bluuebunny/crossref_metadata_2025 huggingface dataset:
Proximity-based activation of AURORA A by MPS1 potentiates error correction
Authors: Leça Nelson , Barbosa Francisca , Rodriguez-Calado Sergi , Moura Margarida , Pedroso Paulo D. , Pinto Inês , Verza Arianna E. , Bange Tanja , Sunkel Claudio E. , Barisic Marin , Maresca Thomas J. , Conde Carlos
Published: June 2024

Faithfull cell division relies on mitotic chromosomes becoming bioriented with each pair of sister kinetochores bound to microtubules oriented toward opposing spindle poles. Erroneous kinetochore-microtubule attachments often form during early mitosis, but are destabilized through the phosphorylation of outer kinetochore proteins by centromeric AURORA B kinase (ABK) and centrosomal AURORA A kinase (AAK), thus allowing for re-establishment of attachments until biorientation is achieved. MPS1-mediated phosphorylation of NDC80 has also been shown to directly weaken the kinetochore-microtubule interface in yeast. In human cells, MPS1 has been proposed to transiently accumulate at end-on attached kinetochores and phosphorylate SKA3 to promote microtubule release. Whether MPS1 directly targets NDC80 and/or promotes the activity of AURORA kinases in metazoans remains unclear. Here, we report a novel mechanism involving communication between kinetochores and centrosomes, wherein MPS1 acts upstream of AAK to promote error correction. MPS1 on pole-proximal kinetochores phosphorylates the C-lobe of AAK thereby increasing its activation at centrosomes. This proximity-based activation ensures the establishment of a robust AAK activity gradient that locally destabilizes mal-oriented kinetochores near spindle poles. Accordingly, MPS1 depletion fromDrosophilacells causes severe chromosome misalignment and erroneous kinetochore-microtubule attachments, which can be rescued by tethering either MPS1 or constitutively active AAK mutants to centrosomes. Proximity-based activation of AAK by MPS1 also occurs in human cells to promote AAK-mediated phosphorylation of the NDC80 N-terminal tail. These findings uncover an MPS1-AAK cross-talk that is required for efficient error correction, showcasing the ability of kinetochores to modulate centrosome outputs to ensure proper chromosome segregation.
An immunocompetent human kidney on-a-chip model to study renal inflammation and immune-mediated injury
Authors: Gijzen Linda , Bokkers Marleen , Hanamsagar Richa , Olivier Thomas , Burton Todd P. , Tool Laura M. , Rahman Mouly F. , Lowman John , Savova Virginia , Means Terry K. , Lanz Henriette L.
Published: June 2024

Kidney damage and dysfunction is an emerging health issue worldwide resulting in high morbidity and mortality rates. Numerous renal diseases are recognized to be driven by the immune system. Despite this recognition, the development of targeted therapies has been challenging as knowledge of the underlying mechanism and complex interactions remains insufficient. Recent advancements in the field offer promising avenues for exploring the interplay between renal cells and immune cells and their role in the development of renal inflammation and diseases. This study describes the establishment of a human immunocompetent 3Din vitroco-culture model of the proximal tubule in a high-throughput microfluidic platform that can be used to study renal functionality and inflammatory processes.

The model incorporated RPTEC in the top compartment and HUVECs in the bottom compartment cultured under flow and in direct contact with a collagen-I ECM gel resulting in the formation of polarized tubular structures. As an immune component, human primary monocytes of different donors were added to the lumen of the endothelium. Renal inflammation was successfully induced using complement activated serum (CAS) as evident by epithelial morphological changes, increased expression of adhesion molecules, release of pro-inflammatory cytokines, and reduced epithelial viability. Realtime migratory behavior of monocytes showed increased extravasation and migration towards the ECM and Renal compartment upon exposure to CAS with donor-to-donor differences observed. Finally, immune modulatory compounds showed efficacious inhibition of monocyte migration under inflammatory conditions in the microfluidic co-culture model.

A successful co-culture model was established and can be applied to study renal functionality in health and disease but also for drug screening due to the compatibility of the platform with automation and relatively high throughput. Overall, the described proximal tubule model has high potential to fill the gap that currently exists to study renal inflammation preclinically.
Brain-derived exosomal hemoglobin transfer contributes to neuronal mitochondrial homeostasis under hypoxia
Authors: Tian Zhengming , Li Yuning , Jin Feiyang , Xu Zirui , Gu Yakun , Guo Mengyuan , Shao Qianqian , Liu Yingxia , Luo Hanjiang , Wang Yue , Zhang Suyu , Yang Chenlu , Liu Xin , Ji Xunming , Liu Jia
Published: June 2024

Hypoxia is an important physiological stress causing nerve injuries and several brain diseases. However, the mechanism of brain response to hypoxia remains unclear, thus limiting the development of interventional strategies. This study conducted combined analyses of single-nucleus transcriptome sequencing and extracellular vesicle transcriptome sequencing on hypoxic mouse brains, described cell-cell communication in the brain under hypoxia from intercellular and extracellular dimensions, confirmed that hemoglobin mRNA was transferred from non-neuronal cells to neurons, and eventually expressed. Then we further explored the role of exosomal hemoglobin transferin vitro, clarified that hypoxia promoted the transfer and expression of exosomal hemoglobin between endothelial cells and neurons. And we found the vital function of exosomal hemoglobin to protect against neurological injury by maintaining mitochondrial homeostasis in neurons. In conclusion, this study identified a novel mechanism of ‘mutual aid’ in hypoxia responses in the brain, involving exosomal hemoglobin transfer, clarified the important role of exosomal communication in the process of brain stress response, and provided a novel interventional perspective for hypoxia-related brain diseases.
The umbrella cell keratin network: organization as a tile-like mesh, formation of a girded layer in response to bladder filling, and dependence on the plectin cytolinker
Authors: Ruiz Wily G. , Clayton Dennis R. , Parakala-Jain Tanmay , Dalghi Marianela G. , Franks Jonathan , Apodaca Gerard
Published: June 2024

