving safety on construction sites. This study applied the concept of differentiating safety compliance into deep compliance (DC) and surface compliance (SC) and relied on trait activation theory to investigate the effects of situational awareness (SA) and emotional intelligence (EI) on safety compliance.

Design/methodology/approach

Cross-sectional survey data were collected from 239 construction workers in Australia, and these responses were statistically analyzed using the partial least squares structural equation modeling (PLS-SEM) to validate the proposed model.

Findings

Results revealed that both EI and SA positively impacted DC and negatively impacted SC. Moreover, SA partially mediated the link between EI and two types of safety compliance (DC and SC). The outcomes showed that construction workers’ ability in regulating their emotions could influence their perception of environmental cues and the effectiveness of safety compliance behavior.

Originality/value

This study sheds light on investigating the antecedents of DC and SC from the perspective of trait activation theory. The findings also have practical implications, stating that construction site managers or safety professionals should consider providing training on construction workers’ EI and SA to enhance their willingness to expend conscious efforts in complying with safety rules and procedures, which can lead to improved safety outcomes.
Analysis of key brake pad parameters on brake system stability
Authors: Lin Dongdong , Yan Xiaoyu , Chen Binsan , She Na , Ding Yining , Dong Shichao
Published: September 2023

Purpose

This study aims to explore the impact of key parameters of brake pads on the dynamic characteristics of the braking system.

Design/methodology/approach

This study conducted experimental research based on a friction testing machine with a slider-disc structure. The experiment studied the impact of key parameters of brake pads (rotation speed, pressure, mass, braking radius, etc.) and the braking environment (dry friction, wetness, sand, etc.) on the stability of the braking system. At the same time, a dynamic model of the brake pad braking system was established and compared with experimental results using the mathematical tool of autocorrelation coefficient.

Findings

The key parameters of brake pads have a significant impact on the dynamic characteristics of the braking system; under different conditions of brake pad mass, tribological parameters, brake pad radius and braking environment, the chaotic characteristics of the braking friction force signal show a trend of expansion or contraction, which can be suppressed by adjusting the key parameters of brake pads.

Originality/value

This study can provide a reference for optimizing the braking strategy and reducing noise and vibration in brake pad systems.
Fuzzy cost, revenue efficiency assessment and target setting in fuzzy DEA: a fuzzy directional distance function approach
Authors: Gerami Javad , Mozaffari Mohammad Reza , Wanke Peter , Tan Yong
Published: September 2023

Purpose

This study aims to present the cost and revenue efficiency evaluation models in data envelopment analysis in the presence of fuzzy inputs, outputs and their prices that the prices are also fuzzy. This study applies the proposed approach in the energy sector of the oil industry.

Design/methodology/approach

This study proposes a value-based technology according to fuzzy input-cost and revenue-output data, and based on this technology, the authors propose an approach to calculate fuzzy cost and revenue efficiency based on a directional distance function approach. These papers incorporated a decision-maker’s (DM) a priori knowledge into the fuzzy cost (revenue) efficiency analysis.

Findings

This study shows that the proposed approach obtains the components of fuzzy numbers corresponding to fuzzy cost efficiency scores in the interval [0, 1] corresponding to each of the decision-making units (DMUs). The models presented in this paper satisfies the most important properties: translation invariance, translation invariance, handle with negative data. The proposed approach obtains the fuzzy efficient targets corresponding to each DMU.

Originality/value

In the proposed approach, by selecting the appropriate direction vector in the model, we can incorporate preference information of the DM in the process of evaluating fuzzy cost or revenue efficiency and this shows the efficiency of the method and the advantages of the proposed model in a fully fuzzy environment.
NPAs in India's banks: trends and determinants
Authors: Das Santosh Kumar
Published: September 2023

Purpose

This paper aims to analyse trends and determinants of NPAs in India's banks. It has empirically examined the bank-specific determinants of NPAs.

Design/methodology/approach

An FE panel estimation of a sample of 44 banks was carried out for the post-crisis time period, from 2010 to 2020 to identify the bank-specific determinants of NPAs. The sample of 44 banks includes 20 PSBs, 19 private banks and 5 foreign banks. Separate FE estimation was also carried out to identify the drivers of NPAs in PSBs.

Findings

The determinant of NPAs during the post-crisis period suggests that faulty earning management and deterioration in loan quality have resulted in high NPAs in India's banks. The result is similar for PSBs as well.

Research limitations/implications

The findings of the study suggest that the banks, especially the Public Sector Banks (PSBs) need to revisit their earning management strategies to maximise income and improve their loan quality in order to reduce the incidence of loan failure.

Originality/value

The paper contributes by empirically analysing the determinants of NPAs during the recent decade, between 2010 and 2020. Separate estimations have been carried out to understand whether the drivers of NPAs differ in the case of PSBs.
The impact of knowledge brokering and role crafting on work engagement: a two-wave panel survey of older Japanese workers
Authors: Ishiyama Nobutaka
Published: September 2023

Purpose

This study aimed to investigate the mechanisms of knowledge brokering and role crafting structures that promote the active engagement of older workers at work.

Design/methodology/approach

The respondents were workers in Japan aged 55–64 years. A two-wave panel survey was conducted. The first and second survey waves included 1,527 and 1,467 respondents, respectively.

Findings

The results showed that knowledge brokering positively influenced work engagement directly and indirectly. In the three dimensions of role crafting, cognitive and task crafting had a positive effect on work engagement.

Research limitations/implications

This study focused on older workers in Japan. Therefore, it is necessary to verify whether the same effect is observed in countries other than Japan or among younger workers.

Practical implications

On an individual level, older workers should aim to keep acquiring new information inside and outside the organisation. On an organisational level, it is effective to increase opportunities for older workers to craft their work according to the socioemotional selectivity and selection optimisation and compensation theories.

Originality/value

This study reveals that knowledge brokering and cognitive crafting in role crafting have an important influence on the work engagement of older workers. Additionally, this study clarifies the impact of job crafting on older workers not only from the perspective of resource crafting to achieve person-job fit but also from the perspective of reframing perceptions through cognitive crafting in role crafting. These findings enable a clearer understanding of the relationship between role crafting and knowledge brokering, as well as the socioemotional selectivity and selection optimisation and compensation theories.
Trust in management and state government mitigate the relationships between individual- and state-level stressors and well-being during COVID-19
Authors: Henderson Alexandra A. , Jeong Sophia S. , Horan Kristin A.
Published: September 2023

Purpose

This study aims to examine the role of trust in management and state government in mitigating the relationships between individual- and state-level stressors and well-being during the COVID-19 pandemic.

Design/methodology/approach

Data were collected from a US sample still working during the first wave of infections (N = 437) and was supplemented with objective state-level data. Data were analyzed using hierarchical regression modeling with the PROC MIXED procedure with SAS software to incorporate both individual- and state-level variables.

Findings

Results indicated that individual-level stressors (work and family role overload) were positively associated with stress; however, the relationship between family role overload and stress was mitigated among those with high trust in state government. Results indicated that state-level stressors (infection rates and population density) were not associated with stress; however, the relationship between state population density and stress was positive among those with low trust in management and negative among those with high trust in management.

Practical implications

This study highlights the need for organization and government leaders to build trust before and during crisis situations, as well as engage in a collaborative approach to managing stressors in crisis situations.

Originality/value

This study highlights the importance of expanding the focus of employee trust across organizational boundaries for understanding employee well-being during a crisis situation. This study also demonstrates the cross-over effects of trust, such that organization leaders can protect workers from community stressors, while government leaders can protect workers from family stressors.