bluuebunny/crossref_metadata_2025 huggingface dataset:
Galleria mellonella as a superficial model for Malassezia globosa and its treatment
Authors: Torres Maritza , Diaz-Ortiz Juliana , Davis Michael G. , Schwartz James R. , Celis Ramírez Adriana Marcela
Published: June 2024

Introduction.
Malassezia globosa is a yeast species that belongs to the mycobiota of humans and animals, associated with dermatological disorders, such as dandruff. This is a chronic scalp skin disorder characterized by flaking and itching. Treatments include commercial shampoo with different formulations that contain antifungal activities like zinc pyrithione (ZPT) or piroctone olamine (PO). The effectiveness of these formulations has been evaluated for decades for dandruff symptom relief of volunteers. To date, non-mammalian, in vivo methods exist to test formulations of these actives.

Aim. To evaluate in vivo in Galleria mellonella larva, two commercial antifungal shampoos (shampoo with 1 % ZPT and 1.6 % zinc Carbonate and shampoo with 0.5 % PO) against this species.

Methodology.
G. mellonella larvae were inoculated with M. globosa on abraded cuticular surface. Then, integument cell viability, histological changes, and fungal burden were evaluated.

Results. Larvae inoculated with M. globosa showed higher lesion melanization and tissue damage. In addition, M. globosa population showed to increase over time. Concerning the shampoo’s effectiveness, both formulations significantly reduced M. globosa burden and tissue damage.

Conclusion.
G. mellonella larvae were allowed to evaluate M. globosa superficial infection and antifungal effectiveness. Shampoos with ZPT and PO showed a positive effect on inoculated larvae.
Roseateles subflavus sp. nov. and Roseateles aquae sp. nov., isolated from artificial pond water and Roseateles violae sp. nov., isolated from a Viola mandshurica root
Authors: Woo Haejin , Chhetri Geeta , Kim Inhyup , So Yoonseop , Park Sunho , Jung Yonghee , Seo Taegun
Published: June 2024

Two novel strains, designated APW6T and APW11T, were isolated from artificial pond water, and one novel strain, designated PFR6T, was isolated from a Viola mandshurica root. These strains were found to be Gram-negative, rod-shaped, motile by means of flagella, and oxidase-positive. Growth conditions of the type strains were as follows: APW6T, 15–43 °C (optimum, 28 °C), pH 6.0–12.0 (optimum, pH 7.0), with no salinity; APW11T, 4–35 °C (optimum, 25 °C), pH 6.0–11.0 (optimum, pH 9.0), with 0–1 % NaCl (w/v, optimum 0 %); PFR6T, 10–38 °C (optimum 28 °C), pH 6.0–12.0 (optimum, pH 7.0), with 0–2 % NaCl (w/v; optimum, 0 %). Strains APW6T, APW11T, and PFR6T belonged to the genus Roseateles, having the most 16S rRNA gene sequence similarity to Roseateles saccharophilus DSM 654T (98.1 %), Roseateles oligotrophus CHU3T (98.7 %), and Roseateles puraquae CCUG 52769T (98.1 %). The estimated genome sizes of APW6T, APW11T, and PFR6T were 50 50 473, 56 70 008, and 52 16 869 bp, respectively and the G+C contents were 69.5, 66, and 68.5 mol%. The digital DNA–DNA hybridization, average amino acid identity, and average nucleotide identity values among the novel strains and related taxa were all lower than 22.4, 74.7, and 78.9 %, respectively. The predominant cellular fatty acids (>10 %) of all strains were summed feature 3 (comprising C16 : 1
 ω6c and/or C16 : 1
 ω7c) and C16 : 0. PFR6T also had summed feature 8 (comprising C18 :  1 ω7c and/or C18 :  1 ω6c) as a major fatty acid. The polar lipid profile of all strains contained phosphatidylethanolamine, phosphoaminoglycolipid, and phosphoglycolipid. The distinct phylogenetic, physiological, and chemotaxonomic features reported in this study indicate that strains APW6T, APW11T, and PFR6T represent novel species within the genus Roseateles, for which the names Roseateles subflavus sp. nov., with the type strain APW6T (=KACC 22877T=TBRC 16606T), Roseateles aquae sp. nov., with the type strain APW11T (=KACC 22878T=TBRC 16607T), and Roseateles violae sp. nov (=KACC 23257T=TBRC 17653T) are respectively proposed.
Hand motor recovery from post-stroke chronic severe hemiplegia with brain-computer interface based neurofeedback exercise: A randomized controlled trial
Authors: Mizuno Katsuhiro , Hayashi Masaaki , Iwama Seitaro , Nishida Daisuke , Honaga Kaoru , Fuseya Hiroshi , Hirose Ryotaro , Okuyama Kohei , Ogura-Hiramoto Miho , Kawakami Michiyuki , Ushiba Junichi , Liu Meigen
Published: June 2024

Background

Post-stroke hemiplegia is a common neurological condition with a significant impact on the daily lives of patients, their families, and society. Since motor imagery and execution are supposed to share common neural networks, repeated motor imagery has been used as a common exercise for motor recovery. However, recent meta-analysis has reported inconsistent results. In the present study, we investigated whether real-time feedback of cortical activities estimated from scalp electroencephalogram (EEG) could enhance the efficacy of motor imagery-based rehabilitation in post-stroke hemiplegic patients.

