bluuebunny/crossref_metadata_2025 huggingface dataset:
Integration of parallel pathways for flight control in a hawkmoth reflects prevalence and relevance of natural visual cues
Authors: Bigge Ronja , Grittner Rebecca , Stöckl Anna
Published: August 2024

An animal’s behaviour is the result of multiple neural pathways acting in parallel, receiving information across and within sensory modalities at the same time. How these pathways are integrated, particularly when their individual outputs are in conflict, is key to understanding complex natural behaviours. We investigated this question in the visually guided flight of the hummingbird hawkmothMacroglossum stellatarum. These insects were recently shown to partition their visual field, using ventrolateral optic-flow cues to guide their flight like most insects, while the same stimuli in the dorsal visual field evoke a novel directional response. Using behavioural experiments which set the two pathways into conflict, we tested whether and how the ventrolateral and dorsal pathway integrate to guide hawkmoth flight. Combined with environmental imaging we demonstrate that the partitioning of the visual field followed the prevalence of visual cues in the hawkmoths’ natural habitats, while the integration hierarchy of the two pathways matched the relevance of these cues for the animals’ flight safety, rather than their magnitude in the experimental setup or in natural habitats. These results provide new mechanistic insights into the vision-based flight control of insects, and link these to their natural context. We anticipate our findings to be the starting point for comparative investigations into parallel pathways for flight guidance in insects from differently structured natural habitats.
Deep Brain Stimulation restores information processing in parkinsonian cortical networks
Authors: Piette Charlotte , Ng Wing Tin Sophie , De Liège Astrid , Bloch-Queyrat Coralie , Degos Bertrand , Venance Laurent , Touboul Jonathan
Published: August 2024

Parkinson’s disease (PD) is a neurodegenerative disorder associated with alterations of neural activity and information processing primarily in the basal ganglia and cerebral cortex. Deep brain stimulation (DBS) of the subthalamic nucleus (STN-DBS) is the most effective therapy when patients experience levodopa-induced motor complications. A growing body of evidence points towards a cortical effect of STN-DBS, restoring key electrophysiological markers, such as excessive beta band oscillations, commonly observed in PD. However, the mechanisms of STN-DBS remain elusive. Here, we aim to better characterize the cortical substrates underlying STN-DBS-induced improvement in motor symptoms. We recorded electroencephalograms (EEG) from PD patients and found that, although apparent EEG features were not different with or without therapy, EEG signals could more accurately predict limb movements under STN-DBS. To understand the origins of this enhanced information transmission under STN-DBS in the human EEG data, we investigated the information capacity and dynamics of a variety of computational models of cortical networks. The extent of improvement in decoding accuracy of complex naturalistic inputs under STN-DBS depended on the synaptic parameters of the network as well as its excitability and synchronization levels. Additionally, decoding accuracy could be optimized by adjusting STN-DBS parameters. Altogether, this work draws a comprehensive link between known alterations in cortical activity and the degradation of information processing capacity, as well as its restoration under DBS. These results also offer new perspectives for optimizing STN-DBS parameters based on clinically accessible measures of cortical information processing capacity.

Significance statement

Parkinson’s disease, a neurodegenerative disorder associated with a variety of motor symptoms, is due to the progressive degeneration of dopaminergic neurons. Neuronal networks in turn display abnormal activity associated with high excitability and abnormal synchronization. Treatments based on the electrical stimulations of deep brain nuclei (DBS) provide major symptomatic improvement, but their mechanisms of action remain unknown. Here, using mathematical models of the corticalcircuits involved, we show that DBS restores neuronal ability to encode and transmit information. We further show that movements from human patients can be better predicted from brain signals under treatment. These new theory and metrics open the way to personalized and adaptive DBS allowing to personalize stimulation patterns to each patient.
Trends and Influences in women authorship of randomized controlled trials in rheumatology: a comprehensive analysis of all published RCTs from 2009 to 2023
Authors: Lauper Kim , Buitrago-Garcia Diana , Courvoisier Delphine , Iudici Michele , Mongin Denis
Published: August 2024

Objectives

This study aims to examine the evolution and influencing factors of women’s authorship in randomized controlled trials (RCTs) published in rheumatology.

Methods

This study included all rheumatology RCTs published from 2009 to 2023. The gender of authors was determined using forenames and countries of affiliation via the gender API service. The percentage of women in RCT publications and its association with potential factors was assessed using generalized estimating equations, considering women gender as the main binary outcome and the RCT’s continent, international collaboration status, industrial funding, intervention type, sample size, journal adherence to ICMJE recommendations, impact factor, publication year, author’s non-academic affiliation, and author position as covariates.

Results

Among the 1,092 RCTs authored by 10,794 persons, women accounted for 34.1% of authors. Woman authorship was more frequent in African-based RCTs compared to North America, when the author had a non-academic affiliation and when the last author was a woman (1.83 [1.46, 2.29], +6.1 percentage points – pp). Woman authorship was less frequent in Asian and European-based RCTs, industry-funded RCTs (OR 0.64 [0.56-0.73]; -10.3pp). Women were less often in the last (0.63 [0.54-0.74]; -10.2 pp) and second to last author position (0.73 [0.62-0.85]; -7.3pp). There were no difference looking at international status or year of publication.

