bluuebunny/crossref_metadata_2025 huggingface dataset:
Localized ejection of dust and chunks on comet 67P/Churyumov–Gerasimenko: testing how comets work
Authors: Attree N , Schuckart C , Bischoff D , Gundlach B , Blum J
Published: October 2024

We extend an existing thermophysical activity model of comet 67P/Churyumov–Gerasimenko to include pressure build-up inside the pebbles making up the nucleus. We test various quantities of H$_{2}$O and CO$_{2}$, in order to simulate the material inside and outside of proposed water enriched bodies (WEBs). We find that WEBs can reproduce the peak water flux observed by Rosetta, but that the addition of a time-resolved heat-flow reduces the water fluxes away from perihelion as compared to the previously assumed equilibrium model. Our modelled WEBs eject dust continuously but with a rate that is much higher than the observed erosion and mass-loss, thus requiring an active area smaller than the total comet surface area or very large quantities of dust fallback. When simulating the CO$_{2}$-rich non-WEB material, we only find the ejection of large chunks under specific conditions (e.g. low diffusivities between the pebbles or intense insolation at southern summer), while we also find CO$_{2}$ outgassing rates that are much greater than observed. This is a general problem in models where CO$_{2}$ drives erosion, alongside difficulties in simultaneously ejecting chunks from deep while eroding the surface layer. We therefore conclude that ejection of chunks by CO$_{2}$ must be a localized phenomenon, occurring separately in space or time from surface erosion and water emission. Simulating the global production rates of gas, dust, and chunks from a comet thus remains challenging, while the activity mechanism is shown to be very sensitive to the material structure (i.e. porosity and diffusivity) at various scales.
Regression of biventricular hypertrophy in acromegalic cardiomyopathy following management of excessive growth hormone secretion
Authors: Faraj Raid , Diallo Thierno Hamidou , Abdelali Mehdi , Lahjouji Reda , Benmessaoud Fatima-azzahra , Doghmi Nawal , Zarzur Jamila , Cherti Mohamed
Published: October 2024

Acromegalic cardiomyopathy is a significant cardiovascular complication associated with acromegaly, caused by excessive growth hormone production from a pituitary adenoma. Early diagnosis can be challenging due to its insidious nature. This case underscores the critical significance of timely medical intervention, illustrating favorable outcomes resulting from prompt therapeutic measures.
Clinical report of metacarpal melorheostosis: a rare disease with “the dripping candle wax” appearance on different imaging modalities
Authors: Mesbah Oumaima , Jidal Manal , Saouab Rachida , El Fenni Jamal
Published: October 2024

Melorheostosis is a rare benign bone dysplasia characterized by dysostosis and sclerosis. The classic “dripping candle wax” appearance on imaging is a typical finding for the diagnosis. The authors report the case of a patient presenting with a hard and painful mass on the dorsal side of the hand.
Differences in Abdominal and Lumbar Muscle Thickness and Contractile Function Between Nulliparous, Primiparous, and Multiparous Women 6 Months Postpartum
Authors: Fuentes-Aparicio Laura , Pérez-Alenda Sofia , Carrasco Juan J , Valls-Donderis Begoña , Dueñas Lirios , Balasch-Bernat Mercè
Published: October 2024

Objective

The purpose of this study was to evaluate the differences between primiparous and multiparous women at 6 months postpartum and nulliparous women regarding the thickness (including thickness pattern) and contractile function of the abdominal and lumbar muscles.

Methods

A cross-sectional observational study of 80 women, both primiparous (n = 29) and multiparous (n = 25), as well as including nulliparous as a comparison group (n = 26), was conducted. B-mode ultrasound imaging was used for the measurement of abdominal and lumbar muscle thickness in two conditions (resting and activation). Moreover, the contractile function of these muscles was determined by the thickness ratio.

Results

Significant differences between groups were observed in abdominal muscle thickness. During activation, the obliques showed a lower thickness in both groups of postpartum women compared to nulliparous women, while lower values for the thickness for the transverse abdominis (TrA) were only observed in primiparous women. The thickness pattern observed in nulliparous women both in resting and in activation (internal oblique [IO] > external oblique [EO] > TrA) was also achieved among postpartum women, despite no statistical differences observed between IO and EO in these groups. No significant differences between groups were observed for contractile function, showing the TrA greater values, followed by IO and EO in both nulliparous and postpartum women.

Conclusions

This study suggests that the thickness (and the thickness pattern) of the abdominal muscles in women at 6 months postpartum differs from nulliparous, while for the lumbar muscles, it is comparable to nulliparous. However, despite the obliques being thinner in postpartum women, the abdominal muscles are functionally competent.

Impact

This is believed to be the first study to compare abdominal and lumbar muscles thickness and contractile function specifically between primiparous and multiparous women. Although at 6 months’ postpartum abdominal thickness differs from nulliparous women, these muscles are functionally competent. These findings provide valuable insights for use in the development of postpartum interventions.
Experiences of People With Persistent Nonspecific Neck Pain Who Used Immersive Virtual Reality Serious Games in the Home Setting: A Qualitative Study
Authors: Luc Alexandre , Lambricht Nicolas , Aujoulat Isabelle , Detrembleur Christine , Pitance Laurent
Published: October 2024

Objective

The purpose of this study was to explore the experiences of individuals with persistent nonspecific neck pain who used immersive virtual reality (VR) serious games at home for 2 weeks.