Methods

Forty post-stroke chronic hemiplegic patients received 10 days of 40-minute mental practice with motor imagery of the paralyzed hand in addition to 40-minute standard occupational therapy. Patients were randomly allocated to REAL and CTRL groups. In the REAL group, the EEG sensorimotor rhythm recorded over the ipsilesional sensorimotor area were fed back during motor imagery though combination of visual cursor movement, neuromuscular electrical stimulation, and robotic movement support. The patients in the CTRL group wore the same EEG headset as the REAL group, but no feedback was provided. The primary outcome was the upper-extremity subscales of the Fugl-Meyer assessment (FMA). Primary outcomes were tested after 28 days of intervention using analysis of covariance models. This trial is registered with UMIN Clinical Trial Registry, UMIN000026372.

Findings

FMA scores showed a significant main effect of time (p = 0·027) with an ANCOVA model considering baseline but not a significant between-group difference. However a significant interaction between time and group (p = 0•037) and greater functional gain in the REAL group (p < 0•001) were found with another model considering patient heterogeneity. The improvement was accompanied with the significant changes in the modulation index of finger extensor muscles in the affected hand in the REAL group. Moreover, imagery-related cortical activation in the sensorimotor area was significantly greater in the REAL group than in the CTRL group. No moderate or serious adverse events were confirmed in both groups.

Interpretation

EEG-based brain-computer interface neurofeedback may enhance the efficacy of mental practice with motor imagery and augment motor recovery in poststroke patients with chronic and severe hemiplegia.

Funding

Sponsored by AMED under Grant Number JP18hk0102032 and JSPS KAKENHI Grant Number 20H05923.
Genetic analysis ofMycobacterium abscessusreveals genomic diversity linked to global plasmid distribution
Authors: Ohse Kensuke , Yoshida Atsushi , Kamada Keisuke , Kitazawa Hironobu , Ito Yusuke , Shoji Takayo , Watanabe Kenichiro , Koganemaru Hiroshi , Kikuchi Ken , Toyoda Masashi
Published: June 2024

Genetic epidemiological analysis of mobile genetic elements, such as plasmids, has rarely been carried out inMycobacterium abscessus,regardless of its usefulness in speculating the past contact between bacteria. In this study, through whole genome sequencing analysis of clinical isolates ofM. abscessussequentially collected from the same patient, we identified a single nucleotide variant that could cause antibiotic resistance, and three plasmids (pMAB625-1, pMAB625-2 and pMAB625-3) not found in the type strain. We investigated the distribution of plasmids previously identified inM. abscessus,including pMAB625 plasmids, in 462 clinical isolates worldwidein silico. pMAB625-3 was detected in the largest number of isolates. Furthermore, phylogenetic tree analysis revealed that these plasmids transferred beyond regions and subspecies and acquired unique mutations. These results indicate that transmission of plasmids increases the genomic diversity inM. abscessus,and plasmid epidemiology is useful for estimating the past contact between bacteria.
Deciphering the regulatory pathways in skeletal muscle lineage organized by the YAP1/TAZ-TEAD transcriptional network
Authors: Gessler Lea , Siudzińska Anna , Prószyński Tomasz J. , Sandri Marco , von Eyss Björn , Hashemolhosseini Said
Published: June 2024

Recently, we reported that YAP1/TAZ-TEAD1/TEAD4 signaling regulates synaptic gene expression and acetylcholine receptor clustering at neuromuscular junctions (NMJs). Here, we looked for further impairments in skeletal muscle of Yap1 and/or Wwtr1 (protein called TAZ) conditional knockout mice. Single knockout muscles have an increased number of central nuclei and Wwtr1-deficient muscles possess more type I and less type IIa fibers. Fiber cross sectional areas were larger in Wwtr1-deficient muscles. However, adult Yap1-, but not Wwtr1-, deficient muscles showed reduced transcript levels of Axin2; Ctnnb1 was lower in both mutants. Both adult single knockout muscles transcribed less Myod and Myog. It was reported that double knockout mice do not survive past birth, likely due to the absence of NMJs. On further inspection, double knockout neonates had severely reduced muscle diameters, consistent with the impaired myogenic proliferation and sarcomere disorganization. Transcriptomic analysis demonstrates severely impaired myogenic transcription of several sarcomere genes in double knockout muscles; particularly Myh genes. Comparisons with available ChIP-seq data identified myogenic targets of YAP1/TAZ-TEAD signaling. ChIP-seq fragments of representative targets, like Myh3, Myl1, Myl2, and Ttn, overlapped with evolutionarily conserved regions and possess M-CAT motifs. Our data identified a role for YAP1/TAZ-TEAD signaling in muscle development and sarcomere structure.
Cathartocytosis: Jettisoning of Unwanted Material during Cellular Reprogramming
Authors: Brown Jeffrey W. , Lin Xiaobo , Nicolazzi Gabriel Anthony , Liu Xuemei , Nguyen Thanh , Radyk Megan D. , Burclaff Joseph , Mills Jason C.
Published: June 2024

