bluuebunny/crossref_metadata_2025 huggingface dataset:
JAK inhibitors in difficult-to-treat adult-onset Still’s disease and systemic-onset juvenile idiopathic arthritis
Authors: Gillard Louise , Pouchot Jacques , Cohen-Aubart Fleur , Koné-Paut Isabelle , Mouterde Gaël , Michaud Martin , Reumaux Héloïse , Savey Léa , Belot Alexandre , Fautrel Bruno , Mitrovic Stéphane
Published: August 2022

Objectives

Excessive and inappropriate production of pro-inflammatory cytokines plays a key role in Still’s disease. Janus kinase inhibitor (JAKi) agents mainly block pro-inflammatory cytokine pathways, notably IL-6 and IFN. The objective was to assess the efficacy and safety of JAKi agents in difficult-to-treat systemic JIA or adult-onset Still’s disease (AOSD).

Methods

This retrospective study was based on a national survey conducted in the departments of rheumatology, paediatric rheumatology and internal medicine of French hospitals regarding systemic JIA and AOSD patients who received JAKi agents. The data were collected with a standardized questionnaire and analysed at different times (treatment initiation, months 1, 3 and 6 and the end of follow-up).

Results

Nine patients (seven adults) were included. All patients showed inadequate response to CS or conventional synthetic or biologic DMARDs. Baricitinib was used in five patients, ruxolitinib in two, tofacitinib in two and upadacitinib in one. A JAKi was used combined with CS in all but two patients. A JAKi was associated with anakinra and CS in one patient, and with MTX, anakinra and CS in another. The median (range) follow-up was 16 (1–33) months. Two cases out of nine showed complete remission, 3/9 partial response and 4/9 treatment failure. At the last visit, CS could be decreased but not stopped. Tolerance of the JAKi was acceptable (no severe adverse events).

Conclusion

JAKi agents may be a therapeutic option for some patients with difficult-to-treat Still’s disease, especially those with partial response to medium- or high-dose CS or biologics.
Differences in symptom experience among patients with systemic sclerosis: a cluster analytic approach to identifying subgroups
Authors: Murphy Susan L , Chen Yen T , Lee Yvonne C , Carns Mary , Aren Kathleen , Korman Benjamin , Hinchcliff Monique , Varga John
Published: August 2022

Objectives

Symptoms of people who have SSc are heterogeneous and difficult to address clinically. Because diverse symptoms often co-occur and may share common underlying mechanisms, identifying symptoms that cluster together may better target treatment approaches. We sought to identify and characterize patient subgroups based on symptom experience.

Methods

An exploratory hierarchical agglomerative cluster analysis was conducted to identify subgroups from a large SSc cohort from a single US academic medical centre. Patient-reported symptoms of pain interference, fatigue, sleep disturbance, dyspnoea, depression and anxiety were used for clustering. A multivariate analysis of variance (MANOVA) was used to examine the relative contribution of each variable across subgroups. Analyses of variance were performed to determine participant characteristics based on subgroup assignment. Presence of symptom clusters were tallied within subgroup.

Results

Participants (n = 587; 84% female, 41% diffuse cutaneous subtype, 59% early disease) divided into three subgroups via cluster analysis based on symptom severity: (i) no/minimal, (ii) mild, and (iii) moderate. Participants in mild and moderate symptoms subgroups had similar disease severity, but different symptom presentation. In the mild symptoms subgroup, pain, fatigue and sleep disturbance was the main symptom cluster. Participants in the moderate symptoms subgroup were characterized by co-occurring pain, fatigue, sleep disturbance, depression and anxiety.

Conclusion

Identification of distinct symptom clusters, particularly among SSc patients who experience mild and moderate symptoms, suggests potential differences in treatment approach and in mechanisms underlying symptom experience that require further study.
Clinically suspect arthralgia patients with a low educational attainment have an increased risk of developing inflammatory arthritis
Authors: Khidir Sarah J H , Boeren Anna M P , Boonen Annelies , de Jong Pascal H P , van Mulligen Elise , van der Helm-van Mil Annette H M
Published: August 2022

Objectives

Cross-sectional studies have shown that rheumatoid arthritis is more prevalent among people with a lower educational attainment. No longitudinal data are present on educational attainment in the at-risk phase of clinically suspect arthralgia (CSA). We therefore analysed the association between educational attainment and progression from CSA to inflammatory arthritis (IA), and performed mediation analysis with subclinical joint inflammation to elucidate pathways of this association.

Methods

A total of 521 consecutive patients presenting with CSA were followed for IA development during median 25 months. Educational attainment was defined as low (lower secondary vocational education), intermediate or high (college/university education). Subclinical inflammation in hand and foot joints was measured at presentation with contrast enhanced 1.5 T-MRI. Cox-regression was used to analyse IA development per educational attainment. A three-step mediation analysis evaluated whether subclinical joint inflammation was intermediary in the path between educational attainment and IA development, before and after age correction. Association between educational attainment and IA development was verified in an independent CSA cohort.