Methods

In this descriptive qualitative study, semi-structured one-on-one interviews were conducted at the participant’s home after the 2-week period. Interviews were analyzed using qualitative content analysis. Sample size was determined using the information power concept (where “information power” refers to the amount of relevant information the sample provides for addressing the research question).

Results

Eleven adults with continuous or recurrent nonspecific neck pain participated in the study. Three main categories were identified. The first revolves around the home environment, revealing that participants had mixed perceptions about being at home, yet held a positive perspective on the utilization of immersive VR in that setting. The second pertains to immersive VR as a novel technology, indicating its overall comfort, user-friendliness, and varying degrees of immersion and presence experienced by the participants. The third focuses on exercising in immersive VR, drawing comparisons with conventional exercises, exploring the facilitators and barriers to usage, and addressing various aspects of integrating this technology into rehabilitation.

Conclusion

Immersive VR was deemed comfortable for almost all participants and easy to use. Participants found exercising in immersive VR motivating and enjoyable, compared to conventional exercises. The home environment proved suitable for using immersive VR, though challenges included autonomy and reduced human contact. Participants highlighted facilitators and barriers in using immersive VR serious games, as well as immersive VR’s rehabilitation potential. They also underscored the crucial role of physical therapists for guidance, remote supervision, and personalized treatment.

Impact

These findings could help clinicians to better understand the experiences of individuals with persistent nonspecific neck pain when using immersive VR, as well as its use at home. This understanding can improve patient care and optimize the effectiveness of immersive VR as a treatment method.
Using the Rehabilitation Treatment Specification System to Describe Experimental and Control Arms of a Clinical Trial for Breast Cancer Survivors
Authors: Lyons Kathleen D. , Hart Tessa , Singh Sheel , Wolfberg Jeremy , Whyte John , Wechsler Stephen , Lin Susan H. , Fasoli Susan E. , Van Stan Jarrad H.
Published: October 2024

Background:

The Rehabilitation Treatment Specification System (RTSS) provides a framework to decompose complex interventions into components, each defined by its known or hypothesized active ingredients. In addition to its value in planning new interventions and understanding existing ones, it can be used to help interpret findings of clinical trials and plan next steps in a research program.

Methods:

This paper presents a secondary analysis in which we used the RTSS to retrospectively delineate targets and ingredients of an experimental treatment, Behavioral Activation and Problem-Solving (BA/PS), and then examined the attention control condition for overlapping ingredients that could clarify the control condition’s unanticipated effects. Three members of the research team worked with two RTSS experts to develop an RTSS specification of BA/PS using the BA/PS treatment manual and study materials. The specification and the comparison to the control condition were then shared with four other RTSS experts for refinement and consensus building.

Results:

Our BA/PS intervention had seven treatment components; three were unique to the BA/PS condition, but the attention control condition contained ingredients that mirrored those found in four of the BA/PS components.

Conclusion:

Our results illuminate the challenges of designing an adequate control condition for behavioral rehabilitation trials among survivors of cancer. This RTSS application was instrumental in refining our conceptual model and preparing for future research. It serves as a model for other cancer rehabilitation researchers, emphasizing the importance of intentional and transparent intervention specification to advance the field.
The Critical Role of the Adipocytokine NOV in Obstructive Sleep Apnea Induced Cardiometabolic Dysfunction: A Review
Authors: Fakhouri Eddie W. , Peterson Stephen J. , Fakhouri William , Minkin Ruth , Frishman William H. , Weingarten Jeremy A.
Published: October 2024

Obstructive sleep apnea (OSA) is highly prevalent and associated with oxidative stress, chronic inflammation, and adverse cardiovascular consequences. The comorbid condition of obesity remains epidemic. Both obesity and OSA are highly comorbid in patients with cardiovascular disease including atrial fibrillation, resistant hypertension, congestive heart failure, and coronary artery disease. Patients with these preexisting cardiovascular conditions should be screened for OSA with a low threshold to treat, even if OSA severity is mild. Nephroblastoma overexpressed (NOV/CCN3) protein has been identified in multiple chronic inflammatory states, most notably in obesity and more recently in OSA, even in the absence of obesity. As such, NOV may represent an important biomarker for oxidative stress in OSA and may lead to a deeper understanding of the relationship between OSA and its clinical sequelae.
Multilevel Resilience and Appointment Attendance Among African American/Black Adults with HIV: A Prospective Multisite Cohort Study
Authors: Wilson-Barthes Marta G. , Park Jee Won , Mugavero Michael J. , Napravnik Sonia , Carey Michael P. , Fava Joseph L. , Dale Sannisha K. , Earnshaw Valerie A. , Agil Deana , Howe Chanelle J. , Dulin Akilah J.
Published: October 2024

Background:

Attending clinic appointments supports HIV viral suppression, yet racial disparities are documented. We assessed whether multilevel resilience resources were associated with appointment attendance among African American/Black (AA/B) adults living with HIV in the United States.

Methods:

We ascertained data from 291 AA/B clinical cohort participants from 2018 to 2021. We assessed resilience using the Multilevel Resilience Resource Measure. Binary outcomes were a nonrepeated indicator of attending ≥87.5% of scheduled HIV appointments over 12 months (i.e., visit adherence) and a repeated measure of attending appointments during two sequential 6-month follow-up windows (i.e., clinic attendance). Modified Poisson models estimated adjusted risk ratios (aRRs).

