bluuebunny/crossref_metadata_2025 huggingface dataset:
Prescription of benzodiazepines and Z-drugs among older patients in primary care: a French, national, cohort study
Authors: Yana Jonathan , Moscova Laura , Le Breton Julien , Boutin Emmanuelle , Siess Tiphaine , Clerc Pascal , Bastuji-Garin Sylvie , Ferrat Emilie
Published: October 2022

Background

In France, general practitioners (GPs) prescribe benzodiazepines and Z-drugs (BZD/ZDs) widely, and especially to older adults. Several characteristics of patients and/or GPs linked to BZD/ZD overprescription have been described in the general population but not among older patients in primary care.

Objectives

To estimate the proportion of GP consultations by patients aged 65 and over that resulted in a BZD/ZD prescription, and determine whether any GP-related factors predicted BZD/ZD overprescription in this setting.

Methods

We analyzed sociodemographic and practice-related GP characteristics, and aggregated data on consultations recorded prospectively by 117 GPs in a database between 2000 and 2010. Next, we used logistic regression models to look for factors potentially associated with BZD/ZD overprescription (defined as an above-median prescription rate).

Results

The GPs’ mean age at inclusion was 47.4 (7.1), and 87.9% were male. During the study period, the median (95% confidence interval) proportion of consultations with patients aged 65 and over resulting in a BZD/ZD prescription was 21.8% (18.1–26.1) (range per GP: 5–34.1%). In a multivariable analysis, a greater number of chronic disease (OR [95% CI] = 2.10 [1.22–3.64]), a greater number of drugs prescribed per consultation (5.29 [2.72–10.28]), and shorter study participation were independently associated with BZD/ZD overprescription.

Conclusions

BZD/ZD overprescription was associated with a greater chronic disease burden and the number of drugs prescribed per consultation but not with any sociodemographic or practice-related GP characteristics. Targeted actions are needed to help GPs limit their prescription of BZD/ZDs to older patients with multiple comorbidities and polypharmacy.
TFIIH mutations can impact on translational fidelity of the ribosome
Authors: Khalid Fatima , Phan Tamara , Qiang Mingyue , Maity Pallab , Lasser Theresa , Wiese Sebastian , Penzo Marianna , Alupei Marius , Orioli Donata , Scharffetter-Kochanek Karin , Iben Sebastian
Published: October 2022

TFIIH is a complex essential for transcription of protein-coding genes by RNA polymerase II, DNA repair of UV-lesions and transcription of rRNA by RNA polymerase I. Mutations in TFIIH cause the cancer prone DNA-repair disorder xeroderma pigmentosum (XP) and the developmental and premature aging disorders trichothiodystrophy (TTD) and Cockayne syndrome. A total of 50% of the TTD cases are caused by TFIIH mutations. Using TFIIH mutant patient cells from TTD and XP subjects we can show that the stress-sensitivity of the proteome is reduced in TTD, but not in XP. Using three different methods to investigate the accuracy of protein synthesis by the ribosome, we demonstrate that translational fidelity of the ribosomes of TTD, but not XP cells, is decreased. The process of ribosomal synthesis and maturation is affected in TTD cells and can lead to instable ribosomes. Isolated ribosomes from TTD patients show an elevated error rate when challenged with oxidized mRNA, explaining the oxidative hypersensitivity of TTD cells. Treatment of TTD cells with N-acetyl cysteine normalized the increased translational error-rate and restored translational fidelity. Here we describe a pathomechanism that might be relevant for our understanding of impaired development and aging-associated neurodegeneration.
Clinical perspectives on the menstrual pictogram for the assessment of heavy menstrual bleeding
Authors: Singh Sukhbir S , Calaf Alsina Joaquin , Vannuccini Silvia , Koga Kaori , Lopes Silva-Filho Agnaldo , Yang Xin , Estrade Jean-Philippe , Catherino William
Published: October 2022

Heavy menstrual bleeding (HMB) has an estimated prevalence of 18–32% but is known to be under-reported due to poor recognition and estimation of menstrual blood loss (MBL). HMB can negatively impact quality of life, affecting social interactions, work productivity and sexual life. Abnormal menstrual bleeding may have an underlying structural or systemic cause, such as endometrial and myometrial disorders; however, for some, there is no identified pathological cause. Several methods are available for assessing MBL, including the alkaline hematin (AH) method and the menstrual pictogram (MP). The AH method is considered to be the most accurate way to monitor MBL; however, it is associated with inconvenience and expense, therefore limiting its value outside of research. The MP requires the user to select an icon from a chart that reflects the appearance of a used sanitary product; the icon is associated with a blood volume that can be used to determine MBL. Validation studies have demonstrated that the results of the MP and AH method are well correlated, showing that the MP can measure MBL with sufficient accuracy. Additionally, the MP is more convenient for users, less expensive than the AH method, may be used in regions where the AH method is unavailable and may also be used as part of a digital application. Overall, the MP offers a convenient approach to monitor MBL both in research and clinical practice settings.
Congenital aortocaval fistula combined with patent ductus arteriosus in an infant: a case report
Authors: Jiao Xianting , Zhao Liqing , Wu Yurong , Chen Sun
Published: October 2022

Congenital aortocaval fistula (ACF) is a rare cardiac malformation. While it can occur in combination with patent ductus arteriosus (PDA), this has not been reported. In this case, a 1-year-old infant had a heart murmur found in a routine physical examination, and PDA was revealed by transthoracic echocardiography and abdominal ACF was detected by three-dimensional coronary artery computed tomography. Percutaneous interventional therapy, used for ACF and PDA, was performed to occlude the malformation. The patient presented good health without any discomfort at a 1-year follow-up. The percutaneous closure of ACF and PDA with an Amplatzer vascular device can be considered an appropriate option.
In vitro activity of fosfomycin alone and in combination against Staphylococcus aureus with reduced susceptibility or resistance to methicillin, vancomycin, daptomycin or linezolid
Authors: Saravolatz Louis D , Pawlak Joan
Published: October 2022

Objectives

To evaluate the activity of fosfomycin against a group of MRSA strains, including isolates with reduced susceptibility or resistance to vancomycin, daptomycin, linezolid and ceftaroline and to determine the effect of combining various combinations of antimicrobial agents used in the therapy of serious Gram-positive infections.