Results

Low educational attainment was associated with increased IA development (HR = 2.35, 95% CI = 1.27, 4.33, P = 0.006), independent of BMI and current smoking status (yes/no). Moreover, patients with a low educational attainment had higher levels of subclinical inflammation, which also was associated with IA development. Partial mediation effect of subclinical inflammation was observed in the relationship between education and IA development. Low educational attainment was also associated with increased IA development in the validation cohort (HR = 5.72, 95% CI = 1.36, 24.08, P = 0.017).

Conclusion

This is the first study providing evidence that lower educational attainment is associated with a higher risk of progressing from arthralgia to IA. This effect was partially mediated by subclinical joint inflammation.
IPO7 Promotes Odontoblastic Differentiation and Inhibits Osteoblastic Differentiation Through Regulation of RUNX2 Expression and Translocation
Authors: Zhang Yue , Zhang Hao , Xiao Ziqiu , Yuan Guohua , Yang Guobin
Published: August 2022

RUNX2, an important transcriptional factor for both odontoblastic and osteoblastic differentiation, is upregulated during osteoblastic differentiation, but downregulated during late odontoblastic differentiation. However, the specific mechanism of the different RUNX2 expression in bone and dentin remains largely unknown. Importin 7 (IPO7), a member of the karyopherin β-superfamily, mediates nucleocytoplasmic transport of proteins. In this study, we found that IPO7 was increasingly expressed from pre-odontoblasts to mature odontoblasts. IPO7 expression was increased with odontoblastic differentiation of mouse dental papilla cells (mDPCs) and knockdown of IPO7-inhibited cell differentiation. While in MC3T3-E1 cells, IPO7 was decreased during osteoblastic differentiation and knockdown of IPO7-promoted cell differentiation. In mPDCs, IPO7 was able to bind with some odontoblastic transcription factors, and imported them into the nucleus, but not with RUNX2. Furthermore, IPO7 inhibited the total RUNX2 expression by promoting HDAC6 nuclear localization during odontoblastic differentiation. However, in MC3T3-E1 cells, IPO7 inhibited the nuclear distribution of RUNX2 but did not affect the total protein level of RUNX2. In conclusion, we found that IPO7 promotes odontoblastic differentiation and inhibits osteoblastic differentiation through regulating RUNX2 expression and translocation differently.
Evaluation of the Impact of Glycemic Control on Mean Platelet Volume and Platelet Activation in Children with Type 1 Diabetes
Authors: Söbü Elif , Demir Yenigürbüz Fatma , Özçora Gül Demet Kaya , Köle Mehmet Tolga
Published: August 2022

Objective

The studies evaluating cases with type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) in the adult population reported hyperreactive platelets and increased activation of prothrombotic factors, resulting in an increased risk of thrombosis. The aim of this study was to evaluate the effects of poor glycemic control and the duration of diabetes on platelet parameters in pediatric population.

Methods

The study included 366 children, out of which 144 (39.3%) were included in the T1DM group and 222 (60.6%) in the healthy control group. The platelet count, mean platelet volume (MPV), platelet distribution width and plateletcrit values were recorded. The children with T1DM were divided into three groups as per their glycated hemoglobin (HbA1c) levels, good (<7.5%), moderate (7.5–9%) and poor metabolic control (>9%).

Results

No significant difference in the MPV level between the T1DM (7.41 ± 1.49 fl) and control (7.15 ± 1.23 fl) groups was observed. However, the MPV levels were significantly higher in the poor glycemic control group than in the healthy control group (p = 0.026). Furthermore, as the duration of diabetes and HbA1c levels increased, the MPV levels also increased (p < 0.001, p = 0.441).

Conclusion

This study suggested as the duration of diabetes and HbA1c levels increased, the MPV levels also increases. Evaluation of hematological parameters can be a cheap and useful method in the evaluation of diabetes regulation in patients with diabetes.
Diagnostic Yield of Cone-beam–Derived Augmented Fluoroscopy and Ultrathin Bronchoscopy Versus Conventional Navigational Bronchoscopy Techniques
Authors: DiBardino David M. , Kim Roger Y. , Cao Yulei , Andronov Michelle , Lanfranco Anthony R. , Haas Andrew R. , Vachani Anil , Ma Kevin C. , Hutchinson Christoph T.
Published: August 2022

Background:

Pulmonary nodules suspicious for lung cancer are frequently diagnosed. Evaluating and optimizing the diagnostic yield of lung nodule biopsy is critical as innovation in bronchoscopy continues to progress.

Methods:

This is a retrospective cohort study. Consecutive patients undergoing guided bronchoscopy for suspicious pulmonary nodule(s) between February 2020 and July 2021 were included. The cone-beam computed tomography (CBCT)+ radial endobronchial ultrasound (r-EBUS) group had their procedure using CBCT-derived augmented fluoroscopy along with r-EBUS. The CBCT+ ultrathin bronchoscope (UTB)+r-EBUS group had the same procedure but with the use of an ultrathin bronchoscope. The r-EBUS group underwent r-EBUS guidance without CBCT or augmented fluoroscopy. We used multivariable logistic regression to compare diagnostic yield, adjusting for confounding variables.

