bluuebunny/crossref_metadata_2025 huggingface dataset:
Chronic Stress, Genetic Risk, and Obesity in US Hispanic/Latinos: Results From the Hispanic Community Health Study/Study of Latinos
Authors: Isasi Carmen R. , Moon Jee-Young , Gallo Linda C. , Qi Qibin , Wang Tao , Sotres-Alvarez Daniela , Llabre Maria M. , Khambaty Tasneem , Daviglus Martha , Estrella Mayra L. , Cai Jianwen , Kaplan Robert
Published: July 2022

Objective

This study aimed to investigate whether the association of chronic stress with obesity is independent of genetic risk and test whether it varies by the underlying genetic risk.

Methods

The analysis included data from the Hispanic Community Health Study/Study of Latinos, a community-based study of Hispanic/Latinos living in four US communities (Bronx, NY; Chicago, IL; Miami, FL; San Diego, CA). The sample consisted of 5336 women and 3231 men who attended the Hispanic Community Health Study/Study of Latinos second in-person examination, had measures of obesity, and chronic stress, and were genotyped. Chronic stress burden was assessed by an eight-item scale. An overall polygenic risk score was calculated based on the summary statistics from GIANT and UK BioBank meta-analysis of body mass index (BMI) genome-wide association studies. Mixed-effect models were used to account for genetic relatedness and sampling design, as well as to adjust for potential confounders.

Results

A higher number of chronic stressors were associated with both BMI (β [log odds] = 0.31 [95% confidence interval = 0.23–0.38]) and obesity (β [log odds] = 0.10 [95% confidence interval = 0.07–0.13]), after adjustment for covariates and genetic risk. No interactions were found between chronic stress and the genetic risk score for BMI or obesity.

Conclusions

We did not find evidence for an interaction between chronic stress and polygenic risk score, which was not consistent with other publications that showed greater BMI or obesity in the groups with high stressors and elevated genetic risk.
Development of the Leapfrog Group’s Bar Code Medication Administration Standard to Address Hospital Inpatient Medication Safety
Authors: Austin J. Matthew , Bane Anne , Gooder Valerie , Saltsman Connie , Wilson Marisa , Stewart Kathryn Burggraf , Derk Jordan , Danforth Melissa , Michalek Christina
Published: July 2022

Medication errors are the most common type of error in hospitals and reflect a leading cause of avoidable harm to patients. Bar code medication administration (BCMA) systems are a technology designed to help intercept medication errors at the point of medication administration. This article describes the process of developing, testing, and refining a standard for BCMA adoption and use in U.S. hospitals, as measured through the Leapfrog Hospital Survey. Building on the published literature and an expert panel’s collective experience in studying, implementing, and using BCMA systems, the expert panel recommended a standard with 4 key domains. Leapfrog’s BCMA standard provides hospitals with a “how-to guide” on what best practice looks like for using BCMA to ensure safe medication administration at the bedside.
Portal Vein Resection in Pancreatic Cancer Surgery: Risk of Thrombosis and Radicality Determine Survival
Authors: Hackert Thilo , Klaiber Ulla , Hinz Ulf , Strunk Susanne , Loos Martin , Strobel Oliver , Berchtold Christoph , Kulu Yakup , Mehrabi Arianeb , Müller-Stich Beat P. , Schneider Martin , Büchler Markus W.
Published: July 2022

Objective:

To evaluate the outcomes of pancreatic cancer [pancreatic ductal adenocarcinoma (PDAC)] surgery with concomitant portal vein resection (PVR), focusing on the PVR type according to the International Study Group of Pancreatic Surgery (ISGPS).

Background:

Surgery offers the only chance for cure in PDAC. PVR is often performed for borderline or locally advanced tumors.

Methods:

Consecutive patients with PDAC operated between January 2006 and January 2018 were included. Clinicopathologic characteristics and outcomes were analyzed and tested for survival prediction.

Results:

Of 2265 PDAC resections, 1571 (69.4%) were standard resections and 694 (30.6%) were resections with PVR, including 149 (21.5%) tangential resections with venorrhaphy (ISGPS type 1), 21 (3.0%) resections with patch reconstruction (type 2), 491 (70.7%) end-to-end anastomoses (type 3), and 33 (4.8%) resections with graft interposition (type 4). The 90-day mortality rate was 2.6% after standard resection and 6.3% after resection with PVR (P<0.0001). Postoperative portal vein thrombosis and pancreas-specific surgical complications most frequently occurred after PVR with graft interposition (21.2% and 48.5%, respectively). In multivariable analysis, age 70 years and above, ASA stages 3/4, increased preoperative serum carbohydrate antigen 19-9, neoadjuvant treatment, total pancreatectomy, PVR, higher UICC stage, and R+ resections were significant negative prognostic factors for overall survival. Radical R0 (>1 mm) resection resulted in 23.3 months of median survival.

Conclusions:

This is the largest single-center, comparative cohort study of PVR in PDAC surgery, showing that postoperative morbidity correlates with the reconstruction type. When radical resection is achieved, thrombosis risk is outweighed by beneficial overall survival times of nearly 2 years.
Percutaneous Coronary Intervention Versus Coronary Artery Bypass Grafting for Patients With Three Vessel Coronary Artery Disease
Authors: EL-Andari Ryaan , Nagendran Jeevan , Hong Yongzhe , Ali Imtiaz , Nagendran Jayan
Published: July 2022

Objectives:

Referral patterns and outcomes of percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) were compared between 2 centers within 1 jurisdiction wherein only 1 center utilizes multidisciplinary review for all patients.