Methods

Broth microdilution testing was used to determine the MICs of fosfomycin, vancomycin, daptomycin, linezolid, ceftaroline and cefazolin. Isolates were selected for further evaluations to determine in vitro synergy between fosfomycin and select antimicrobial agents using chequerboard broth microdilution testing. Fosfomycin was tested in combination with vancomycin, linezolid, daptomycin, ceftaroline and cefazolin.

Results

Fosfomycin maintained activity against 100% of strains of vancomycin-resistant Staphylococcus aureus (VRSA) and linezolid-resistant S. aureus (LRSA), 86% of VISA and 95% of daptomycin-resistant S. aureus (DRSA) strains. The combination of fosfomycin with ceftaroline consistently demonstrated synergy among all 18 isolates against the strains tested. The next most potent combination regimen was linezolid with fosfomycin, which demonstrated synergy in 16 of the 18 strains. Daptomycin demonstrated synergy in only 7 of the 18 strains tested when combined with fosfomycin. Cefazolin demonstrated synergy in 6 of 6 strains and vancomycin demonstrated no interaction in 6 of 6 strains tested.

Conclusions

Fosfomycin demonstrated excellent activity against MRSA as well as isolates with resistance or reduced activity to other anti-MRSA drugs including vancomycin, daptomycin and linezolid. When combined with linezolid or daptomycin, fosfomycin demonstrated synergy for all or most strains tested. Thus, these combinations may have potential clinical utility when treating patients with serious infections caused by MRSA.
How iconic news images travel: republishing and reframing historic photographs in Israeli newspapers
Authors: Boudana Sandrine , Cohen Akiba A , Frosh Paul
Published: October 2022

Iconic photographs are symbolically dense images characterized by broad circulation over time and recognition by large publics. Following this definition, we track the republication and reframing, over nearly 70 years, of 15 news photographs previously identified as most recognized by the Israeli public. Distinguishing between “discrete icons” (singular photographs of particular scenes) and “aggregate icons” (where several variants of the same event are continually reproduced), our quantitative and qualitative analyses show that iconic images are both resistant to the passing of time and kept in motion through renewed media use. We identify four “iconic modalities,” corresponding to different ways in which iconic status and meanings are achieved, transformed, or denied through republishing and reframing. This concept improves our understanding of iconicity as a fluctuating material and symbolic process, whereby the circulation of images not only produces shifts in meaning, but constructs powerful aggregative frameworks of collective visual memory.
Concurrent Psychosocial Concerns and Post-Concussive Symptoms Following Pediatric mTBI: An A-CAP Study
Authors: Sparanese Sydney , Yeates Keith Owen , Bone Jeffrey , Beauchamp Miriam H , Craig William , Zemek Roger , Doan Quynh
Published: October 2022

Objectives

To measure the association between psychosocial problems and persistent post-concussive symptoms (PCS) in youth who were seen in the emergency department with mild traumatic brain injury (mTBI) or orthopedic injury (OI).

Methods

From a larger prospective cohort study, Advancing Concussion Assessment in Pediatrics (A-CAP), 122 child–guardian pairs who presented to the emergency department with mTBI (N = 70) or OI (N = 52) were recruited for this cross-sectional sub-study. Each pair completed 2 measures assessing PCS burden at 2 weeks, 3 months, and 6 months post-injury. At one visit, pairs concurrently completed MyHEARTSMAP, a comprehensive, psychosocial self-assessment tool to evaluate 4 domains of mental wellness.

Results

When measured at the same visit, children who self-reported moderate or severe Psychiatry domain concerns concurrently experienced a greater burden of cognitive symptoms (β = 5.49; 0.93–10.05) and higher overall PCS count (β = 2.59; 0.70–4.48) after adjusting for covariables, including retrospective pre-injury symptoms and injury group. Additionally, reports indicating mild Function domain severity were associated with increased cognitive (β = 3.34; 95% CI: 0.69–5.99) and somatic symptoms (β = 6.79; 2.15–11.42) and total symptom count (β = 1.29; 0.18–2.39).

Conclusion

Increasing severity in multiple domains of mental health is associated with more PCS in youth. While the differences in PCS between the mTBI and OI groups appeared somewhat larger for children with more mental health concerns, the interaction was not statistically significant; larger sample sizes are needed to evaluate the moderating effect of psychosocial difficulties on post-concussion symptoms.
VLBI observations of a sample of Palomar–Green quasars – I. Parsec-scale morphology
Authors: Wang Ailing , An Tao , Cheng Xiaopeng , Ho Luis C , Kellermann Kenneth I , Baan Willem A , Yang Jun , Zhang Yingkang
Published: October 2022