Results:

A total of 116 patients were included. The median pulmonary lesion diameter was 19.5 mm (interquartile range, 15.0 to 27.5 mm), and 91 (78.4%) were in the peripheral half of the lung. Thirty patients (25.9%) underwent CBCT+UTB, 27 (23.3%) CBCT, and 59 (50.9%) r-EBUS alone with unadjusted diagnostic yields of 86.7%, 70.4%, and 42.4%, respectively (P<0.001). The adjusted diagnostic yields were 85.0% (95% CI, 68.6% to 100%), 68.3% (95% CI, 50.1% to 86.6%), and 44.5% (95% CI, 31.0% to 58.0%), respectively. There was significantly more virtual navigational bronchoscopy use in the r-EBUS group (45.8%) compared with the CBCT+UTB (13.3%) and CBCT (18.5%) groups, respectively. CBCT procedures required dose area product radiation doses of 7602.5 µGym2.

Conclusion:

Compared with the r-EBUS group, CBCT + UTB + r-EBUS was associated with higher navigational success, fewer nondiagnostic biopsy results, and a higher diagnostic yield. CBCT procedures are associated with a considerable radiation dose.
Approach to FNA of Thyroid Gland Cysts
Authors: Rossi Esther Diana , Tralongo Pietro , Fiorentino Vincenzo , Curatolo Mariangela , Bruno Carmine , De Crea Carmen , Raffaelli Marco , Pontecorvi Alfredo , Larocca Luigi Maria
Published: August 2022

Fine needle aspiration is a well-known procedure for the diagnosis and management of thyroid lesions, representing the first diagnostic tool for the definition of their nature. In clinical practice, a thyroid nodule can be classified as solid, cystic, and partially cystic based on its internal components. Different thyroid imaging reporting systems and cytologic diagnostic systems have focused their attention on solid nodules, which are more frequently linked with a malignant outcome. In fact, numerous papers demonstrated that nodules with microcalcifications, a taller-than-wide shape, hypoechogeneity, and irregular margins, are more likely to be malignant on histology. Nevertheless, according to the literature, the risk of malignancy in a partially cystic thyroid nodule ranges between 3.3 and 17-5%, including, for instance, the possible diagnosis of a cystic papillary thyroid carcinoma and other malignant entities. Therefore, in the current review article, we are going to discuss the approach to thyroid cystic lesions on fine needle aspiration cytology.
Pitcher geometry facilitates extrinsically powered ‘springboard trapping' in carnivorousNepenthes gracilispitcher plants
Authors: Lenz Anne-Kristin , Bauer Ulrike
Published: August 2022

Carnivorous pitcher plants capture insects in cup-shaped leaves that function as motionless pitfall traps.Nepenthes gracilisevolved a unique ‘springboard' trapping mechanism that exploits the impact energy of falling raindrops to actuate a fast pivoting motion of the canopy-like pitcher lid. We superimposed multiple computed micro-tomography images of the same pitcher to reveal distinct deformation patterns in lid-trappingN. gracilisand closely related pitfall-trappingN. rafflesiana. We found prominent differences between downward and upward lid displacement inN. gracilisonly. Downward displacement was characterized by bending in two distinct deformation zones whist upward displacement was accomplished by evenly distributed straightening of the entire upper rear section of the pitcher. This suggests an anisotropic impact response, which may help to maximize initial jerk forces for prey capture, as well as the subsequent damping of the oscillation. Our results point to a key role of pitcher geometry for effective ‘springboard' trapping inN. gracilis.
Impact of disease characteristics and knowledge on public risk perception of zoonoses
Authors: Spence Caroline E. , Jenkins Sarah C. , Osman Magda
Published: August 2022

Zoonoses represent a global public health threat. Understanding lay perceptions of risk associated with these diseases can better inform proportionate policy interventions that mitigate their current and future impacts. While individual zoonoses (e.g. bovine spongiform encephalopathy) have received scientific and public attention, we know little about how multiple zoonotic diseases vary relative to each other in lay risk perceptions. To this end, we examined public perceptions of 11 zoonoses across 12 qualitative attributes of risk among the UK public (
n
= 727, volunteer sample), using an online survey. We found that attribute ratings were predominantly explained via two basic dimensions of risk related to public knowledge and dread. We also show that, despite participants reporting low familiarity with most of the diseases presented, zoonoses were perceived as essentially avoidable. These findings imply that infection is viewed as dependent upon actions under personal control which has significant implications for policy development.
Density-dependent dispersal promotes female-biased sex allocation in viscous populations
Authors: Chokechaipaisarn Chedhawat , Gardner Andy
Published: August 2022

A surprising result emerging from the theory of sex allocation is that the optimal sex ratio is predicted to be completely independent of the rate of dispersal. This striking invariance result has stimulated a huge amount of theoretical and empirical attention in the social evolution literature. However, this sex-allocation invariant has been derived under the assumption that an individual's dispersal behaviour is not modulated by population density. Here, we investigate how density-dependent dispersal shapes patterns of sex allocation in a viscous-population setting. Specifically, we find that if individuals are able to adjust their dispersal behaviour according to local population density, then they are favoured to do so, and this drives the evolution of female-biased sex allocation. This result obtains because, whereas under density-independent dispersal, population viscosity is associated not only with higher relatedness—which promotes female bias—but also with higher kin competition—which inhibits female bias—under density-dependent dispersal, the kin-competition consequences of a female-biased sex ratio are entirely abolished. We derive analytical results for the full range of group sizes and costs of dispersal, under haploid, diploid and haplodiploid modes of inheritance. These results show that population viscosity promotes female-biased sex ratios in the context of density-dependent dispersal.
Anticipating infectious disease re-emergence and elimination: a test of early warning signals using empirically based models
Authors: Tredennick Andrew T. , O’Dea Eamon B. , Ferrari Matthew J. , Park Andrew W. , Rohani Pejman , Drake John M.
Published: August 2022