Background:

Management of advanced coronary artery disease often involves PCI and CABG for improvements in quality of life and survival. Indications exist for PCI and CABG, with CABG demonstrating benefit in three-vessel disease (TVD).

Methods:

A total of 27,961 patients underwent cardiac catheterization in 2 centers within the same single-payer health jurisdiction (Center A and B) from 2017 to 2018. Rates of PCI, CABG, and outcomes of 1-year mortality, rehospitalization, myocardial infarction, and stroke were compared.

Results:

More patients in Center A received PCI and less received CABG compared with Center B even among patients with TVD (P<0.001). Multivariable logistic regression identified Center B as protective for mortality for TVD patients (P<0.001) and those undergoing PCI (P=0.004), but not CABG (P=0.06). Center A’s 1-year mortality was increased for all patients (P=0.004) and those with TVD (P=0.011).

Conclusion:

Discordant outcomes exist between these 2 centers. While patients in Center A were more likely to undergo PCI than Center B and experienced decreased 1-year survival, the difference was not significant for CABG. In part, the differences are attributable to contrasting referral practices and the discrepant rates of PCI and CABG between centers. Review of all coronary artery disease patients with a multidisciplinary Heart Team including a surgical opinion may lead to a more evidence-based referral practice aligned with current clinical guidelines.
COVID-19 related stress and the risk of perforated peptic ulcer: a cross-sectional study
Authors: Ristiyanto Eko , Moenadjat Yefta , Kusumadewi Irmia , Lalisang Toar J.M.
Published: July 2022

Introduction:

Perforated peptic ulcer (PPU) is the fatal complication of peptic ulcer disease and is associated with increased morbidity and mortality of patients. Psychological stress significantly increases the risk of developing PPU. This coronavirus disease 2019 (COVID-19) pandemic causes fear and uncertainty, increasing psychological stress and perceived stress. This study aims to analyze the effect of COVID-19 pandemic high psychological stress as a risk factor for developing PPU.

Methods:

A cross-sectional study was conducted on all adult patients diagnosed and that underwent surgery for PPU from July 2017 to March 2021. The nonpandemic group consists of patients who underwent PPU surgery from July 2017 to February 2020 and the pandemic group from March 2020 to March 2021. Perceived stress is collected from the patient during the follow-up visit using an Indonesian version of the Perceived Stress Scale (PSS-10) questionnaire.

Results:

A total of 53 patients with PPU underwent surgery in our hospital. Twenty-five patients from the nonpandemic period and 28 patients during the pandemic period. There was a significant increase in postoperative complication or morbidity rate (78.5% vs. 52%; prevalence ratio: 1.51, 95% confidence interval: 0.99–2.31; P=0.041) in pandemic group. Stress level were also higher in the pandemic group compared with the nonpandemic group (42.1% vs. 5.6%; prevalence ratio: 7.58; 95% confidence interval: 1.05–54.69; P=0.006).

Conclusions:

COVID-19 pandemic impacts psychological stress, consequently increasing the risk of PPU and increasing morbidity.
Size always matters, shape matters only for the big: potential optical effects of silica bodies in
Selaginella
Authors: Shih Ming-Chih , Xie Pei-Jung , Chen Jiannyeu , Chesson Peter , Sheue Chiou-Rong
Published: July 2022

Silica bodies are commonly found in
Selaginella
, but their function is unclear. Lens-like appearance and location in many species above giant chloroplasts of dorsal epidermal cells suggest optical functions. Silica body morphology in three
Selaginella
species was studied by microscopy. Optical effects were assessed by wave-optic simulations. Large convex, approximately hemispherical (papillose) and small approximately conical (concave–convex) silica bodies were found in different species. Both types lead to a concentrated spot of light high in the dorsal epidermal cell. Large convex bodies concentrate light 10–25 times in a shape-dependent manner by refraction, and small silica bodies concentrate light in a shape-insensitive, but wavelength-dependent, manner by diffraction (red light: approx. 2.3 times; blue light: approx. 1.5 times). Due to chloroplast movement, this concentrated light is above the chloroplast under high light, but within it under low light. Beyond the spot of concentration, light is dispersed into the chloroplast. Thin
Selaginella
leaves mean these effects may enhance light capture and minimize photodamage, but other effects such as inhibition of herbivory, mechanical support, and immune responses need to be considered. Silica bodies undoubtedly have optical effects, but their significance to the functioning of the plant requires direct studies of ecophysiological performance.
Model-Informed Unsupervised Deep Learning Approaches to Frequency and Phase Correction of MRS Signals
Authors: Shamaei Amir M , Starcukova Jana , Pavlova Iveta , Starcuk Zenon
Published: July 2022

Purpose

A supervised deep learning (DL) approach for frequency-and-phase Correction (FPC) of MR spectroscopy (MRS) data recently showed encouraging results, but obtaining transients with labels for supervised learning is challenging. This work investigates the feasibility and efficiency of unsupervised DL-based FPC.