The keratin cytoskeleton and associated desmosomes contribute to the mechanical stability of epithelial tissues, but their organization in bladder umbrella cells and their responses to bladder filling are poorly understood. Using super-resolution confocal microscopy, along with 3D image reconstruction and platinum replica electron microscopy, we observed that the apical keratin network of umbrella cells was organized as a dense tile-like mesh comprised of tesserae bordered on their edges by cortical actin filaments, filled with woven keratin filaments, and crosslinked by plectin. A band of keratin was also observed at the cell periphery that was linked to the junction-associated actin ring by plectin. During bladder filling, the junction-localized desmosomal necklace expanded, and a subjacent girded layer was formed that linked the keratin network to desmosomes, including those at the umbrella cell-intermediate cell interface. Disruption of plectin led to focal keratin network dissolution, loss of the junction-associated band of keratin, perturbation of tight junction continuity, and loss of cell-cell cohesion. Our studies reveal a novel tile-like organization of the umbrella cell keratin cytoskeleton that is dependent on plectin, that reorganizes in response to bladder filling, and that likely serves to maintain umbrella cell continuity in the face of mechanical distension.
Actinomycin D and bortezomib disrupt protein homeostasis in Wilms tumor
Authors: Tiburcio Patricia D.B. , Chen Kenian , Xu Lin , Chen Kenneth S.
Published: June 2024

Wilms tumor is the most common kidney cancer in children, and diffuse anaplastic Wilms tumor is the most chemoresistant histological subtype. Here, we explore how Wilms tumor cells evade the common chemotherapeutic drug actinomycin D, which inhibits ribosomal RNA biogenesis. Using ribosome profiling, protein arrays, and a genome-wide knockout screen, we describe how actinomycin D disrupts protein homeostasis and blocks cell cycle progression. We found that, when ribosomal capacity is limited by actinomycin D treatment, anaplastic Wilms tumor cells preferentially translate proteasome components and upregulate proteasome activity. Based on these findings, we tested whether the proteasome inhibitor bortezomib sensitizes cells to actinomycin D treatment. Indeed, we found that the combination induces apoptosis bothin vitroandin vivoand prolongs survival in xenograft models. Lastly, we show that increased levels of proteasome components are associated with anaplastic histology and worse prognosis in Wilms tumor patients. In sum, maintaining protein homeostasis is critical for Wilms tumor proliferation, and it can be therapeutically disrupted by blocking protein synthesis or turnover.
FoldToken2: Learning compact, invariant and generative protein structure language
Authors: Gao Zhangyang , Tan Cheng , Li Stan Z.
Published: June 2024

The equivariant nature of 3D coordinates has posed long term challenges in protein structure representation learning, alignment, and generation. Can we create a compact and invariant language that equivalently represents protein structures? Towards this goal, we propose FoldToken2 to transfer equivariant structures into discrete tokens, while maintaining the recoverability of the original structures. From FoldToken1 to FoldToken2, we improve three key components: (1) invariant structure encoder, (2) vector-quantized compressor, and (3) equivariant structure decoder. We evaluate FoldToken2 on the protein structure reconstruction task and show that it outperforms previous FoldToken1 by 20% in TMScore and 81% in RMSD. FoldToken2 is likely the first method that works well for both single-chain and multi-chain protein structure quantization. We believe that FoldToken2 will inspire further improvement in protein structure representation, alignment, and generation tasks. Online example is available atColab.
Percutaneous aspiration for shortening time to blood cultures sterilization in right-sided infective endocarditis and vegetations
Authors: Polo Francisco Tirado , Nakhle Asaad , Gnall Eric , Rozenbaum Zach
Published: June 2024

Background

Surgical intervention is associated with earlier clearance of bacteremia in infective endocarditis (IE).

Aim

We hypothesized that vegetectomies using percutaneous aspiration shortens time to sterilization of blood cultures in patients with right-sided IE and vegetations.

Results

The cohort included 37 patients, 23 treated conservatively, and 14 underwent percutaneous vegetectomy. The median time to blood culture sterilization among patients with bacteremia over 7 days, was 16.5 (IQR 9.75-29) for patients treated conservatively and 11.5 (IQR 8.5-11.5) for those who underwent vegetectomy. The 2 patients who required mechanical ventilation were among the vegetectomy group, and the single patient who died during the same admission was treated conservatively. There were no complications in the vegetectomy group.