Timely forecasts of the emergence, re-emergence and elimination of human infectious diseases allow for proactive, rather than reactive, decisions that save lives. Recent theory suggests that a generic feature of dynamical systems approaching a tipping point—early warning signals (EWS) due to critical slowing down (CSD)—can anticipate disease emergence and elimination. Empirical studies documenting CSD in observed disease dynamics are scarce, but such demonstration of concept is essential to the further development of model-independent outbreak detection systems. Here, we use fitted, mechanistic models of measles transmission in four cities in Niger to detect CSD through statistical EWS. We find that several EWS accurately anticipate measles re-emergence and elimination, suggesting that CSD should be detectable before disease transmission systems cross key tipping points. These findings support the idea that statistical signals based on CSD, coupled with decision-support algorithms and expert judgement, could provide the basis for early warning systems of disease outbreaks.
Plant root growth against a mechanical obstacle: the early growth response of a maize root facing an axial resistance is consistent with the Lockhart model
Authors: Quiros Manon , Bogeat-Triboulot Marie-Béatrice , Couturier Etienne , Kolb Evelyne
Published: August 2022

Plant root growth is dramatically reduced in compacted soils, affecting the growth of the whole plant. Through a model experiment coupling force and kinematics measurements, we probed the force–growth relationship of a primary root contacting a stiff resisting obstacle, which mimics the strongest soil impedance variation encountered by a growing root. The growth of maize roots just emerging from a corseting agarose gel and contacting a force sensor (acting as an obstacle) was monitored by time-lapse imaging simultaneously to the force. The evolution of the velocity field along the root was obtained from kinematics analysis of the root texture with a particle image velocimetry derived technique. A triangular fit was introduced to retrieve the elemental elongation rate or strain rate. A parameter-free model based on the Lockhart law quantitatively predicts how the force at the obstacle modifies several features of the growth distribution (length of the growth zone, maximal elemental elongation rate and velocity) during the first 10 min. These results suggest a strong similarity of the early growth responses elicited either by a directional stress (contact) or by an isotropic perturbation (hyperosmotic bath).
Walking on water: revisiting the role of water in articular cartilage biomechanics in relation to tissue engineering and regenerative medicine
Authors: Cederlund Anna A. , Aspden Richard M.
Published: August 2022

The importance, and the difficulty, of generating biosynthetic articular cartilage is widely recognized. Problems arise from obtaining sufficient stiffness, toughness and longevity in the material and integration of new material into existing cartilage and bone. Much work has been done on chondrocytes and tissue macromolecular components while water, which comprises the bulk of the tissue, is largely seen as a passive component; the ‘solid matrix’ is believed to be the main load-bearing element most of the time. Water is commonly seen as an inert filler whose restricted flow through the tissue is believed to be sufficient to generate the properties measured. We propose that this model should be turned on its head. Water comprises 70–80% of the matrix and has a bulk modulus considerably greater than that of cartilage. We suggest that the macromolecular components structure the water to support the loads applied. Here, we shall examine the structure and organization of the main macromolecules, collagen, aggrecan and hyaluronan, and explore how water interacts with their polyelectrolyte nature. This may inform the biosynthetic process by identifying starting points to enable developing tissue properties to guide the cells into producing the appropriate macromolecular composition and structure.
Contrast solution properties and scan parameters influence the apparent diffusivity of computed tomography contrast agents in articular cartilage
Authors: Hall Mary E. , Wang Adam S. , Gold Garry E. , Levenston Marc E.
Published: August 2022

The inability to detect early degenerative changes to the articular cartilage surface that commonly precede bulk osteoarthritic degradation is an obstacle to early disease detection for research or clinical diagnosis. Leveraging a known artefact that blurs tissue boundaries in clinical arthrograms, contrast agent (CA) diffusivity can be derived from computed tomography arthrography (CTa) scans. We combined experimental and computational approaches to study protocol variations that may alter the CTa-derived apparent diffusivity. In experimental studies on bovine cartilage explants, we examined how CA dilution and transport direction (absorption versus desorption) influence the apparent diffusivity of untreated and enzymatically digested cartilage. Using multiphysics simulations, we examined mechanisms underlying experimental observations and the effects of image resolution, scan interval and early scan termination. The apparent diffusivity during absorption decreased with increasing CA concentration by an amount similar to the increase induced by tissue digestion. Models indicated that osmotically-induced fluid efflux strongly contributed to the concentration effect. Simulated changes to spatial resolution, scan spacing and total scan time all influenced the apparent diffusivity, indicating the importance of consistent protocols. With careful control of imaging protocols and interpretations guided by transport models, CTa-derived diffusivity offers promise as a biomarker for early degenerative changes.
From philanthropy to business: the economics of Royal Society journal publishing in the twentieth century
Authors: Fyfe Aileen
Published: August 2022