Method

Two novel DL-based FPC methods (deep learning-based Cr referencing [dCrR] and deep learning-based spectral registration [dSR]) which use a priori physics domain knowledge are presented. The proposed networks were trained, validated, and evaluated using simulated, phantom, and publicly accessible in-vivo MEGA-edited MRS data. The performance of our proposed FPC methods was compared to other generally used FPC methods, in terms of precision and time efficiency. A new measure was proposed in this study to evaluate the FPC method performance. The ability of each of our methods to carry out FPC at varying SNR levels was evaluated. A Monte Carlo (MC) study was carried out to investigate the performance of our proposed methods.

Result

The validation using low-SNR manipulated simulated data demonstrated that the proposed methods could perform FPC comparably to other methods. The evaluation showed that the dCrR method achieved the highest performance in phantom data. The applicability of the proposed method for FPC of GABA-edited in-vivo MRS data was demonstrated. Our proposed networks have the potential to reduce computation time significantly.

Conclusion

The proposed physics-informed deep neural networks trained in an unsupervised manner with complex data can offer efficient FPC of MRS data in a shorter time.
Enteric glial cells of the two plexi of the enteric nervous system exhibit phenotypic and functional inter- and intra-heterogeneity
Authors: Melissa Touvron , Bradley Wieland A. , Mariant Chloe L. , Alex Hattenhauer R. , Van Landeghem Laurianne
Published: July 2022

Enteric glial cells (EGC) are a prominent cell type of all layers of the gut wall, virtually controlling all gastrointestinal functions. While the development of transgenic mice has led to major advances in understanding EGC biology, in vitro models are still fairly limited and do not allow for the robust and reproducible establishment of primary cultures discriminating EGC from the inner versus outer layers of the gut wall. Here we report a novel method to separately grow EGC from the inner and outer layers of the intestinal wall from the same mouse with a high degree of purity and cell heterogeneity. Our results indicate that EGC from the inner layers of the gut wall exhibit higher calcium response to ATP when compared to EGC from the outer layers. We also show that inner EGC cultures express lower levels of the transcription factor Sox 10 as compared to outer EGC cultures, which mirrors in situ differential expression of Sox10 in submucosal (inner) versus myenteric (outer) plexus assessed using wholemounts. Confocal microscopy analyses of wholemounts further demonstrate that a majority of calretinin-expressing ganglionic cells of the submucosal plexus express the EGC marker S-100β, while this population is marginally represented in ganglia of the myenteric plexus. Altogether this study describes a novel method of EGC primary cultures permitting for the first time to compare inner versus outer EGC and provides in vitro and ex vivo evidence that inner EGC and outer EGC are phenotypically and functionally distinct.
Silencing of ApoE with Divalent siRNAs Drives Activation of Immune Clearance Pathways and Improves Amyloid Pathology in Mouse Models of Alzheimer’s Disease
Authors: Ferguson Chantal M. , Hildebrand Samuel , Godinho Bruno M.D.C , Buchwald Julianna , Echeverria Dimas , Coles Andrew , Grigorenko Anastasia , Vanjielli Lorenc , Sousa Jacquelyn , McHugh Nicholas , Hassler Matthew , Santarelli Francesco , Heneka Michael T. , Rogaev Evgeny , Khvorova Anastasia
Published: July 2022

The most common genetic risk factor for late-onset Alzheimer’s disease (AD) is the APOE4 allele, with evidence for gain- and loss-of-function mechanisms. ApoE knockout in mice abrogates AD phenotypes but causes severe atherosclerosis due to the role of liver ApoE in cholesterol homeostasis. Previous attempts to inhibit brain-specific ApoE with anti-sense oligonucleotides only modestly reduced ApoE expression and had no effect on amyloid burden in adult AD mice. Here, we optimized a divalent small interfering RNA (di-siRNA) to selectively and potently silence ApoE in the brain. Silencing brain ApoE in AD mice significantly reduced amyloid plaque formation without affecting systemic cholesterol levels, confirming that brain and liver APOE pools are spatially and functionally distinct. Mechanistically, APOE appears to be a scaffold for beta-amyloid aggregation that limits clearance by microglia. Di-siRNAs from this study can be taken to pre-clinical and clinical trials to accelerate development of AD-modifying therapies and establish siRNA-based modulation of ApoE as a viable path towards therapeutic development.
Cerebrospinal fluid and blood profiles of transfer RNA fragments show age, sex and Parkinson’s disease-related changes
Authors: Paldor Iddo , Madrer Nimrod , Vaknine-Treidel Shani , Shulman Dana , Greenberg David S , Soreq Hermona
Published: July 2022

Transfer RNA fragments (tRFs) have recently been shown to be an important family of small regulatory RNAs with diverse functions. Recent reports have revealed modified tRF blood levels in a number of nervous system conditions including epilepsy, ischemic stroke and neurodegenerative diseases, but little is known about tRF levels in the cerebrospinal fluid (CSF). To address this issue, we studied age, sex and Parkinson’s disease (PD) distributions of tRFs in the CSF and blood data of PD patients and healthy controls from the NIH and the PPMI small RNA-seq datasets. The higher levels of long tRFs were found in the CSF than in the blood. Furthermore, the CSF showed pronounced age-associated declines of the level of 3’-tRFs and i-tRFs and more pronounced differences between the sexes. Blood showed moderate elevation of 3’-tFs levels with age. In addition, different distinct sets of tRFs segregated PD patients from controls in the CSF and in the blood. Finally, we found enrichment of tRFs predicted to target cholinergic mRNAs (Cholino-tRFs) in the mitochondrial originated tRFs, raising the possibility that the neurodegeneration-related mitochondrial impairment may lead to deregulation of cholinergic tone. Our findings suggest that CSF expressed tRFs are not a mirror of blood tRFs but rather potentially reflect the cerebral changes. Further, both CSF and blood present modified levels of tRFs in a sex-, age-and disease-related manner, calling for including this important subset of small RNA regulators to future studies.
Activity-dependent decline and recovery of synaptic transmission in central parts of surviving primary afferents after their peripheral cut
Authors: Le Bon-Jégo Morgane , Cabirol Marie-Jeanne , Cattaert Daniel
Published: July 2022