Injury can cause differentiated cells to undergo massive reprogramming to become proliferative to repair tissue via a cellular program called paligenosis. Gastric digestive-enzyme-secreting chief cells use paligenosis to reprogram into progenitor-like Spasmolytic-Polypeptide Expressing Metaplasia (SPEM) cells. Stage 1 of paligenosis is the downscaling of mature cell architecture via a process involving lysosomes. Here, we noticed that sulfated glycoproteins were not only digested during paligenosis but also excreted into the gland lumen. Various genetic and pharmacological approaches showed that endoplasmic reticulum membranes and secretory granule cargo were also excreted and that the process proceeded in parallel with, but was mechanistically independent of autophagy. 3-dimensional light and electron-microscopy demonstrated that excretion occurred via unique, complex, multi-chambered invaginations of the apical plasma membrane. As this lysosome-independent cell cleansing process does not seem to have been priorly described, we termed it “cathartocytosis”. Cathartocytosis allows a cell to rapidly eject excess material without waiting for autophagic and lysosomal digestion. We speculate the ejection of sulfated glycoproteins would aid in downscaling and might also help bind and flush pathogens away from tissue.
Mechanism of an animal toxin-antidote system
Authors: Caro Lews , Wei Aguan D. , Thomas Christopher A. , Posch Galen , Uremis Ahmet , Franzi Michaela C. , Abell Sarah J. , Laszlo Andrew H. , Gundlach Jens H. , Ramirez Jan-Marino , Ailion Michael
Published: June 2024

Toxin-antidote systems are selfish genetic elements composed of a linked toxin and antidote. Thepeel-1 zeel-1toxin-antidote system inC. elegansconsists of a transmembrane toxin protein PEEL-1 which acts cell autonomously to kill cells. Here we investigate the molecular mechanism of PEEL-1 toxicity. We find that PEEL-1 requires a small membrane protein, PMPL-1, for toxicity. Together, PEEL-1 and PMPL-1 are sufficient for toxicity in a heterologous system, HEK293T cells, and cause cell swelling and increased cell permeability to monovalent cations. Using purified proteins, we show that PEEL-1 and PMPL-1 allow ion flux through lipid bilayers and generate currents which resemble ion channel gating. Our work suggests that PEEL-1 kills cells by co-opting PMPL-1 and creating a cation channel.
Metabolic remodelling in hiPSC-derived myofibres carrying the m.3243A>G mutation
Authors: Valdebenito Gabriel E. , Chacko Anitta R. , Chung Chih-Yao , Sheshadri Preethi , Chi Haoyu , O’Callaghan Benjamin , Houlden Henry , Rouse Hannah , Morales Valle , Bianchi Katiuscia , Tedesco Francesco Saverio , Pitceathly Robert D. S. , Duchen Michael R.
Published: June 2024

Mutations in mitochondrial DNA cause severe multisystem disease, frequently associated with muscle weakness. The m.3243A>G mutation is the major cause of Mitochondrial Encephalomyopathy Lactic Acidosis and Stroke Like episodes (MELAS). Experimental models that recapitulate the disease phenotypein vitrofor disease modelling or drug screening are very limited. We have therefore generated hiPSC-derived muscle fibres with variable heteroplasmic mtDNA mutation load without significantly affecting muscle differentiation potential. The cells are excitable and show physiological characteristics of muscle fibres and show well organised myofibrillar structure. In cells carrying the m.3243A>G, the mitochondrial membrane potential and oxygen consumption were reduced in relation to the mutant load. We have shown through proteomic, phosphoproteomic, and metabolomic analyses that the m.3243A>G mutation variably affects the cell phenotype in relation to the mutant load. This variation is reflected by an increase in the NADH/NAD+ratio, which in turns influences key nutrient-sensing pathways in the myofibres. This model enables detailed study of the impact of the mutation on cellular bioenergetics and on muscle physiology with the potential to provide a platform for drug screening.
Diet-wide analyses for risk of colorectal cancer: prospective study of 12,250 incident cases among 543,000 women in the UK
Authors: Papier Keren , Bradbury Kathryn E , Balkwill Angela , Barnes Isobel , Smith-Byrne Karl , Gunter Marc J. , Berndt Sonja I , Le Marchand Loic , Wu Anna H , Peters Ulrike , Beral Valerie , Key Timothy J , Reeves Gillian K ,   the Million Women Study Collaborators
Published: June 2024

Background

Apart from alcohol and processed meat, uncertainty remains regarding the role of diet in the aetiology of colorectal cancer. We conducted a large diet-wide association study of colorectal cancer risk, together with a targeted genetic analysis.

Methods

We examined associations of 97 foods and nutrients with risk of colorectal cancer in 542,778 women enrolled in the Million Women Study using multivariable-adjusted Cox regression models. We also assessed the association between genetically predicted milk intake (as a proxy of dairy and/or calcium intake) and colorectal cancer risk in the ColoRectal Transdisciplinary Study, the Colon Cancer Family Registry, and the Genetics and Epidemiology of Colorectal Cancer consortium (GECCO) using a two-sample Mendelian randomisation (MR) analysis.

Results

During a mean (SD) 16.6 (4.8) years of follow-up, 12,251 women were diagnosed with colorectal cancer. Seventeen dietary factors were associated with risk of colorectal cancer (False Discovery Rate <0.05). Of these associations, alcohol and calcium intakes had the strongest associations with colorectal cancer risk; a positive association for alcohol (relative risk [RR] per 20 g/day=1.15, 95% confidence interval [CI] 1.09-1.20, p<0.0000001) and an inverse association for calcium (RR per 300 mg/day=0.83, 95% CI 0.77-0.89, p<0.000001). Other dairy-related factors including dairy milk, yogurt, riboflavin, magnesium, phosphorus, and potassium were also inversely associated with colorectal cancer risk, though further analysis showed that calcium intake was likely to account for these associations. Of the remaining dietary factors that were associated with colorectal cancer risk, only red and processed meat intake was associated with increased risk. Breakfast cereal, fruit, wholegrains, carbohydrates, fibre, total sugars, folate, and vitamin C were inversely associated with risk, though these associations may have been influenced by residual confounding by lifestyle and other dietary factors. In MR analyses, genetically predicted milk consumption was inversely associated with risk of colorectal cancer (RR per 200 g/day=0.60, 95% CI 0.46-0.74), colon cancer (RR per 200 g/day=0.60, 95% CI 0.43-0.77), and rectal cancer (RR per 200 g/day=0.49, 95% CI 0.31-0.67).