Conclusion

These data are hypothesis-generating, suggesting that utilizing percutaneous aspiration in patients with right-sided IE and vegetations shortens time to sterilization of blood cultures, and possibly improves outcomes.
Characterizing hepatitis B virus infection in children in the Democratic Republic of Congo to inform elimination efforts
Authors: Morgan CE , Powers KA , Edwards JK , Devkota U , Biju S , Lin FC , Schmitz JL , Cloherty G , Muwonga J , Mboyo A , Tshiamala P , Kashamuka MM , Tshefu A , Emch M , Yotebieng M , Becker-Dreps S , Parr JB , Thompson P
Published: June 2024

Objective

Despite global reductions in hepatitis B virus (HBV) prevalence, an estimated 6.2 million children are infected, two-thirds of whom live in the WHO Africa region. We sought to characterize childhood HBV to inform elimination efforts in the Democratic Republic of Congo (DRC), one of the largest and most populous African countries.

Methods

Using the most recent (2013–14) nationally representative Demographic and Health Survey in the DRC, we analyzed HBV surface antigen (HBsAg) on dried blood spots and associated survey data from children aged 6-59 months. We estimated HBsAg-positivity prevalence nationally, regionally, and by potential correlates of infection. We evaluated spatial variation in HBsAg-positivity prevalence, overall and by age, sex, and vaccination status.

Findings

Using data from 5,679 children, we found national HBsAg-positivity prevalence was 1.3% (95% CI: 0.9%-1.7%), but ranged from 0.0% in DRC’s capital city province, Kinshasa, to 5.6% in northwestern Sud-Ubangi Province. Prevalence among boys (1.8%, 95% CI: 1.2%-2.7%) was double that among girls (0.7%, 95%CI: 0.4%-1.3%). Tetanus antibody-negativity, rurality, and lower household wealth were also significantly associated with higher HBsAg-positivity prevalence. We observed no difference in prevalence by age. Children had higher HBsAg-positivity odds if living with ≥1 HBsAg-positive adult household member (OR: 2.3, 95%CI: 0.7-7.8), particularly an HBsAg-positive mother (OR: 7.2, 95%CI:1.6-32.2).

Conclusion

In the largest national survey of HBV among children and household contacts in the DRC, we found that childhood HBV prevalence was 10-60 times the global target of 0.1%. We highlight specific regions and populations for further investigation and focused prevention efforts.
Exploring penetrance of clinically relevant variants in over 800,000 humans from the Genome Aggregation Database
Authors: Gudmundsson Sanna , Singer-Berk Moriel , Stenton Sarah L. , Goodrich Julia K. , Wilson Michael W. , Einson Jonah , Watts Nicholas A ,   Genome Aggregation Database Consortium, Lappalainen Tuuli , Rehm Heidi L. , MacArthur Daniel G. , O’Donnell-Luria Anne
Published: June 2024

Incomplete penetrance, or absence of disease phenotype in an individual with a disease-associated variant, is a major challenge in variant interpretation. Studying individuals with apparent incomplete penetrance can shed light on underlying drivers of altered phenotype penetrance. Here, we investigate clinically relevant variants from ClinVar in 807,162 individuals from the Genome Aggregation Database (gnomAD), demonstrating improved representation in gnomAD version 4. We then conduct a comprehensive case-by-case assessment of 734 predicted loss of function variants (pLoF) in 77 genes associated with severe, early-onset, highly penetrant haploinsufficient disease. We identified explanations for the presumed lack of disease manifestation in 701 of the variants (95%). Individuals with unexplained lack of disease manifestation in this set of disorders rarely occur, underscoring the need and power of deep case-by-case assessment presented here to minimize false assignments of disease risk, particularly in unaffected individuals with higher rates of secondary properties that result in rescue.
Fluorescein-Based SynNotch Adaptors for Regulating Gene Expression Responses to Diverse Extracellular Cues
Authors: Tran Jeremy C. , Kuffner Christopher J. , Marzilli Alexander M. , Miller Ryan Emily , Silfen Zachary E. , McMahan Jeffrey B. , Sloas D. Christopher , Chen Christopher S. , Ngo John T.
Published: June 2024

We introduce an adaptor-based strategy for regulating fluorescein-binding synthetic Notch (SynNotch) receptors using ligands based on conjugates of fluorescein isomers and analogs. To develop a versatile system, we evaluated the surface expression and activities of multiple constructs containing distinct extracellular fluorescein-binding domains. Using an optimized receptor, we devised ways to regulate signaling via fluorescein-based chemical transformations, including an approach based on a bio-orthogonal chemical ligation and a spatially controllable strategy via the photo-patterned uncaging of ano-nitrobenzyl-caged fluorescein conjugate. We further demonstrate that fluorescein-conjugated extracellular matrix (ECM)-binding peptides can regulate SynNotch activity depending on the folding state of collagen-based ECM networks. Treatment with these conjugates enabled cells to distinguish between folded versus denatured collagen proteins and enact dose-dependent gene expression responses depending on the nature of the signaling adaptors presented. To demonstrate the utility of these tools, we applied them to control the myogenic conversion of fibroblasts into myocytes with spatial and temporal precision and in response to denatured collagen-I, a biomarker of multiple pathological states. Overall, we introduce an optimized fluorescein-binding SynNotch as a versatile tool for regulating transcriptional responses to extracellular ligands based on the widely used and clinically-approved fluorescein dye.
Divergent cytokine and transcriptional signatures control functional T follicular helper cell heterogeneity
Authors: Dalit Lennard , Tan Chin Wee , Sheikh Amania A. , Munnings Ryan , Alvarado Carolina , Hussain Tabinda , Zaini Aidil , Cooper Lucy , Kirn Alana , Hailes Lauren , Nguyen Angela , Mackay Laura , Harris Nicola , Zaph Colby , La Gruta Nicole L. , Nutt Stephen L. , Good-Jacobson Kim L. , Davis Melissa J , Bryant Vanessa L. , Groom Joanna R.
Published: June 2024