Results:

The aRR for clinic attendance among participants with greater versus lesser multilevel resilience resource endorsement was 0.95 (95% confidence interval: 0.88, 1.0). The aRR for visit adherence among participants with greater versus lesser multilevel resilience resource endorsement was 1.2 (0.95, 1.4).

Conclusions:

This analysis is one of the first to assess appointment attendance as a function of resilience. Findings should be confirmed in larger cohorts.
Carbapenem-resistant Citrobacter amalonaticus and VRE bacteraemia in an immunocompetent patient after a urological Rezum procedure
Authors: Midlick David , Harhay Jason , Summers Nathan A.
Published: October 2024

In this report, we discuss the case of a 62-year-old man who presented with gross haematuria, fever, and chills 1 day after undergoing a Rezum procedure and was found to have carbapenem-resistant Citrobacter amalonaticus and vancomycin-resistant Enterococcus faecalis bacteraemia. The patient was treated with daptomycin, eravacycline, and ceftalozane–tazobactam with positive results. We discuss our case and treatment of C. amalonaticus bacteraemia, a pathogen with limited existing literature on its incidence, presentation, and treatment.
Impact assessment and indigenous rights: Cumulative impact assessment of forestry on winter pastures in Mudusjävri reindeer herding co-operative in Finland
Authors: Saijets Jan , Raitio Kaisa , Pyykkö Jarmo , Hansen Leena , Aikio Esko , Feodoroff Pauliina , Seurujärvi Osmo ,   “What form can an atonement take?” group.
Published: October 2024

Assessing the cumulative effects of competing land uses on traditional indigenous livelihoods and culture is a critical component of ensuring the protection of indigenous peoples’ rights. Lack of appropriate methodologies for conducting cumulative impact assessment is a major concern in Sámi indigenous communities across Sápmi, the traditional Sámi territory covering the northern parts of Finland, Sweden, Norway and parts of north-western Russia. We report from a project in which a new type of GIS based impact assessment methodology was developed to assess effects of forestry on winter pastures of the Mudusjävri reindeer herding co-operative in northern Finland. Winter pasture quality was studied as a function of cumulative impacts from forestry. The aim was to develop a way to measure the level of harm caused by forestry on Sámi culture and rights that are protected by national laws and international conventions - in order to assess whether the threshold for significant and hence unacceptable impact has been exceeded. An existing static model for lichen – the main natural winter fodder for reindeer – both for its biomass and growth was used along with mapped forest data to simulate the impacts of forestry on reindeer herding. Our assessment shows that the intensive industrial loggings that started in the 1950s have reduced the ground lichen biomass in Mudusjävri’s pastures by over 30% by 2020. The yearly lichen production has been reduced by 23 - 31% and the yearly lichen depending on the model version used. The respective cost of forestry for Mudusjävri reindeer herding is approximately 370 – 530 000 €/year which is approximately half of the total turnover of the co-operative. Thus, our study indicates that significant harm has been caused on Sámi reindeer herding by other land uses and especially forestry.
Age-induced BMP signaling inhibits the ICAT-mediated Wnt pathway to promote osteoarthritis
Authors: Kumar Bhupendra , Iqbal Sayeda Fauzia , Jena Ankita , Arora Shuchi , Gupta Pankaj , Thaleshwari Saahiba , Taketo Makoto Mark , Bandyopadhyay Amitabha
Published: October 2024

A mechanistic framework for age-induced osteoarthritis (OA) has remained largely elusive, leading to challenges in designing effective therapies for this debilitating disorder. Meanwhile, the models that induce OA in young animals through surgical, pharmacological, or genetic alterations fail to mimic OA that stems with age. In this study, we examined the molecular, cellular, and radiological changes in the articular cartilage (AC) of the C57BL/6J wild-type mice from postnatal day 15 to 3 years of age. In juvenile mice, AC, while all the layers express the BMPR1A receptor, only a thin layer of cells in the deep zone of AC express BMP ligands, and chondrocyte hypertrophy ensues first in this layer. With age, the BMP ligands’ expression domain expands throughout the AC, leading to BMP signaling activation and resultant chondrocyte hypertrophy. Further, exposure to healthy AC with BMP ligands was sufficient to induce premature OA-like changes in the young adult mice, suggesting BMP signaling is the limiting factor behind age-induced OA. We found that activation of BMP signaling upregulates ICAT expression, a known inhibitor of the canonical Wnt pathway in the AC. Our results suggest that with aging, the spread of BMP signaling throughout the cartilage is a certainty and the underlying cause for age-induced OA. Further,in situinhibition of BMP signaling appears to be a potent therapeutic strategy for age-induced OA.