Conclusion

The overall presence of women authors was 34.1%. The stagnant year-over-year representation of women in RCTs, and the lower likelihood of a woman having a position as senior author, underscores the need for more effective strategies to bridge the gender gap. RCTs with a woman last author were more likely to have a woman first author, suggesting a potential role-model effect.
Survival Following Diagnosis of HIV-Associated Kaposi Sarcoma Among Adults in East Africa in the “Treat-All” Era
Authors: Byakwaga Helen , Semeere Aggrey , Laker-Oketta Miriam , Busakhala Naftali , Freeman Esther , Rotich Elyne , Wenger Megan , Kadama-Makanga Philippa , Kisuya Job , Semakadde Matthew , Mwine Bronia , Kasozi Charles , Mwebesa Bwana , Maurer Toby , Glidden David V. , Kaloustian Kara Wools- , Kambugu Andrew , Martin Jeffrey
Published: August 2024

Background

Despite widespread access to antiretroviral therapy (ART) in the “Treat All” era, HIV-associated Kaposi sarcoma (KS) remains among the most common malignancies in sub-Saharan Africa. Survival after KS diagnosis has historically been poor in Africa, but knowledge whether survival has changed at the population level in the contemporary era has been limited by lack of community-representative surveillance and monitoring systems.

Methods

We identified all adult persons living with HIV (PLWH) with a new diagnosis of KS made between 2016 and 2019 during outpatient or inpatient care at prototypical primary care-providing medical facilities in Kenya and Uganda using rapid case ascertainment. Participants were subsequently followed for vital status, including community tracking for those who became lost to follow-up.

Findings

Among 411 participants with newly diagnosed KS, 71% were men, median age was 34 (IQR: 30 to 41) years, and 91% had ACTG T1 tumor extent. Over a median follow-up of 7.8 (IQR: 2.4 to 17.9) months, cumulative incidence of death (95% CI) at months 6, 12 and 18 were 34% (30% to 39%), 41% (36% to 46%) and 45% (40% to 51%), respectively. Having the highest number of anatomic sites (11 to 16) harboring KS lesions (hazard ratio 2.2 (95% CI: 1.3-3.8) compared to 1 to 3 sites) and presence of oral KS lesions (hazard ratio 2.2 (95% CI: 1.4-3.3)) were independently associated with higher mortality. Lower hemoglobin and CD4 count as well as higher plasma HIV RNA were also associated with higher mortality.

Interpretation

Among PLWH with newly diagnosed KS in East Africa in the “Treat All” era, survival was poor and related to mucocutaneous extent of KS. The findings emphasize the need for better control of KS in Africa, including novel approaches for earlier detection, better linkage to oncologic care, and more potent therapy.
Multi-omics biomarker selection and outlier detection across WHO glioma classifications via robust sparse multinomial regression
Authors: Carrilho João F. , Coletti Roberta , Costa Bruno M. , Lopes Marta B.
Published: August 2024

Gliomas are aggressive brain tumors difficult to treat mostly due to their large molecular heterogeneity. This requires continuous improvement in the molecular characterization of the glioma types to identify potential therapeutic targets. Advances in glioma research are rapidly evolving, contributing to the updates of the WHO classification of tumors. Data analysis of multiple omics layers through classification and feature selection methods holds promise in identifying crucial molecular features for distinguishing between glioma types. We developed a robust and sparse classification workflow based on multinomial logistic regression to investigate the molecular landscape of gliomas. We considered transcriptomics and methylomics glioma profiles of patients labeled following the latest WHO glioma classification updates (2016 and 2021). Overall, our results show a notable improvement in glioma types separability for the 2021 WHO updated patient labels at both omics levels. Patients flagged as outliers for the 2016 WHO classification exhibited a molecular profile deviating from the one of the respective classes, which was more aligned with the current associated glioma type according to the 2021 WHO update. The methylomics profiles were particularly promising in the identification of outliers. These contributions will support further revisions of glioma molecular characterization and the development of novel targeted therapies.
Carotid plaques show more unstable characteristics between 2010-2021 after a prior decade of stabilization
Authors: Motsak Tetiana , Mol Barend M. , Hoekstra Joost K.R. , Pasterkamp Gerard , de Borst Gert J. , de Kleijn Dominique P.V.
Published: August 2024

Background

Previously we reported a time dependent change in atherosclerotic carotid plaque characteristics, with decreasing destabilising characteristics between 2002 -2011. This observation was considered confirmative with a parallel improved adherence to medication and decrease in overall cardiovascular mortality in Western Europe. In the present study, we investigated if these time dependent changes in plaque characteristics still occurred over the last decade.

Methods

Using the Athero Express biobank, atherosclerotic plaques of 1,277 consecutive carotid endarterectomy patients included between 2010 and 2021 were analysed to examine time dependent changes in histological plaque characteristics in intervals of 2 years. These results were compared with our previous time dependent plaque composition data between 2002-2011.

Results

In contrast to the period 2002-2011, the period 2010-2021 showed a significant increase in vulnerable plaque characteristics: large lipid cores, intraplaque hemorrhage, macrophages, and calcification. When adjusted for confounders related to these plaque characteristics, such as time to operation and pre-operative type of symptoms, the adjusted odds ratios per 2 years increase in time were 1,177 (95% confidence interval, 1,070-1,293; p<0,001) for calcification, 1,352 (95% confidence interval, 1,229-1,487; p<0,000) for intraplaque hemorrhage, 1,277 (95% confidence interval, 1,159-1,407; p<0,001) for plaques consisting of >40% of fat and 1,388 (95% confidence interval, 1,262-1,528; p<0,001) for macrophages. Use of statins increased in both the 2002-2011 and 2010-2021 period.