We observed 20 Palomar–Green quasars at low redshift (z < 0.5) with total flux density >1 mJy, including four radio-loud quasars (RLQs) and 16 radio-quiet quasars (RQQs), using the Very Long Baseline Array (VLBA) at 5 GHz. 10 RQQs are clearly detected in the VLBA images, and a compact radio core is identified in eight of them, indicating the prevalence of active galactic nucleus (AGN)-related radio emission in this flux-density-limited RQQ sample. The RQQs and RLQs in our sample have a division at ∼30 mJy. The radio emission from RQQs appears to be the result of a combination of star formation and AGN-associated activities. All RQQs in our sample have a 5 GHz flux density ratio of Very Large Array (VLA) A-array to D-array $f_{\rm c} = S_{\rm A}^{\rm VLA}/S_{\rm D}^{\rm VLA}$ above 0.2. The RQQs with fa (VLBA and VLA flux density ratio $S^{\rm VLBA}/S_{\rm A}^{\rm VLA}) \gt 0.2$ versus fa < 0.2 show significant differences in morphology, compactness, and total flux density. fa of RQQs is systematically lower than that of RLQs, probably due to the extended jets or relic jets of RQQs on tens to hundreds parsecs that are resolved out in VLBA images. Future larger samples, especially with the addition of milliarcsec resolution radio images of RQQs with total flux densities below 1 mJy, can test the conclusions of this paper and contribute to the understanding of the radio emission mechanism of RQQs, and the dichotomy and physical connection between RQQs and RLQs.
Taking off the edge – simultaneous filament and end core formation
Authors: Heigl S , Hoemann E , Burkert A
Published: October 2022

Simulations of idealized star-forming filaments of finite length typically show core growth that is dominated by two cores forming at its respective end. The end cores form due to a strong increasing acceleration at the filament ends that leads to a sweep-up of material during the filament collapse along its axis. As this growth mode is typically faster than any other core formation mode in a filament, the end cores usually dominate in mass and density compared to other cores forming inside a filament. However, observations of star-forming filaments do not show this prevalence of cores at the filament ends. We explore a possible mechanism to slow the growth of the end cores using numerical simulations of simultaneous filament and embedded core formation, in our case a radially accreting filament forming in a finite converging flow. While such a set-up still leads to end cores, they soon begin to move inwards and a density gradient is formed outside of the cores by the continued accumulation of material. As a result, the outermost cores are no longer located at the exact ends of the filament and the density gradient softens the inward gravitational acceleration of the cores. Therefore, the two end cores do not grow as fast as expected and thus do not dominate over other core formation modes in the filament.
Cosmic evolution of the incidence of active galactic nuclei in massive clusters: simulations versus observations
Authors: Muñoz Rodríguez Iván , Georgakakis Antonis , Shankar Francesco , Allevato Viola , Bonoli Silvia , Brusa Marcella , Lapi Andrea , Viitanen Akke
Published: October 2022

This paper explores the role of small-scale environment (<1 Mpc) in modulating accretion events on to supermassive black holes by studying the incidence of active galactic nuclei (AGNs) in massive clusters of galaxies. A flexible, data-driven semi-empirical model is developed based on a minimal set of parameters and under the zero-order assumption that the incidence of AGNs in galaxies is independent of environment. This is used to predict how the fraction of X-ray selected AGN among galaxies in massive dark matter haloes ($\gtrsim 3\times 10^{14}\, \mathrm{M}_{\odot }$) evolves with redshift and reveal tensions with observations. At high redshift, z ∼ 1.2, the model underpredicts AGN fractions, particularly at high X-ray luminosities, $L_X(\rm 2\rm{-}10\, keV) \gtrsim 10^{44}\, erg \, s^{-1}$. At low redshift, z ∼ 0.2, the model estimates fractions of moderate luminosity AGN ($L_X(\rm 2\rm{-}10\, keV) \gtrsim 10^{43}\, erg \, s^{-1}$) that are a factor of 2–3 higher than the observations. These findings reject the zero-order assumption on which the semi-empirical model hinges and point to a strong and redshift-dependent influence of the small-scale environment on the growth of black holes. Cluster of galaxies appear to promote AGN activity relative to the model expectation at z ∼ 1.2 and suppress it close to the present day. These trends could be explained by the increasing gas content of galaxies towards higher redshift combined with an efficient triggering of AGNs at earlier times in galaxies that fall on to clusters.
The mystery in Gaia DR3 triples: occurrence rates, orientations, and eccentricities of wide tertiaries around close binaries
Authors: Hwang Hsiang-Chih
Published: October 2022

The formation of close binaries has been an open question for decades. A large fraction of close binaries are in triple systems, suggesting that their formation may be associated with the Kozai–Lidov mechanism. However, this picture remains under debate because the configurations of many observed triples are unlikely to trigger the Kozai–Lidov mechanism. In this paper, we use the close binary samples, including eclipsing, spectroscopic, and astrometric binaries, from Gaia Data Release 3 to investigate the mysterious connection between inner binaries and their wide tertiaries. We show that the wide tertiary (at 103–104 au) fraction increases with decreasing orbital periods of the inner binaries. The wide tertiary fraction of eclipsing binaries (a median orbital period of 0.41 d) is 2.33 ± 0.11 times higher than the field wide binary fraction. Furthermore, there is a tentative excess at ∼104 au for tertiaries of eclipsing binaries. Using the v − r angle distributions, we show that wide tertiaries have isotropic orientations with respect to the inner binaries, and the co-planar orbits can be ruled out. The inferred eccentricity distribution of wide tertiaries is consistent (<1σ) with being thermal (f(e) ∝ e), similar to wide binaries at similar separations. The dynamical unfolding scenario is disfavoured because it predicts highly eccentric wide tertiaries, which is inconsistent with our findings. For the Kozai–Lidov mechanism to be effective for wide tertiaries at >103 au, the initial separations of the inner binaries need to be >3 au. Future theoretical investigations are needed to explore the parameter space at these large initial separations and large tertiary separations.
A two-gene strategy increases iron and zinc concentrations in wheat flour, improving mineral bioaccessibility
Authors: Harrington Sophie A , Connorton James M , Nyangoma Natasha I M , McNelly Rose , Morgan Yvie M L , Aslam Mohamad F , Sharp Paul A , Johnson Alexander A T , Uauy Cristobal , Balk Janneke
Published: October 2022