Scientific journal publishing has become a lucrative enterprise, for commercial firms and (some) society publishers alike; but it was not always thus. The Royal Society is the publisher of the world's longest-running scientific journal, and for most of the history of the
Philosophical Transactions
, its publication was a severe drain on the Society's finances. This paper uses the rich archives of the Royal Society to investigate the economic transformation of journal publishing over the course of the twentieth century. It began the century as a scholarly mission activity heavily subsidized by the Society, but ended it as a valuable income stream. Never-before-seen data reveal three phases: the end of the philanthropic model of circulation; the transition to a sales-based commercial model amidst the post-war boom in subscriber numbers; and the challenges facing that new business model once subscriber numbers went into decline in the late twentieth century. The paper does not directly address the open access movement of the twenty-first century, but is essential reading to understand the financial background.
Population demography of feral honeybee colonies in central European forests
Authors: Kohl Patrick L. , Rutschmann Benjamin , Steffan-Dewenter Ingolf
Published: August 2022

European honeybee populations are considered to consist only of managed colonies, but recent censuses have revealed that wild/feral colonies still occur in various countries. To gauge the ecological and evolutionary relevance of wild-living honeybees, information is needed on their population demography. We monitored feral honeybee colonies in German forests for up to 4 years through regular inspections of woodpecker cavity trees and microsatellite genotyping. Each summer, about 10% of the trees were occupied, corresponding to average densities of 0.23 feral colonies km
−2
(an estimated 5% of the regional honeybee populations). Populations decreased moderately until autumn but dropped massively during winter, so that their densities were only about 0.02 colonies km
−2
in early spring. During the reproductive (swarming) season, in May and June, populations recovered, with new swarms preferring nest sites that had been occupied in the previous year. The annual survival rate and the estimated lifespan of feral colonies (
n
= 112) were 10.6% and 0.6 years, respectively. We conclude that managed forests in Germany do not harbour self-sustaining feral honeybee populations, but they are recolonized every year by swarms escaping from apiaries.
Nano assembly of plasmonic probe-virus particles enabled rapid and ultrasensitive point-of-care SARS-CoV-2 detection
Authors: Park Younggeun , Ryu Byunghoon , Ki Seungjune , Chen Mingze , Liang Xiaogan , Kurabayashi Katsuo
Published: August 2022

The current COVID-19 global pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) coronavirus has become a major public health concern. The ability to identify the virus’s presence in infected hosts with sufficient speed and sensitivity is critical to control the epidemic timely. Here, we use self-assembly of arrayed gold nanoparticles (AuNPs) on the coronavirus, which we call the “plasmo-virus particle,” to achieve a rapid, sensitive, sample preparation-free assay enabling direct detection of SARS-CoV-2 in a point-of-care (POC) setting. The AuNPs of the plasmo-virus particle serve as plasmonic nanoprobes that specifically bind to the spike protein (S-protein) sites on the surface of SARS-CoV-2. Optical interactions between the self-assembled plasmonic nanoprobes generate multiple modes of highly enhanced plasmonic coupling. Measuring changes of the multimode plasmonic coupling-induced extinction peaks allows for quantifying SARS-CoV-2 at low titers with a limit of detection (LOD) of 1.4 × 101 pfu/mL. Using a miniaturized standalone biochip reading device, we further demonstrate the nano assembly assay for smartphone-operated SARS-CoV-2 detection for viral transport medium (VTM) samples within 10 min without any sample purification steps. We anticipate that the high sensitivity and speed of the POC detection performance of this biosensor technology could be broadly accepted for timely personalized diagnostics of infectious agents under low-resource settings.
Brief report: Determinants of potential sexual activity reduction in the face of the Monkeypox epidemic
Authors: Wang Haoyi , d’Abreu de Paulo Kennedy J.I. , Gültzow Thomas , Zimmermann Hanne M.L. , Jonas Kai. J.
Published: August 2022

The current monkeypox epidemic is most prevalent among men-who-have-sex-with-men (MSM). Vaccination programs are being rolled-out to curb the epidemic. Behavioural measures have been called for as well, e.g., by the WHO to reduce the number of sexual partners and sexual activity. We investigated intentions and determinants among Dutch MSM to follow such measures. Early July 2022, 394 MSM answered an online questionnaire. The overall intentions to reduce number of partners and sexual activity was high, but only a minority had developed definite intentions. Determinant analysis revealed that dating/open relationship status was a positive predictor, vaccination intentions did not predict sexual behaviour change; those not on PrEP were more likely to change their sexual behaviour. Monkeypox infection concern was negatively related to weaker intentions and only predicted definite intentions. Our results show that additional public health measures are necessary to reach and convince MSM to engage in sexual behaviour change.
Divergent risky decision-making and impulsivity behaviors in Lewis rat substrains with low genetic difference
Authors: Gabriel Daniel B.K. , Liley Anna E. , Franks Hunter , Tutaj Monika , Dwinell Melinda R. , de Jong Tristan , Williams Robert W. , Mulligan Megan K. , Chen Hao , Simon Nicholas W.
Published: August 2022