Conclusion

Our study did not support a further increase in plaque stabilizing features in carotid atherosclerotic plaques between 2010-2021. In contrast, plaques even showed features of destabilisation in the present cohort.
Practitioner, patient and public views on the acceptability of Mobile Stroke Units in England and Wales: a mixed methods study
Authors: Moseley L. , McMeekin P. , Price C. , Shaw L. , Allen M. , Ford G.A. , James M. , Laws A. , McCarthy S. , McClelland G , Park L.J. , Pearn K. , Phillips D. , White P. , Wilson D. , Scott J.
Published: August 2024

Background

Evidence for Mobile Stroke Units (MSUs) demonstrates that onset to treatment times for intravenous thrombolysis can be reduced and access to mechanical thrombectomy might be improved. Despite growing use of MSUs internationally, to date there have been no studies in NHS England and NHS Wales exploring the acceptability of MSUs to clinicians, patient and public representatives and other key stakeholders, which are important when considering potential feasibility and implementation.

Methods

This study used a mixed methods design with a cross-sectional survey and qualitative workshops and interviews between October 2023 to May 2024. Survey data were collected from clinicians involved in emergency stroke care. Qualitative data involved clinical and non-clinical professionals involved in stroke care alongside patient and public representatives with experience of stroke. Survey data were descriptively analysed while content analysis was used on open-ended questions. Qualitative data were thematically analysed, prior to triangulation using a convergent coding matrix.

Results

The study results, drawn from 25 respondents to the survey and 21 participants in qualitative workshops, found that almost all participants had positive affective attitudes to the concept of MSUs. However, several key areas of concern were identified that need to be addressed prior to implementing MSUs. These concerns included how MSUs would be staffed; whether and how telemedicine could contribute; the types of economic impacts; extent to which triage systems could accurately identify stroke patients for MSUs to attend; where the base location and geographic coverage of MSUs should be, the impact of MSUs on equitable access to stroke care, and how to improve public awareness of MSUs.

Conclusion

Whilst MSUs are mostly acceptable to key stakeholders, numerous areas of concern need to be addressed prior to MSU implementation. We recommend further research to address these issues prior to implementation in the NHS.
Data-guided direct reprogramming of human fibroblasts into the hematopoietic lineage
Authors: Stansbury Cooper , Cwycyshyn Jillian , Pickard Joshua , Meixner Walter , Rajapakse Indika , Muir Lindsey A.
Published: August 2024

Direct reprogramming of human fibroblasts into hematopoietic stem cells (HSCs) shows promise for generating autologous cells for treatment of blood and immune-related diseases. However, low conversion efficiency of existing protocols points to gaps in our understanding and opportunities for identification of optimal transcription factor (TF) combinations, which is a major bottleneck for HSC generation. In this study, we tested a novel algorithmically-predicted TF recipe (GATA2, GFIB1, FOS, REL, and STAT5A) for inducing HSC-like states. Our recipe induced CD34+surface expression and single-cell transcriptomic signatures similar to those of native HSCs. Transcriptional heterogeneity within reprogrammed cells included differences in expression of HSC and endothelial-associated genes and in alternatively spliced transcripts as measured by single-cell long- read RNA-sequencing. Further, we proposed an approach to quantify the relative position of reprogrammed cells within the spectrum of initial and target cell states. This study lays the foundation for efficient optimization of direct reprogramming protocols.
Phospho-proteomics identifies D-group MAP kinases as substrates of the Arabidopsis tyrosine phosphatase RLPH2
Authors: Labandera Anne-Marie , Toth Ryan , Mitchell Sierra , Johnson Jayde J , Puyaubert Juliette , Baudouin Emmanuel , Uhrig R. Glen , Moorhead Greg B
Published: August 2024

Despite being one of the few bona fide plant tyrosine phosphatases, RLPH2 has no known substrates. Utilizing phospho-proteomics, we identified the activation loop phospho-tyrosine of several D-group mitogen activated protein kinases (MPKs) as potential RLPH2 substrates. All Arabidopsis D-Group MPKs possess a TDY activation loop phosphorylation motif, whereas other MPKs (Groups A, B and C) contain a TEY motif. Our findings reveal that RLPH2 has a strong preference for aspartate (D) in the TXY motif, providing specificity for RLPH2 to exclusively target and dephosphorylate the D-Group MPKs. Additionally, D-Group MPKs contain a unique activation loop insertion that conforms to a protein phosphatase 1 (PP1) binding motif, with findings presented here confirming Arabidopsis PP1 phosphatases dock at this site. Intriguingly, only D-group MPKs among all identified Arabidopsis protein kinases possess this PP1 recruiting motif. Using multiple RLPH2 deficient plant lines, we demonstrate that RLPH2 represses seed dormancy release. Overall, this work highlights the power of phospho-proteomics in identifying substrates of this novel plant tyrosine phosphatase, while also revealing new complexities in the interactions between MPK activation loops and multiple phospho-mediated cell signaling events.