Dietary deficiencies of iron and zinc cause human malnutrition that can be mitigated by biofortified staple crops. Conventional breeding approaches to increase grain mineral concentrations in wheat (Triticum aestivum L.) have had only limited success, and our understanding of the genetic and physiological barriers to altering this trait is incomplete. Here we demonstrate that a transgenic approach combining endosperm-specific expression of the wheat VACUOLAR IRON TRANSPORTER gene TaVIT2-D with constitutive expression of the rice (Oryza sativa) NICOTIANAMINE SYNTHASE gene OsNAS2 significantly increases the total concentration of zinc and relocates iron to white-flour fractions. In two distinct bread wheat cultivars, we show that the so called VIT-NAS construct led to a two-fold increase in zinc in wholemeal flour, to ∼50 µg g−1. Total iron was not significantly increased, but redistribution within the grain resulted in a three-fold increase in iron in highly pure, roller-milled white flour, to ∼25 µg g−1. Interestingly, expression of OsNAS2 partially restored iron translocation to the aleurone, which is iron depleted in grain overexpressing TaVIT2 alone. A greater than three-fold increase in the level of the natural plant metal chelator nicotianamine in the grain of VIT-NAS lines corresponded with improved iron and zinc bioaccessibility in white flour. The growth of VIT-NAS plants in the greenhouse was indistinguishable from untransformed controls. Our results provide insights into mineral translocation and distribution in wheat grain and demonstrate that the individual and combined effects of the two transgenes can enhance the nutritional quality of wheat beyond what is possible by conventional breeding.
Comprehensive and reliable sonographic assessment and scoring system for inflammatory lesions of the paediatric ankle
Authors: Vega-Fernandez Patricia , De Ranieri Deirdre , Oberle Edward , Clark Matthew , Bukulmez Hulya , Lin Clara , Shenoi Susan , Thatayatikom Akaluck , Woolnough Leandra , Benham Heather , Brunner Emily , Henrickson Michael , Pratt Laura R , Proulx-Gauthier Jean-Philippe , Janow Ginger , Cassedy Amy , Ting Tracy V , Roth Johannes
Published: October 2022

Objective

The clinical decision-making process in paediatric arthritis lacks an objective, reliable bedside imaging tool. The aim of this study was to develop a US scanning protocol and assess the reliability of B-mode and Doppler scoring systems for inflammatory lesions of the paediatric ankle.

Methods

As part of the Childhood Arthritis and Rheumatology Research Alliance (CARRA) US group, 19 paediatric rheumatologists through a comprehensive literature review developed a set of standardized views and scoring systems to assess inflammatory lesions of the synovial recesses as well as tendons of the paediatric ankle. Three rounds of scoring of still images were followed by one practical exercise. Agreement among raters was assessed using two-way single score intraclass correlation coefficients (ICC).

Results

Of the 37 initially identified views to assess the presence of ankle synovitis and tenosynovitis, nine views were chosen for each B-mode and Doppler mode semi-quantitative evaluation. Several scoring exercises and iterative modifications resulted in a final highly reliable scoring system: anterior tibiotalar joint ICC: 0.93 (95% CI 0.92, 0.94), talonavicular joint ICC: 0.86 (95% CI 0.81, 0.90), subtalar joint ICC: 0.91 (95% CI 0.88, 0.93) and tendons ICC: 0.96 (95% CI 0.95, 0.97).

Conclusion

A comprehensive and reliable paediatric ankle US scanning protocol and scoring system for the assessment of synovitis and tenosynovitis were successfully developed. Further validation of this scoring system may allow its use as an outcome measure for both clinical and research applications.
How to Help My Older Patient With Obesity Lose Weight Safely When the Evidence Is Not Clear
Authors: Nowicki Kylie , Daugherty Janice E. , Craven Kay , Kolasa Kathryn M.
Published: October 2022

Until recently, despite the deleterious the health consequences of their obesity, intentional weight loss by older adults usually was not recommended. Factors such as maladaptive metabolic changes and declines in physiologic function predispose this population to sarcopenic obesity, frailty, and impaired mobility, while accumulation of chronic comorbidities often results in polypharmacy. These considerations and more complicate both the decision to pursue weight loss and the safest method of doing so. Currently, specific guidelines for managing weight loss in older adults with obesity are widely lacking. We present a case from our Family Medicine practice of an older woman with obesity struggling with weight management. We present our recommendations for safely navigating the weight loss she desires using an evidence-based approach that incorporates a medically supervised calorie restricted diet, improved diet quality, and healthy physical activity recommendations that include resistance exercise.
Non-Synonymous, Synonymous, and Non-Coding Nucleotide Variants Contribute to Recurrently Altered Biological Processes During Retinoblastoma Progression
Authors: Stachelek Kevin , Harutyunyan Narine , Lee Susan , Beck Assaf , Kim Jonathan , Xu Liya , Berry Jesse L. , Nagiel Aaron , Reynolds C. Patrick , Murphree A. Linn , Lee Thomas C. , Aparicio Jennifer G. , Cobrinik David
Published: October 2022

