bluuebunny/crossref_metadata_2025 huggingface dataset:
A Road Map for Academic Developmental-Behavioral Pediatric Practices to Increase Access
Authors: Godwin Dinah L. , Cervantes Jennifer , Torres Jennifer Y. , Ostermaier Kathryn K. , Berry Leandra N. , Voigt Robert G.
Published: September 2022

There are currently at least 19 million children and adolescents in the United States with disorders of development (learning disorders, attention-deficit/hyperactivity disorder, intellectual disabilities, autism, motor incoordination/cerebral palsy, etc.) and only approximately 800 board-certified developmental-behavioral pediatricians (DBPs) practicing nationally. Given the astronomical mismatch between the number of children and adolescents with developmental disorders and the number of board-certified DBPs, developmental-behavioral pediatric consultations are likely the most inaccessible in all of medicine. With the goal of increasing access to these consultations, an academic developmental-behavioral practice in a large urban hospital system developed a longitudinal “Road Map,” led by our team of social workers, which is designed to provide such services while continuing to focus DBP efforts on initial consultative evaluation and diagnosis of as many children as possible. The programs that this new Road Map has provided have allowed the DBP practice not only to increase access to developmental evaluations but also to provide more holistic and targeted care from the point of being added to the waiting list and then throughout the life span at vital transition periods. Especially given the extreme mismatch between the scarce number of practicing DBPs and the prodigious number of pediatric patients with disorders of development, our hope is that other centers will consider replicating this innovative care model to address the ever-growing need for specialized DBP consultation and longitudinal wraparound care for our patients and families.
Effect of All-trans Retinoic Acid on Panniculus Carnosus Muscle Regeneration in Fetal Mouse Wound Healing
Authors: Takaya Kento , Aramaki-Hattori Noriko , Sakai Shigeki , Okabe Keisuke , Asou Toru , Kishi Kazuo
Published: September 2022

Background:

The dermal panniculus carnosus (PC) muscle is critical for wound contraction in lower mammals and is a useful model of muscle regeneration owing to its high cellular metabolic turnover. During wound healing in mice, skin structures, including PC, are completely regenerated up to embryonic day (E) 13, but PC is only partially regenerated in fetuses or adult animals after E14. Nevertheless, the mechanisms underlying wound repair for complete regeneration in PC have not been fully elucidated. We hypothesized that retinoic acid (RA) signaling, which is involved in muscle differentiation, regulates PC regeneration.

Methods:

Surgical injury was induced in ICR mice on E13 and E14. RA receptor alpha (RARα) expression in tissue samples from embryos was evaluated using immunohistochemistry and reverse transcription-quantitative polymerase chain reaction. To evaluate the effects of RA on PC regeneration, beads soaked in all-trans RA (ATRA) were implanted in E13 wounds, and tissues were observed. The effects of RA on myoblast migration were evaluated using a cell migration assay.

Results:

During wound healing, RARα expression was enhanced at the cut surface in PCs of E13 wounds but was attenuated at the cut edge of E14 PCs. Implantation of ATRA-containing beads inhibited PC regeneration on E13 in a concentration-dependent manner. Treatment of myoblasts with ATRA inhibited cell migration.

Conclusions:

ATRA inhibits PC regeneration, and decreased RARα expression in wounds after E14 inhibits myoblast migration. Our findings may contribute to the development of therapies to promote complete wound regeneration, even in the muscle.
Combined ALT, Estlander, and Upper Lip Flap for Defects Involving the Oral Commissure
Authors: Matsui Chihiro , Tachibana Kiyomi , Arai Toshihiro , Ikeda Yusuke , Escandón Joseph M. , Mohammad Arbab , Mizuno Hiroshi
Published: September 2022