One sentence summary

Phospho-proteomic analysis revealsArabidopsistyrosine phosphatase RLPH2 dephosphorylates the activation loop of D-Group mitogen activated protein kinases.
Environmental DNA Transport at an Offshore Mesophotic Bank in the Northwestern Gulf of Mexico
Authors: McCartin Luke J , Govindarajan Annette F , McDermott Jill M , Herrera Santiago
Published: August 2024

Accurately constraining the transport of environmental DNA (eDNA) after it is shed from an animal is vital to appropriately geolocate species detections and biodiversity measurements from eDNA sequencing data. Modeling studies predict the horizontal transport of eDNA at concentrations detectable using quantitative PCR over scales of tens of kilometers, but more limited vertical transport. Field studies routinely find that eDNA metabarcoding data distinguishes biological communities at small spatial scales, over scales of tens of meters. Here, we leverage the unique bathymetry of an offshore, mesophotic bank and the benthic invertebrate community that it supports to determine the extent to which vertical and horizontal eDNA transport may affect the interpretation of species detections from eDNA metabarcoding data. We found that in a stratified water column, eDNA from benthic invertebrates was vertically constrained to depths close to the seafloor in the thermocline versus in the surface mixed layer above. However, when using primers that are taxonomically specific to corals, we found evidence for the horizontal transport of coral eDNA at distances at least ~1.5 km from where they can be reasonably expected to occur. On the contrary, there was minimal evidence for horizontal transport of benthic eDNA in data generated using primers that broadly targeted sequences from eukaryotes. These results highlight the importance of horizontal transport as well as considering methodological details, like the taxonomic specificity of PCR primers, when interpreting eDNA sequencing data.
IMMUNE AND MOLECULAR CORRELATES OF RESPONSE TO IMMUNOTHERAPY REVEALED BY BRAIN-METASTATIC MELANOMA MODELS
Authors: Daugherty-Lopès Amélie , Pérez-Guijarro Eva , Gopalan Vishaka , Rappaport Jessica , Chen Quanyi , Huang April , Lam Khiem C. , Chin Sung , Ebersole Jessica , Wu Emily , Needle Gabriel A. , Church Isabella , Kyriakopoulos George , Xie Shaojun , Zhao Yongmei , Gruen Charli , Sassano Antonella , Araya Romina E. , Thorkelsson Andres , Smith Cari , Lee Maxwell P. , Hannenhalli Sridhar , Day Chi-Ping , Merlino Glenn , Goldszmid Romina S.
Published: August 2024

Despite the promising results of immune checkpoint blockade (ICB) therapy, outcomes for patients with brain metastasis (BrM) remain poor. Identifying resistance mechanisms has been hindered by limited access to patient samples and relevant preclinical models. Here, we developed two mouse melanoma BrM models that recapitulate the disparate responses to ICB seen in patients. We demonstrate that these models capture the cellular and molecular complexity of human disease and reveal key factors shaping the tumor microenvironment and influencing ICB response. BR1-responsive tumor cells express inflammatory programs that polarize microglia into reactive states, eliciting robust T cell recruitment. In contrast, BR3-resistant melanoma cells are enriched in neurological programs and exploit tolerance mechanisms to maintain microglia homeostasis and limit T cell infiltration. In humans, BR1 and BR3 expression signatures correlate positively or negatively with T cell infiltration and BrM patient outcomes, respectively. Our study provides clinically relevant models and uncovers mechanistic insights into BrM ICB responses, offering potential biomarkers and therapeutic targets to improve therapy efficacy.
Non-guided, Mobile, CBT-I-based Sleep Training in War-torn Ukraine: A Feasibility Study
Authors: Kurapov Anton , Blechert Jens , Hinterberger Alexandra , Topalidis Pavlos , Schabus Manuel
Published: August 2024

Objectives

To study whether a mobile, unguided Cognitive Behavior Therapy-based Intervention for Sleep Disturbance, Sleep2is feasible, acceptable, and reduces mental health/sleep disturbance symptoms among the Ukrainian population during the ongoing war.

Methods

A single-arm, open-label, uncontrolled pre-post evaluation study was conducted with 487 registered participants: 283 started, out of which 95 completed without an ambulatory heart rate (HR) sensor and 65 with. Assessments were conducted using online questionnaires and continuous objective measurements via HR sensors. Key outcome measures included sleep disturbance, insomnia, fear of sleep, anxiety, depression, PTSD, perceived stress, and somatic symptoms.

Results

Engagement with the program was robust, achieving an 80.72% compliance rate, alongside high levels of feasibility and acceptance. Participants reported significant pre- post reductions in the severity of sleep disturbance (by 22.60%), insomnia (by 35.08%), fear of sleep (by 32.43%), anxiety (by 27.72%), depression (by 28.67%), PTSD (by 32.41%), somatic symptoms (by 24.52%), and perceived stress (by 17.90%), all with medium to high effect sizes. Objective sleep measurements showed a slight reduction in sleep onset latency.

Conclusion

The ‘Sleep2Ukraine’ program demonstrated high feasibility and acceptance, with significant improvements in subjective sleep and mental health measures among participants. These findings demonstrate the potential of scalable mobile-based CBT-I interventions in war-torn regions with or without the instrument, based on the heart rate assessment.
Genetic modifiers and ascertainment drive variable expressivity of complex disorders
Authors: Jensen Matthew , Smolen Corrine , Tyryshkina Anastasia , Pizzo Lucilla , Banerjee Deepro , Oetjens Matthew , Shimelis Hermela , Taylor Cora M. , Pounraja Vijay Kumar , Song Hyebin , Rohan Laura , Huber Emily , El Khattabi Laila , van de Laar Ingrid , Tadros Rafik , Bezzina Connie , van Slegtenhorst Marjon , Kammeraad Janneke , Prontera Paolo , Caberg Jean-Hubert , Fraser Harry , Banka Siddhartha , Van Dijck Anke , Schwartz Charles , Voorhoeve Els , Callier Patrick , Mosca-Boidron Anne-Laure , Marle Nathalie , Lefebvre Mathilde , Pope Kate , Snell Penny , Boys Amber , Lockhart Paul J. , Ashfaq Myla , McCready Elizabeth , Nowacyzk Margaret , Castiglia Lucia , Galesi Ornella , Avola Emanuela , Mattina Teresa , Fichera Marco , Bruccheri Maria Grazia , Mandarà Giuseppa Maria Luana , Mari Francesca , Privitera Flavia , Longo Ilaria , Curró Aurora , Renieri Alessandra , Keren Boris , Charles Perrine , Cuinat Silvestre , Nizon Mathilde , Pichon Olivier , Bénéteau Claire , Stoeva Radka , Martin-Coignard Dominique , Blesson Sophia , Le Caignec Cedric , Mercier Sandra , Vincent Marie , Martin Christa , Mannik Katrin , Reymond Alexandre , Faivre Laurence , Sistermans Erik , Kooy R. Frank , Amor David J. , Romano Corrado , Andrieux Joris , Girirajan Santhosh
Published: August 2024