Significance

Contrived models fail to mimic age-induced osteoarthritis (OA), which poses a challenge to comprehending the molecular mechanisms and thereby developing an effective therapy. We examined cellular and molecular interplay during aging mouse articular cartilage. Our results reveal that in the juvenile stage, expression of BMP ligands and thereby BMP signaling-induced hypertrophy is restricted to the deep zone of articular cartilage. However, with age, BMP ligands begin to express in the entire tissue and trigger BMP signaling, which inhibits ICAT-mediated Wnt-β-catenin signaling to promote chondrocyte hypertrophy resulting in articular cartilage degeneration. Thus, our study provides a previously unknown molecular insight into BMP ligand/signaling dynamics during articular cartilage degeneration and therefore could help develop an effective therapy for age-induced osteoarthritis.
“A circadian clock drives behavioral activity in Antarctic krill (Euphausia superba) and provides a potential mechanism for seasonal timing”
Authors: Hüppe Lukas , Bahlburg Dominik , Driscoll Ryan , Helfrich-Förster Charlotte , Meyer Bettina
Published: October 2024

Antarctic krill is a species with fundamental importance for the Southern Ocean ecosystem. Their large biomass and synchronized movements, like diel vertical migration (DVM), significantly impact ecosystem structure and the biological carbon pump. Despite decades of research, the mechanistic basis of DVM remains unclear. Circadian clocks help organisms anticipate daily environmental changes, optimizing adaptation. In this study, we used a recently developed activity monitor to record swimming activity of individual, wild-caught krill under various light conditions and across different seasons. Our data demonstrate how the krill circadian clock, in combination with light, drives a distinct bimodal pattern of swimming activity, which could facilitate ecologically important behavioral patterns, such as DVM. Rapid damping and flexible synchronization of krill activity indicate that the krill clock is adapted to a life at high latitudes and seasonal activity recordings suggest a clock-based mechanism for the timing of seasonal processes. Our findings advance our understanding of biological timing and high-latitude adaptation in this key species.
p53 isoforms have a high aggregation propensity, interact with chaperones and lack binding to p53 interaction partners
Authors: Brdar Anamari , Osterburg Christian , Münick Philipp , Machel Anne Christin , Rathore Rajeshwari , Osterburg Susanne , Yüksel Büşra , Schäfer Birgit , Desch Kristina , Langer Julian , Dikic Ivan , Dötsch Volker
Published: October 2024

The p53 transcription factor family consists of the three members p53, p63 and p73. Both p63 and p73 exist in different isoforms that are well characterized. Isoforms have also been identified for p53 and it has been proposed that they are responsible for increased cancer metastasis. In contrast to the p63 and p73 isoforms, which do not contain truncations in folded domains, most of the p53 isoforms contain only parts of either the DNA binding domain or the oligomerization domain. To better understand the effect of p53 isoforms in cancer we provide here a comprehensive biochemical characterization. With the exception of the Δ40p53α isoform none of the other variants can bind to DNA with high affinity and none can upregulate transcription. Probing with antibodies, DARPins and other interaction partners confirmed that isoforms harboring deletions in the DNA binding domain cannot interact specifically with them, but instead are bound to chaperones and other factors known to interact with misfolded proteins. Expression of isoforms with deletions in the DNA binding domain results in upregulation of cellular chaperones. If the expression level surpasses a threshold, the chaperone system can no longer keep these isoforms soluble resulting in aggregation and co-aggregation with other factors.
PII1/MRC interaction with Starch Synthase 4 (SS4) fromArabidopsis thalianainhibits SS4 enzymatic activity
Authors: Bossu M. , Osman R. , Brysbaert G. , Lensink Marc F. , Dauvillée D. , Bompard C.
Published: October 2024

Starch is the major energy storage compound in plants. It accumulates in the form of insoluble, partly crystalline granules whose number and shape are specific to each plant species. These characteristics are defined very early in starch biosynthesis, at the initiation stage.

Starch biosynthesis initiation is a complex process that relies on the coordinated action of several proteins that interact together in the so-called complex of initiation. Starch Synthase 4 (SS4) is the only initiation protein with enzymatic activity. It catalyzes the formation of glucan primers, which serve as substrates for the enzymatic machinery that synthesizes starch granules. Previous studies have highlighted the importance of interactions between SS4 and regulatory proteins in this process. Among them, Protein Involved in Initiation 1 (PII1) interacts with SS4 but its function is not yet established. In this study, we explored the structural and functional implications of PII1 on SS4’s enzymatic activity. Our findings reveal that PII1 contains a long coiled-coil domain that specifically interacts with SS4, leading to significant inhibition of SS4’s glucan elongation activity. Importantly, this inhibition is specific to SS4 and does not affect other known synthases, suggesting a targeted regulatory mechanism. This work describes the structural specificities of PII1 and SS4 and reveals a function for PII1 in the initiation complex. These results allow us to re-examine these complex mechanisms and propose new hypotheses about the important steps in the initiation of starch biosynthesis.
Genetic diversity and population structure of soybean (Glycine max(L.) Merril) germplasm
Authors: Silue Tenena , Agre Paterne Angelot , Olasanmi Bunmi , Adewumi Adeyinka Saburi , Adejumobi Idris Ishola , Abebe Abush Tesfaye
Published: October 2024

