bluuebunny/crossref_metadata_2025 huggingface dataset:
Fatal SARS-CoV-2-Associated Panton-Valentine Leukocidin-producing Staphylococcal Bacteremia
Authors: Nygaard Ulrikka , Petersen Andreas , Larsen Anders Rhod , Rytter Maren Johanne Heilskov , Hartling Ulla , Kirkby Nikolai , Hansen Rikke Nymark , Nielsen Allan Bybeck , Lundstrøm Kaare , Holm Mette , Vissing Nadja Hawwa
Published: January 2022

We reviewed all cases of Panton-Valentine leukocidin-producing Staphylococcus aureus (PVL-SA) bacteremia in Danish children between 2016 and 2021. We found 2 fatal cases with preceding viral prodrome due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Given the usual benign course of SARS-CoV-2 infection in children, awareness of possible superinfection with PVL-SA in a child with rapid deterioration is crucial to ensure adequate treatment, including antimicrobial drugs with antitoxin effect.
Titanium T-Plate as a Stabilizing Platform in the Management of Acquired Nystagmus and Oscillopsia Without a Null Zone
Authors: Chen Ying , Stevens Shanlee , Topilow Nicole , Capo Hilda , Tse David
Published: January 2022

The primary goal of nystagmus treatment is to improve visual function and quality of life. Current surgical interventions are limited by regression of effect, serious complications, and reliance on a null zone. Tse and colleagues in 2017 reported the use of a T-plate/suture fixation platform for globe stabilization to treat acquired nystagmus and oscillopsia without a null zone in a patient with bilateral internuclear ophthalmoplegia. However, the improvement in nystagmus was not objectively quantified. This case series reports 2 patients who underwent bilateral T-plate placement which resulted in immediate and sustained improvement of nystagmus objectively measured by videonystagmography.
Bilateral Concurrent Endocrine Mucin-Producing Sweat Gland Carcinoma and Mucinous Carcinoma of the Eyelids
Authors: Wang Diane , Deng Wenyu , LoBue Stephen , Giovinazzo Katherine , Rosen Meryl , Heilman Edward , Hodgson Nickisa M.
Published: January 2022

Endocrine mucin-producing sweat gland carcinoma (EMPSGC) is thought to be a precursor to mucinous carcinoma, both of which are rare. In this case report, the authors present a 55-year-old woman with concurrent EMPSGC and mucinous carcinoma manifesting with 2 distinct lesions on her left upper and lower eyelid and 1 lesion on her right lower eyelid. Biopsy and immunohistochemical staining supported primary cutaneous origin of the tumors. Systemic metastatic workup was initiated and thus far negative. The patient underwent staged slow Mohs micrographic surgery to remove one tumor at a time, with delayed reconstruction. This is the first reported case of EMPSGC and mucinous carcinoma presenting as distinct lesions both bilaterally and synchronously.
Long-term Outcome After Acute Peripheral Facial Palsy
Authors: Ramsey David J. , Haas Laura P. , Tucker Susan M.
Published: January 2022

Purpose:

To analyze long-term outcomes in a large cohort of patients with acute peripheral facial palsy (APFP).

Methods:

Hospital-based, cross-sectional study. Data were abstracted from the electronic medical record. Time to recovery was assessed with Kaplan-Meier survival analyses. Binary logistic regression analysis was used to identify factors associated with outcome.

Results:

Three hundred seventy-two patients with APFP seen at a tertiary hospital between February 2015 and March 2021 were analyzed. Seasonal variation of APFP peaked in the early fall (September 29) and had a peak-to-low ratio of 1.36 (R2 = 0.329, p < 0.001). Patients who tested positive for Lyme disease (10%) had an earlier peak (July 16) compared with those who were negative (October 15). Eighty-seven percent of patients had complete recovery (averaging 64 ± 61 days). Patients, with higher House-Brackmann (H-B) grades at presentation took longer to recover, were more likely to have aberrant regeneration and had lower final rates of recovery compared with those with lower H-B grades (χ2 = 12.03, p < 0.001). Of the patients with residual palsies, 70% had evidence of aberrant regeneration, and nearly half of those had hemifacial spasm.

Conclusions:

Most patients with APFP achieve complete recovery within 1 year, including those positive for Lyme. More severe palsy at presentation portends a worse outcome.
Orbital Exenteration for Advanced Periocular Adnexal Malignancies: Curative Versus Palliative Surgical Intent
Authors: Malik Mohsan , Vahdani Kaveh , Rose Geoffrey E. , Daniel Claire , Uddin J. M. , Verity D. H. , Collin J. R. O.
Published: January 2022

Purpose:

To evaluate the survival benefit of orbital exenteration in periocular malignancy, taking account of preoperative intent.

Patients and methods:

Patients undergoing exenteration had retrospective chart review for demographics, clinical features, radiology, histology, and outcome. Based on systemic tumor status, the patient was either “Class I” (with absent or well-controlled systemic disease) or “Class II” (incurable active metastatic disease), and based on the extent of orbital disease and exenteration intent, was classed as either “Group A” (locally curative) or “Group B” (locally palliative).