Discussion

This comprehensive diet-wide study provides robust evidence for the protective role of dairy milk and dairy products in colorectal cancer incidence, which is likely to be driven largely if not wholly by calcium. More research is needed to understand the potential health impacts of increasing calcium intake in some populations.
The murine lung microbiome is dysbalanced by the human pathogenic fungusAspergillus fumigatusresulting in enrichment of anaerobic bacteria
Authors: Nikitashina Liubov , Chen Xiuqiang , Radosa Lukas , Li Kexin , Straßburger Maria , Seelbinder Bastian , Böhnke Wibke , Vielreicher Sarah , Nietzsche Sandor , Heinekamp Thorsten , Jacobsen Ilse D. , Panagiotou Gianni , Brakhage Axel A.
Published: June 2024

Here, we report significant changes in the composition of the lung microbiome and metabolome of mice under immune suppression, infection of immunosuppressed mice with virulent and avirulent strains of the clinically important human-pathogenic fungusAspergillus fumigatus, and treatment with the clinically used antifungal drug voriconazole. Our data also indicate the important role of the gut microbiome for the lung homeostasis mediated by the plasma metabolome. In the lung microbiome, infection byA. fumigatusled to a significant increase of anaerobic bacteria, most prominently ofLigilactobacillus murinus,which was confirmed by the isolation of live bacteria from the murine lower respiratory tract.In vitro,L. murinusis tolerated and even internalized by alveolar epithelial cells. Co-cultivation ofL. murinusandA. fumigatusled to a reduction in oxygen concentration accompanied by an increase ofL. murinuscells suggesting thatA. fumigatusestablishes a microaerophilic niche, thereby promoting growth of anaerobic bacteria.
Development of SYK NanoBRET Cellular Target Engagement Assays for Gain–of–Function Variants
Authors: Capener Jacob L. , Vasta James D. , Katis Vittorio L. , Michaud Ani , Beck Michael T. , Daglish Sabrina C. D. , Cohen-Kedar Sarit , Barda Efrat Shaham , Howell Stefanie , Dotan Iris , Robers Matthew B. , Axtman Alison D. , Bashore Frances M.
Published: June 2024

Spleen tyrosine kinase (SYK) is a non-receptor tyrosine kinase that is activated by phosphorylation events downstream of FcR, B-cell and T-cell receptors, integrins, and C-type lectin receptors. When the tandem Src homology 2 (SH2) domains of SYK bind to phosphorylated immunoreceptor tyrosine-based activation motifs (pITAMs) contained within these immunoreceptors, or when SYK is phosphorylated in interdomain regions A and B, SYK is activated. SYK gain-of-function (GoF) variants were previously identified in six patients that had higher levels of phosphorylated SYK and phosphorylated downstream proteins JNK and ERK. Furthermore, the increased SYK activation resulted in the clinical manifestation of immune dysregulation, organ inflammation, and a predisposition for lymphoma. The knowledge that the SYK GoF variants have enhanced activity was leveraged to develop a SYK NanoBRET cellular target engagement assay in intact live cells with constructs for the SYK GoF variants. Herein, we developed a potent SYK-targeted NanoBRET tracer using a SYK donated chemical probe, MRL-SYKi, that enabled a NanoBRET cellular target engagement assay for SYK GoF variants, SYK(S550Y), SYK(S550F), and SYK(P342T). We determined that ATP-competitive SYK inhibitors bind potently to these SYK variants in intact live cells. Additionally, we demonstrated that MRL-SYKi can effectively reduce the catalytic activity of SYK variants, and the phosphorylation levels of SYK(S550Y) in an epithelial cell line (SW480) stably expressing SYK(S550Y).
NFκB and JNK pathways mediate metabolic adaptation upon ESCRT-I deficiency
Authors: Cendrowski Jaroslaw , Wrobel Marta , Mazur Michal , Jary Bartosz , Wang Surui , Korostynski Michal , Dziewulska Anna , Rohm Maria , Dobrzyn Agnieszka , Zeigerer Anja , Miaczynska Marta
Published: June 2024

Endosomal Sorting Complexes Required for Transport (ESCRTs) are crucial for delivering membrane receptors or intracellular organelles for lysosomal degradation. Yet, how ESCRT dysfunction affects cell metabolism remained elusive. To address this, we analyzed transcriptomes of cells lacking TSG101 or VPS28 proteins, components of ESCRT-I subcomplex. ESCRT-I deficiency reduced the expression of genes encoding enzymes involved in oxidation of fatty acids and amino acids, and increased the expression of genes encoding glycolytic enzymes. Although depletion of ESCRT-I components did not impair mitochondrial biogenesis and ATP-linked respiration it caused intracellular accumulation of lipids and increased lactate production, hallmarks of aerobic glycolysis. Mechanistically, the observed transcriptional reprogramming towards glycolysis in the absence of ESCRT-I occurred due to activation of the canonical NFκB and JNK signaling pathways. Moreover, inhibiting lysosomal activity phenocopied the altered expression of metabolic genes and lipid homeostasis observed for ESCRT-I deficiency, indicating that ESCRT-I restricts glycolysis by mediating lysosomal degradation.
Functional characterization of pathway inhibitors for the ubiquitin-proteasome system (UPS) as tool compounds for CRBN and VHL-mediated targeted protein degradation
Authors: Schwalm Martin P. , Menge Amelie , Elson Lewis , Greco Francesco A. , Robers Matthew B. , Müller Susanne , Knapp Stefan
Published: June 2024