Retinoblastomas form in response to biallelicRB1mutations orMYCNamplification and progress to more aggressive and therapy-resistant phenotypes through accumulation of secondary genomic changes. Progression-related changes include recurrent somatic copy number alterations and typically non-recurrent nucleotide variants, including synonymous and non-coding variants, whose significance has been unclear. To assess synonymous and non-coding variant contributions to recurrently altered processes, we identified altered genes and over-represented variant gene ontologies in 168 exome or whole-genome-sequenced retinoblastomas and 12 tumor-matched cell lines. In addition to initiatingRB1mutations,MYCNamplification, and established retinoblastoma SCNAs, the analyses revealed enrichment of variant genes related to diverse biological processes including histone monoubiquitination, mRNA processing (P) body assembly, and mitotic sister chromatid segregation and cytokinesis. Importantly, inclusion of non-coding and synonymous variants increased the enrichment significance of each over-represented biological process term. To assess the effects of such mutations, we performed functional tests of 3’ UTR variants ofPCGF3(a BCOR-binding component of Polycomb repressive complex I) andCDC14B(a regulator of sister chromatid segregation) and a synonymous variant ofDYNC1H1(a regulator of P-body assembly).PCGF3andCDC14B3’ UTR variants impaired gene expression whereas a base-editedDYNC1H1synonymous variant altered protein structure and stability. Compared to tumors, retinoblastoma cell lines had a partially overlapping variant gene spectrum and enrichment for p53 pathway mutations. These findings reveal potentially important differences in retinoblastoma cell lines and antecedent tumors and implicate synonymous and non-coding variants, along with non-synonymous variants, in retinoblastoma oncogenesis.
Prediction of Electric Fields Induced by Transcranial Magnetic Stimulation in the Brain using a Deep Encoder-Decoder Convolutional Neural Network
Authors: Tashli Mohannad , Alam Muhammad Sabbir , Gong Jiaying , Lewis Connor , Peterson Carrie L. , Eldardiry Hoda , Atulasimha Jayasimha , Hadimani Ravi L.
Published: October 2022

Transcranial magnetic stimulation (TMS) is a non-invasive, effective, and safe neuromodulation technique to diagnose and treat neurological and psychiatric disorders. However, the complexity and heterogeneity of the brain composition and structure pose a challenge in accurately determining whether critical brain regions have received the right level of induced electric field. Numerical computation methods, like finite element analysis (FEA), can be used to estimate electric field distribution. However, these methods need exceedingly high computational resources and are time-consuming. In this work, we developed a deep convolutional neural network (DCNN) encoder-decoder model to predict induced electric fields, in real-time, from T1-weighted and T2-weighted magnetic resonance imaging (MRI) based anatomical slices. We recruited 11 healthy subjects and applied TMS to the primary motor cortex to measure resting motor thresholds. Head models were developed from MRIs of the subjects using the SimNIBS pipeline. Head model overall size was scaled to 20 new size scales for each subject to form a total of 231 head models. Scaling was done to increase the number of input data representing different head model sizes. Sim4Life, a FEA software, was used to compute the induced electric fields, which served as the DCNN training data. For the trained network, the peak signal to noise ratios of the training and testing data were 32.83dB and 28.01dB, respectively. The key contribution of our model is the ability to predict the induced electric fields in real-time and thereby accurately and efficiently predict the TMS strength needed in targeted brain regions.
Mechanical force induces DRP1-dependent asymmetrical mitochondrial fission for quality control
Authors: Liu Xiaoying , Xu Linyu , Song Yutong , Li Xinyu , Wong Cheuk-Yiu , Chen Rong , Feng Jianxiong , Chow Hei-Man , Yao Shuhuai , Gao Song , Liu Xingguo , Duan Liting
Published: October 2022

Mitochondria are membrane-bound organelles that perform diverse critical biological functions. They undergo constant fission and fusion, which are important for mitochondrial inheritance, functions, and quality control. While tremendous efforts have identified many factors governing mitochondria dynamics, emerging evidence indicates the involvement of various intracellular or extracellular mechanical cues. However, how mechanical stress directly modulates mitochondrial dynamics remains largely unknown. Here utilizing an optogenetic mitochondria-specific mechanostimulator to apply pulling forces to intracellular mitochondria, we find that mechanostimulation can promote mitochondrial fission, with sustained mechanostimulation triggering fission more effectively than transient one. Asymmetrical fission can occur at different sub-mitochondrial sites after force-induced mitochondrial elongation. Such force-induced fission is dependent on DRP1 and involves the wrapping of ER tubules. Moreover, mechanical force generates mitochondrial fragments without mtDNA which recruit Parkin proteins. Our results prove the mechanosensitivity and mechanoresponsiveness of mitochondria and reveal the role of mechanical cues in directly regulating mitochondrial dynamics.
Human acute microelectrode array recordings with broad cortical access, single-unit resolution and parallel behavioral monitoring
Authors: Eisenkolb Viktor M. , Held Lisa M. , Utzschmid Alexander , Lin Xiao-Xiong , Krieg Sandro M. , Meyer Bernhard , Gempt Jens , Jacob Simon N.
Published: October 2022

Human single-unit studies currently rely on neurosurgical procedures that provide only limited brain coverage and on recording devices that do not integrate easily into established surgical routines. Here, we report reliable and robust acute multi-channel recordings with broad cortical access using planar microelectrode arrays (MEA) implanted intracortically in awake brain surgery. We provide a comprehensive characterization of extracellular neuronal activity acquired intraoperatively in tumor patients with large open craniotomies. MEA implantation was fast, safe and yielded high-quality signals at the microcircuit, local field potential level, and at the cellular, single-unit level. Recording from parietal association cortex, a region previously unexplored in human single-unit studies, we demonstrate applications on these complementary spatial scales and describe travelling waves of oscillatory activity as well as single-neuron and neuronal population responses during numerical cognition including operations with uniquely human number symbols. Intraoperative MEA recordings are practicable and can be scaled up to explore cellular and microcircuit mechanisms of a wide range of human brain functions.
Multi-omics Analysis Identifies IgG2b Class-Switching with ALCAM-CD6 Co-Stimulation in Lymph Nodes During Advanced Inflammatory-Erosive Arthritis
Authors: Kenney H. Mark , Rangel-Moreno Javier , Peng Yue , Chen Kiana L. , Bruno Jennifer , Embong Abdul , Pritchett Elizabeth , Fox Jeffrey I. , Quataert Sally , Muthukrishnan Gowrishankar , Wood Ronald W. , Korman Benjamin D. , Anolik Jennifer H. , Xing Lianping , Ritchlin Christopher T. , Schwarz Edward M. , Wu Chia-Lung
Published: October 2022