Adaptive immune responses protect against multiple classes of pathogens, including viral, bacterial, fungal, and helminth infections. In all these settings, CD4+T follicular helper (Tfh) cells tailor high-affinity class-switched B cells responses. How Tfh lineage sovereignty is established while allowing for this context-specific functional heterogeneity is unclear. Here, we identify Tfh transcriptional networks in response to diverse infections. While Bcl-6 is the transcriptional linchpin of the core Tfh signature, this is overlayed with pathogen-specific transcriptional modules that shape Tfh function. Cytokine-transcriptional Tfh programing in mouse and human lymphoid tissue demonstrated that type I interferon and TGFβ signaling direct individual Tfh subpopulations to instruct B cell output. Here, we provide a transcriptional map and cell surface resource to interrogate Tfh diversity in humans and mice. This resource can be leveraged to further understand the origins of immune flexibility, perform immune monitoring in infection and antibody-mediated diseases and to develop context-specific vaccines.

ONE-SENTENCE SUMMARY

Dalit, Tan and colleagues provide a resource that functionally and transcriptionally profiles T follicular helper cells (Tfh) during diverse pathogen responses to reveal a blueprint for transcriptional flexibility and new tools to interrogate Tfh heterogeneity in mice and humans.
A hydrophobic core stabilizes the residual structure in the RRM2 intermediate state of the ALS-linked protein TDP-43
Authors: Mackness Brian C. , Morgan Brittany R. , Deveau Laura M. , Kathuria Sagar V. , Zitzewitz Jill A. , Massi Francesca
Published: June 2024

Folding intermediates mediate both protein folding and the misfolding and aggregation observed in human diseases, including amyotrophic lateral sclerosis (ALS), and are prime targets for therapeutic interventions. In this study, we identified the core nucleus of structure for a folding intermediate in the second RNA recognition motif (RRM2) of the ALS-linked RNA-binding protein, TDP-43, using a combination of experimental and computational approaches. Urea equilibrium unfolding studies revealed that the RRM2 intermediate state consists of collapsed residual secondary structure localized to the N-terminal half of RRM2, while the C-terminus is largely disordered. Steered molecular dynamics simulations and mutagenesis studies yielded key stabilizing hydrophobic contacts that, when mutated to alanine, severely disrupt the overall fold of RRM2. In combination, these findings suggest a role for this RRM intermediate in normal TDP-43 function as well as serving as a template for misfolding and aggregation through the low stability and non-native secondary structure.
Spaceflight Shifts in Community rRNA Copy Number in the Salivary Microbiome of Astronauts
Authors: Williamson Mark R.
Published: June 2024

The oral microbiome is stable, easily sampled, and can indicate disease. Using metagenomic data from GeneLab, I examined the effects of spaceflight on the human salivary microbiome using a composite community measure, average rRNA copy number. A higher copy number is associated with a faster growth rate and primary microbial succession. I found a significant increase in community weighted mean copy number between pre-spaceflight and during-spaceflight samples (p=0.0082). Furthermore, changes in abundance suggest a greater impact on individual species rather than phyla-level changes. Finally, a robustness analysis highlighted the importance of accurate copy number estimates and species-level identification.

Graphical Abstract
Acquisition, Evolution, and Diversification of Genomic Islands: A Case Study of a Virulence Gene Cluster inPseudomonas syringae
Authors: de Oliveira Luiz Orlando , Rody Hugo Vianna Silva , Aguilera Selene , Murillo Jesús
Published: June 2024

Genomic islands are widely distributed among bacteria, facilitating the dissemination of genes relevant to human, animal, and plant health. Herein, we explore the evolutionary history of a genomic island (Tox island) composed of a novel mobile genetic element (GInt) carrying an ∼25 kb gene cluster (Pht cluster) responsible for the biosynthesis of the phytotoxin phaseolotoxin, a virulence factor of the plant pathogenPseudomonas syringae. The Pht cluster has been acquired, either naked or associated with a GInt, on seven independent occasions by four phylogroups ofP. syringaeand the distant rhizobacteriumPseudomonassp. JAI115. The Pht cluster was independently captured by three distinct GInt elements, suggesting specific mechanisms for gene capture. Once acquired, the Tox island tends to be stably maintained, evolving with the genome. An array of molecular analyses delineated the likely evolutionary trajectory of the Pht cluster withinP. syringaepv. actinidiae (Psa) andP. amygdalipv. phaseolicola (Pph), involving: 1) acquisition by Pph; 2) transfer of haplotype G to Psa biovar 1; 3) acquisition or replacement by a haplotype of haplogroup D in Psa biovar 1; 4) acquisition of haplotype C by Psa biovar 6; and 5) replacement of the Tox island in Pph by a distantly related GInt. These findings underscore the potential role of phaseolotoxin in bacterial fitness and contribute to our understanding of virulence evolution in plant pathogens. Furthermore, GInts provide a model for studying the evolutionary dynamics of mobile genetic elements and the dissemination of adaptive genes among bacterial pathogens.
Anatomically distinct cortical tracking of music and speech by slow (1-8Hz) and fast (70-120Hz) oscillatory activity
Authors: Osorio Sergio , Assaneo M. Florencia
Published: June 2024