Whereas axons deprived of their nucleus degenerate within a few days in Mammals, they survive for several months in Crustacean. However, it is not known if central synapses from sensory axons may preserve their molecular machinery in the absence of spiking activity, after peripheral axotomy, which suppress their nucleus. Using electrophysiology techniques and electron microscopy imaging we report that 1) Electron microscopy analysis confirms previous observations that glial cell nucleus present in sensory nerve, proliferate an migrate to axon tubes, in which they form close contact with surviving axons; 2) after peripheral axotomy performed in vivo on Coxo-Basipodite chordotonal organ (CBCO) sensory nerve does not convey any sensory message, but antidromic volleys are observed; 3) Central synaptic transmission to motoneurons (MNs) progressively declines over #200 days (90% of monosynaptic excitatory transmission is lost after 3 weeks, whereas 60% of polysynaptic inhibitory transmission persist up to 6 months). After #200 days no transmission is observed anymore; 4) However, this total loss is only apparent, because repetitive electrical stimulation of the sensory nerve in vitro progressively restores first inhibitory post-synaptic potentials (IPSPs) then excitatory post-synaptic potentials (EPSPs); 5) The loss of synaptic transmission can be prevented by in vivo chronic sensory nerve stimulation; 6) Using simulations based on the geometric arrangements of synapses of the monosynaptic excitatory transmission and disynaptic inhibitory pathways, we have shown that antidromic activity in CBCO nerve could play a role in maintenance of synaptic function of inhibitory pathways to MNs, but not on monosynaptic excitatory transmission to MNs. Taken together, our study confirms the key role of glial nucleus in axon survival, that machinery for spike conduction and synaptic release even if no activity is present for several months. After long silence periods (>6 months) spike conduction and synaptic function can still be restored by electrical activity.
Evaluating the efficacy of multi-echo ICA denoising on model-based fMRI
Authors: Steel Adam , Garcia Brenda D. , Silson Edward H. , Robertson Caroline E.
Published: July 2022

fMRI is an indispensable tool for neuroscience investigation, but this technique is limited by multiple sources of physiological and measurement noise. These noise sources are particularly problematic for analysis techniques that require high signal-to-noise ratio for stable model fitting, such as voxel-wise modeling. Multi-echo data acquisition in combination with echo-time dependent ICA denoising (ME-ICA) represents one promising strategy to mitigate physiological and hardware-related noise sources as well as motion-related artifacts. However, most studies employing ME-ICA to date are resting-state fMRI studies, and therefore we have a limited understanding of the impact of ME-ICA on task or model-based fMRI paradigms. Here, we addressed this knowledge gap by comparing data quality and model fitting performance on data acquired during a visual population receptive field (pRF) mapping paradigm (N=13 participants) after using one of three preprocessing procedures: ME-ICA, optimally combined multi-echo data without ICA-denoising, and typical single echo processing. As expected, multi-echo fMRI improved temporal signal-to-noise compared to single echo fMRI, with ME-ICA amplifying the improvement compared to optimal combination alone. However, unexpectedly, this boost in temporal signal-to-noise did not directly translate to improved model fitting performance: compared to single echo acquisition, model fitting was only improved after ICA-denoising. Specifically, compared to single echo acquisition, ME-ICA resulted in improved variance explained by our pRF model throughout the visual system, including anterior regions of the temporal and parietal lobes where SNR is typically low, while optimal combination without ICA did not. ME-ICA also improved reliability of parameter estimates compared to single echo and optimally combined multi-echo data without ICA-denoising. Collectively, these results suggest that ME-ICA is effective for denoising task-based fMRI data for modeling analyses and maintains the integrity of the original data. Therefore, ME-ICA may be beneficial for complex fMRI experiments, including task fMRI studies, voxel-wise modeling, and naturalistic paradigms.
CCR5 deficiency normalizes TIMP levels, working memory, and gamma oscillation power in APOE4 targeted replacement mice
Authors: Greco Griffin A. , Rock Mitchell , Amontree Matthew , Lanfranco Maria Fe , Korthas Holly , Hong Sung Hyeok , Turner R. Scott , Rebeck G. William , Conant Katherine
Published: July 2022