Results:

One hundred thirty-three patients (78 females; 59%) underwent exenteration at an average age of 61 years (median 64; range 5–91) for sebaceous, squamous and basal cell carcinomas, or for melanoma (22%, 19%, 11%, and 28%, respectively). There were 20% systemically incurable patients (26/133; Class II), and incurable local disease (“Group B”) in 5% (5/107) of Class I and 15% (4/26) Class II patients. The overall survival (OS) was 88% at 12 months, 57% at 5 years, and 41% at 10 years, prognosis being worse with age more than 70 years (p = 0.005), prior local radiotherapy (p = 0.005) or positive resection margins (p = 0.002). The mean OS for Type IA exenteration (145 months; 95% CI 122–168) was significantly different to 50 months for Type IB (95% CI 22–79; p = 0.02); likewise, OS for Type IIA procedures (31 months; 95% CI 11–51) was different to Type IIB (19 months; 95% CI 2–36) (p = 0.001).

Conclusion:

Exenteration confers a significant survival with advanced periocular malignancies, even in patients with uncontrollable systemic disease, or where the local disease is deemed incurable.
Emotion Management for College Students: Effectiveness of a Mindfulness-Based Emotion Management Intervention on Emotional Regulation and Resilience of College Students
Authors: Jia-Yuan Zhang , Xiang-Zi Ji , Yi-Nan Fan , Yu-Xia Cui
Published: January 2022

The discovery of psychological healing methods that are easy to master and can be developed by the individual as a means of improving students' self-psychological adjustment ability is of great practical value. This study is a randomized control trial intended to investigate the effectiveness of mindfulness-based emotion management interventions and to test their effects on the mood state and resilience of college students. A total of 72 students were recruited and randomly divided into an intervention group and a control group. Thirty-six students in the intervention group received a modified mindfulness-based emotion management intervention once per week for 4 weeks, with each intervention having a duration of 80 minutes. Participants were assessed by questionnaires to measure mindfulness level, emotion, and resilience before and after intervention. There were significant interaction effects on mindfulness level (F = 97.76, p < 0.00), mood state (F = 353.52, p < 0.00), and resilience (F = 178.99, p < 0.00) scores. A modified 4-week mindfulness-based emotion management intervention can improve the mindfulness level and resilience of college students and is an innovative and feasible strategy for enhancing mental health in college students.
Uncertainty, Stress, and Resilience During the COVID-19 Pandemic in Greece
Authors: Nikopoulou Vasiliki A. , Gliatas Ioannis , Blekas Apostolos , Parlapani Eleni , Holeva Vasiliki , Tsipropoulou Virginia , Karamouzi Panayiota , Godosidis Athanasios , Diakogiannis Ioannis
Published: January 2022

The COVID-19 outbreak imposed stress worldwide, as daily routine changed almost overnight, with no time to prepare. A pandemic like this may trigger a chain reaction starting out as surprise, continuing to uncertainty and ending up either in adaptation or in symptoms of fear, anxiety, and/or depression. Resilience on the other hand could lessen anxiety and prove to be a prophylactic coping mechanism against distress. This study explored peritraumatic distress, intolerance of uncertainty (IU), and resilient coping in a sample of 2717 adults who voluntarily and anonymously participated in an online survey conducted in April 2020, in Greece.

Results indicated a moderate pandemic-related mental burden and medium resilient coping and designated IU as a significant positive predictor of peritraumatic distress; resilient coping proved to be a significant moderator that alters the strength of the association between IU and distress reactions.
Examining Web-Based Learning to Enhance Nurse Training and the Standardization of Clinical Practice Within Complex Global Nursing Systems
Authors: Schneider Mary Beth , Hoffman Sarah J. , Mann Erin , Miko Shanna
Published: January 2022

Nurses are the backbone of health assessments and key to safeguarding health services for people who are displaced and migrating. Training and dissemination of information among an international workforce requires innovative delivery methods that address the barriers of traditional in-person training. This quality improvement project endorsed web-based learning as a viable platform to disseminate information and support a standardized approach to professional development of nurses working in a complex and dynamic international healthcare setting.
Partner-Level and Sexual Networking Factors Are Associated With Vaccine-Type and Nonvaccine-Type Human Papillomavirus Infection After Vaccine Introduction in Young Women
Authors: Kahn Jessica , Washington Chalita , Ding Lili , Wyllie Tornia , Rosen Brittany , Gorbach Pamina
Published: January 2022

Background

The aim of this study was to determine individual-level, partner-level, and sexual networking factors associated with vaccine- and non–vaccine-type human papillomavirus (HPV) in young women, by vaccination status.

Methods

Sexually experienced women 13 to 26 years old (n = 784) completed a survey and were tested for 36 HPV genotypes. We determined factors associated with 4-valent vaccine-type HPV (HPV-6, HPV-11, HPV-16, HPV-18) and non–vaccine-type HPV among vaccinated and unvaccinated women, using univariable and multivariable logistic regression models.

Results

Participants' mean age was 19.2 years, 77.7% had received ≥1 vaccine dose, and 7.7% were positive for vaccine-type HPV (HPV-6, HPV-11, HPV-16, and/or HPV-18). Factors associated with vaccine-type HPV in vaccinated women included gonorrhea history (adjusted odds ratio [AOR], 2.71), new female sex partner(s) (AOR, 4.79), age at vaccination (≥15 vs. <15 years; AOR, 2.47), and age discordance with most recent partner (don't know vs. discordant; AOR, 9.17). Factors associated with non–vaccine-type HPV in vaccinated women included history of sexually transmitted infection (AOR, 2.69), male most recent partner (AOR, 2.85), age of first sex (AOR, 1.15), and partner concurrency (don't know vs. 1 other partner; AOR, 2.03). Factors associated with vaccine-type HPV in unvaccinated women included new female sex partner(s) (AOR, 7.45) and partner concurrency (don't know vs. no; AOR, 2.95). Factors associated with non–vaccine-type HPV in unvaccinated women included race (White vs. multiracial; AOR, 4.10) and partner concurrency (don't know vs. 0; AOR, 4.65).