Small molecule degraders such as PROteolysis TArgeting Chimeras (PROTACs) or molecular glues are new modalities for drug development and important tools for target validation. Both modalities recruit an E3 ubiquitin ligase to a protein of interest (POI) either via two independent, but linked ligands (PROTACs) or through binding of a small molecule that alters the E3 binding surface to recruit a neo-substrate (molecular glues). If optimized appropriately, both modalities result in the degradation of the POI. Due to the complexity of the induced multistep degradation process, controls for degrader evaluation are critical and they are commonly used in the literature. However, comparative studies and evaluation of cellular potencies of these control compounds and their appropriate uses have not been published so far. Additionally, the high diversity of mechanisms requires diverse small molecule controls to ensure appropriate inhibition of the investigated system while keeping potential cellular toxicity and unintended effects on cellular pathways as low as possible. Here, we scrutinized a diverse set of ubiquitin pathway inhibitors and evaluated their potency and utility within the CRBN and VHL mediated POI degradation pathway. We used the HiBiT system to measure the levels of target rescue after treatment with control compounds. Additionally, cell health was investigated using a multiplex high content assay. This assay panel allows us to determine non-toxic effective concentrations for control experiments and to perform rescue experiments in the absence of cellular toxicity, which has a profound effect on target degradation by ubiquitin-dependent and -independent pathways.
Dysregulated Skeletal Muscle Myosin Super-relaxation and Energetics in Type II Diabetes
Authors: Lewis Christopher T. A. , Moreno-Justicia Roger , Savoure Lola , Calvo Enrique , Bak Agata , Laitila Jenni , Seaborne Robert A.E. , Larsen Steen , Iwamoto Hiroyuki , Cefis Marina , Morais Jose A. , Gouspillou Gilles , Alegre-Cebollada Jorge , Hawke Thomas J. , Vazquez Jesús , Adrover Miquel , Marcangeli Vincent , Deshmukh Atul S. , Ochala Julien
Published: June 2024

Disrupted energy balance is critical for the onset and development of Type II diabetes. The exact underlying metabolic mechanisms remain incomplete but skeletal muscle is thought to play an important pathogenic role. As the super-relaxed state of its most abundant protein, myosin, regulates cellular energetics, here, we aimed to investigate whether it is altered in patients with type II diabetes. For that, we used vastus lateralis biopsy specimens (obtained from patients with type II diabetes and matched controls) and run a combination of structural and functional assays consisting of loaded Mant-ATP chase experiments, X-ray diffraction and LC-MS/MS proteomics in isolated muscle fibres. Our studies revealed a greater muscle myosin super-relaxation and decreased cellular ATP demand in patients than controls. Subsequent proteomic analyses indicated that these (mal)adaptations likely originated from remodeled sarcomeric proteins and greater myosin glycation levels in patients than controls. Overall, our findings emphasize a complex molecular dysregulation of myosin super-relaxed state and energy consumption in type II diabetes. Ultimately, pharmacological targeting of myosin could benefit skeletal muscle and whole-body metabolic health through the enhancement of ATP consumption.

Significance Statement

Myosin super-relaxation, essential for the regulation of skeletal muscle metabolic rate, is disrupted in type II diabetes due to protein hyper-glycation. As a consequence, myosin ATP demand is significantly lowered. Overall, our findings provide a strong rationale for the use of activators of myosin ATPase to enhance basal energy expenditure in type II diabetes.
Convergent gene pairs restrict chromatin looping in Dictyostelium discoideum, acting as directional barriers for extrusion
Authors: Zhegalova Irina V. , Ulianov Sergey V. , Galitsyna Aleksandra A. , Pletenev Ilya A. , Tsoy Olga V. , Luzhin Artem V. , Vasiluev Petr A. , Bulavko Egor S. , Ivankov Dmitry N. , Gavrilov Alexey A. , Khrameeva Ekaterina E. , Gelfand Mikhail S. , Razin Sergey V.
Published: June 2024

Dictyostelium discoideum is a unicellular slime mold, developing into a multicellular fruiting body upon starvation. Development is accompanied by large-scale shifts in gene expression program, but underlying features of chromatin spatial organization remain unknown. Here, we report that the Dictyostelium 3D genome is organized into positionally conserved, largely consecutive, non-hierarchical and weakly insulated loops at the onset of multicellular development. The transcription level within the loop interior tends to be higher than in adjacent regions. Loop interiors frequently contain functionally linked genes and genes which coherently change expression level during development. Loop anchors are predominantly positioned by the genes in convergent orientation. Our data suggest that the loop profile may arise from the interplay between transcription and extrusion-driven chromatin folding. In particular, a convergent gene pair serves as a bidirectional extrusion barrier or a "diode" that controls passage of the cohesin extruder by relative transcription level of paired genes.
The effect of a dominant kinase-deadCsf1rmutation associated with adult-onset leukoencephalopathy on brain development and neuropathology
Authors: Stables Jennifer , Pal Reiss , Bradford Barry M. , Carter-Cusack Dylan , Taylor Isis , Pridans Clare , Khan Nemat , Woodruff Trent , Irvine Katharine M. , Summers Kim M. , Mabbott Neil A. , Hume David A.
Published: June 2024