TheAPOE4allele increases the risk for Alzheimer’s disease (AD) in a dose-dependent manner and is also associated with cognitive decline in non-demented elderly controls. In mice with targeted gene replacement (TR) of murineAPOEwith humanAPOE3orAPOE4, the latter show reduced neuronal dendritic complexity and impaired learning.APOE4TR mice also show reduced gamma oscillation power and sharp wave ripple (SWR) abundance, neuronal population activities important to learning and memory. Published work has shown that brain extracellular matrix (ECM) can reduce neuroplasticity as well as gamma power and SWR abundance, while attenuation of ECM can instead enhance these endpoints. In the present study we examine human cerebrospinal fluid (CSF) samples fromAPOE3andAPOE4individuals and brain lysates fromAPOE3andAPOE4TR mice for levels of ECM effectors that can increase matrix deposition and restrict neuroplasticity. We find that CCL5, a molecule linked to ECM deposition in liver and kidney, is increased in CSF samples fromAPOE4individuals. Levels of tissue inhibitor of metalloproteinases (TIMPs), which inhibit the activity of ECM-degrading enzymes, are also increased inAPOE4CSF as well as protein lysates fromAPOE4TR mice. Importantly, as compared to wildtype/APOE4heterozygotes, CCR5 knockout/APOE4heterozygotes show reduced TIMP levels and enhanced EEG gamma power. The latter also show improved learning and memory, suggesting that the CCR5/CCL5 axis could represent a therapeutic target forAPOE4individuals.
Machine Learning Electroencephalography Biomarkers Predictive of Epworth Sleepiness Scale
Authors: Araujo Matheus , Ghosn Samer , Wang Lu , Hariadi Nengah , Wells Samantha , Carl Saab Y , Mehra Reena
Published: July 2022

Excessive daytime sleepiness (EDS) causes difficulty in concentrating and continuous fatigue during the day. In a clinical setting, the assessment and diagnosis of EDS relies mostly on subjective questionnaires and verbal reports, which compromises the effectiveness of available therapies. In this study, we used a computational pipeline for the automated, rapid, high-throughput and objective analysis of retrospective encephalography (EEG) data to develop objective, surrogate biomarkers for EDS, thereby defining the quantitative EEG changes in individuals with High Epworth Sleepiness Scale (ESS) (n=31), compared to a group of individuals with Low ESS (n=41) at Cleveland Clinic. Signal processing of EEG showed significantly different EEG features in the Low ESS group compared to High ESS, including power enhancement in the alpha and beta bands, and attenuation in the delta and theta bands. Moreover, machine learning algorithms trained on the binary classification of High vs Low ESS reached >80% accuracy. These results demonstrate that EEG data contain information in the form of rhythmic activity that could be leveraged for the quantitative assessment of EDS using machine learning.
Pixel size limit of the PRIMA implants: from humans to rodents and back
Authors: Wang Bing-Yi , Chen Zhijie Charles , Bhuckory Mohajeet , Goldstein Anna Kochnev , Palanker Daniel
Published: July 2022

Objective

Retinal prostheses aim at restoring sight in patients with retinal degeneration by electrically stimulating the inner retinal neurons. Clinical trials with patients blinded by atrophic Age-related Macular Degeneration (AMD) using the PRIMA subretinal implant, a 2×2 mm array of 100μm-wide photovoltaic pixels, have demonstrated a prosthetic visual acuity closely matching the pixel size. Further improvement in resolution requires smaller pixels, which necessitates more intense stimulation.

Approach

Here, we examine the lower limit of the pixel size for PRIMA implants by modeling the electric field, leveraging the clinical benchmarks, as well as using a preclinical animal data to assess the stimulation strength and contrast of various patterns. Visually evoked potentials were measured in RCS rats with photovoltaic implants of 100 and 75μm pixels and compared to clinical thresholds with 100 μm pixels. Electrical stimulation model calibrated by these clinical and rodent data was used to predict the performance of the implant with smaller pixels.

Main Results

We found that PRIMA implants with 75μm pixels under the maximum safe near-infrared (880nm) illumination of 8 mW/mm2 with 30% duty cycle (10ms pulses at 30Hz) should provide a similar perceptual brightness as with 100 μm pixels under 3 mW/mm2 irradiance, used in the current clinical trials. Contrast of the Landolt C pattern scaled down to 75μm pixels is also similar under such illumination to that with 100μm pixels in clinical settings, increasing the maximum acuity from 20/420 to 20/300.

Significance

Computational model of the photovoltaic subretinal prosthesis defines the minimum pixel size of the PRIMA implants as 75μm. Increasing the implant width from 2 to 3 mm and reducing the pixel size from 100 to 75μm will nearly quadrupole the number of pixels and thereby should significantly improve the visual performance. Smaller pixels of the same bipolar flat geometry would require excessively intense illumination, and therefore a different pixel design should be considered for further improvement in resolution.
Online grocery shopping during the COVID-19 pandemic - perspectives of adolescents and young adults
Authors: Brandt Eric J , Hadler Nicole , Locher Ione , Hoffs Charlie T , Waselewski Marika E , Chang Tammy
Published: July 2022

Objective

To assess perspectives of online grocery shopping during the COVID-19 pandemic among youth, rural residents, and Supplemental Nutrition Assistance Program (SNAP) participants.

Design

Open-ended text message survey data. Survey questions assessed rates of use and perspectives of online grocery shopping among youth and their families during the COVID-19 pandemic. Qualitative analysis of survey data from 875 participants (response rate=76.4%) to identify themes in experience with multivariable logistic regression to test associations between online grocery shopping (pickup, delivery, or either) with rurality and SNAP participation.

Setting

United States

Participants

Nationwide text-messaging poll of youth (14-24 years-old) recruited to meet benchmarks based on the American Community Survey.