Conclusions

Novel findings of this study, including associations between female sex partners and HPV, and between not knowing about partner concurrency and HPV, have implications for sexual education, clinical counseling, and public health interventions.
Transcranial Magnetic Stimulation Therapy of Major Depressive Disorder Improves Heart Rate Variability
Authors: Onyilo Chukwuemeka V. , McCall William V. , Rosenquist Peter
Published: January 2022

Transcranial magnetic stimulation is typically administered daily for 6 to 9 weeks with gradual resolution of major depressive disorder. However, there is little evidence to guide clinicians when clinical improvement is not forthcoming as the course proceeds. We describe a patient whose depression score remained unchanged after 10 single daily intermittent thetaburst transcranial magnetic stimulation sessions targeting F3 in the dorsolateral prefrontal cortex and our efforts to modify the technique and monitor progress with heart rate variability (HRV) measures. The motor threshold position and intensity were verified to be unchanged from the baseline visit. Stimulation of F3 and treatment target 6 cm anterior to the mapped motor cortex site seemed to slow heart rate and increase HRV equally. We increased the number of daily intermittent thetaburst pulse trains for the remainder of the treatment course, targeting the 6-cm target. Our patient subsequently improved, and we observed concurrent changes in HRV suggestive of enhanced parasympathetic activity. These improvements were found to be durable at 10-week follow-up.
Distinct genetic determinants and mechanisms of SARS-CoV-2 resistance to remdesivir
Authors: Stevens Laura J. , Pruijssers Andrea J. , Lee Hery W. , Gordon Calvin J. , Tchesnokov Egor P. , Gribble Jennifer , George Amelia S. , Hughes Tia M. , Lu Xiaotao , Li Jiani , Perry Jason K. , Porter Danielle P. , Cihlar Tomas , Sheahan Timothy P. , Baric Ralph S. , Götte Matthias , Denison Mark R.
Published: January 2022

The nucleoside analog remdesivir (RDV) is an FDA-approved antiviral for the treatment of SARS- CoV-2 infections, and as such it is critical to understand potential genetic determinants and barriers to RDV resistance. In this study, SARS-CoV-2 was subjected to 13 passages in cell culture with increasing concentrations of GS-441524, the parent nucleoside of RDV. At passage 13 the RDV resistance of the lineages ranged from 2.7-to 10.4-fold increase in EC50. Sequence analysis of the three lineage populations identified non-synonymous mutations in the nonstructural protein 12 RNA-dependent RNA polymerase (nsp12-RdRp): V166A, N198S, S759A, V792I and C799F/R. Two of the three lineages encoded the S759A substitution at the RdRp Ser759-Asp-Asp active motif. In one lineage, the V792I substitution emerged first then combined with S759A. Introduction of the S759A and V792I substitutions at homologous nsp12 positions in viable isogenic clones of the betacoronavirus murine hepatitis virus (MHV) demonstrated their transferability across CoVs, up to 38-fold RDV resistance in combination, and a significant replication defect associated with their introduction. Biochemical analysis of SARS-CoV-2 RdRp encoding S759A demonstrated a ∼10- fold decreased preference for RDV-triphosphate (RDV-TP) as a substrate, while nsp12-V792I diminished the UTP concentration needed to overcome the template-dependent inhibition associated with RDV. The in vitro selected substitutions here identified were rare or not detected in the >6 million publicly available nsp12-RdRp consensus sequences in the absence of RDV selection. The results define genetic and biochemical pathways to RDV resistance and emphasize the need for additional studies to define the potential for emergence of these or other RDV resistance mutations in various clinical settings.

One Sentence Summary

SARS-CoV-2 develops in vitro resistance to remdesivir by distinct and complementary mutations and mechanisms in the viral polymerase
Mass-Sensitive Particle Tracking to Characterize Membrane-Associated Macromolecule Dynamics
Authors: Steiert Frederik , Heermann Tamara , Hundt Nikolas , Schwille Petra
Published: January 2022

Short-lived or transient interactions of macromolecules at and with lipid membranes, an interface where a multitude of essential biological reactions take place, are inherently difficult to assess with standard biophysical methods. The introduction of mass-sensitive particle tracking (MSPT) constitutes an important step towards a thorough quantitative characterization of such processes. Technically, this was made possible through the advent of interferometric scattering microscopy (iSCAT)-based mass photometry (MP). When the background removal strategy is optimized to reveal the two-dimensional motion of membrane-associated particles, this technique allows the real-time analysis of both diffusion and molecular mass of unlabeled macromolecules on biological membranes. Here, a detailed protocol to perform and analyze mass-sensitive particle tracking of membrane-associated systems is described. Measurements performed on a commercial mass photometer achieve time resolution in the millisecond regime and, depending on the MP system, a mass detection limit down to 50 kDa. To showcase the potential of MSPT for the in-depth analysis of membrane-catalyzed macromolecule dynamics in general, results obtained for exemplary protein systems such as the native membrane interactor annexin V are presented.