Amino acid substitutions in the kinase domain of the humanCSF1Rprotein are associated with autosomal dominant adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). To model the human disease, we created a disease-associated mutation (Glu631Lys; E631K) in the mouseCsf1rlocus. Previous analysis demonstrated that heterozygous mutation (Csf1rE631K/+) had a dominant inhibitory effect on CSF1R signalingin vitroandin vivobut did not recapitulate the pathology of the human disease. We speculated that leukoencephalopathy in humans requires an environmental trigger and/or epistatic interaction with common neurodegenerative disease-associated alleles. Here we examine the impact of heterozygousCsf1rmutation on microglial phenotype, normal postnatal brain development, age-related changes in gene expression and on two distinct pathologies in which microgliosis is a prominent feature, prion disease and experimental autoimmune encephalitis (EAE). The heterozygousCsf1rE631K/+mutation reduced microglial abundance and the expression of microglial-associated transcripts relative to wild-type controls at 12 weeks and 43 weeks of age but had no selective effect on homeostatic markers such asP2ry12. An epistatic interaction was demonstrated betweenCsf1rE631K/+andCxc3r1EGFP/+genotypes leading to dysregulated microglial and neuronal gene expression in both hippocampus and striatum. HeterozygousCsf1rE631Kmutation reduced the microgliosis associated with both diseases. There was no significant impact on disease severity or progression in prion disease. In EAE, induced expression of inflammation-associated transcripts in the hippocampus and striatum was suppressed in parallel with microglia-specific transcripts, but spinal cord demyelination was exacerbated. The results support a dominant-negative model of CSF1R-associated leukoencephalopathy and likely contributions of an environmental trigger and/or genetic background to neuropathology.
Decoding movie content from neuronal population activity in the human medial temporal lobe
Authors: Gerken Franziska , Darcher Alana , Gonçalves Pedro J , Rapp Rachel , Elezi Ismail , Niediek Johannes , Kehl Marcel S , Reber Thomas P , Liebe Stefanie , Macke Jakob H , Mormann Florian , Leal-Taixé Laura
Published: June 2024

Neurons of the medial temporal lobe (MTL) form the basis of semantic representation in the human brain. While known to contain category-selective cells, it is unclear how the MTL processes naturalistic, dynamic stimuli. We studied 2286 neurons recorded from the hippocampus, parahippocampal cortex, amygdala, and entorhinal cortex of 29 intracranially-implanted patients during a full-length movie. While few neurons responded preferentially to semantic features, we could reliably predict the presence of characters, location, and visual transitions from the neuronal populations using a recurrent neural network. We show that decoding performance differs across regions based on the feature category, and that the performance is driven by feature-selective single neurons when decoding visual transitions such as camera cuts. These findings suggest that semantic representation in the MTL varies based on semantic category, with decoding information embedded in specific subsets of neurons for event-related features or distributed across the entire population for character and location-related features.
Mapping the evolution of financial inclusion: a retrospective overview using bibliometric analysis
Authors: Suryavanshi Urvashi , Chaudhry Rishi , Arora Meenal , Mittal Amit
Published: June 2024

Purpose

The purpose of this paper is to analyze the existing literature in the domain of financial inclusion and emphasizing forthcoming trends. It examines recent literature while assessing the geographical distribution, identifying well-known authors, publications, journals and keyword occurrences.

Design/methodology/approach

Based on a scientific search technique, bibliometric analysis in the field of financial inclusion was carried out on a sample of 2,125 Scopus documents for the years 2004–2022. A VOS viewer was used in the study as a tool for performance evaluation and analysis of the science mapping.

Findings

The bibliometric analysis illustrates that India and the USA are dominating in financial inclusion field with significant contributions. The most well-known authors were Ghosh, S. and Munene, J.C. and International Journal of Social Economics was considered as the best journal. Finally, six prominent clusters were identified through keyword analysis. The major themes revolve around digitalization, economic development, demographic and geographic factors and financial literacy.

Practical implications

The research helps in providing information for formulating financial inclusion policies for RBI and Government of India. A comprehensive literature assessment is useful for future scholars to develop a solid conceptual framework. This research would help practitioners to formulate strategies for rural population to enhance their earnings, investments and money.

Originality/value

This study can supply data to describe the framework of earlier financial inclusion studies and provides potential directions for future research.
Empirical modeling of stress concentration factors using artificial neural networks for fatigue design of tubular T-joint under in-plane and out-of-Plane bending moments
Authors: Rasul Adnan , Karuppanan Saravanan , Perumal Veeradasan , Ovinis Mark , Iqbal Mohsin , Alam Khurshid
Published: June 2024

Purpose

Stress concentration factors (SCFs) are commonly used to assess the fatigue life of tubular T-joints in offshore structures. SCFs are usually estimated from parametric equations derived from experimental data and finite element analysis (FEA). However, these equations provide the SCF at the crown and saddle points of tubular T-joints only, while peak SCF might occur anywhere along the brace. Using the SCF at the crown and saddle can lead to inaccurate hotspot stress and fatigue life estimates. There are no equations available for calculating the SCF along the T-joint's brace axis under in-plane and out-of-plane bending moments.