Soybean (Glycine max(L.) Merril) is a significant legume crop for oil and protein. However, its yield in Africa is less than half the global average resulting in low production, which is inadequate for satisfying the continent’s needs. To address this disparity in productivity, it is crucial to develop new high-yielding cultivars by utilizing the genetic diversity of existing germplasms. Consequently, the genetic diversity and population structure of various soybean accessions were evaluated in this study. In pursuit of this objective, a collection of 147 soybean accessions was genotyped via the Diversity Array Technology Sequencing method. This method enables high-throughput analysis of single-nucleotide polymorphisms (SNPs), resulting in the identification of 7,083 high-quality SNPs distributed throughout the soybean genome. The average values observed for polymorphism information content (PIC), minor allele frequency, expected heterozygosity and observed heterozygosity were 0.277, 0.254, 0.344, and 0.110, respectively. The soybean genotypes were categorized into four groups on the basis of model-based population structure, principal component analysis, and discriminant analysis of the principal component. Alternatively, hierarchical clustering was used to organize the accessions into three distinct clusters. Analysis of molecular variance indicated that the genetic variance within the populations exceeded the variance among them. The insights gained from this study will assist breeders in selecting parental lines for genetic recombination. Overall, this study provides valuable information regarding soybean genetic diversity and lays the groundwork for conservation and genetic enhancement initiatives.
Defining a tandem repeat catalog and variation clusters for genome-wide analyses and population databases
Authors: Weisburd Ben , Dolzhenko Egor , Bennett Mark F. , Danzi Matt C. , English Adam , Hiatt Laurel , Tanudisastro Hope , Kurtas Nehir Edibe , Jam Helyaneh Ziaei , Brand Harrison , Sedlazeck Fritz J. , Gymrek Melissa , Dashnow Harriet , Eberle Michael A. , Rehm Heidi L.
Published: October 2024

Tandem repeat (TR) catalogs are important components of repeat genotyping studies as they define the genomic coordinates and expected motifs of all TR loci being analyzed. In recent years, genome-wide studies have used catalogs ranging in size from fewer than 200,000 to over 7 million loci. Where these catalogs overlapped, they often disagreed on locus boundaries, hindering the comparison and reuse of results across studies. Now, with multiple groups developing public databases of TR variation in large population cohorts, there is a risk that, without sufficient consensus in the choice of locus definitions, the use of divergent repeat catalogs will lead to confusion, fragmentation, and incompatibility across future resources.

In this paper, we compare existing TR catalogs and discuss desirable features of a comprehensive genome-wide catalog. We then present a new, richly annotated catalog designed for large-scale analyses and population databases. Our catalog stratifies TRs into two groups: 1) isolated TRs suitable for repeat copy number analysis using short read or long read data and 2) so-called variation clusters that contain TRs within wider polymorphic regions that are best studied through sequence-level analysis. To define variation clusters, we present a novel algorithm that leverages long-read HiFi sequencing data to group repeats with surrounding polymorphisms. We show that the human genome contains at least 25,000 complex variation clusters, most of which span over 120 bp and contain five or more TRs. Resolving the sequence of entire variation clusters instead of individually genotyping constituent TRs leads to a more accurate analysis of these regions and enables us to profile variation that would have been missed otherwise.
Suppression of NRF2-dependent cancer growth by a covalent allosteric molecular glue
Authors: Roy Nilotpal , Wyseure Tine , Lo I-Chung , Metzger Justine , Eissler Christie L. , Bernard Steffen M. , Bok Ilah , Snead Aaron N. , Parker Albert , Green Jason C. , Inloes Jordon , Jacinto Sarah R. , Kuenzi Brent , Horning Benjamin D. , Ibrahim Noah , Grabow Stephanie , Panda Harit , Bhatt Dhaval P. , Saeidi Soma , Zolkind Paul , Rush Zoe , Negri Kathleen , Williams Heather N. , Walton Eric , Pastuszka Martha K. , Sigler John J. , Tran Eileen , Hee Kenneth , McLaughlin Joseph , Ambrus-Aikelin Géza , Pollock Jonathan , Abraham Robert T. , Kinsella Todd M. , Simon Gabriel M. , Major Michael B. , Weinstein David S. , Patricelli Matthew P.
Published: October 2024

The NRF2 transcription factor is constitutively active in cancer where it functions to maintain oxidative homeostasis and reprogram cellular metabolism. NRF2-active tumors exhibit NRF2-dependency and resistance to chemo/radiotherapy. Here we characterize VVD-065, a first-in-class NRF2 inhibitor that acts via an unprecedented allosteric molecular glue mechanism. In the absence of stress or mutation, NRF2 is rapidly degraded by the KEAP1-CUL3 ubiquitin-ligase complex. VVD-065 specifically and covalently engages C151 on KEAP1, which in turn promotes KEAP1-CUL3 complex formation, leading to enhancement of NRF2 degradation. Previously reported C151-directed compounds decrease KEAP1-CUL3 interactions and stabilize NRF2, thus establishing KEAP1_C151 as a tunable regulator of the KEAP1-CUL3 complex and NRF2 stability. VVD-065 inhibited NRF2-dependent tumor growth and sensitized cancers to chemo/radiotherapy, supporting an open Phase I clinical trial (NCT05954312).
Human gray matter microstructure mapped using Neurite Exchange Imaging (NEXI) on a clinical scanner
Authors: Uhl Quentin , Pavan Tommaso , Feiweier Thorsten , Piredda Gian Franco , Jelescu Ileana
Published: October 2024

Biophysical models of diffusion in gray matter (GM) can provide unique information about microstructure of the human brain, in health and disease. Therefore, their compatibility with clinical settings is key. Neurite Exchange Imaging (NEXI) is a two-compartment model of GM microstructure that accounts for inter-compartment exchange, whose parameter estimation requires multi-shell multi-diffusion time data. In this work, we report the first estimates of NEXI in human cortex obtained on a clinical MRI scanner. To do that, we establish an acquisition protocol and fitting routine compatible with clinical scanners.