Lip defects (including the corners of the mouth) are a reconstructive challenge in terms of both aesthetic and functional outcomes. When oral cancer resection results in defects that extend beyond the corners of the mouth to the buccal mucosa and buccal skin, it is difficult to perform reconstructive surgery using only a local flap, and a free flap must be used in combination. In this report, we present a case of reconstructive surgery of the corners of the mouth, buccal mucosa, and buccal skin after tumor resection for buccal mucosal squamous cell carcinoma in a 70-year-old man. The patient presented with a change in an oral mucosal ulcer for a period of 1 year. After biopsy of the ulcerated area, he was pathologically diagnosed with squamous cell carcinoma. After tumor resection, including the corners of the mouth, lips, and cheek skin, and neck dissection, the patient underwent reconstructive surgery using an extended upper lip flap combined with an Estlander flap and a free anterolateral thigh flap. Two months after surgery, the patient was able to consume regular food. At 24 months of follow-up, the patient was able to speak normally without any restrictive symptoms such as fluid leakage from the corner of the mouth. Lip sensation restoration was optimal. This method using the combination of an anterolateral thigh flap and extended Estlander flap is a markedly useful option for reconstructive surgery of defects around the corner of the mouth caused by wide excision of invasive cancer.
Fluid balance in pediatric critically ill patients (with and without kidney dysfunction)
Authors: Ricci Zaccaria , Bjornstad Erica
Published: September 2022

Purpose of review

The issues of fluid balance and fluid overload are currently considered crucial aspects of pediatric critically ill patients’ care.

Recent findings

This review describes current understanding of fluid management in critically ill children in terms of fluid balance and fluid overload and its effects on patients’ outcomes. The review describes current evidence surrounding definitions, monitoring, and treatment of positive fluid balance. In particular, the review focuses on specific patient conditions, including perioperative cardiac surgery, severe acute respiratory failure, and extracorporeal membrane oxygenation therapy, as the ones at highest risk of developing fluid overload and poor clinical outcomes. Gaps in understanding include specific thresholds at which fluid overload occurs in all critically ill children or specific populations and optimal timing of decongestion of positive fluid balance.

Current evidence on fluid balance in critically ill children is mainly based on retrospective and observational studies, and intense research should be recommended in this important field. In theory, active decongestion of patients with fluid overload could improve mortality and other clinical outcomes, but randomized trials or advanced pragmatic studies are needed to better understand the optimal timing, patient characteristics, and tools to achieve this.
Physical Activity Coaching via Telehealth for People With Parkinson Disease: A Cohort Study
Authors: Shih Hai-Jung Steffi , Macpherson Chelsea E. , King Miriam , Delaney Elizabeth , Gu Yu , Long Katrina , Reid Jennifer , Fineman Julie , Yu Geraldine , Rieger Jamie , Satchidanand Ashrita , Shah Hiral , Alcalay Roy N. , Quinn Lori
Published: September 2022

Background and Purpose:

Physical activity (PA) has many known benefits for people with Parkinson disease (PD); however, many people do not meet recommended levels of frequency or intensity. We designed Engage-PD, a PA coaching program delivered via telehealth and grounded in self-determination theory to promote PA uptake and facilitate exercise self-efficacy in people with Parkinson disease. This study aimed to determine the feasibility and preliminary efficacy of Engage-PD, and to explore whether baseline characteristics were associated with outcomes.

Methods:

A single cohort of people with PD (n = 62, Hoehn and Yahr I-III) participated in the 3-month Engage-PD program, which consisted of up to 5 telehealth coaching sessions delivered by physical therapists. Feasibility was evaluated based on recruitment and retention rates, along with participants' feedback. Planned and unplanned PA, exercise self-efficacy (ESE), and individualized goals were assessed pre- and post-intervention. Relationships between baseline characteristics and changes in planned PA and ESE were also evaluated.

Results:

Recruitment (62%) and retention (85%) rates were high, and the intervention was well accepted and perceived by the participants. From pre- to postintervention, participants increased planned PA (d = 0.33), ESE (d = 1.20), and individualized goal performance (d = 1.63) and satisfaction (d = 1.70). Participants with lower baseline planned PA experienced greater improvements in planned PA, and those with lower baseline ESE experienced greater improvements in ESE.