Defective lymphatic drainage and B-cell translocation into joint-draining lymph node sinuses are pathogenic phenomena in patients with severe rheumatoid arthritis (RA). However, the molecular mechanisms underlying this lymphatic dysfunction remain poorly understood. Here, by utilizing spatial and single-cell transcriptomics in tumor necrosis factor transgenic (TNF-Tg) mice, we characterized functional genomic changes in popliteal lymph nodes (PLNs) of “Early” and “Advanced” RA to determine the mechanisms orchestrating B-cell differentiation. We first show thatIghg2bexpression localized to Marco+sinuses and negatively correlated with bone volumes in ipsilateral joints. We further reveal that Advanced PLNs exhibited a concomitant accumulation of iron-laden macrophages and T-cells. Mechanistically, crosstalk between ALCAM+macrophages and CD6+T-cells was identified as a co-stimulatory pathway promoting IgG2b class-switching. These findings were validated by immunohistochemistry, flow cytometry, ELISPOT, and clinical correlates. Collectively, we propose that ALCAM-CD6 co-stimulation activates T cells, initiating IgG2b class-switching and plasma cell differentiation in RA flare.
Ancestry-related differences in chromatin accessibility and gene expression ofAPOE4are associated with Alzheimer disease risk
Authors: Celis Katrina , Muniz Moreno Maria DM. , Rajabli Farid , Whitehead Patrice , Hamilton-Nelson Kara , Dykxhoorn Derek M. , Nuytemans Karen , Wang Liyong , Dalgard Clifton L. , Flanagan Margaret , Weintraub Sandra , Geula Changiz , Gearing Marla , Bennett David A. , Schuck Theresa , Jin Fulai , Pericak-Vance Margaret A. , Griswold Anthony J. , Young Juan I. , Vance Jeffery M.
Published: October 2022

Background

European local ancestry (ELA) surroundingAPOE4is associated with a higher risk for Alzheimer Disease (AD) compared to African local ancestry (ALA). We previously demonstrated significantly higherAPOE4expression in ELA vs ALA in the frontal cortex ofAPOE4/4AD patients. Differences in chromatin accessibility could contribute to these differences inAPOE4expression.

Methods

We performed single nuclei Assays for Transposase Accessible Chromatin sequencing (snATAC-seq) and single nuclei RNA sequencing (snRNA-seq) from frozen frontal cortex of six ALA and six ELA AD patients, all homozygous for local ancestry andAPOE4.

Results

We demonstrated thatAPOE4, including its promoter area, has greater chromatin accessibility in ELA vs ALA astrocytes. This increased accessibility in ELA astrocytes extended genome wide. Genes with increased accessibility and expression in ELA in astrocytes were enriched for synaptic function, cholesterol processing and astrocyte reactivity.

Conclusion

Our results suggest that increased chromatin accessibility ofAPOE4in astrocyte with the ELA contributes to the observed elevatedAPOE4expression, corresponding to the increased AD risk in ELA vs ALAAPOE4/4carriers.
Drug Reinforcement Impairs Cognitive Flexibility by Inhibiting Striatal Cholinergic Neurons
Authors: Gangal Himanshu , Xie Xueyi , Cheng Yifeng , Wang Xuehua , Lu Jiayi , Zhuang Xiaowen , Essoh Amanda , Huang Yufei , Smith Laura N. , Smith Rachel J. , Wang Jun
Published: October 2022

The mechanisms underlying the reduction in cognitive flexibility associated with reinforcement of addictive substance use are unknown. This reinforcement is mediated by substance-induced synaptic plasticity in direct-pathway medium spiny neurons (dMSNs) that project to the substantia nigra (SNr). Cognitive flexibility is mediated by cholinergic interneurons (CINs), which receive extensive local inhibition from the striatum. Here, we report that cocaine or alcohol administration caused a long-lasting potentiation of local inhibitory dMSN→CIN transmission in the dorsomedial striatum (DMS), a brain region critical for goal-directed behavior and cognitive flexibility. This dMSN→CIN potentiation reduced CIN firing activity. Furthermore, chemogenetic and time-locked optogenetic inhibition of DMS CINs suppressed cognitive flexibility in an instrumental reversal learning task. Importantly, rabies-mediated tracing and physiological studies revealed that SNr-projecting dMSNs, which mediate reinforcement, sent axonal collaterals to inhibit DMS CINs, which mediate flexibility. Our findings demonstrate that the local inhibitory dMSN→CIN circuit mediates a reinforcement-induced reduction in cognitive flexibility.

HIGHLIGHTS

Cocaine reinforcement inhibits striatal cholinergic interneurons (CINs) and impairs cognitive flexibility.

Optogenetic and chemogenetic CIN inhibition impairs cognitive flexibility.

Reinforcement behaviors potentiate inhibitory transmission from direct-pathway medium spiny neurons (dMSNs) to CINs.