Results

During the pandemic online grocery shopping was used frequently (46.7%). Safety and convenience were the primary reasons for preferring a shopping mode (in-person or online). Most online shoppers had positive experiences (59.4%), primarily due to convenience; negative experiences (28.3%) were from inaccuracies, inconveniences of the process, and delivery costs. Rural and suburban residence was associated with higher pickup (OR 2.02 and 1.51, respectively, p=.03) and lower delivery use (OR 0.33 and 0.72, respectively, p=.003) compared to urban residence. SNAP participation was not associated with any type of online grocery shopping.

Conclusions

Online grocery shopping is common among youth and their families regardless of rurality or SNAP participation, but there are several youth-identified areas for improvement.

GRAPHICAL ABSTRACT
Brain dynamics predictive of response to psilocybin for treatment-resistant depression
Authors: Vohryzek Jakub , Cabral Joana , Lord Louis-David , Fernandes Henrique M , Roseman Leor , Nutt David J , Carhart-Harris Robin L , Deco Gustavo , Kringelbach Morten L
Published: July 2022

Psilocybin therapy for depression has started to show promise, yet the underlying causal mechanisms are not currently known. Here we leveraged the differential outcome in responders and non-responders to psilocybin (10mg and 25mg, 7 days apart) therapy for depression - to gain new insights into regions and networks implicated in the restoration of healthy brain dynamics. We used whole-brain modelling to fit the spatiotemporal brain dynamics at rest in both responders and non-responders before treatment. Dynamic sensitivity analysis of systematic perturbation of these models enabled us to identify specific brain regions implicated in a transition from a depressive brain state to a heathy one. Binarizing the sample into treatment responders (>50% reduction in depressive symptoms) versus non-responders enabled us to identify a subset of regions implicated in this change. Interestingly, these regions correlate with in vivo density maps of serotonin receptors 5-HT2A and 5-HT1A, which psilocin, the active metabolite of psilocybin, has an appreciable affinity for, and where it acts as a full-to-partial agonist. Serotonergic transmission has long been associated with depression and our findings provide causal mechanistic evidence for the role of brain regions in the recovery from depression via psilocybin.
Slice’N’Dice: Maximising the value of predicted models for structural biologists
Authors: Simpkin Adam J. , Elliott Luc G. , Stevenson Kyle , Krissinel Eugene , Rigden Daniel J. , Keegan Ronan M.
Published: July 2022

With the advent of next generation modelling methods, such as AlphaFold2, structural biologists are increasingly using predicted structures as search models for Molecular Replacement (MR) when experimental structures of homologues are unavailable. Inaccuracy in domain-domain orientations is often a key limitation when using predicted models for MR. Slice’N’Dice is a software package designed to address this issue by first slicing models into distinct structural units and then automatically placing the slices using Phaser. The slicing step can use AlphaFold2’s predicted aligned error (PAE), or can operate via a variety of Cα atom clustering algorithms, extending applicability to structures of any origin. The number of splits can be selected by the user. Slice’N’Dice is available in CCP4 8.0 and is currently being adapted for cryo-EM use cases.
Developmental spontaneous activity promotes sensory domains, frequency tuning and proper gain in central auditory circuits
Authors: Kersbergen Calvin J. , Babola Travis A. , Rock Jason , Bergles Dwight E.
Published: July 2022

Neurons that process sensory information exhibit bursts of electrical activity during development, providing early training to circuits that will later encode similar features of the external world. In the mammalian auditory system, this intrinsically generated activity emerges from the cochlea prior to hearing onset, but its role in maturation of auditory circuitry remains poorly understood. We show that selective disruption of cochlear supporting cell spontaneous activity suppressed patterned burst firing of central auditory neurons without impacting cell survival or acoustic thresholds. However, neurons within the inferior colliculus of these mice exhibited enhanced acoustic sensitivity and broader frequency tuning, resulting in wider isofrequency lamina. Despite this enhanced neural responsiveness, total tone-responsive regions of the midbrain and cortex were substantially smaller. Thus, loss of pre-hearing cochlear activity causes profound changes in neural encoding of sound, with important implications for restoration of hearing in individuals that experience disrupted activity during this critical developmental period.
Photovoltaic Implant Simulator Reveals the Resolution Limits in Subretinal Prosthesis
Authors: Chen Zhijie Charles , Wang Bing-Yi , Goldstein Anna Kochnev , Butt Emma , Mathieson Keith , Palanker Daniel
Published: July 2022

Objective

The photovoltaic subretinal prosthesis, PRIMA, restores central vision in patients blinded by atrophic age-related macular degeneration (AMD), with a resolution closely matching the 100 µm pixel size of the implant. Improvement in resolution requires smaller pixels, but the resultant electric field may not provide sufficient stimulation strength in the inner nuclear layer (INL) or may lead to excessive crosstalk between neighboring electrodes, giving low contrast stimulation patterns. We study approaches to shaping the electric field in the retina for prosthetic vision with higher resolution and improved contrast.

Approach

We present a new computational framework, RPSim, that efficiently computes the electric field in the retina generated by a photovoltaic implant with thousands of electrodes. Leveraging the PRIMA clinical results as a benchmark, we use RPSim to predict the stimulus strength and contrast of the electric field in the retina with various pixel designs and stimulation patterns.