The model signal equation can be expressed either in the narrow-pulse approximation, NEXINPA, or accounting for the actual width of the diffusion gradient pulses, NEXIWP. While NEXINPAenables a faster analytical fit and is a valid approximation for data acquired on high-performance gradient systems (preclinical and Connectom scanners), on which NEXI was first implemented, NEXIWPhas significant relevance for data acquired on clinical scanners with longer gradient pulses. We establish that, in the context of broad pulses, NEXIWPestimates were more comparable to previous literature values.

Furthermore, we evaluate the repeatability of NEXI estimates in the human cortex on a clinical MRI scanner and show intra-subject variability to be lower than inter-subject variability, which is promising for characterizing healthy and patient cohorts.

Finally, we analyze the relationship of NEXI parameters on the cortical surface to the Myelin Water Fraction (MWF), estimated using an established multicomponent T2relaxation technique. Indeed, although it is present in small quantities in the cortex, myelin can be expected to decrease permeability. We confirm a strong correlation between the exchange time (tex) estimates and the MWF, although the spatial correspondence between the two is brain-region specific and other drivers oftexthan myelin density are likely at play.
Temperature-induced membrane trafficking drives antibody delivery to the brain
Authors: Du Fusheng , Wan Qi , Glebov Oleg O.
Published: October 2024

Despite quotidian occurrence of fever and hyperthermia, cell biological mechanisms underlying their effects remain unclear. Neurological complications of severe (>40°C) fever have been associated with increased blood-brain barrier (BBB) permeability due to structural disruption, while little is known about brain physiology of moderate fever. Here, we show that a temperature increase to 39-40°C increased fluid-phase uptake in PC12 cells and primary neurons. Uptake of selective cargoes showed that clathrin-mediated endocytosis and macropinocytosis were induced in a translation-dependent manner, consistent with a role for heat shock response. Exocytic recycling was also increased by hyperthermia, suggesting a comprehensive boost of membrane trafficking. Mild (<39°C) whole-body hyperthermiain vivotriggered fluid-phase uptake in various organs, notably enabling brain accumulation of an intravenously injected antibody that was blocked by dynamin inhibition. Taken together, our findings show that fever systemically regulates membrane trafficking, reveal dynamin-dependent endocytosis as a cell biological mechanism for temperature control of BBB permeability, and demonstrate a clinical potential of mild hyperthermia for facilitating brain delivery of biologic drugs.

Highlights

Temperature increase of 2-3°C upregulates endocytosis and exocytosis

Temperature-induced upregulation of membrane trafficking requires protein translation and dynamin function

Mild whole-body hyperthermia enhances fluid-phase endocytosis across the body

Mild hyperthermia enables delivery of an exogenous antibody from the bloodstream into the brain through a dynamin-dependent pathway
Structural Basis for the Improved RNA-Clamping of Amidino-Rocaglates to eIF4A1
Authors: Conley James F. , Brown Lauren E. , McNeely James H. , Pelletier Jerry , Porco John A. , Allen Karen N.
Published: October 2024

Eukaryotic Initiation Factor 4A-1 (eIF4A1) is an ATP-dependent RNA helicase that unwinds 5’-UTR mRNA secondary structures to facilitate cap-dependent translation initiation. Rocaglates, a class of natural products typified by rocaglamide A (RocA), possess anti-neoplastic and anti-infectious activity mediated by their interaction with eIF4A1. Rocaglates inhibit cap-dependent translation initiation by “clamping” eIF4A1 onto polypurine RNA, impeding ribosome scanning. A novel class of rocaglate derivatives, amidino-rocaglates (ADRs) which feature an amidine ring fused to the rocaglate core, are particularly effective at promoting eIF4A1-RNA-clamping compared to other rocaglate congeners. Herein, we present the X-ray crystal structure of an ADR in complex with eIF4A1, the nonhydrolyzable ATP ground-state mimic adenylyl-imidodiphosphate (AMPPNP), and poly r(AG)5RNA refined to 1.69 Å resolution. The binding pose and interactions of the ADR with eIF4A1 do not differ substantially from those of RocA, prompting investigation of the basis for enhanced target engagement. Computational modeling suggests that the rigidified ADR scaffold is inherently preorganized in an eIF4A1-RNA-binding-competent conformation, thereby avoiding entropic penalties associated with RocA binding. This study illustrates how conformational rigidification of the rocaglate scaffold can be leveraged to improve potency for the development of rocaglates as potential anticancer and anti-infectious agents.

Abstract Figure
Determining accurate conformational ensembles of intrinsically disordered proteins at atomic resolution
Authors: Borthakur Kaushik , Sisk Thomas R. , Panei Francesco P. , Bonomi Massimiliano , Robustelli Paul
Published: October 2024

Determining accurate atomic resolution conformational ensembles of intrinsically disordered proteins (IDPs) is extremely challenging. Molecular dynamics (MD) simulations provide atomistic conformational ensembles of IDPs, but their accuracy is highly dependent on the quality of physical models, or force fields, used. Here, we demonstrate how to determine accurate atomic resolution conformational ensembles of IDPs by integrating all-atom MD simulations with experimental data from nuclear magnetic resonance (NMR) spectroscopy and small-angle x-ray scattering (SAXS) with a simple, robust and fully automated maximum entropy reweighting procedure. We demonstrate that when this approach is applied with sufficient experimental data, IDP ensembles derived from different MD force fields converge to highly similar conformational distributions. The maximum entropy reweighting procedure presented here facilitates the integration of MD simulations with extensive experimental datasets and enables the calculation of accurate, force-field independent atomic resolution conformational ensembles of IDPs.
Siglec-F Deficiency Prevents Fibrosis After Bleomycin-Induced Acute Lung Injury
Authors: Orlov Marika , Rangarajan Sunad , Jaramillo Ana M. , Ye Qihua , Hara Naoko , Ngo Kenny , NeeDell James C. , Harder Anna Q. , Jia Fan , Vestal Brian , Blumhagen Rachel Z. , Tu Ting-Hui , McClendon Jazalle , McCubbrey Alexandra L. , Smith Bradford J. , Schwartz David A. , Janssen William J. , Evans Christopher M.
Published: October 2024