Variable expressivity of disease-associated variants implies a role for secondary variants that modify clinical features. We assessed the effects of modifier variants towards clinical outcomes of 2,252 individuals with primary variants. Among 132 families with the 16p12.1 deletion, distinct rare and common variant classes conferred risk for specific developmental features, including short tandem repeats for neurological defects and SNVs for microcephaly, while additional disease-associated variants conferred multiple genetic diagnoses. Within disease and population cohorts of 773 individuals with the 16p12.1 deletion, we found opposing effects of secondary variants towards clinical features across ascertainments. Additional analysis of 1,479 probands with other primary variants, such as 16p11.2 deletion andCHD8variants, and 1,084 without primary variants, showed that phenotypic associations differed by primary variant context and were influenced by synergistic interactions between primary and secondary variants. Our study provides a paradigm to dissect the genomic architecture of complex disorders towards personalized treatment.
Load and muscle dependent changes in triceps surae motor unit firing properties and motor unit firing-torque relationships in individuals with non-insertional Achilles tendinopathy
Authors: Contreras-Hernandez Ignacio , Falla Deborah , Arvanitidis Michail , Negro Francesco , Jimenez-Grande David , Martinez-Valdes Eduardo
Published: August 2024

Non-insertional Achilles tendinopathy (NIAT) induces morpho-mechanical changes to the Achilles tendon (AT). However, evidence on how triceps surae motor unit firing properties are influenced by altered tendon mechanics in NIAT is limited. This study investigated motor unit firing properties (mean discharge rate (DR), recruitment and de-recruitment thresholds, and discharge rate variability (COVisi)), motor unit firing-torque relationships (cross-correlation coefficient between cumulative spike train (CST) and torque, and neuromechanical delay), and neural drive distribution (connectivity strength and functional networks) of the medial gastrocnemius (MG), lateral gastrocnemius (LG), and soleus (SO) muscles during isometric plantarflexion contractions at 10%, 40%, and 70% maximal voluntary contraction (MVC) using high-density surface electromyography on 26 individuals with NIAT and 25 healthy controls. Furthermore, AT’s morpho-mechanical properties (thickness, cross-sectional area, length and stiffness) were assessed via ultrasound imaging. NIAT individuals showed reduced tendon stiffness and increased thickness (p<0.01). Motor unit properties changed in a load and muscle-dependent manner. LG DR increased (p=0.002) and de-recruitment threshold decreased (p=0.039) at 70%MVC in the NIAT group compared to controls. The CST-torque cross-correlation coefficient of the LG decreased at 10%MVC (p<0.0001) and increased at 70%MVC (p=0.013) in the NIAT group. Connectivity strength for the 0-5 Hz and 5-15 Hz frequency bands decreased (p<0.01) in the NIAT group at 10%MVC. This study shows that individuals with NIAT exhibit load-dependent changes in motor unit firing properties, motor unit-torque relationships, and neural drive distribution to the triceps surae. These alterations may be due to muscle-specific compensations for the modified mechanical properties of the AT.

KEY POINTS

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Individuals with non-insertional Achilles tendinopathy (NIAT) have changes of the neural drive to the lateral gastrocnemius (LG) muscle and altered contribution of the LG to the net plantarflexion torque.

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Individuals with NIAT show a more uneven distribution of neural drive to the triceps surae muscle at low force levels, characterized by reduced intermuscular coherence between the medial and lateral gastrocnemius in the 0-5 Hz and 5-15 Hz bands compared to the control group.

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Our findings support the idea that the LG may have a central role in the pathophysiology of this condition, possibly affecting the load transmission to the Achilles tendon (AT).
Association between choroidal microvasculature in the eye and Alzheimer’s disease risk in cognitively healthy midlife adults: a pilot study
Authors: Burke Jamie , Gibbon Samuel , Low Audrey , Hamid Charlene , Reid-Schachter Megan , Muniz-Terrera Graciela , Ritchie Craig W , Dhillon Baljean , O’Brien John T , King Stuart , MacCormick Ian JC , MacGillivray Thomas J
Published: August 2024

INTRODUCTION

We explored associations between measurements of the ocular choroid microvasculature and Alzheimer’s disease risk.

METHODS

We measured the choroidal vasculature appearing in optical coherence tomography scans of 69 healthy, mid-life individuals in the PREVENT Dementia cohort. The cohort was prospectively split into low, medium, and high-risk groups based on the presence of known risk factors (APOE4 genotype and family history of dementia). We used ordinal logistic regression to test for cross-sectional associations between choroidal measurements and Alzheimer’s disease risk.

RESULTS

Choroidal vasculature was progressively larger between ordinal risk groups, and significantly associated with risk group prediction. APOE4 carriers had thicker choroids and larger vascularity compared to non-carriers. Similar trends were observed for those with a family history of dementia.