Substance use disorder (SUD) is associated with a cluster of cognitive disturbances that engender vulnerability to ongoing drug seeking and relapse. Two of these endophenotypes—risky decision-making and impulsivity—are amplified in individuals with substance use disorder and are augmented by repeated exposure to illicit drugs. Identifying genetic factors underlying variability in these traits is critical for early identification, prevention, and treatment of SUD-vulnerable individuals. Here, we compared risky decision-making and different facets of impulsivity between two fully inbred substrains of Lewis rats—LEW/NCrl and LEW/NHsd. We performed whole genome sequencing of both substrain to identify almost all relevant variants. We observed substantial differences in risky decision-making and impulsive behaviors. Relative to LEW/HHsd, the LEW/NCrl substrain accepts higher risk options in a decision-making task and higher rates of premature responses in thedifferential reinforcement of low rates of responding(DRL) task. These phenotypic differences were more pronounced in females than males. We defined a total of ∼9,000 polymorphisms between these substrains at 40X whole genome short-read coverage. Roughly half of variants are located within a single 1.5 Mb region of chromosome 8, but none impact protein-coding regions. In contrast, other variants are widely distributed, and of these 38 are predicted to cause protein-coding variants. In conclusion, Lewis rat substrains differ significantly in risk-taking and impulsivity and only a small number of easily mapped variants are likely to be causal. Sequencing combined with a reduced complexity cross (RCC) should enable identification of one or more variants underlying multiple complex addiction-relevant traits.
Next generation digital PCR: high dynamic range single molecule DNA counting via ultra-partitioning
Authors: Shum Eleen Y. , Lai Janice H. , Li Sixing , Lee Haeun G. , Soliman Jesse , Raol Vedant K. , Lee Cavina K. , Fodor Stephen P.A. , Fan H. Christina
Published: August 2022

Digital PCR (dPCR) was first conceived for single molecule quantitation. However, current dPCR systems often require DNA templates to share partitions due to limited partitioning capacities. Here, we introduce Ultra-dPCR, a next generation dPCR system where DNA counting is performed in a single-molecule regimen through a 6-log dynamic range using a swift and parallelized workflow. Each Ultra-dPCR reaction is divided into >30 million partitions without microfluidics to achieve single template occupancy. Combined with a unique emulsion chemistry, partitions are optically clear and enable the use of a 3D imaging technique to rapidly detect DNA-positive partitions. Single molecule occupancy also allows for more straightforward multiplex assay development due to the absence of partition-specific competition. As a proof-of-concept, we developed a 222-plex Ultra-dPCR assay and demonstrated its potential use as a rapid, low-cost screening assay for non-invasive prenatal testing (NIPT) for as low as 4% trisomy fraction samples with high precision, accuracy, and reproducibility.
Quantitative multiplexed imaging of chromatin ultrastructure with Decode-PAINT
Authors: Sasaki Hiroshi M. , Kishi Jocelyn Y. , Wu Chao-ting , Beliveau Brian J. , Yin Peng
Published: August 2022

Super-resolution chromatin imaging techniques are emerging as powerful tools for spatial genomics. However, it remains challenging to visualize the genome on the order of tens of nanometers, a scale that can reveal rich structural detail about the nuclear organization. Here we introduce Decode-PAINT, a multiplexed in situ method, which leverages rapid diffraction-limited pre-decoding and DNA-PAINT (DNA points accumulation for imaging nanoscale topography). Decode-PAINT visualizes multiple discrete genomic regions at a resolution close to the nucleosome scale with a simple and easy-to-implement optical setup, reduces total imaging time by omitting multiple rounds of single-molecule recording, and enables the interrogation of the ultrastructure of the targets with <12 nm lateral and <20 nm axial resolution. We showcase the ability of our approach to perform multiplexed, high-resolution profiling of chromatin structure by performing targeted imaging of nine regions of active and inactive X chromosomes in individual cells. In short, Decode-PAINT accelerates in situ structural genomics.
A spatiotemporal gradient of mesoderm assembly governs cell fate and morphogenesis of the early mammalian heart
Authors: Dominguez Martin H. , Krup Alexis Leigh , Muncie Jonathon M. , Bruneau Benoit G.
Published: August 2022

Using four-dimensional whole-embryo light sheet imaging with improved and accessible computational tools, we longitudinally reconstruct early murine cardiac development at single-cell resolution. Nascent mesoderm progenitors form opposing density and motility gradients, converting the temporal birth sequence of gastrulation into a spatial anterolateral-to-posteromedial arrangement. Migrating precardiac mesoderm doesn’t strictly preserve cellular neighbor relationships; spatial patterns only become solidified as the cardiac crescent emerges. Progenitors undergo a heretofore unknown mesenchymal-to-epithelial transition, with a first heart field (FHF) ridge apposing a motile juxtacardiac field (JCF). Anchored along the ridge, the FHF epithelium rotates the JCF forward due to push-pull morphodynamics of the second heart field, which forms the nascent heart tube. In Mesp1 mutants that fail to make a cardiac crescent, mesoderm remains highly motile but directionally incoherent, resulting in density gradient inversion. Our practicable live embryo imaging approach defines spatial origins and behaviors of cardiac progenitors, and identifies their unanticipated morphological transitions.
Persistence of FoxJ1+ Pax6+ Sox2+ ependymal cells throughout life in the human spinal cord
Authors: Ripoll Chantal , Poulen Gaetan , Chevreau Robert , Lonjon Nicolas , Vachiery-Lahaye Florence , Bauchet Luc , Hugnot Jean-Philippe
Published: August 2022

Spinal cord ependymal cells have stem cell properties in mice. They surround the central canal and keep expressing spinal cord developmental transcription factors. Similar cells exist in young humans however their persistence with aging is debated.