Injury to the lungs causes acute inflammation that can lead to pathological lung fibrosis. Airspace macrophages (AMs) are critical for repair of injured tissue, but they can contribute fibrosis through mechanisms that are incompletely understood. Siglecs are expressed by immune cells. In mice, Siglec-F is chiefly expressed AMs where it is considered inflammosuppressive. We hypothesized that its deletion would worsen lung injury and fibrosis in response to intratracheal bleomycin challenge. We evaluated Siglec-F expression and function in mice challenged with bleomycin on days 7, 14, and 21 post-challenge (2.5 U/kg). AMs were the predominant inflammatory cells at all timepoints, and they included resident (RAM) and recruited (RecAM) subsets. Siglec-F deficiency prevented fibrosis than in Siglecf−/− mouse lungs, as evident from biochemical and histologic readouts. We performed RNAseq on pooled RAMs and RecAMs from wild type and Siglec-F deficient mice. Lung fibrosis 21 d after bleomycin challenge was associated with differentially expressed genes (DEGs) related to cholesterol synthesis and metabolism. In AMs from healthy lung lavage fluid and idiopathic pulmonary fibrosis patient tissues, the human paralogs Siglec-7 and Siglec-9 were expressed. Findings here identify novel mechanisms that control protective and detrimental functions of AMs after lung injury.
Transport and InsP8 activation mechanisms of the human inorganic phosphate exporter XPR1
Authors: Zhu Qinyu , Yaggi Madeleine F. , Jork Nikolaus , Jessen Henning J. , Diver Melinda M.
Published: October 2024

Inorganic phosphate (Pi) has essential metabolic and structural roles in living organisms. The Pi exporter, XPR1/SLC53A1, is critical for maintaining cellular Pi homeostasis. When intercellular Pi is high, cells synthesize inositol pyrophosphate (1,5-InsP8) – a signaling molecule that is required for XPR1 function. Inactivating mutations of XPR1 lead to brain calcifications causing neurological symptoms that include migraine, movements disorders, psychosis, and dementia. Distinct cryo-electron microscopy structures of dimeric XPR1 and functional characterization define the substrate translocation pathway and delineate how binding of InsP8initiates the transport cycle. InsP8binding rigidifies the intracellular SPX domains with InsP8acting as a bridge between dimers and the SPX and transmembrane domains. When locked in this state, the C-terminal tail is sequestered revealing the entrance to the transport pathway, thus explaining the obligate roles of the SPX domain and InsP8. Together, these findings advance our understanding of XPR1 transport activity and expand opportunities for rationalizing disease mechanisms and therapeutic intervention.
Stretch-induced recruitment of myosin into transversal actin rings stabilizes axonal large cargo transport
Authors: Rahman Nizhum , Oelz Dietmar B.
Published: October 2024

We study the axonal transport of large cargo vesicles and its feedback with contractile transversal actomyosin rings in axons through modelling and simulation. To this end, we simulate a mathematical model that integrates forces generated by the molecular motors and forces exerted by transversal actin rings. Our results predict that cargo vesicles exhibit bidirectional movement along with pauses in agreement with observations. It has been observed that during predominantly retrograde axonal cargo transport, blebbistatin treatment prolongs the periods spent by the cargo in anterograde transport. Our simulations show that this can be explained by mechanotransductive stretch-induced recruitment of myosin motors into transversal actin rings. These findings offer valuable insights into the complex dynamics of axonal cargo transport and propose potential avenues for further experimental research.
Comprehensive sequencing of the lung neuroimmune landscape in response to asthmatic induction
Authors: McSwiggin Hayden , Wang Rui , Magalhães Rubens Daniel Miserani , Zhu Fengli , Doherty Taylor A. , Yan Wei , Jendzjowsky Nicholas
Published: October 2024

Evidence demonstrates that sensory neurons respond to pathogenic/allergic infiltration and mediate immune responses, forming an integral part of host defense that become hypersensitized during allergy. Our objective was to investigate how asthmatic induction alters the pulmonary neuroimmune transcriptome. We hypothesized that asthmatic induction would upregulate genes in the vagal ganglia (nodose/jugular ganglia), which would be associated with asthmatic immunity, and that these would be clustered, primarily in nodose neurons. Furthermore, lungs would increase transcripts associated with nerve activation, and these would be centered in neural and neuroendocrine-like cells. Bulk RNA-seq revealed that genes related to allergen sensing were increased in asthmatic ganglia nodose/jugular ganglia compared to control ganglia. These genes were associated with nodose clusters as shown by single-nucleus RNA sequencing, and a distinct caudal-to-rostral spatial arrangement was presented as delineated by spatial transcriptomics. The distinct clusters closely match previous identification of nodose neuron clusters. Correspondingly, the lung transcriptome was altered with asthmatic induction such that transcripts associated with neural excitation were upregulated. The spatial distribution of these transcripts was revealed by spatial transcriptomics to illustrate that these were expressed in neuroendocrine-like cells/club cells, and neurons. These results show that the neuroimmune transcriptome is altered in response to asthmatic induction in a cell cluster and spatially distinct manner.