DISCUSSIONS

Our results suggest a potential link between the choroidal vasculature and Alzheimer’s disease risk. However, these exploratory findings should be replicated in a larger sample.
Overlap between ultra-processed food and food that is high in fat, salt or sugar: analysis of 11 annual waves of the UK National Diet and Nutrition Survey 2008/09-2018/19
Authors: Kesaite Viktorija , Chavez-Ugalde Yanaina , White Martin , Adams Jean
Published: August 2024

While many countries use guidance and policies based on nutrients and food groups to support citizens to consume healthy diets, fewer have explicitly adopted the concept of ultra-processed foods (UPF). UPF consumption is associated with many adverse health outcomes in cohort studies. In the UK, a nutrient profiling model (NPM) is used to identify foods high in fat, salt or sugar (HFSS) and several policies target these. It is not known how well the NPM also captures UPF. We aimed to quantify the proportion of food and drink items consumed in the UK that are HFSS, UPF, both or neither and describe the food groups making the largest contributions to each category. We analysed data from the National Diet and Nutrition Survey (NDNS), between 2008/09 and 2018/19, using descriptive statistics. We used three metrics of food consumption: all foods, % of energy in all foods (reflecting that different foods are consumed in different portion sizes and are of different energy densities), and % of food weight in all foods (reflecting that some UPFs have few calories but are consumed in large volumes). We found that, 33.4% of foods, 47.4% of energy, and 16.0% of food weight were HFSS; 36.2%, 59.8% and 32.9% respectively were UPFs; 20.1%, 35.1% and 12.6% were both; and 50.5%, 27.9% and 63.7% were neither. In total, 55.6% of UPF foods, 58.7% of energy from UPFs and 38.3% of food weight from UPF consumed were also HFSS. The most common food groups contributing to foods that were UPF but not HFSS were low calorie soft drinks and white bread. The UK NPM captures at best just over half of UPFs consumed in the UK. Expanding the NPM to include ingredients common in UPFs would capture a larger percentage of UPFs and could incentivise de-formulation of UPF products.
Loss to follow-up of ambulatory patients in the transition to telemedicine in the COVID-19 pandemic at a reference center for mental health in Lima, Peru
Authors: Ruiz-Grosso Paulo , Sagastegui Abel , Zevallos-Bustamante Sonia
Published: August 2024

Problem Statement

During the COVID-19 pandemic, health care services were limited by the restrictive measures implemented. As an adaptation mechanism, telemedicine was introduced for ambulatory care at the Honorio Delgado Hideyo Noguchi National Institute of Mental Health (NIMH). This study aimed to estimate the survival function (SF) for loss to follow-up (LTFU) over two years before and after the onset of the COVID-19 pandemic, and its association with clinical and sociodemographic variables.

Study Design

A single-cohort study was conducted, following a random sample of adult ambulatory patients at NIHM from April 15, 2018, to April 15, 2022. Patients were followed until LTFU, referral to another institution, death, or the end of study. The main analysis involved estimating the SF for LTFU for the overall follow up period, as well as separately for the periods pre and post implementation of telemedicine. Also, risk factors hypotheses were tested using Cox’s regression.

Results

Data from 4887 visits of 356 patients were collected. A total of 118 (33.1%) presented LTFU, with SF of 53.9% during the overall four years of follow-up. After two years of follow-, those starting treatment at NIMH before the implementation of telemedicine had a higher SF (77.3 vs 63%). A higher hazard ratio (HR) for LTFU was found in the group that started care at NIMH after the implementation of telemedicine, compared to those who started previously (HR=2.53; 95% CI: 1.55-4.51). Additionally, receiving care in the anxiety disorders (HR=1.86; 95% CI: 1.03-3.33) and personality disorders programs (HR=1.81; 95% CI: 1.02-3.22) was associated with a higher risk of LTFU compared to the psychosis program. No significant difference was found in the risk of LTFU between telemedicine vs. face-to face attention.

Conclusions

A significant association was found between LTFU and starting treatment at NIMH after the onset of the COVID-19 pandemic and implementation of telemedicine. However, no evidence supports that this might be due to the practice of telemedicine. A different clinical profile of patients that started treatment at NIMH following the government implementation of changes to the public health system might explain these findings and should be studied.

Significant Outcomes

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A moderate association was found between starting treatment at NIMH and loss to follow up in the period after the implementation of telemedicine due to the onset of COVID-19.

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This, however, does not seem to be related to the practice of telemedicine, but to changes in the characteristics of patients across pre and post COVID 19.

Limitations

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The reason for loss to follow up (death, return to a lower-level health service, improvement of symptoms, etc.), our main outcome variable, could not be determined using the clinical and administrative data available.
A fluorescent probe enables the discovery of improved antagonists targeting the intracellular allosteric site of the chemokine receptor CCR7
Authors: Wurnig Silas L. , Huber Max E. , Weiler Corinna , Baltrukevich Hanna , Merten Nicole , Stötzel Isabel , Chang Yinshui , Klammer René H. L. , Baumjohann Dirk , Kiermaier Eva , Kolb Peter , Kostenis Evi , Schiedel Matthias , Hansen Finn K.
Published: August 2024