Music and speech encode hierarchically organized structural complexity at the service of human expressiveness and communication. Previous research has shown that populations of neurons in auditory regions track the envelope of acoustic signals within the range of slow and fast oscillatory activity. However, the extent to which cortical tracking is influenced by the interplay between stimulus type, frequency band, and brain anatomy remains an open question. In this study, we reanalyzed intracranial recordings from thirty subjects implanted with electrocorticography (ECoG) grids in the left cerebral hemisphere, drawn from an existing open-access ECoG database. Participants passively watched a movie where visual scenes were accompanied by either music or speech stimuli. Cross-correlation between brain activity and the envelope of music and speech signals, along with density-based clustering analyses and linear mixed effect modeling, revealed both anatomically overlapping and functionally distinct mapping of the tracking effect as a function of stimulus type and frequency band. We observed widespread left-hemisphere tracking of music and speech signals in the Slow Frequency Band (SFB, band-passed filtered low-frequency signal between 1-8Hz), with near zero temporal lags. In contrast, cortical tracking in the High Frequency Band (HFB, envelope of the 70-120Hz band-passed filtered signal) was higher during speech perception, was more densely concentrated in classical language processing areas, and showed a frontal-to-temporal gradient in lag values that was not observed during perception of musical stimuli. Our results highlight a complex interaction between cortical region and frequency band that shapes temporal dynamics during processing of naturalistic music and speech signals.
A dual-inducible control system for multistep biosynthetic pathways
Authors: Rincón Andrés Felipe Carrillo , Cabral Alexandra J. , Gyorgy Andras , Farny Natalie G.
Published: June 2024

Background

The successful production of industrially relevant natural products hinges on two key factors: the cultivation of robust microbial chassis capable of synthesizing the desired compounds, and the availability of reliable genetic tools for expressing target genes. The development of versatile and portable genetic tools offers a streamlined pathway to efficiently produce a variety of compounds in well-established chassis organisms. The σ70lacandtetexpression systems – adaptations of the widely usedlacandtetregulatory systems developed in our laboratory – have shown effective regulation and robust expression of recombinant proteins in various Gram-negative bacteria. Understanding the strengths and limitations of these regulatory systems in controlling recombinant protein production is essential for progress in this area.

Results

To assess their capacity for combinatorial control, both the σ70lacandtetexpression systems were combined into a single plasmid and assessed for their performance in producing fluorescent reporters as well as the terpenoids lycopene and β-carotene. We thoroughly characterized the induction range, potential for synergistic effects, and metabolic costs of our dual σ70lacandtetexpression system in the well-established microorganismsEscherichia coli,Pseudomonas putida, andVibrio natriegensusing combinations of fluorescent reporters. The dynamic range and basal transcriptional control of the σ70expression systems were further improved through the incorporation of translational control mechanisms via toehold switches. This improvement was assessed using the highly sensitive luciferase reporter system. The improvement in control afforded by the integration of the toehold switches enabled the accumulation of a biosynthetic intermediate (lycopene) in the β-carotene synthesis pathway.

Conclusion

This study presents the development and remaining challenges of a set of versatile genetic tools that are portable across well-established gammaproteobacterial chassis and capable of controlling the expression of multigene biosynthetic pathways. The enhanced σ70expression systems, combined with toehold switches, facilitate the biosynthesis and study of enzymes, recombinant proteins, and natural products, thus providing a valuable resource for producing a variety of compounds in microbial cell factories.

GRAPHICAL ABSTRACT
Nub1 traps unfolded FAT10 for ubiquitin-independent degradation by the 26S proteasome
Authors: Arkinson Connor , Dong Ken C. , Gee Christine L. , Costello Shawn M. , Marqusee Susan , Martin Andreas
Published: June 2024

The ubiquitin-like modifier FAT10 targets hundreds of proteins in the mammalian immune system to the 26S proteasome for degradation. This degradation pathway requires the cofactor Nub1, yet the underlying mechanisms remain unknown. Here, we reconstituted a minimalin vitrosystem and revealed that Nub1 utilizes FAT10’s intrinsic instability to trap its N-terminal ubiquitin-like domain in an unfolded state and deliver it to the 26S proteasome for engagement, allowing the degradation of FAT10-ylated substrates in a ubiquitin– and p97-independent manner. Through hydrogen-deuterium exchange, structural modeling, and site-directed mutagenesis, we identified the formation of a peculiar complex with FAT10 that activates Nub1 for docking to the 26S proteasome, and our cryo-EM studies visualized the highly dynamic Nub1 complex bound to the proteasomal Rpn1 subunit during FAT10 delivery and the early stages of ATP-dependent degradation. These studies thus identified a novel mode of cofactor-mediated, ubiquitin-independent substrate delivery to the 26S proteasome that relies on trapping partially unfolded states for engagement by the proteasomal ATPase motor.
Stage 2a IDEAL evaluation of a third-generation biocomposite suture anchor in arthroscopic rotator cuff repair: Subgroup cohort analysis of the PRULO registry with 12-month follow up
Authors: Scholes Corey , Fatima Manaal , Moody Cooper , Eng Kevin , Page Richard S
Published: June 2024

Background

Poly-lactic co-glycolide with tricalcium phosphate (PLGA)/β-TCP is both bioactive and biodegradable, and is considered a third generation biomaterial for suture anchors. This study aims to describe the incidence of adverse events and the trajectory of patient-reported outcomes up to 12 months follow up in patients undergoing rotator cuff repair with this type of anchor.