Main results

We demonstrate that by utilizing monopolar pixels as both, anodes and cathodes to suppress crosstalk, most patients may achieve resolution no worse than 48 µm. Closer proximity between the electrodes and the INL, achieved with pillar electrodes, enhances the stimulus strength and contrast and may enable 24 µm resolution with 20 µm pixels, at least in some patients.

Significance

A resolution of 24 µm on the retina corresponds to a visual acuity of 20/100, which is over 4 times higher than the current best prosthetic acuity of 20/438, promising a significant improvement of central vision for many AMD patients.
Genetic requirements for repair of lesions caused by single genomic ribonucleotides in S phase
Authors: Schindler Natalie , Tonn Matthias , Kellner Vanessa , Fung Jia Jun , Lockhart Arianna , Vydzhak Olga , Juretschke Thomas , Möckel Stefanie , Beli Petra , Khmelinskii Anton , Luke Brian
Published: July 2022

Single ribonucleoside monophosphates (rNMPs) are transiently present in eukaryotic genomes. The RNase H2-dependent ribonucleotide excision repair (RER) pathway ensures error-free genomic rNMP removal. In pathological conditions, genomic rNMP levels can rise and persist. If these rNMPs hydrolyse in, or prior to, S phase, toxic single-ended double-strand breaks (seDSBs) can occur upon an encounter with replication forks. How such rNMP-derived seDSB lesions are repaired is unclear. We employed a cell cycle phase restricted allele of RNase H2 as a genetic tool to induce nicks at rNMPs specifically in S phase to generate such lesions and study their repair. Here, we introduce a network of genes that maintain DNA integrity when rNMP-derived nick lesions arise during DNA replication. We use genetic methods to characterise the molecular requirements of a Top1-independent, rNMP-derived nick lesion repair (NLR). In NLR, the RAD52 epistasis group becomes essential for homology-directed repair (HDR). Moreover, the previously described Rtt101Mms1-Mms22 dependent ubiquitylation of histone H3 is essential for NLR in cells with high rNMP load, and loss of Rtt101Mms1-Mms22 combined with RNase H2 dysfunction leads to compromised cellular fitness. We discuss the genetic NLR network in the context of human disease, where cancer therapies may be able to exploit these synthetic lethalities.
Modeling Hippocampal Spatial Cells in Rodents navigating in 3D environments
Authors: Aziz Azra , Patil Bharat Kailas , Lakshmikanth Kailash , Sreeharsha Peesapati S S , Mukhopadhay Ayan , Chakravarthy V Srinivasa
Published: July 2022

Studies on the neural correlates of navigation in 3D environments are plagued by several unresolved issues. For example, experimental studies show markedly different place cell responses in rats and bats, both navigating in 3D environments. In an effort to understand this divergence, we propose a deep autoencoder network to model the place cells and grid cells in a simulated agent navigating in a 3D environment. We also explore the possibility of a vital role that Head Direction (HD) tuning plays in determining the isotropic or anisotropic nature of the observed place fields in different species. The input layer to the autoencoder network model is the HD layer which encodes the agent’s HD in terms of azimuth (θ) and pitch angles (ϕ). The output of this layer is given as input to the Path Integration (PI) layer, which integrates velocity information into the phase of oscillating neural activity. The output of the PI layer is modulated and passed through a low pass filter to make it purely a function of space before passing it to an autoencoder. The bottleneck layer of the autoencoder model encodes the spatial cell like responses. Both grid cell and place cell like responses are observed. The proposed model is verified using two experimental studies with two 3D environments in each. This model paves the way for a holistic approach of using deep networks to model spatial cells in 3D navigation.
Unexpected long-term retention of subcutaneous beeswax implants and additional notes on dose and composition from four testosterone implant studies
Authors: Boersma Jordan , McQueen Alexandra , Peters Anne , Welklin Joseph F. , Khalil Sarah , Quispe René , Goymann Wolfgang , Schwabl Hubert
Published: July 2022

Experimental manipulations of testosterone have advanced our understanding of the hormonal control of traits across vertebrates. Implants are commonly used to supplement testosterone and other hormones to organisms, as they can be readily scaled to produce desired hormone levels in circulation. Concerns about pharmacological (i.e. unnatural) doses of traditional silastic implants led to innovation in implant methods, with time-release pellets and beeswax implants proposed as solutions. A study comparing silastic, time-release pellets, and beeswax implants found the latter to be most effective in delivering a physiologically relevant dose. One proposed advantage to subcutaneous beeswax implants is that they are expected to degrade within the body, thus removing the obligation to recapture implanted individuals in the field. However, few studies have reported on dosage and no published literature has examined the assumption that beeswax implants readily degrade as expected. Here we present time-release androgen data in relation to implants containing varying levels of testosterone from four separate implant studies. In addition, we report long-term persistence of subcutaneous implants, including two cases of implants being retained for > 2 years. Finally, we offer recommendations on the composition and implementation of beeswax implants to aid the pursuit of minimally invasive and physiologically relevant manipulations of circulating hormones.
Integrated single-nucleus and spatial transcriptomics captures transitional states in soybean nodule symbiosis establishment
Authors: Liu Zhijian , Kong Xiangying , Long Yanping , Zhang Hong , Jia Jinbu , Qiu Lijuan , Zhai Jixian , Yan Zhe
Published: July 2022