Intracellularly acting ligands of G protein-coupled receptors (GPCRs) are gaining significant interest in GPCR drug discovery. In this study, we report the development of the fluorescent ligand Mz437 (4) targeting the CC chemokine receptor CCR7 at an intracellular allosteric site. We demonstrate its experimental power by applying4to identify two improved intracellular CCR7 antagonists, SLW131 (10) and SLW132 (21m), developed by converting two weakly active antagonists into single- or double-digit nanomolar ligands with minimal modifications. The thiadiazoledioxide10was derived from the CCR7 antagonist Cmp2105 by removing a methyl group from the benzamide moiety, while the squaramide21mwas obtained from the CXCR1/CXCR2 antagonist and clinical candidate navarixin by replacing the ethyl substituent by atert-butyl group to engage a lipophilic subpocket. We show that10and21mqualify to probe CCR7 biology both in recombinant cells and in the endogenous signaling environment of immune cells. Our novel probes are expected to facilitate the design of next-generation intracellular CCR7 ligands and serve as molecular tools to interrogate CCR7 biology in human and murine endogenous settings.

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A robust evaluation of TDP-43, poly GP, cellular pathology and behavior in a AAV-C9ORF72 (G4C2)66mouse model
Authors: Thompson Emily G. , Spead Olivia , Akerman S. Can , Curcio Carrie , Zaepfel Benjamin L. , Kent Erica R. , Philips Thomas , Vijayakumar Balaji G. , Zacco Anna , Zhou Weibo , Nagappan Guhan , Rothstein Jeffrey D.
Published: August 2024

The G4C2hexanucleotide repeat expansion inC9ORF72is the major genetic cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (C9-ALS/FTD). Despite considerable efforts, the development of mouse models of C9-ALS/FTD useful for therapeutic development has proven challenging due to the intricate interplay of genetic and molecular factors underlying this neurodegenerative disorder, in addition to species differences. This study presents a robust investigation of the cellular pathophysiology and behavioral outcomes in a previously described AAV mouse model of C9-ALS expressing 66 G4C2hexanucleotide repeats. Despite displaying key molecular ALS pathological markers including RNA foci, dipeptide repeat (DPR) protein aggregation, p62 positive stress granule formation as well as mild gliosis, the AAV-(G4C2)66mouse model in this study exhibits negligible neuronal loss, no motor deficits, and functionally unimpaired TAR DNA-binding protein-43 (TDP-43). While our findings indicate and support that this is a robust and pharmacologically tractable model for investigating the molecular mechanisms and cellular consequences of (G4C2) repeat driven DPR pathology, it is not suitable for investigating the development of disease associated neurodegeneration, TDP-43 dysfunction, gliosis, and motor performance. Our findings underscore the complexity of ALS pathogenesis involving genetic mutations and protein dysregulation and highlight the need for more comprehensive model systems that reliably replicate the multifaceted cellular and behavioral aspects of C9-ALS.
BICC1 Interacts with PKD1 and PKD2 to Drive Cystogenesis in ADPKD
Authors: Tran Uyen , Streets Andrew J , Smith Devon , Decker Eva , Kirschfink Annemarie , Izem Lahoucine , Hassey Jessie M. , Rutland Briana , Valluru Manoj K , Bräsen Jan Hinrich , Ott Elisabeth , Epting Daniel , Eisenberger Tobias , Ong Albert CM , Bergmann Carsten , Wessely Oliver
Published: August 2024

Background

Autosomal dominant polycystic kidney disease (ADPKD) is primarily of adult-onset and caused by pathogenic variants inPKD1orPKD2. Yet, disease expression is highly variable and includes very early-onset PKD presentationsin uteroor infancy. In animal models, the RNA-binding molecule Bicc1 has been shown to play a crucial role in the pathogenesis of PKD.

Methods

To study the interaction betweenBICC1, PKD1 and PKD2we combined biochemical approaches, knockout studies in mice andXenopus,genetic engineered human kidney cells as well as genetic association studies in a large ADPKD cohort.

Results

We first demonstrated that BICC1 physically binds to the proteins Polycystin-1 and -2 encoded byPKD1andPKD2via distinct protein domains. Furthermore, PKD was aggravated in loss-of-function studies inXenopusand mouse models resulting in more severe disease whenBicc1was depleted in conjunction withPkd1 or Pkd2. Finally, in a large human patient cohort, we identified a sibling pair with a homozygousBICC1variant and patients with very early onset PKD (VEO-PKD) that exhibited compound heterozygosity ofBICC1in conjunctionwith PKD1 and PKD2variants. Genome editing demonstrated that theseBICC1variants were hypomorphic in nature and impacted disease-relevant signaling pathways.

Conclusions

These findings support the hypothesis thatBICC1cooperates functionally withPKD1 and PKD2, and thatBICC1variants may aggravate disease severity highlighting RNA metabolism as an important new concept for disease modification in ADPKD.
Effects Of Aryl Hydrocarbon Receptor Ligand TCDD On Human Trophoblast Cell Development
Authors: Shukla Vinay , Iqbal Khursheed , Okae Hiroaki , Arima Takahiro , Soares Michael J.
Published: August 2024