This protocol describes an iSCAT-based image processing and single-particle tracking approach that enables the simultaneous investigation of the molecular mass and the diffusive behavior of macromolecules interacting with lipid membranes. Step-by-step instructions for sample preparation, mass-to-contrast conversion, movie acquisition, and post-processing are provided along-side directions to prevent potential pitfalls.
Return of the Tbx5; lineage-tracing reveals ventricular cardiomyocyte-like precursors in the injured adult mammalian heart
Authors: Siatra Panagiota , Vatsellas Giannis , Chatzianastasiou Athanasia , Balafas Evangelos , Manolakou Theodora , Papapetropoulos Andreas , Agapaki Anna , Mouchtouri Eleni-Taxiarchia , Korovesi Artemis G. , Mavroidis Manolis , Thanos Dimitrios , Beis Dimitris , Kokkinopoulos Ioannis
Published: January 2022

The single curative measure for heart failure patients is total heart transplantation, which is limited due to a shortage of donors, the need for immunosuppression and economic costs. Therefore, there is an urgent unmet need for identifying cell populations capable of cardiac regeneration that we will be able to trace and monitor. Injury to the adult mammalian cardiac muscle, often leads to a heart attack through the irreversible loss of a large number of cardiomyocytes, due to an idle regenerative capability. Recent reports in zebrafish indicate that Tbx5a is a vital transcription factor for cardiomyocyte regeneration. Preclinical data underscore the cardioprotective role of Tbx5 upon heart failure. Data from our earlier murine developmental studies have pinpointed a prominent unipotent Tbx5-expressing embryonic cardiac precursor cell population able to form cardiomyocytes,in vivo,in vitroandex vivo.

Using a developmental approach to an adult heart injury model and by employing a lineage-tracing mouse model as well as the use of single-cell RNA-seq technology, we identify a Tbx5-expressing ventricular cardiomyocyte-like precursor population, in the injured adult mammalian heart. The transcriptional profile of that precursor cell population is closer to that of neonatal than embryonic cardiomyocyte precursors. Tbx5, a cardinal cardiac development transcription factor, lies in the centre of a ventricular adult precursor cell population, which seems to be affected by neurohormonal spatiotemporal cues.

The identification of a Tbx5-specific cardiomyocyte precursor-like cell population, which is capable of dedifferentiating and potentially deploying a cardiomyocyte regenerative program, provides a clear target cell population for translationally-relevant heart interventional studies.
Circadian volume changes in hippocampal glia studied by label-free interferometric imaging
Authors: Kouzehgarani Ghazal Naseri , Kandel Mikhail E. , Sakakura Masayoshi , Dupaty Joshua S. , Popescu Gabriel , Gillette Martha U.
Published: January 2022

Complex brain functions, including learning and memory, arise in part from the modulatory role of astrocytes on neuronal circuits. Functionally, the dentate gyrus (DG) exhibits differences in the acquisition of long-term potentiation (LTP) between day and night. We hypothesize that the dynamic nature of astrocyte morphology plays an important role in the functional circuitry of hippocampal learning and memory, specifically in the DG. Standard microscopy techniques, such as differential interference contrast (DIC), present insufficient contrast for detecting changes in astrocyte structure and function and are unable to inform on the intrinsic structure of the sample in a quantitative manner. Recently, gradient light interference microscopy (GLIM) has been developed to upgrade a DIC microscope with quantitative capabilities such as single-cell dry mass and volume characterization. Here, we present a methodology for combining GLIM and electrophysiology to quantify the astrocyte morphological behavior over the day-night cycle. Colocalized measurements of GLIM and fluorescence allowed us to quantify the dry masses and volumes of hundreds of astrocytes. Our results indicate that, on average, there is a 25% cell volume reduction during the nocturnal cycle. Remarkably, this cell volume change takes place at constant dry mass, which suggests that the volume regulation occurs primarily through aqueous medium exchange with the environment.
Characterization of the minimal residual disease state reveals distinct evolutionary trajectories of human glioblastoma
Authors: Qazi Maleeha A. , Salim Sabra K. , Brown Kevin R. , Mickolajewicz Nicholas , Savage Neil , Han Hong , Subapanditha Minomi K. , Bakhshinyan David , Nixon Allison , Vora Parvez , Desmond Kimberly , Chokshi Chirayu , Singh Mohini , Khoo Amanda , Macklin Andrew , Khan Shahbaz , Tatari Nazanin , Winegarden Neil , Richards Laura , Pugh Trevor , Bock Nicholas , Mansouri Alireza , Venugopal Chitra , Kislinger Thomas , Goyal Sidhartha , Moffat Jason , Singh Sheila K.
Published: January 2022

Recurrence of solid tumors renders patients vulnerable to a distinctly advanced, highly treatment-refractory disease state that has an increased mutational burden and novel oncogenic drivers not detected at initial diagnosis. Improving outcomes for recurrent cancers requires a better understanding of cancer cell populations that expand from the post-therapy, minimal residual disease (MRD) state. We profiled barcoded tumor stem cell populations through therapy at tumor initiation/engraftment, MRD and recurrence in our therapy-adapted, patient-derived xenograft models of glioblastoma (GBM). Tumors showed distinct patterns of recurrence in which clonal populations exhibited either an a priori, pre-existing fitness advantage, or a priori equipotency fitness acquired through therapy. Characterization of the MRD state by single-cell and bulk RNA sequencing revealed a tumor-intrinsic immunomodulatory signature with strong prognostic significance at the transcriptomic level and in proteomic analysis of cerebrospinal fluid (CSF) collected from GBM patients at all stages of disease. Our results provide insight into the innate and therapy-driven dynamics of human GBM, and the prognostic value of interrogating the MRD state in solid cancers.
Sparse spike trains and the limitations of rate codes underlying rapid behaviour
Authors: Fabian Joseph M. , O’Carroll David C. , Wiederman Steven D.
Published: January 2022