Methods

A sub-group analysis of a prospective clinical registry embedded in an orthopaedic clinic was conducted. Patients undergoing surgery with the Healix Advance BR were identified and data on patient demographics, treatment details, complications and adverse events, as well as patient-reported outcomes (QuickDASH, WORC Index Normalised) were retrieved. Summary statistics were generated for patient characteristics and PROMs analysed using multiple imputation and a linear model to assess changes between baseline and 12 month follow up.

Results

A consecutive cohort of 68 cases receiving the anchor of interest was included for analysis. Complications were recorded in six cases (8.8%, 95%CI 3.6 - 18.9), presenting as postoperative capsulitis/stiffness (N=3), persistent shoulder pain (N=1), a case of hemi-diaphragm palsy and a case of complex regional pain syndrome in the hand. No infections or reoperations were encountered in this series. The QuickDASH scores improved significantly from 45 (IQR 34-57) preoperatively to 5 (IQR 2-22) at 12 months. WORC Index scores improved from 46 (IQR 27-60) preoperatively to 85 (IQR 62-93) at 12 months.

Conclusion

This study found a low incidence of adverse events, no requirement for reoperation or revision, and favourable recovery of patient-reported outcomes in patients treated with arthroscopic rotator cuff repair with a third-generation biocomposite suture anchor at up to 12 months follow up.
A multilevel analysis of the prevalence and factors associated with multimorbidity in South Africa using 2016 Demographic and Health Survey data
Authors: Hazell Matthew , Kengne Andre Pascal , Gill Paramjit , Taylor Dylan , Uthman Olalekan A.
Published: June 2024

Multimorbidity in Sub-Saharan Africa is under researched and includes distinct disease combinations to those seen in high income countries. The aim of this study was to determine the prevalence and distribution of multimorbidity in South Africa, as well as the associated individual, area-level and contextual factors. Multilevel logistic regression analyses were conducted on nationally representative 2016 South Africa Demographic Health Survey Data. The sample included 5,342 individuals (level 1) who completed the Adult Health questionnaire living in 691 neighbourhoods (level 2) from nine provinces (level 3). Multimorbidity was present in 44.6% of the study population and ranged from 36.8% in Gauteng to 52.8% in Eastern Cape. Individuals who were older, women, formerly married, black, obese, consumed a medium amount of sugary drinks, received education to primary or secondary school level or exposed to smoke at work had an increased risk of multimorbidity. Province level factors including poverty, rurality and unemployment, as well as neighbourhood level poverty were associated with multimorbidity. Some evidence of residual multimorbidity clustering was observed at the neighbourhood but not province level. Therefore, strategies that aim to tackle multimorbidity should address the risk factors identified and the wider determinants of health within neighbourhoods.
PI(3,5)P2asymmetry during mitosis is essential for asymmetric vacuolar inheritance
Authors: Huda Mariam , Koyuncu Mukadder , Dilege Cansu , Caydasi Ayse Koca
Published: June 2024

Phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2) is a low-abundance signaling lipid that plays crucial roles in various cellular processes, including endolysosomal system structure/function, stress response, and cell cycle regulation. PI(3,5)P2synthesis increases in response to environmental stimuli, yet its behavior in cycling cells under basal conditions remained elusive. Here, we analyzed spatiotemporal changes in PI(3,5)P2levels during the cell cycle ofS. cerevisiae.We found that PI(3,5)P2accumulates on the vacuole in the daughter-cell while it disappears from the vacuole in the mother-cell during mitosis. Concomitant with the changes in PI(3,5)P2distribution, the daughter-vacuole became more acidic, whereas the acidity of the mother-vacuole decreased during mitosis. Our data further showed that both PI(3,5)P2and the PI(3,5)P2effector protein Atg18 are determinants of vacuolar-pH asymmetry and acidity. Our work, thus, identifies PI(3,5)P2as a key factor for establishment of vacuolar-pH asymmetry, providing insights into how the mother cell ages while the daughter cell is rejuvenated.
Redistribution of fragmented mitochondria ensure symmetric organelle partitioning and faithful chromosome segregation in mitotic mouse zygotes
Authors: Gekko Haruna , Nomura Ruri , Kuzuhara Daiki , Kaneyasu Masato , Koseki Genpei , Adhikari Deepak , Mio Yasuyuki , Carroll John , Kono Tomohiro , Funahashi Hiroaki , Wakai Takuya
Published: June 2024

In cleavage-stage embryos, preexisting organelles partition evenly into daughter blastomeres without significant cell growth after symmetric cell division. The presence of mitochondrial DNA within mitochondria and its restricted replication during preimplantation development makes their inheritance particularly important. While chromosomes are precisely segregated by the mitotic spindle, the mechanisms controlling mitochondrial partitioning remain poorly understood. In this study, we investigate the mechanism by which Dynamin-related protein 1 (Drp1) controls the mitochondrial redistribution and partitioning during embryonic cleavage. Deletion of Drp1 in mouse zygotes causes marked mitochondrial aggregation, and the majority of embryos arrest at the 2-cell stage. Clumped mitochondria are located in the center of mitotic Drp1-depleted zygotes with less uniform distribution, thereby preventing their symmetric partitioning. Asymmetric mitochondrial inheritance is accompanied by functionally inequivalent blastomeres with biased ATP and endoplasmic reticulum Ca2+levels. We also find that marked mitochondrial centration in Drp1-depleted zygotes prevents the assembly of parental chromosomes, resulting in chromosome segregation defects and binucleation. Thus, mitochondrial fragmentation mediated by Drp1 ensure proper organelle positioning and partitioning into functional daughters during the first embryonic cleavage.