Discussion and Conclusions:

A telehealth PA coaching program for people with PD was feasible and potentially efficacious. Physical therapist-led coaching may be an important component of a consultative model of care starting early in the disease process.

Video Abstract available for more insights from the authors (see the Video, Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A393).
Effects of virtual reality-based exercise on balance in patients with stroke: a systematic review and meta-analysis
Authors: Shen Jie , Gu Xudong , Yao Yunhai , Li Liang , Shi Meifang , Li Hui , Sun Ya , Bai Hefeng , Li Yan , Fu Jianming
Published: September 2022

Objective

To quantify the effects of virtual reality (VR)-based exercise on balance after stroke.

Design

The PubMed, Embase, Cochrane Library, Cumulative Index of Nursing and Allied Health Literature, and Web of Science databases were searched until December 31, 2021. Independent investigators abstracted data, assessed the quality of the evidence, and rated the certainty of the evidence. The intergroup differences were determined by calculating mean difference (MD) and 95% confidence interval (CI) by RevMan 5.3 software.

Results

Fourteen RCTs involving 423 stroke patients were included. Patients who received VR-based exercise illustrated marked improvements in the Berg Balance Scale (BBS) (MD = 1.35, 95% CI: 0.58 to 1.86, P<0.00001, I2
= 44%), Timed Up and Go test (TUG) (MD = -0.81, 95% CI: -1.18 to -0.44, P < 0.0001, I2
= 0%), Functional Reach Test (FRT) (MD = 3.06, 95% CI: 1.31 to 4.80, P = 0.0006, I2
= 0%), 10 Meters Walking Test (10MWT) (MD = -1.53, 95% CI: -2.92 to -0.13, P = 0.03, I2
= 33%), and Modified Barthel Index (MBI) (MD = 5.26, 95% CI: 1.70 to 8.82, P = 0.004, I2
= 0%) compared with the control group.

Conclusion

Existing low-evidence analyses showed that VR-based exercise could effectively and safely improve balance in chronic stroke. Longer-term VR-based exercise was more effective on functional ability of stroke.
Effects of Motor Imagery Training for Lower Limb Dysfunction in Patients with Stroke A Systematic Review and Meta-Analysis of Randomized Controlled Trials
Authors: Zhao Li Juan , Jiang Lin Hong , Zhang Hong , Li Yang , Sun Pingping , Liu Yang , Qi Rui
Published: September 2022

Objective

To determine the effects of motor imagery training (MIT) associated with conventional rehabilitation therapies (CRTs) on lower extremity motor function (LEMF) recovery in poststroke patients.

Design

Comprehensive literature searches were performed to identify studies published before June 5, 2022. RevMan 5.3 software was used for meta-analysis. The quality of the included studies was assessed using the Cochrane risk-of-bias tool and the modified Jadad scale. The certainty of the evidence was evaluated with GRADE system.

Result

Twenty-three trials/1109 participants with MIT ability were included in this review. MIT combined with CRTs (MIT-CRTs) versus CRTs demonstrated significant benefits in motor function, balance function, temporospatial gait variables (walking speed, stride length, and cadence) and activities of daily living (ADLs). Subgroup analysis demonstrated that MIT-CRTs had a better effect on improvement in motor function and ADLs in the acute phase and had a greater benefit on walking speed in the chronic phase. Additionally, MIT-CRTs resulted in greater improvements in stride length, cadence, walking ability, and balance function in the subacute phase.

Conclusions

MIT-CRTs have better effects on the recovery of LEMF in poststroke patients than CRTs, which may be most beneficial for LEMF recovery in the first 7 days to 6 months.
Spectrum of EEG Abnormalities in COVID-19 Patients
Authors: Hameed Sajid , Saleem Shafaq , Sajjad Ali , Fahim Quratulain , Wasay Mohammad , Kanwar Dureshahwar
Published: September 2022

Purpose:

Neurologic involvement is commonly reported in coronavirus disease (COVID-19) patients. The published literature regarding the COVID-19–related neurophysiological findings, including the EEG findings, is still quite limited. The objective of this study was to evaluate the EEG findings in patients with a COVID-19 infection and look for a possible correlations and prognosis.