Animals live in highly dynamic worlds, utilising sensorimotor circuits to rapidly process information and drive behaviours. For example, dragonflies are aerial predators which react to movements of prey within tens of milliseconds. These pursuits are likely controlled by identified neurons in the dragonfly, which have well-characterized physiological responses to moving targets. Predominantly, neural activity in these circuits are interpreted in the context of a rate code, where information is conveyed by changes in the number of spikes over a given time. However, such a description of neuronal activity is difficult to achieve in real-world, real-time scenarios. Here, we contrast a neuroscientists’ post-hoc view of spiking activity with the information available to the animal in real-time. We describe how performance of a rate code is readily overestimated and outline a rate code’s significant limitations in driving rapid behaviours.
Protein-Nucleic Acid Interactions for RNA Polymerase II Elongation Factors by Molecular Dynamics Simulations
Authors: Gallardo Adan , Bogart Brandon M. , Dutagaci Bercem
Published: January 2022

RNA polymerase II (Pol II) forms a complex with elongation factors to proceed the elongation stage of the transcription process. In this work, we studied elongation factor SPT5 and explored protein nucleic acid interactions for the isolated systems of KOW1 and KOW4 domains of SPT5 with DNA and RNA, respectively. We performed molecular dynamics (MD) simulations using three commonly used force fields that are CHARMM c36m, AMBER ff14sb and ff19sb. These simulations showed that most of the protein-nucleic acid interactions in the native state were retained with an increased electrostatic binding free energy for all force fields used. RNA was found highly dynamic with all force fields while DNA had relatively more stable conformations with the AMBER force fields compared to CHARMM. Furthermore, we performed MD simulations of the complete elongation complex using CHARMM c36m force field to compare the dynamics and interactions in the isolated systems. Similar strong KOW1 and DNA interactions were observed in the complete elongation complex simulations and DNA was further stabilized by a network of interactions involving SPT5-KOW1, SPT4 and rpb2 of Pol II. Overall, our study showed that the accuracy of force fields and the presence of the entire interaction network are important for elucidating the dynamics of protein-nucleic acid systems.
An allosteric agonist activates BK channels by perturbing coupling between Ca2+ binding and pore opening
Authors: Zhang Guohui , Xu Xianjin , Jia Zhiguang , Geng Yanyan , Liang Hongwu , Shi Jingyi , Marras Martina , Abella Carlota , Magleby Karl L. , Silva Jonathan R. , Chen Jianhan , Zou Xiaoqin , Cui Jianmin
Published: January 2022

BK type Ca2+-activated K+ channels activate in response to both the membrane voltage and intracellular Ca2+ with distinct mechanisms. Ca2+ binds to the cytosolic domain (CTD) to open the pore across the membrane, but the mechanism that couples Ca2+ binding to pore opening is not clear. Here we show that a compound, BC5, identified using in silico screening, interacts with BK channels at the interface between the CTD and the transmembrane voltage sensing domain (VSD) and enhances channel activity by specifically affecting the Ca2+ dependent mechanism. BC5 activates the channel in the absence of Ca2+ binding but Ca2+ binding inhibits BC5 effects. Thus, BC5 perturbs the pathway that couples Ca2+ binding to pore opening to allosterically affect both, which is supported by atomistic simulations and mutagensis. The results suggest that the CTD- VSD interaction makes a major contribution to the mechanism of Ca2+ dependent activation and is an important site for allosteric agonists to modulate BK channel activation.
The propensity to sign-track is associated with externalizing behaviour and distinct patterns of reward-related brain activation in youth
Authors: Colaizzi Janna M. , Flagel Shelly B. , Gearhardt Ashley N. , Borowitz Michelle A. , Kuplicki Rayus , Zotev Vadim , Clark Grace , Coronado Jennifer , Abbott Talia , Paulus Martin P.
Published: January 2022

Externalizing behaviours in childhood often predict impulse control disorders in adulthood; however, the underlying biobehavioural risk factors are incompletely understood. In animals, the propensity to signtrack, or the degree to which incentive motivational value is attributed to reward cues, is associated with externalizing-type behaviours and deficits in executive control. Using a Pavlovian conditioned approach paradigm, we quantified sign-tracking in healthy 9-12-year-olds. We also measured parent-reported externalizing behaviours and anticipatory neural activations to outcome-predicting cues using the monetary incentive delay fMRI task. Sign-tracking was associated with attentional and inhibitory control deficits and the degree of amygdala, but not cortical, activation during reward anticipation. These findings support the hypothesis that youth with a propensity to sign-track are prone to externalizing tendencies, with an over-reliance on subcortical cue-reactive brain systems. This research highlights sign-tracking as a promising experimental approach delineating the behavioural and neural circuitry of individuals at risk for externalizing disorders.
Development of an Ultra Low-Cost SSVEP-based BCI Device for Real-Time On-Device Decoding
Authors: Teversham James , Wong Steven S. , Hsieh Bryan , Rapeaux Adrien , Troiani Francesca , Savolainen Oscar , Zhang Zheng , Maslik Michal , Constandinou Timothy G.
Published: January 2022