Impact statement

Depletion of Dynamin-related protein 1, a key regulator of mitochondrial fission, in mouse zygotes impair symmetric organelle partitioning and chromosome segregation leading to early developmental arrest.
Sphaleron damping and effects on vector and axial charge transport in high-temperature QCD plasmas
Authors: de Bruin Lillian , Schlichting Sören
Published: June 2024

We modify the anomalous hydrodynamic equations of motion to account for dissipative effects due to quantum chromodynamic (QCD) sphaleron transitions. By investigating the linearized hydrodynamic equations, we show that sphaleron transitions lead to nontrivial effects on vector and axial charge transport phenomena in the presence of a magnetic field. Due to the dissipative effects of sphaleron transitions, a wave number threshold kCMW emerges characterizing the onset of chiral magnetic waves. Sphaleron damping also significantly impacts the time evolution of both axial and vector charge perturbations in a QCD plasma in the presence of a magnetic field. Based on our analysis of the linearized hydrodynamic equations, we also investigate the dependence of the vector charge separation on the sphaleron transition rate, which may have implications for the experimental search for the chiral magnetic effect in heavy ion collisions.

Published by the American Physical Society
2024
Classical and quantum computing of shear viscosity for
(2+1)D
SU(2) gauge theory
Authors: Turro Francesco , Ciavarella Anthony , Yao Xiaojun
Published: June 2024

We perform a nonperturbative calculation of the shear viscosity for (2+1)-dimensional SU(2) gauge theory by using the lattice Hamiltonian formulation. The retarded Green’s function of the stress-energy tensor is calculated from real time evolution via exact diagonalization of the lattice Hamiltonian with a local Hilbert space truncation, and the shear viscosity is obtained via the Kubo formula. When taking the continuum limit, we account for the renormalization group flow of the coupling but no additional operator renormalization. We find the ratio of the shear viscosity and the entropy density ηs is consistent with a well-known holographic result 14π at several temperatures on a 4×4 honeycomb lattice with the local electric representation truncated at jmax=12. We also find the ratio of the spectral function and frequency ρxy(ω)ω exhibits a peak structure when the frequency is small. Both the exact diagonalization method and simple matrix product state classical simulation method beyond jmax=12 on bigger lattices require exponentially growing resources. So we develop a quantum computing method to calculate the retarded Green’s function and analyze various systematics of the calculation including jmax truncation and finite size effects, Trotter errors and the thermal state preparation efficiency. Our thermal state preparation method still requires resources that grow exponentially with the lattice size, but with a very small prefactor at high temperature. We test our quantum circuit on both the Quantinuum emulator and the IBM simulator for a small lattice and obtain results consistent with the classical computing ones.

Published by the American Physical Society
2024
Topological modes and spectral flows in inhomogeneous PT-symmetric continuous media
Authors: Fu Yichen , Qin Hong
Published: June 2024

In classical Hermitian continuous media, the spectral-flow index of topological modes is linked to the bulk topology via index theorem. However, the interface between two bulks is usually non-Hermitian due to the inhomogeneities of system parameters. We show that the connection between topological modes and bulk topology still exists despite the non-Hermiticity at the interface if the system is endowed with PT symmetry. The theoretical framework developed is applied to the Hall magnetohydrodynamic model to identify a topological mode called topological Alfvén sound wave in magnetized plasmas.

Published by the American Physical Society
2024
Rebuttal to the article Pathological crystal structures
Authors: Chen Hong , Olmstead Marilyn M. , Fish Richard H.
Published: June 2024

A section in the Acta Crystallographica Section C article by Raymond & Girolami [Acta Cryst. (2023), C79, 445–455] stated that the product of the reaction of [(Cp*Rh)2(μ-OH)3]+ (Cp* is 1,2,3,4,5-pentamethylcyclopentadiene) with 1-methylthymine (1-MT) at pH 10 and 60 °C, to synthesize the anionic component [RhI(η1-N
3-1-MT)2]−, was not an RhI complex, but rather an AgI complex, due to the use of silver triflate (AgOTf) to remove Cl− from [Cp*RhCl2]2 to synthesize [Cp*Rh(H2O)3](OTf)2, a water-soluble crystalline complex. We will clearly show that this premise, as stated, is invalid, while the authors have simply avoided several important facts, including that Cp*OH, a reductive elimination product, at pH 10 and 60 °C, was unequivocally identified, thus leading to the RhI anionic component [RhI(η1-N
3-1-MT)2]−. More importantly, AgOH, from the reaction of NaOH at pH 10 with any potentially remaining AgOTf, after the AgCl was filtered off, would be insoluble in water. Furthermore, a control experiment with the inorganic complex Rh(OH)3, reacting with 1-methylthymine at pH 10, provided no product, and this bodes well for a similar fate with AgOTf and 1-methylthymine, i.e. at pH 10, AgOTf would again be converted to the water-insoluble AgOH; therefore, no reaction would occur! Finally, a 1H NMR spectroscopy experiment was carried out with synthesized and crystallized [Cp*Rh(H2O)3](OTf)2 in D2O at various pD values; at pD 8.65 no reaction took place, while at pD 13.6, and at 60 °C for 2 h, a reductive elimination reaction caused the precipitation of Cp*OH. The subsequent 1H NMR spectrum clearly demonstrated, in the absence of any AgI complexes, that the solution structure and the X-ray crystals in D2O were similar. A postulated mechanism for this novel anionic component structure, as published previously [Smith et al. (2014). Organometallics, 33, 2389–2404], will be presented, along with the experimental data, to insure the credibility of our results. We will also answer the comments in the response of Drs Raymond and Girolami to this rebuttal.
Graduate employability skills, trending avenues and research gaps: a systematic literature review and bibliometric analysis
Authors: Amarathunga Buddhini , Khatibi Ali , Talib Zunirah Mohd , Azam S.M. Ferdous , Tham Jacquline
Published: June 2024