We clarified this issue by collecting 17 spinal cords from organ donors, aged between 37 and 83 years old. We examined the presence of ependymal cells using immunohistochemistry on lightly-fixed tissue.

We found the presence of cells expressing the typical ependymal marker FOXJ1 in the spinal cord central region in 100% of cases. In addition, a lumen surrounded by FOXJ1+ cells was observed in half of the cases. Like in mice, these human ependymal cells maintain the expression of SOX2 and PAX6 proteins together with RFX2 a master transcriptional regulator of ciliogenesis and ARL13B, a regulatory GTPase enriched in cilia. Reminiscent of the situation observed in mice and in young human spinal cord, a fetal-like regionalization of neurodevelopmental transcription factors was observed in three donors aged over 75 years: MSX1 and ARX/FOXA2 was preferentially expressed by dorsal and ventral ependymal cells, respectively.

These results provide new evidence for the persistence of ependymal cells expressing neurodevelopmental genes throughout human life. The persistence of these cells in humans opens new opportunities to regenerate the spinal cord.
Ligand Binding Free Energy Evaluation by Monte Carlo Recursion
Authors: de Souza Joao Victor , Nogueira Victor H. R. , Nascimento Alessandro S.
Published: August 2022

The correct evaluation of ligand binding free energies by computational methods is still a very challenging active area of research. The most employed methods for these calculations can be roughly classified into four groups: (i) the fastest and less accurate methods, such as molecular docking, designed to sample a large number of molecules and rapidly rank them according to the potential binding energy; (ii) the second class of methods use a thermodynamic ensemble, typically generated by molecular dynamics, to analyze the endpoints of the thermodynamic cycle for binding and extract differences, in the so-called ‘end-point’ methods; (iii) the third class of methods is based on the Zwanzig relationship and computes the free energy difference after a chemical change of the system (alchemical methods); and (iv) methods based on biased simulations, such as metadynamics, for example. These methods require increased computational power and as expected, result in increased accuracy for the determination of the strength of binding. Here, we describe an intermediate approach, based on the Monte Carlo Recursion (MCR) method first developed by Harold Scheraga. In this method, the system is sampled at increasing effective temperatures, and the free energy of the system is assessed from a series of termsW(b, T), computed from Monte Carlo (MC) averages at each iteration. We show the application of the MCR for ligand binding with datasets of guest-hosts systems (N=75) and we observed that a good correlation is obtained between experimental data and the binding energies computed with MCR. We also compared the experimental data with an end-point calculation from equilibrium Monte Carlo calculations that allowed us to conclude that the lower-energy (lower-temperature) terms in the calculation are the most relevant to the estimation of the binding energies, resulting in similar correlations between MCR and MC data and the experimental values. On the other hand, the MCR method provides a reasonable view of the binding energy funnel, with possible connections with the ligand binding kinetics, as well. The codes developed for this analysis are publicly available on GitHub as a part of theLiBELa/MCLiBELaproject (https://github.com/alessandronascimento/LiBELa).
Full-length optic nerve regeneration in the absence of genetic manipulations
Authors: Feng Qian , Wong Kimberly , Benowitz Larry I.
Published: August 2022

The inability of mature retinal ganglion cells (RGCs) to regenerate axons after optic nerve injury can be partially reversed by manipulating cell-autonomous and/or -non-autonomous factors, among which are neuroimmune interactions. We report here that preconditioning resulting from a mild lens injury (conditioning LI, cLI) prior to optic nerve damage induces far greater axon regeneration than LI or the pro-inflammatory agent zymosan after nerve injury or preconditioning with Zymosan. Unlike other instances of immune-supported regeneration, cLI is unaltered by depleting mature neutrophils, T cells or blocking receptors for identified inflammation-associated growth factors (Oncomodulin, SDF1, CCL5), and is only partially diminished by suppressing peripheral monocyte recruitment. Repeated LI leads to full-length optic nerve regeneration, and pharmacological removal of local resident macrophages with the colony stimulating factor 1 receptor (CSF-1R) inhibitor PLX5622 enables some axons to re-innervate the brain in just 6 weeks. Thus, cell non-autonomous interventions not involving genetic manipulations can induce high levels of optic nerve regeneration, paving the way to uncover potent, translatable therapeutic targets for CNS repair.
Imputed genomes and haplotype-based analyses of the Picts of early medieval Scotland reveal fine-scale relatedness between Iron Age, early medieval and the modern people of the UK
Authors: Morez Adeline , Britton Kate , Noble Gordon , Günther Torsten , Götherström Anders , Rodríguez-Varela Ricardo , Kashuba Natalija , Martiniano Rui , Talamo Sahra , Evans Nicholas J. , Irish Joel D. , Donald Christina , Girdland-Flink Linus
Published: August 2022