Substantia nigra-projecting dMSNs mediate reinforcement and also send collaterals that inhibit CINs.
Bacterial Strategies for Damage Management
Authors: Joshi Kunaal , Gandhi Rhea , Krakauer David C. , Iyer-Biswas Srividya , Kempes Christopher P.
Published: October 2022

Organisms are able to partition resources adaptively between growth and repair. The precise nature of optimal partitioning and how this emerges from cellular dynamics including insurmountable trade-offs remains an open question. We construct a mathematical framework to estimate optimal partitioning and the corresponding maximal growth rate constrained by empirical scaling laws. We model a biosynthesis tradeoff governing the partitioning of the ribosome economy between replicating functional proteins and replicating the ribosome pool, and also an energy tradeoff arising from the finite energy budget of the cell. Through exact analytic calculations we predict limits on the range of values partitioning ratios take while sustaining growth. We calculate how partitioning and cellular composition scale with protein and ribosome degradation rates and organism size. These results reveal different classes of optimizing strategies corresponding to phenotypically distinct bacterial lifestyles. We summarize these findings in a quadrant-based taxonomy including: a “greedy” strategy maximally prioritizing growth, a “prudent” strategy maximally prioritizing the management of damaged pools, and “strategically limited” intermediates.
High air humidity dampens salicylic acid pathway and plant resistance via targeting of NPR1
Authors: Yao Lingya , Jiang Zeyu , Wang Yiping , Wan Shiwei , Xin Xiu-Fang
Published: October 2022

The occurrence of plant disease is determined by interactions among host, pathogen and climate conditions. Air humidity has long been recognized to profoundly influence diseases in the phyllosphere and high air humidity (e.g., after rain falls) is known as a prerequisite for numerous disease outbreaks in the field1–3. However, the molecular basis of how high humidity interferes with plant resistance mechanisms to favor disease remained elusive. Here we show that high humidity is associated with an “immune-compromised” status of plants, revealed by lower expression of defense genes during bacterial infection of Arabidopsis plants. Examination of humidity’s effect on individual immune pathways showed that the accumulation and signaling of salicylic acid (SA), an essential hormone conferring plant resistance against infectious microbes4,5, are significantly inhibited under high humidity. Surprisingly, NPR1 protein, an SA receptor and central transcriptional co-activator of SA-responsive genes6–9, accumulated to a significantly higher level in the nucleus under high humidity. Further investigation indicated a decreased binding affinity of NPR1 protein to the target gene promoter, suggestive of an “inactive” nature of NPR1, under high humidity and an impaired ubiquitination and degradation of NPR1 protein, likely due to down-regulation of Cullin 3-mediated cellular ubiquitination pathway and 26S proteasome pathway under high humidity. Our study uncovers disruption of NPR1 protein turnover as a major mechanism, by which high humidity dampens plant immune strength against pathogens, and provides new insights into the long-observed air humidity influence on diseases in nature.
Structural and Functional insights into the action mode of a Mitochondrial AAA+ Disaggregase CLPB
Authors: Wu Damu , Liu Yan , Dai Yuhao , Wang Guopeng , Lu Guoliang , Chen Yan , Li Ningning , Lin Jinzhong , Gao Ning
Published: October 2022

“The authors have withdrawn their manuscript because of duplicate posting. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.

The correct preprint can be found athttps://doi.org/10.1101/2022.03.10.483744”
A two-pool mechanism of vesicle release in medial habenula terminals underlies GABABreceptor-mediated potentiation
Authors: Koppensteiner Peter , Bhandari Pradeep , Önal Cihan , Borges-Merjane Carolina , Le Monnier Elodie , Nakamura Yukihiro , Sadakata Tetsushi , Sanbo Makoto , Hirabayashi Masumi , Brose Nils , Jonas Peter , Shigemoto Ryuichi
Published: October 2022

GABABreceptor (GBR) activation inhibits neurotransmitter release in axon terminals in the brain, except in medial habenula (MHb) terminals, which show robust potentiation. However, mechanisms underlying this enigmatic potentiation remain elusive. Here, we report that GBR activation induces a transition from tonic to phasic release accompanied by a 4-fold increase in readily releasable pool (RRP) size in MHb terminals, mirrored by a similar increase in the docked vesicle number at the presynaptic active zone (AZ). The tonic and phasic release vesicles have distinct coupling distances. We identified two vesicle-associated molecules, synaptoporin and CAPS2, selectively involved in tonic and phasic release, respectively. Synaptoporin mediates augmentation of tonic release and CAPS2 stabilizes readily releasable vesicles during phasic release. A newly developed “Flash and Freeze-fracture” method revealed selective recruitment of CAPS2 to the AZ during phasic release. Thus, we propose a novel two-pool mechanism underlying the GBR-mediated potentiation of release from MHb terminals.
Mice lackingPtprdexhibit deficits in goal-directed behavior and female-specific impairments in sensorimotor gating
Authors: Ho EV , Welch A , Knowles JA , Dulawa SC
Published: October 2022