This study details the development of a novel, approx. £20 electroencephalogram (EEG)-based brain-computer interface (BCI) intended to offer a financially and operationally accessible device that can be deployed on a mass scale to facilitate education and public engagement in the domain of EEG sensing and neurotechnologies. Real-time decoding of steady-state visual evoked potentials (SSVEPs) is achieved using variations of the widely-used canonical correlation analysis (CCA) algorithm: multi-set CCA and generalised CCA. All BCI functionality is executed on board an inexpensive ESP32 microcontroller. SSVEP decoding accuracy of 95.56 ± 3.74% with an ITR of 102 bits/min was achieved with modest calibration.
No priming, just fighting – endophytic yeast attenuates the defense response and the stress induced by Dutch elm disease inUlmus minor
Authors: Sobrino-Plata J. , Martínez-Arias C. , Ormeño-Moncalvillo S. , Fernández I. , Collada C. , Gil L. , Pieterse C.M.J. , Martín J.A.
Published: January 2022

One century after the first report of Dutch Elm Disease (DED), there is still no practical solution for this problem threatening European and American elms (Ulmusspp.). The long breeding cycles needed to select resistant genotypes and the lack of efficient treatments keep disease incidence at high levels. In the present work, the expression of defense-related genes to the causal agent of DED,Ophiostoma novo-ulmi, were analyzed in in vitro clonal plantlets from two DED-resistant and two DED-susceptibleU. minortrees. In addition, the effect of the inoculation of an endophytic pink-pigmented yeast (Cystobasidiumsp.) on the plant’s defense system was tested both individually and in combination withO. novo-ulmi. The multifactorial nature of the resistance to DED was confirmed, as no common molecular response was found in the two resistant genotypes. However, the in vitro experimental system allowed to discriminate the susceptible from the resistant genotypes, showing higher levels of oxidative stress and phenolic compounds in the susceptible genotypes after pathogen inoculation. Inoculation of the endophyte beforeO. novo-ulmiattenuated the plant molecular response induced by the pathogen and moderated oxidative stress levels. Niche competition, endophyte-pathogen antagonism, and molecular crosstalk between the host and the endophyte are discussed as possible mechanisms of stress reduction. In sum, our results confirm the multifactorial nature of DED resistance mechanisms and highlight the possibility of using certain endophytic yeasts as biological tools to improve tree resilience against biotic stress.
Hyperactivation of YAP/TAZ drives alterations in mesangial cells through stabilization of N-MYC in diabetic nephropathy
Authors: Choi Seunghyeok , Suh Sang Heon , Bae Hosung , Kang Kyung Pyo , Lee Hyuek Jong , Koh Gou Young
Published: January 2022

Mesangial cells (MCs) in the kidney are central to maintaining glomerular integrity, and their impairment leads to major glomerular diseases including diabetic nephropathy (DN). Although high blood glucose elicits abnormal alterations in MCs, the underlying molecular mechanism is poorly understood. Here, we show that YAP and TAZ, the final effectors of the Hippo pathway, are highly increased in MCs of patients with DN and of Zucker diabetic fatty rats. Moreover, high glucose directly induces activation of YAP/TAZ through the canonical Hippo pathway in cultured MCs. Hyperactivation of YAP/TAZ in mouse model MCs recapitulates the hallmarks of DN, including excessive proliferation of MCs and extracellular matrix deposition, endothelial cell impairment, glomerular sclerosis, albuminuria, and reduced glomerular filtration rate. Mechanistically, activated YAP/TAZ bind and stabilize N-Myc protein, one of the Myc family of oncogenes. N-Myc stabilization leads to aberrant enhancement of its transcriptional activity and eventually to MC impairments and DN pathogenesis. Together, these findings shed light on how high blood glucose in diabetes mellitus leads to DN and support a rationale that lowering blood glucose in diabetes mellitus could delay DN pathogenesis.
Nonlinear super-resolution signal processing allows intracellular tracking of calcium dynamics
Authors: Calcini Niccolò , da Silva Lantyer Angelica , Zeldenrust Fleur , Celikel Tansu
Published: January 2022

Fluorescence imaging of calcium dynamics has revolutionized cellular biology, and especially neuroscience as it allows the study of neural activity across spatially well defined populations. Quantification of fluorescence signals is commonly performed using ratiometric measures. These measures, such as ΔF/F, are easy to implement, but they depend on the definition of a baseline, which is often not trivial outside of the measurement of evoked responses, and needs to be defined for every cell (or other cellular compartment) separately. Here, we present a new quantitative measure of fluorescence by taking advantage of the time dimension of the signal. The new method, which we named ARES (Autoregressive RESiduals), is based on the quantification of residuals after linear autoregression and does not require arbitrary baseline assignment. We detail the basic characteristics of the ARES signal, compare it against ΔF/F, and quantify the improvement in spatial and temporal resolution of recorded calcium data. We further exemplify its utility in the study of intracellular calcium dynamics by describing the propagation of a calcium wave inside a dendrite. As a robust and accurate method for quantifying fluorescence signals, ARES is particularly well-suited for the study of spontaneous as well as evoked calcium dynamics, subcellular localization of calcium signals, and spatiotemporal tracking of calcium dynamics.