Purpose

Current study theoretically and technically analyzed the empirical literature on Graduate Employability Skills (GES) and aimed to investigate ten research questions: 1) the specific features of the retrieved empirical studies on GES, 2) the trends of empirical scientific production of GES, 3) the most relevant and high-impact sources in the field of GES, 4) clustering the sources through Bradford’s Law of Scattering, 5) the highly cited articles on GES, 6) the most relevant countries on GES, 7) the most pertinent and high-impact authors on GES, 8) authors' productivity through Lotka’s Law of authors’ Scientific Productivity, 9) the trending research avenues for future investigations on GES, and 10) identified research gaps relevant to the field of GES.

Design/methodology/approach

The Scopus database was used to extract data, and VOSviewer and Biblioshony tools were used for the study's bibliometric analysis and systematic literature evaluation.

Findings

The present study analyzed 864 sources containing 1816 articles from 4378 authors that address GES. Publications on GES were steadily increasing, with a notable upswing beginning in 2010 and reaching a record high of 232 articles in 2019. The UK, Australia, and Malaysia are the top three nations in terms of number of publications and cumulative citations. The thematic map of keywords revealed which themes future researchers need to investigate: work-integrated learning, entrepreneurship, industry 4.0, sustainability, management education, business education, project-based learning, education, curriculum development, learning, and graduate skills.

Originality/value

The present study provides theoretical, practical, and social implications for graduates, the higher education industry, policymakers, the economy, and society.
Greening the future: analyzing green entrepreneurial orientation, green knowledge management and digital transformation for sustainable innovation and circular economy
Authors: Al Halbusi Hussam , Popa Simona , Alshibani Safiya Mukhtar , Soto-Acosta Pedro
Published: June 2024

Purpose

Green innovation, digitization and sustainability have attracted considerable attention in recent years due to their transformative potential in organizations. This study, grounded in the resource-based view, explores the intricate relationship among green entrepreneurial orientations, sustainability-oriented innovation, and the circular economy, employing green knowledge management as a pivotal mechanism.

Design/methodology/approach

The proposed model and hypotheses were tested using Partial Least Squares (PLS) structural equation modeling (SEM) with a sample of 274 valid questionnaires collected from manufacturing firms in Saudi Arabia.

Findings

Results unveil positive relationships between green entrepreneurial orientations and sustainability-oriented innovation, as well as the circular economy, along with a positive mediation of green knowledge management in these relationships. In addition, these relationships exhibit heightened strength with increased levels of digital transformation.

Originality/value

The contributions of this research extend to both theoretical and practical realms, offering valuable insights for startups and traditional businesses as they explore the landscape of green innovation and digitization.
Good for all, good for me: the influences of dedication- and constraint-based switching barriers on user-generated contributions
Authors: Chou En-Yi , Lin Cheng-Yu
Published: June 2024

Purpose

Prior research on user-generated content (UGC) contributions has primarily focused on self-centered or other-centered motives, paying limited attention to the concept of enlightened self-interest, in which both motives coexist in a single organism. Additionally, the factors influencing enlightened self-interest and their effects in different circumstances are yet to be explored. Drawing on theoretical lenses rooted in the switching barriers perspective and stimulus–organism–response framework, this study posits that dedication-based switching barriers (community–member relationship quality, member–member relationship quality, and content attractiveness) positively relate to enlightened self-interest, whereas constraint-based switching barriers (switching costs) moderate the relationship between dedication-based switching barriers and enlightened self-interest in social media communities (SMCs). Members' enlightened self-interest in turn influences both the creation and co-creation of UGC.

Design/methodology/approach

This study comprised two quantitative studies: an online survey-based study (Study 1) and an online scenario-based experiment (Study 2). Study 1 surveyed 613 respondents, while Study 2 included 749 participants. Both studies employed structural equation modeling and bootstrapping techniques for analysis.

Findings

The findings indicate that dedication-based switching barriers positively affect users' enlightened self-interest, which in turn is positively associated with UGC creation and co-creation. Switching costs moderate the relationship between relationship quality (community–member and member–member) and enlightened self-interest.

Originality/value

This study complements the current understanding of how the association between dedication- and constraint-based switching barriers and users' enlightened self-interests influence user-generated contributions.