STUDY QUESTION How does activation of AHR signaling affect human trophoblast cell development and differentiation? SUMMARY ANSWER AHR activation leads to altered gene expression but does not hinder the ability of trophoblast cells to remain in a stem cell state or differentiate into essential cell types, such as extravillous trophoblast cells (EVT) or syncytiotrophoblast (ST). It also promotes the production of 2 methoxy estradiol (2ME), a compound that could influence placental development. WHAT IS KNOWN ALREADY The placenta serves both as a nutrient delivery system and a protective barrier against environmental toxins. AHR signaling is known to mediate cellular responses to environmental pollutants, potentially affecting trophoblast cell functions, but the specific impacts of AHR activation on these cells were not fully understood. STUDY DESIGN, SIZE, DURATION This study utilized an in vitro model of human trophoblast stem (TS) cells to investigate the downstream effects of AHR activation. The study focused on both undifferentiated TS cells and cells undergoing differentiation. PARTICIPANTS/MATERIALS, SETTING, METHODS Human trophoblast stem (TS) cells were used as the model system. Researchers examined the effects of TCDD exposure in both TS cells maintained in their stem state and those induced to differentiate into EVT or ST. The study assessed changes in gene expression, particularly focusing on CYP1A1 and CYP1B1, as well as the production of 2ME. MAIN RESULTS AND THE ROLE OF CHANCE AHR activation stimulated the expression of CYP1A1 and CYP1B1, key genes associated with AHR signaling, in both undifferentiated and differentiating trophoblast cells. While AHR activation did not impact the cells ability to remain in a stem state or differentiate, it increased the production of 2ME, which may influence placental function. These effects were dependent on AHR signaling. LIMITATIONS, REASONS FOR CAUTION This study was conducted in vitro, which may not fully replicate human conditions. Further research is needed to confirm whether these findings apply to actual placental development in humans. WIDER IMPLICATIONS OF THE FINDINGS The results suggest that AHR signaling activated by environmental pollutants could have a subtle but significant impact on placental development through mechanisms involving AHR activation. These findings may have broader implications for understanding how environmental factors affect fetal development. STUDY FUNDING/COMPETING INTEREST(S) This work was funded by the National Institutes of Health: ES028957, HD020676, ES029280, HD105734 and the Sosland Foundation. The authors declare no conflicts of interest.
Genomes of nitrogen-fixing eukaryotes reveal a non-canonical model of organellogenesis
Authors: Frail Sarah , Steele-Ogus Melissa , Doenier Jon , Moulin Solène L.Y. , Braukmann Tom , Xu Shouling , Yeh Ellen
Published: August 2024

Endosymbiotic gene transfer and import of host-encoded proteins are considered hallmarks of organelles necessary for stable integration of two cells. However, newer endosymbiotic models have challenged the origin and timing of such genetic integration during organellogenesis. Epithemia diatoms contain diazoplasts, obligate endosymbionts that are closely related to recently-described nitrogen-fixing organelles and share similar function as integral cell compartments. We report genomic analyses of two species which are highly divergent but share a common ancestor at the origin of the endosymbiosis. We found minimal evidence of genetic integration in E.clementina: nonfunctional diazoplast-to-nucleus DNA transfers and 6 host-encoded proteins of unknown function in the diazoplast proteome, far fewer than detected in other recently-acquired endosymbionts designated organelles. Epithemia diazoplasts are a valuable counterpoint to existing organellogenesis models, demonstrating that endosymbionts can function as integral compartments absent significant genetic integration. The minimal genetic integration makes diazoplasts valuable blueprints for bioengineering endosymbiotic compartments de novo.
Loss of the tumor suppressor NUMB drives aggressive bladder cancer through hyperactivation of a RhoA/ROCK/YAP signaling circuitry
Authors: Tucci F. A. , Pennisi R. , Rigiracciolo D. C. , Filippone M. G. , Bonfanti R. , Romeo F. , Freddi S. , Soriani C. , Rodighiero S. , Jodice G. , Sanguedolce F. , Renne G. , Fusco N. , Di Fiore P.P. , Pruneri G. , Musi G. , Vago G. , Tosoni D. , Pece S.
Published: August 2024

Bladder cancer (BCa) is one of the most challenging and costly cancers to treat, yet little progress has been made on the development of predictive biomarkers and targeted therapies. Here, we uncover a critical function of Numb as a tumor suppressor in the bladder, identifying loss of Numb expression as a causal alteration in BCa that underlies biological aggressiveness and disease progression. Through retrospective cohort studies, we established that a Numb-deficient tumor status correlates with worse overall survival in post-cystectomy muscle-invasive bladder cancer (MIBC) patients and increased risk of MIBC progression in non-muscle-invasive bladder cancer (NMIBC) patients. The prognostic value of Numb loss can be attributed to its crucial role as a determinant of aggressive bladder tumorigenesis, as demonstrated in mouse and human models. TargetedNumbablation in the basal layer of the urothelium was alone sufficient to trigger spontaneous bladder tumorigenesis and drive progression from preneoplastic to preinvasive and, ultimately, overtly invasive tumors. Additionally,Numbablation sensitized the urothelium to other oncogenic insults, accelerating tumor onset and progression. Using 3D-Matrigel organoid cultures to recapitulate bladder tumorigenesisin vitro, we found that Numb loss heightens the proliferative and invasive potential of both mouse and human BCa cells. Integrative transcriptomic and functional analyses revealed that downregulation of the canonical Hippo pathway, resulting in enhanced YAP transcriptional activity, underlies the biological aggressiveness of Numb-deficient BCa. These molecular events are dependent on the activation of RhoA/ROCK signaling subsequent to Numb loss. Thus, a dysfunctional Numb–RhoA/ROCK–Hippo/YAP regulatory network is at play in aggressive Numb-deficient BCa and represents a therapeutic vulnerability. A 27-gene prognostic signature capable of identifying high-risk Numb-deficient patients could provide the basis of a clinical tool to stratify patients for innovative RhoA/ROCK/YAP targeted therapies.

One Sentence Summary

Numb loss-directed hyperactivation of RhoA/ROCK/YAP underlies aggressive bladder cancer biology.