Highlights

A baseline-free quantitative measure of fluorescence is introduced

The method, called ARES, is based on autoregression

ARES improves the spatiotemporal resolution of calcium imaging recordings

Its utility for the localization and spatiotemporal tracking of calcium is shown
Altered meningeal immunity contributing to the autism-like behavior of BTBRT+Itpr3tf/J mice
Authors: Uddin Mohammad Nizam , Manley Kevin , Lawrence David A.
Published: January 2022

Autism spectrum disorder (ASD) is a complicated neurodevelopmental disorder, which is categorized by deficiency of social contact and communication, and stereotyped forms of performance. Meningeal immunity conditions the immune reflection and immune defense in the meningeal area involving meningeal lymphatic organization, glymphatic structure, immune cells, and cytokines. The development of meningeal immunity dysfunction might be the leading cause for many neural diseases including ASD. The inbred mouse strain BTBRT+Itpr3tf/J (BTBR) shows multiple ASD-like behavioral phenotypes, thus making this strain a widely used animal model for ASD. In our previous study, we reported an altered peripheral immune profile in BTBR mice. Herein, we are investigating immunological and neural interactions associated with the aberrant behavior of BTBR mice. BTBR mice have an increased level of immune cell deposition in the meninges along with a higher level of CD4+T cells expressing CD25 and of B and myeloid cells expressing more MHCII than C57BL/6 (B6) mice, which have normal behaviors. BTBR mice also have higher levels of autoantibodies to dsDNA, Aquaporin-4, NMDAR1, Pentraxin/SAP and Caspr2 than B6 mice, which may affect neural functions. Interestingly, the T regulatory (Treg) cell population and their function was significantly reduced in the meninges and brain draining lymph nodes, which may explain the increased level of activated B and T cells in the meninges of BTBR mice. A low level of Treg cells, less IL-10 production by Treg, and activated T and B cells in meninges together with higher autoantibody levels might contribute to the development of autism-like behavior through neuroinflammation, which is known to be increased in BTBR mice.

Highlights

BTBR mice have higher level of immune cell deposition in the meninges compared to C57BL/6 (B6) mice.

Meningeal T cells and B cells of BTBR mice express a higher level of CD25 and MHCII, respectively, than those of B6 mice.

BTBR mice have a higher level of serum autoantibodies to dsDNA and brain antigens (Aquaporin-4, NMDAR1, Pentraxin/SAP and Caspr2) than B6 mice.

T regulatory (Treg) cell population was reduced in the meninges and brain draining lymph nodes of BTBR mice with lower cytokine production of IL-10.

Fewer Treg cells and more activated meningeal T and B cells together with higher autoantibody levels might contribute to the development of the autism-like behavior of BTBR mice.
Categorization and discrimination of human and non-human primate affective vocalizations: investigation of the frontal cortex activity through fNIRS
Authors: Debracque C. , Ceravolo L. , Clay Z. , Grandjean D. , Gruber T.
Published: January 2022

Many species, including humans and non-human primates, react differently to threatening or pleasant situations. Because of its adaptiveness, recognizing affective signals is likely to be reflected in a capability of modern humans to recognize other closely related species’ call content. However, at both behavioural and neural levels, only few studies have used a comparative approach to understand affective decoding processes in humans, particularly with respect to affective vocalizations. Previous research in neuroscience about the recognition of human affective vocalizations has shown the critical involvement of temporal and frontal regions. In particular, frontal regions have been reported as crucial in the explicit decoding of vocal emotions especially in different task complexity such as discrimination or categorization. The aim of this study using functional Near Infrared Spectroscopy (fNIRS) was to specifically investigate the neural activity of the inferior frontal cortexpars triangularis(IFGtri) and the prefrontal cortex (PFC) underlying categorization (A versus B) and discrimination (A versus non-A) mechanisms of positive and negative affects in human, great apes (chimpanzee and bonobo), and monkey (rhesus macaque) vocalizations. We also analysed participants’ behavioural responses and correlated them with the recorded frontal activations. While performing the tasks, fNIRS data revealed a clear distinction between the two frontal regions, with a general positive activation of IFGtricompared to a decrease of PFC activity. We also found a modulation of IFGtriand PFC activations depending on both the species considered and on task complexity; with generally more activity in the IFGtriduring discrimination compared to categorization, and a more intense decrease of the PFC in categorization compared to discrimination. Behaviourally, participants recognized almost all affective cues in all species vocalizations at above chance levels in the discrimination task (except for threatening bonobo calls). For categorization, they mostly correctly identified at levels significantly above chance affective contents in human and great ape vocalizations but not in macaque calls. Overall, these findings support the hypothesis of a pre-human origin of affective recognition processing inherited from our common ancestor with other great apes and processed in the frontal cortex. Our results also highlight behavioural differences related to task complexity, i.e. between categorization and discrimination processes, and the differential involvement of the PFC and the IFGtri, which seems necessary to explicitly decode affects in all primate vocalizations.
Fast rule switching and slow rule updating in a perceptual categorization task
Authors: Bouchacourt F. , Tafazoli S. , Mattar M.G. , Buschman T.J. , Daw N.D.
Published: January 2022