Design/methodology/approach

In this work, parametric equations for estimating SCFs are developed based on the training weights and biases of an artificial neural network (ANN), as ANNs are capable of representing complex correlations. 1,250 finite element simulations for tubular T-joints with varying dimensions subjected to in-plane bending moments and out-of-plane bending moments were conducted to obtain the corresponding SCFs for training the ANN.

Findings

The ANN was subsequently used to obtain equations to calculate the SCFs based on dimensionless parameters (α, β, γ and τ). The equations can predict the SCF around the T-joint's brace axis with an error of less than 8% and a root mean square error (RMSE) of less than 0.05.

Originality/value

Accurate SCF estimation for determining the fatigue life of offshore structures reduces the risks associated with fatigue failure while ensuring their durability and dependability. The current study provides a systematic approach for calculating the stress distribution at the weld toe and SCF in T-joints using FEA and ANN, as ANNs are better at approximating complex phenomena than typical data fitting techniques. Having a database of parametric equations enables fast estimation of SCFs, as opposed to costly testing and time-consuming FEA.
Protection of traditional villages in China: a review on the development process and policy evolution
Authors: Jing Feng , Ramele Ramli Rohaslinda , Nasrudin Na'asah
Published: June 2024

Purpose

This study discusses the protection of traditional villages and understand the role, policy environment and characteristics of traditional village protection. This study also constructs an analytical framework of “historical timing - policy orientation” to study the development process and policy evolution of traditional village protection in China.

Design/methodology/approach

This study selects the policy documents related to traditional village protection since 1980 as the research samples to explore the origin and evolution of traditional village protection in China. Then, the paper systematically combs the temporal evolution of the policy theme and orientation at each stage, which would provide a reference direction for the protection and development of traditional villages.

Findings

The interpretation of traditional village protection and its institutional background can be divided into three stages: relying on the protection system of historical and cultural towns and villages (1982–2012) and the stage of construction and improvement of traditional villages protection system (2012–2017). After 2017, traditional village protection entered a new rural revitalization journey.

Research limitations/implications

This study is limited to: documents issued from 1982 to the end of 2022; Central Committee of the Communist Party of China, the State Council, and central ministries and administrations directly governing the protection of traditional villages; policies that can directly reflect the central government’s attitude towards protecting traditional villages; and excluding the documents for some particular regions and particular problems.

Originality/value

This study fulfills as the guidance of traditional village protection and development in different periods.
Navigating uncertainty: a study of the S&P GCC composite index’s connectedness during times of crises
Authors: Alshater Muneer M. , El Khoury Rim , Almansour Bashar
Published: June 2024

Purpose

This study aims to investigate the dynamics of return connectedness of the Standard & Poor’s (S&P) Gulf Cooperation Council (GCC) composite index with five regional equity indices, three global equity indices and other different asset classes during the COVID-19 pandemic period.

Design/methodology/approach

This study uses daily data spanning from January 2, 2018, to December 23, 2021. A subsample analysis is conducted to determine the role of uncertainty in modifying the connectedness structure during the ongoing pandemic period.

Findings

The results of this study show that the nature of connectedness is time-frequent, with clear evidence for a higher level of connectedness during stress periods, especially after the onset of the pandemic. The GCC index is found to be a net receiver of shocks to other assets, with an increase in magnitude during the COVID period.

Research limitations/implications

This study is limited by the use of only daily data, and future research could consider using higher frequency data.

Practical implications

The results of this study confirm the disturbing effects of the pandemic on the GCC index and its connectedness with other assets, which matters for policymakers and investors.

Originality/value

This study provides new insights into the dynamics of return connectedness of the GCC index with other assets during the COVID-19 pandemic period, which has not been previously explored.
Purpose is the new branding: understanding conscientious purpose-driven marketing and its impact on brand outcomes
Authors: Fernandes Teresa , Guzman Francisco , Mota Mafalda
Published: June 2024

Purpose

Consumers increasingly expect brands to have a social purpose. Yet, guidelines on how to effectively engage in conscientious purpose-driven branding are lacking. This study aims to better understand what the key drivers of a successful conscientious purpose-driven branding strategy are and what is its impact on key brand outcomes.

Design/methodology/approach

Data was gathered using a self-administered survey, answered by 670 young adults belonging to generations Y and Z. The study integrates in a single moderated-mediation model, tested using partial least squares structural equation modelling, the joint effects of cause–brand–consumer congruences, cause-brand authenticity and brand image, on consumers’ intention to purchase and recommend the brand.

Findings

Consumer-brand congruence mediates the path from cause-brand congruence and authenticity to brand image, which in turn impacts purchase and recommendation intentions, with authenticity playing a dominant role. Moreover, for consumers highly congruent with the cause/purpose, the direct effect of cause-brand congruence on brand image becomes non-significant and only works through consumer-brand congruence.