Legumes form symbiosis with rhizobium leading to the development of nitrogen-fixing nodules. By integrating single-nucleus and spatial transcriptomics, we established a cell atlas of soybean nodules and roots. In central infected zone of nodule, we found that uninfected cells specialize into functionally distinct sub-groups during nodule development and revealed a transitional subtype of infected cells with enriched nodulation-related genes. Overall, our results provide a single-cell perspective for understanding rhizobium-legume symbiosis.
DeepsmirUD: Precise prediction of regulatory effects on miRNA expression mediated by small molecular compounds using competing deep learning frameworks
Authors: Sun Jianfeng , Ru Jinlong , Chen Zihao , Qi Fei , Ramos-Mucci Lorenzo , Chen Suyuan , Cribbs Adam P. , Deng Li , Wang Xia
Published: July 2022

Aberrant miRNA expression has pervasively been found to relate to a growing number of human diseases. Therefore, targeting miRNAs to regulate their expression levels has become an important therapy against diseases that stem from the dysfunction of oncogenic pathways regulated by the miRNAs. In recent years, small molecule compounds have demonstrated enormous potential as drugs to regulate miRNA expression (i.e., SM-miR). A clear understanding of the mechanism of action of small molecules on down- and up-regulating miRNA expression allows precise diagnosis and treatment of oncogenic pathways. However, outside of a slow and costly process of experimental determination, computational strategies to assist this in an ad hoc manner have still not been enabled. In this work, we develop, to the best of our knowledge, the first prediction tool, DeepsmirUD, to infer small molecule-mediated regulatory effects on miRNA expression. This method is powered by an ensemble of 12 cutting-edged deep learning frameworks and achieves state-of-the-art performance with AUC values of 0.840/0.969 and AUCPR values of 0.866/0.983 on two independent test datasets. With a complementarily constructed network inference approach based on similarity, we report a significantly improved accuracy of 0.813 in determining regulatory effects of nearly 650 SM-miR relations formed with either novel small molecules or novel miRNAs. By further integrating miRNA-cancer relations, we established a database of potentially pharmaceutical drugs to aid in understanding the drug mechanisms of action in diseases and to offer novel insight into drug repositioning. Taken together, our method shows great promise to assist and accelerate the therapeutic development of potential miRNA targets and small molecule drugs. Furthermore, we have employed DeepsmirUD to predict regulatory effects of a large number of high-confidence SM-miR relations curated from Psmir, which are publicly available through https://github.com/2003100127/deepsmirud and https://rujinlong.github.io/deepsmirud/ alongside the DeepsmirUD standalone package.
Arabidopsis FIBRILLIN6 regulates carotenoid biosynthesis by directly promoting phytoene synthase activity
Authors: Iglesias-Sanchez Ariadna , Morelli Luca , Rodriguez-Concepcion Manuel
Published: July 2022

Carotenoids are health-promoting plastidial isoprenoids with essential functions in plants as photoprotectants and photosynthetic pigments in chloroplasts. They also accumulate in specialized plastids named chromoplasts, providing color to non-photosynthetic tissues such as flower petals and ripe fruit. Carotenoid accumulation in chromoplast requires specialized structures and proteins such as fibrillins. Although fibrillins were first reported as structural components of carotenoid sequestering structures in chromoplasts, later work revealed roles in chloroplasts and other plastid types. However, the association of fibrillins with carotenoids in plastids other than chromoplasts has remained unexplored. Here we show that a member of the fibrillin family, FBN6, interacts with phytoene synthase (PSY, the first committed and rate-determining step of the carotenoid pathway) to promote its enzymatic activity. Transient overexpression of FBN6 in Nicotiana benthamiana leaves results in a higher production of phytoene, the product of PSY activity, whereas loss of FBN6 activity in Arabidopsis thaliana mutants dramatically reduces the production of carotenoids during seedling deetiolation and after exposure to high light. Our work hence demonstrates that fibrillins not only promote the accumulation of carotenoids but also their biosynthesis.
Endothelial NCK2 Promotes Atherosclerosis Progression in Male but not Female Nck1-null Atheroprone Mice
Authors: Bywaters Briana C. , Pedraza Gladys , Trache Andreea , Rivera Gonzalo M.
Published: July 2022

A better understanding of endothelial dysfunction holds promise for more effective interventions for atherosclerosis prevention and treatment. Endothelial signaling by the non-catalytic region of the tyrosine kinase (NCK) family of adaptors, consisting of NCK1 and NCK2, has been implicated in cardiovascular development and postnatal angiogenesis but its role in vascular disease remains incompletely understood. Here, we report stage- and sex-dependent effects of endothelial NCK2 signaling on arterial wall inflammation and atherosclerosis development. Male and female Nck1-null atheroprone mice enabling inducible, endothelial-specific Nck2 inactivation were fed a high fat diet (HFD) for 8 or 16 weeks to model atherosclerosis initiation and progression, respectively. Analysis of aorta preparations en face during disease progression, but not initiation, showed a significant reduction in plaque burden in males, but not females, lacking endothelial NCK2 relative to controls. Markers of vascular inflammation were reduced by endothelial NCK2 deficiency in both males and females during atherosclerosis progression but not initiation. At advanced stages of disease, plaque size and severity of atherosclerotic lesions were reduced by abrogation of endothelial NCK2 signaling only in males. Collectively, our results demonstrate stage- and sex-dependent modulation of atherosclerosis development by endothelial NCK2 signaling.