To adapt to a changing world, we must be able to switch between rules already learned and, at other times, learn rules anew. Often we must do both at the same time, switching between known rules while also constantly re-estimating them. Here, we show these two processes, rule switching and rule learning, rely on distinct but intertwined computations, namely fast inference and slower incremental learning. To this end, we studied how monkeys switched between three rules. Each rule was compositional, requiring the animal to discriminate one of two features of a stimulus and then respond with an associated eye movement along one of two different response axes. By modeling behavior we found the animals learned the axis of response using fast inference (rule switching) while continuously re-estimating the stimulus-response associations within an axis (rule learning). Our results shed light on the computational interactions between rule switching and rule learning, and make testable neural predictions for these interactions.
Adjustment for Unmeasured Spatial Confounding in Settings of Continuous Exposure Conditional on the Binary Exposure Status: Conditional Generalized Propensity Score-Based Spatial Matching
Authors: Kim Honghyok , Bell Michelle
Published: February 2022

Propensity score (PS) matching to estimate causal effects of exposure is biased when unmeasured spatial confounding exists. Some exposures are continuous yet dependent on a binary variable (e.g., level of a contaminant (continuous) within a specified radius from residence (binary)). Further, unmeasured spatial confounding may vary by spatial patterns for both continuous and binary attributes of exposure. We propose a new generalized propensity score (GPS) matching method for such settings, referred to as conditional GPS (CGPS)-based spatial matching (CGPSsm). A motivating example is to investigate the association between proximity to refineries with high petroleum production and refining (PPR) and stroke prevalence in the southeastern United States. CGPSsm matches exposed observational units (e.g., exposed participants) to unexposed units by their spatial proximity and GPS integrated with spatial information. GPS is estimated by separately estimating PS for the binary status (exposed vs. unexposed) and CGPS on the binary status. CGPSsm maintains the salient benefits of PS matching and spatial analysis: straightforward assessments of covariate balance and adjustment for unmeasured spatial confounding. Simulations showed that CGPSsm can adjust for unmeasured spatial confounding. Using our example, we found positive association between PPR and stroke prevalence. Our R package, CGPSspatialmatch, has been made publicly available.
High temperature limits leaf size via direct control of cell cycle by coordinated functions of PIF4 and TCP4
Authors: Saini Kumud , Dwivedi Aditi , Ranjan Aashish
Published: February 2022

High ambient temperature suppresses Arabidopsis rosette leaf area, in contrast to elongation of stem and petiole. While the mechanism underlying temperature-induced elongation response is extensively studied, the genetic basis of temperature-regulation of leaf size is largely unknown. Here we show that warm temperature inhibits cell proliferation in the Arabidopsis leaves resulting in fewer cells compared to the control condition. Cellular phenotyping, genetic, and biochemical analyses established the key roles of PIF4 and TCP4 transcription factors in the suppression of Arabidopsis leaf area under high temperature by a reduction in cell number. We show that temperature-mediated suppression of cell proliferation requires PHYTOCHROME INTERACTING FACTOR 4 (PIF4). PIF4 interacts with TEOSINTE BRANCHED1/CYCLOIDEA/PCF4 (TCP4) and regulates the expression of cell cycle inhibitor, KIP-RELATED PROTEIN 1 (KRP1), to control the leaf size under high temperature. Warm temperature induces binding of both PIF4 and TCP4 to the KRP1 promoter. PIF4 binding to KRP1 under high temperature is TCP4 dependent as TCP4 regulates PIF4 levels under high temperature. We propose a model where a warm temperature-mediated accumulation of PIF4 in the leaf cells promotes its binding to the KRP1 promoter in a TCP4-dependent way to regulate cell production and leaf size. Our finding of high temperature-mediated transcriptional upregulation of KRP1 integrates a developmental signal with an environmental signal that converges on a basal cell regulatory process.

One sentence summary

High ambient temperature suppresses Arabidopsis leaf area by reducing cell proliferation via PIF4- and TCP4-dependent transcription control of KRP1.
Plakoglobin regulates adipocyte differentiation independently of the Wnt/β-catenin signalling pathway
Authors: Abou Azar F , Mugabo Y , Yuen S , Allali S , Del Veliz S , Lavoie G , Roux PP , Lim GE
Published: February 2022

The scaffold protein 14-3-3ζ is an established regulator of adipogenesis and postnatal adiposity. We and others have demonstrated that the 14-3-3ζ interactome to be diverse and dynamic, and it can be examined to identify novel regulators of physiological processes, including adipogenesis. In the present study, we sought to determine if factors that influence adipogenesis could be identified in the 14-3-3ζ interactome found in white adipose tissue of lean or obese TAP-tagged-14-3-3ζ overexpressing mice. Using mass spectrometry, changes in the abundance of novel, as well as established, adipogenic factors within the 14-3-3ζ interactome could detected. One novel candidate is plakoglobin, the homolog of the known adipogenic inhibitor β-catenin, and herein, we report that plakoglobin is involved in adipocyte differentiation. Plakoglobin is expressed in murine 3T3-L1 cells and is primarily localized to the nucleus, where its abundance decreases during adipogenesis. Ectopic overexpression and siRNA-mediated depletion of plakoglobin had dual effects on inhibiting adipogenesis and reducing PPARγ2 expression. Plakoglobin depletion in human adipose-derived stem cells also impaired adipogenesis and reduced lipid accumulation post-differentiation. Transcriptional assays indicated that plakoglobin does not participate in Wnt/β-catenin signaling, as its depletion did not affect Wnt3a-mediated SUPERTOPFlash activity. Taken together, our results establish plakoglobin as a novel regulator of adipogenesis in vitro and highlights the ability of using the 14-3-3ζ interactome to discover undiscovered pro-obesogenic factors.