Significance statement

This study provides a comprehensive transcriptomic map of the neuroimmune alterations in response to asthmatic induction.
Cross-species protection suggestsEntamoeba histolyticatrogocytosis enables complement resistance through the transfer of negative regulators of complement activation
Authors: Ruyechan Maura C. , Huang Wesley , Ralston Katherine S.
Published: October 2024

Entamoeba histolyticais a major cause of diarrheal disease.E. histolyticatrophozoites (“amoebae”) can invade the intestine and disseminate via the bloodstream, resisting complement lysis through unknown mechanisms. Amoebae kill human cells by performing trogocytosis. After performing trogocytosis, amoebae display human proteins on their own surface and are resistant to lysis by human serum. In this study we sought to further evaluate the mechanism by which amoebae resist complement. To test if complement is responsible for lysis of amoebae, C3-depleted serum was compared to replete serum, and C3 was required for lysis. Amoebae were allowed to perform trogocytosis of human cells and exposed to mouse serum. Although they had performed trogocytosis on a different species than the source of the serum, they were protected from lysis. To test if the protection from lysis by mouse serum was due to the functional interchangeability of human and mouse complement pathway proteins, human CD46 or CD55 (negative regulators of complement activation) were exogenously expressed. Amoebae that expressed human CD46 or CD55 were protected from lysis by mouse serum, indicating that display of human proteins was sufficient to inhibit mouse complement activation. Finally, amoebae were allowed to perform trogocytosis of a cell type in which the complement pathway is not conserved, and they did not become resistant to lysis. Overall, these findings are consistent with the model that trogocytosis enables amoebic acquisition and display of host proteins, including negative regulators of the complement pathway, that provide protection from complement lysis. Since other microbes can perform trogocytosis, this novel mechanism for complement resistance might apply to other infections.
Gut Bacteria Encode Reductases that Biotransform Steroid Hormones
Authors: Arp Gabriela , Jiang Angela , Dufault-Thompson Keith , Levy Sophia , Zhong Aoshu , Wassan Jyotsna Talreja , Grant Maggie , Li Yue , Hall Brantley , Jiang Xiaofang
Published: October 2024

The metabolism of steroids by the gut microbiome affects hormone homeostasis, impacting host development, mental health, and reproductive functions. In this study, we identify the Δ4-3-ketosteroid 5β-reductase, 3β-hydroxysteroid dehydrogenase/Δ5-4isomerase, and Δ6-3-ketosteroid reductase enzyme families encoded by common human gut bacteria. Through phylogenetic reconstruction and mutagenesis, We show that 5β-reductase and Δ6-3-ketosteroid reductase have evolved to specialize in converting diverse 3-keto steroid hormones into their 5β- and Δ6-reduced derivatives. We also find that the novel 3β-hydroxysteroid dehydrogenase/Δ5-4isomerase is fused with 5β-reductase in multiple species, streamlining the multi-step conversion of pregnenolone, a steroid hormone precursor, into epipregnanolone. Through metagenomic analysis, we reveal that these enzymes are prevalent in healthy populations, being enriched in females over males. These findings provide the molecular basis for studying microbial steroid metabolism in the gut, offering insights into its potential impact on hormonal health in hosts, especially in the context of women’s health.
Human and Mouse Models for Kabuki Syndrome Reveal Increase in Inhibitory Synapse Development
Authors: Knopp James , Weaver Alexander , Miller Sean , Nomura Toshihiro , Whitlark Ava , Swantkowski Jack , Noble Alexandra , Nam Sandy , Hutson Katharyn , Bergqvist-Patzke Jenny , Contractor Anis , Patzke Christopher
Published: October 2024

Intellectual disability, affecting 2-3% of the general population, often coincides with neurodevelopmental disorders and is frequently caused by mutations that impair synaptic function. Kabuki syndrome (KS), a rare multisystem disorder associated with developmental delay and intellectual disability, results from mutations in eitherKMT2D(KS type 1) orKDM6A(KS type 2), which encode a chromatin-modifying methyltransferase and demethylase, respectively. However, the mechanisms contributing to intellectual disability in KS remain poorly understood. Here, we generated human iPS cells carrying a conditional Cre/lox-dependentKMT2DorKDM6Aloss-of-function mutation, used for directed differentiation into inhibitory or excitatory neurons. Analysis of Cre-mediated induction of KS type 1 and KS type 2 in inhibitory neurons unexpectedly revealed an increase in GABAergic synapse development. Mutant excitatory neurons, however, displayed a reduction in synapse development and impaired information transfer within neural networks. We confirmed these findings in hippocampal neuronsin vitroandin vivousing a mouse model for KS type 1. Synapse numbers and synaptic transmission in acute brain slices were shifted to increased inhibition/excitation ratio. Thus, our results, using purely inhibitory or purely excitatory human neurons with conditional deletion ofKMT2DorKDM6A,and mouse withKmt2ddeletion, reveal a novel disease mechanism of KS and provide a mechanistic explanation for intellectual disability observed in individuals affected by KS highlighting imbalanced excitation to inhibition in neural circuits.