Protein Tyrosine Phosphatase receptor type D (PTPRD) is a member of the protein tyrosine phosphatase family that mediates cell adhesion and synaptic specification. Genetic studies have linkedPtprdto several neuropsychiatric phenotypes, including Restless Leg Syndrome (RLS), opioid abuse disorder, and antipsychotic-induced weight gain. Genome-wide association studies (GWAS) of either pediatric obsessive-compulsive traits, or Obsessive-Compulsive Disorder (OCD), have identified loci nearPtprdas genome-wide significant, or strongly suggestive for this trait. We assessedPtprdwild-type (WT), heterozygous (HT), and knockout (KO) mice for behavioral dimensions that are altered in OCD, including anxiety and exploration (open field test, dig test), perseverative behavior (splash-induced grooming, spatiald), sensorimotor gating (prepulse inhibition), and home cage goal-directed behavior (nest building). No effect of genotype was observed in any measure of the open field test, dig test, or splash test. However,PtprdKO mice of both sexes showed impairments in nest building behavior. Finally, female, but not male,PtprdKO mice showed deficits in prepulse inhibition, an operational measure of sensorimotor gating that is reduced in female, but not male, OCD patients. Our results indicate that constitutive lack ofPtprdmay contribute to the development of certain domains that are altered OCD, including goal-directed behavior, and reduced sensorimotor gating specifically in females.
Palmitoylation regulates neuropilin-2 localization and function in cortical neurons and conveys specificity to semaphorin signaling via palmitoyl acyltransferases
Authors: Koropouli Eleftheria , Wang Qiang , Mejias Rebeca , Hand Randal , Wang Tao , Ginty David D. , Kolodkin Alex L.
Published: October 2022

Secreted semaphorin 3F (Sema3F) and semaphorin 3A (Sema3A) exhibit remarkably distinct effects on deep layer excitatory cortical pyramidal neurons; Sema3F mediates dendritic spine pruning, whereas Sema3A promotes the elaboration of basal dendrites. Sema3F and Sema3A signal through distinct holoreceptors that include neuropilin-2 (Nrp-2)/plexinA3 (PlexA3) and neuropilin-1 (Nrp-1)/PlexA4, respectively. We find that Nrp-2 and Nrp-1 are S-palmitoylated in cortical neurons and that palmitoylation of select Nrp-2 cysteines is required for its proper subcellular localization and also for Sema3F/Nrp-2-dependent dendritic spine pruning in cortical neurons, both in vitro and in vivo. Moreover, we show that the palmitoyl acyltransferase DHHC15 is required for Nrp-2 palmitoylation and Sema3F/Nrp-2-dependent dendritic spine pruning, but it is dispensable for Nrp-1 palmitoylation and Sema3A/Nrp-1-dependent basal dendritic elaboration. Therefore, palmitoyl acyltransferase-substrate specificity is essential for establishing compartmentalized neuronal structure and functional responses to extrinsic guidance cues.

HIGHLIGHTS

Neuropilins (Nrps) are S-palmitoylated in vitro and in vivo in the central nervous system

S-palmitoylation of select Nrp-2 cysteines confers subcellular localization specificity and is required for semaphorin 3F-dependent dendritic spine pruning in cortical neurons

Distinct palmitoyl acyltransferases mediate Nrp-2 and Nrp-1 palmitoylation and function, imparting specificity to semaphorin signaling
Matrix Metalloproteinase Activity During Methamphetamine Cued Relapse
Authors: Lewandowski Stacia I. , Hodebourg Ritchy , Wood Samuel K. , Carter Jordan S. , Nelson Katherine , Kalivas Peter W. , Reichel Carmela M.
Published: October 2022

Relapse to drug seeking involves transient synaptic remodeling that occurs in response to drug associated cues. This remodeling includes activation of matrix metalloproteinases (MMPs) to initiate catalytic signaling in the extracellular matrix (ECM) in the nucleus accumbens core (NAcore). We hypothesized that MMP activity would be increased in the NAcore during cue-induced methamphetamine (meth) seeking in a rat model of meth use and relapse. Male and female rats had indwelling jugular catheters and bilateral intracranial cannula targeting the NAcore surgically implanted. Following recovery, rats underwent meth or saline self-administration (6hr/day for 15 days) in which active lever responding was paired with a light+tone stimulus complex, followed by home cage abstinence. Testing occurred after 7 or 30 days of abstinence. On test day, rats were microinjected with a FITC-quenched gelatin substrate that fluoresces following cleavage by MMPs, allowing for the quantification of gelatinase activity by MMP-2 and −9 during cued relapse testing. MMP-2,9 activity was significantly increased in the NAcore by meth cues presentation after 7 and 30 days of abstinence, indicating that remodeling by MMPs occurs during presentation of meth associated cues. Surprisingly, while cue-induced seeking increased between days 7 and 30, suggesting behavioral incubation, MMP-2,9 activity did not increase. These findings indicate that while MMP activation is elicited during meth cue-induced seeking, MMP activation did not parallel the behavioral incubation that occurs during extended drug abstinence.
Circadian regulation of glutamate release pathways shapes synaptic throughput in the brainstem nucleus of the solitary tract (NTS)
Authors: Ragozzino Forrest J. , Peterson BreeAnne , Karatsoreos Ilia N. , Peters James H.
Published: October 2022

Circadian regulation of autonomic reflex pathways pairs physiological function with the daily light cycle. The brainstem nucleus of the solitary tract (NTS) is a key candidate for rhythmic control of the autonomic nervous system. Here we investigated circadian regulation of NTS neurotransmission and synaptic throughput using patch-clamp electrophysiology in brainstem slices from mice. We found that spontaneous quantal glutamate release on to NTS neurons showed strong circadian rhythmicity, with the highest rate of release during the light phase and the lowest in the dark, that were sufficient to drive day / night differences in constitutive postsynaptic action potential firing. In contrast, afferent-evoked action potential throughput was enhanced during the dark and diminished in the light. Afferent-driven synchronous release pathways showed a similar decrease in release probability that did not explain the enhanced synaptic throughput during the night. However, analysis of postsynaptic membrane properties revealed diurnal changes in conductance; which, when coupled with the circadian changes in glutamate release pathways, tuned synaptic throughput between the light and dark phases. These coordinated pre- / postsynaptic changes encode nuanced control over synaptic performance and pair NTS action potential firing and vagal throughput with time of day.