Originality/value

Theoretically, this study contributes to a better understanding of how and when conscientious purpose-driven branding can be effective. Its findings further advance prior research, by providing an alternative path anchored on cause-brand authenticity to explain positive effects of conscientious purpose-driven marketing on brand outcomes. Moreover, it challenges prior assumptions regarding the impact of consumer-cause congruence on the effectiveness of these strategies. Finally, it highlights that cause-consumer and brand-consumer congruencies also play a role, offering an integrated, triadic view of conscientious purpose-driven branding strategies. Managerially, it provides insights to brand managers wishing to successfully implement these strategies and better understand the role of brands as “purpose-driven entities”.
Reorganization of motor network in patients with Parkinson's disease after deep brain stimulation
Authors: Luo Bei , Chang Lei , Qiu Chang , Dong Wenwen , Zhao Liang , Lu Yue , Sun Jian , Yan Jiuqi , Wei Xiang , Yan Jun , Zhang Wenbin
Published: June 2024

Aims

Parkinson's disease (PD) patients experience improvement in motor symptoms after deep brain stimulation (DBS) and before initiating stimulation. This is called the microlesion effect. However, the mechanism remains unclear. The study aims to comprehensively explore the changes in functional connectivity (FC) patterns in movement‐related brain regions in PD patients during the microlesion phase through seed‐based FC analysis.

Methods

The study collected the resting functional magnetic resonance imaging data of 49 PD patients before and after DBS surgery (off stimulation). The cortical and subcortical areas related to motor function were selected for seed‐based FC analysis. Meanwhile, their relationship with the motor scale was investigated.

Results

The motor‐related brain regions were selected as the seed point, and we observed various FC declines within the motor network brain regions. These declines were primarily in the left middle temporal gyrus, bilateral middle frontal gyrus, right supplementary motor area, left precentral gyrus, left postcentral gyrus, left inferior frontal gyrus, and right superior frontal gyrus after DBS.

Conclusion

The movement‐related network was extensively reorganized during the microlesion period. The study provided new information on enhancing motor function from the network level post‐DBS.
Rethinking Subjectification: On the Limits of Biesta's Educational Theory
Authors: Thompson Andrew
Published: June 2024

In this article, Andrew Thompson explores the tension between Gert Biesta's concept of educational purpose and education's historical function. For Biesta, the purpose of education consists of three overlapping spheres: qualification, socialization, and subjectification. While scholars have devoted a great deal of attention to Biesta's notion of subjectification, there is not enough consideration of his treatment of socialization and its limits on human freedom. Here, Thompson examines the historical role of socialization as it relates to the cultivation of self‐reflecting and self‐governing citizens through a process Ian Hunter describes as pastoral pedagogy. Both Biesta and Hunter critique essentialist notions of subjectivity, noting that critical pedagogy in both liberal and Marxian iterations has relied upon a metaphysics informed by Kantian moral definition in which the subject must freely exercise rational autonomy toward self‐realization. While Biesta suggests redefining the subject, Hunter dismisses any attempt at redefinition as irrelevant since the school's historical process of moral development is inevitably linked to the antiquated liberal ideal. In Hunter's view, all attempts to escape the school's moral teleology inexorably employ a pedagogy that is based on the moral ideal its critics wish to eliminate. This article illustrates the agonism inherent in Biesta's concept of educational purpose and explores the role of the theorist as the expression of a particular moral self that informs the ideal persona of the teacher.
Amino‐terminally elongated Aβ peptides are generated by the secreted metalloprotease ADAMTS4 and deposit in a subset of Alzheimer's disease brains
Authors: Wirths Oliver , Lehnen Christina , Fricke Merle , Talucci Ivan , Klafki Hans‐Wolfgang , Morgado Barbara , Lehmann Sandra , Münch Carolina , Liepold Thomas , Wiltfang Jens , Rostagno Agueda , Ghiso Jorge , Maric Hans Michael , Jahn Olaf , Weggen Sascha
Published: June 2024

Aims

The aggregation and deposition of amyloid‐β (Aβ) peptides in the brain is thought to be the initial driver in the pathogenesis of Alzheimer's disease (AD). Aside from full‐length Aβ peptides starting with an aspartate residue in position 1, both N‐terminally truncated and elongated Aβ peptides are produced by various proteases from the amyloid precursor protein (APP) and have been detected in brain tissues and body fluids. Recently, we demonstrated that the particularly abundant N‐terminally truncated Aβ4–x peptides are generated by ADAMTS4, a secreted metalloprotease that is exclusively expressed in the oligodendrocyte cell population. In this study, we investigated whether ADAMTS4 might also be involved in the generation of N‐terminally elongated Aβ peptides.

Methods

We used cell‐free and cell‐based assays in combination with matrix‐assisted laser desorption/ionisation time‐of‐flight mass spectrometry (MALDI‐TOF) and electrochemiluminescence sandwich immunoassays to identify and quantify N‐terminally elongated Aβ peptide variants. Antibodies against these Aβ variants were characterised by peptide microarrays and employed for the immunohistochemical analyses of human brain samples.

Results

In this study, we discovered additional ADAMTS4 cleavage sites in APP. These were located N‐terminal to Asp‐(1) in the Aβ peptide sequence between residues Glu‐(‐7) and Ile‐(‐6) as well as Glu‐(‐4) and Val‐(‐3), resulting in the release of N‐terminally elongated Aβ‐6‐x and Aβ‐3‐x peptides, of which the latter serve as a component in a promising Aβ‐based plasma biomarker. Aβ‐6/‐3‐40 peptides were detected in supernatants of various cell lines and in the cerebrospinal fluid (CSF), and ADAMTS4 enzyme activity promoted the release of Aβ‐6/‐3‐x peptides. Furthermore, by immunohistochemistry, a subset of AD cases displayed evidence of extracellular and vascular localization of N‐terminally elongated Aβ‐6/‐3‐x peptides.

Discussion

The current findings implicate ADAMTS4 in both the pathological process of Aβ peptide aggregation and in the early detection of amyloid pathology in AD.