The origins and ancestry of the Picts of early medieval Scotland (ca. AD 300-900) has been traditionally seen as a problem, prompted in part by exotic medieval origin myths, their enigmatic symbols and inscriptions, and the meagre textual evidence. The Picts, first mentioned in the late 3rd century AD resisted the Romans and went on to form a powerful kingdom that ruled over a large territory in northern Britain. In the 9th and 10th centuries Gaelic language, culture and identity became dominant, transforming the Pictish realm into Alba, the precursor to the medieval kingdom of Scotland. To date, no comprehensive analysis of Pictish genomes has been published, and questions about their biological relationships to other cultural groups living in Britain remain unanswered. Here we present two high-quality Pictish genomes (2.4 and 16.5X coverage) from central and northern Scotland dated from the 5th-7th century which we impute and co-analyse with >8,300 previously published ancient and modern genomes. Using allele frequency and haplotype-based approaches, we can firmly place the Pictish genomes within the Iron Age gene pool in Britain and demonstrate local biological affinity. We also demonstrate the presence of population structure within Pictish groups, with Orcadian Picts being genetically distinct from their mainland contemporaries. When investigating Identity-By-Descent (IBD) with present-day genomes, we observe broad affinities between the mainland Pictish genomes and the present-day people living in western Scotland, Wales, Northern Ireland and Northumbria, but less with the rest of England, the Orkney islands and eastern Scotland - where the political centres of Pictland were located. The pre-Viking Age Orcadian Picts evidence a high degree of IBD sharing across modern Scotland, Wales, Northern Ireland, and the Orkney islands, demonstrating substantial genetic continuity in the Orkney for the last ~2,000 years. Analysis of mitochondrial DNA diversity at the Pictish cemetery of Lundin Links (n = 7) reveals absence of female endogamy, with implications for broader social organisation. Overall, our study provides novel insights into the genetic affinities and population structure of the Picts and direct relationships between ancient and present-day groups of the UK.
ADrosophilaglial cell atlas reveals a mismatch between detectable transcriptional diversity and morphological diversity
Authors: Lago-Baldaia Inês , Cooper Maia , Seroka Austin , Trivedi Chintan , Powell Gareth T. , Wilson Stephen , Ackerman Sarah D. , Fernandes Vilaiwan M.
Published: August 2022

Morphology is a defining feature of neuronal identity. Like neurons, glia display diverse morphologies, both across and within glial classes, but are also known to be morphologically plastic. Here, we explored the relationship between glial morphology and transcriptional signature using theDrosophilacentral nervous system, where glia are categorized into five main classes (outer and inner surface glia, cortex glia, ensheathing glia, and astrocytes), which show within-class morphological diversity. We analysed and validated single cell RNA sequencing data ofDrosophilaglia in two well-characterized tissues from distinct developmental stages, containing distinct circuit types: the embryonic ventral nerve cord (motor) and the adult optic lobes (sensory). Our analysis identified a new morphologically and transcriptionally distinct surface glial population in the ventral nerve cord. However, many glial morphological categories could not be distinguished transcriptionally, and indeed, embryonic and adult astrocytes were transcriptionally analogous despite differences in developmental stage and circuit type. While we did detect extensive within-class transcriptomic diversity for optic lobe glia, this could be explained entirely by glial residence in the most superficial neuropil (lamina) and an associated enrichment for immune-related gene expression. In summary, we generated a single-cell transcriptomic atlas of glia inDrosophila, and our extensivein vivovalidation revealed that glia exhibit more diversity at the morphological level than was detectable at the transcriptional level. This atlas will serve as a resource for the community to probe glial diversity and function.
YAP antagonizes TEAD-mediated AR signaling and prostate cancer growth
Authors: Zhuo Shu , Li Xu , Cho Yong Suk , Liu Yuchen , Yang Yingzi , Zhu Jian , Jiang Jin
Published: August 2022

Hippo signaling restricts tumor growth by inhibiting the oncogenic potential of YAP/TAZ-TEAD transcriptional complex. Here we uncover a context-dependent tumor suppressor function of YAP in androgen receptor (AR) positive prostate cancer (PCa) and show that YAP impedes AR+ PCa growth by antagonizing TEAD-mediated AR signaling. TEAD forms a complex with AR to enhance its promoter/enhancer occupancy and transcriptional activity. YAP and AR compete for TEAD binding and consequently, elevated YAP in the nucleus disrupts AR-TEAD interaction and prevents TEAD from promoting AR signaling. Pharmacological inhibition of Hippo/MST1/2 kinase or transgenic activation of YAP suppressed the growth of PCa expressing therapy resistant AR splicing variants. Our study uncovers an unanticipated crosstalk between Hippo and AR signaling pathways, reveals an antagonistic relationship between YAP and TEAD in AR+ PCa, and suggests that targeting the Hippo signaling pathway may provide a therapeutical opportunity to treat PCa driven by therapy resistant AR variants.

YAP acts as a context-dependent tumor suppressor in AR+ PCa

TEAD interacts with AR to enhance its promoter/enhancer occupancy

YAP inhibits AR activity by competing for TEAD binding

Small molecule Hippo pathway inhibitor impedes AR+ PCa growth