Methods:

This is an inpatient hospital-based retrospective observational study. All admitted COVID-19 patients undergoing an EEG study between January 1, 2020 and June 30, 2021 were included in this study. EEG was ordered by the primary intensive care physician or a neurologist taking part in the clinical care of patients.

Results:

Sixty-six EEG studies in 57 patients were included. Mean age was 62.2 ± 16.3 years with male predominance (65%). Encephalopathy (70%) was the most common indication for an EEG. Background EEG abnormalities were seen in most of the patients (92.4%) with severe abnormalities correlating with the prognosis of the patient. Epileptiform discharges were only seen in 7.5% of the EEGs, with majority of the discharges arising from the frontal region. Mortality reported was high (47%).

Conclusions:

Nonspecific diffuse background EEG abnormalities are commonly seen in COVID-19 patients. Epileptiform discharges are less common but mostly originate from frontal region. Most of these patients also had an abnormal neuroimaging. The significance of this peculiar finding needs further research.

Significance:

Nonspecific background EEG changes are common in COVID-19 patients. Among epileptiform discharges, focal epileptiform discharges arising from the frontal region were common, usually associated with an abnormal neuroimaging.
Boredom is the root of all evil—or is it? A psychometric network approach to individual differences in behavioural responses to boredom
Authors: Bieleke Maik , Ripper Leonie , Schüler Julia , Wolff Wanja
Published: September 2022

Functional accounts of boredom propose that boredom serves as an impartial signal to change something about the current situation, which should give rise to adaptive and maladaptive behaviour alike. This seemingly contrasts with research on boredom proneness, which has overwhelmingly shown associations with maladaptive behaviour. To shed light on this discrepancy, we disentangled boredom proneness from individual differences in (i) the
urge to avoid and escape boredom
and (ii)
adaptive and maladaptive ways of dealing with boredom
by developing corresponding trait scales. In a study with
N
= 636 participants, psychometric network modelling revealed tight associations between boredom proneness and less adaptive and (especially) more maladaptive ways of dealing with boredom. However, its associations with the urge to avoid and escape boredom were rather weak. Importantly, a higher urge to avoid and escape boredom was linked not only to more maladaptive but also to more adaptive ways of dealing with boredom. This pattern of results was robust across various specific behaviours that have previously been linked to boredom. Our findings provide novel evidence for functional accounts of boredom from an individual difference perspective, cautioning against a shallow view of boredom as being associated with purely maladaptive behaviour.
Single cell classification of macrophage subtypes by label-free cell signatures and machine learning
Authors: Dannhauser David , Rossi Domenico , De Gregorio Vincenza , Netti Paolo Antonio , Terrazzano Giuseppe , Causa Filippo
Published: September 2022

Pro-inflammatory (M1) and anti-inflammatory (M2) macrophage phenotypes play a fundamental role in the immune response. The interplay and consequently the classification between these two functional subtypes is significant for many therapeutic applications. Albeit, a fast classification of macrophage phenotypes is challenging. For instance, image-based classification systems need cell staining and coloration, which is usually time- and cost-consuming, such as multiple cell surface markers, transcription factors and cytokine profiles are needed. A simple alternative would be to identify such cell types by using single-cell, label-free and high throughput light scattering pattern analyses combined with a straightforward machine learning-based classification. Here, we compared different machine learning algorithms to classify distinct macrophage phenotypes based on their optical signature obtained from an ad hoc developed wide-angle static light scattering apparatus. As the main result, we were able to identify unpolarized macrophages from M1- and M2-polarized phenotypes and distinguished them from naive monocytes with an average accuracy above 85%. Therefore, we suggest that optical single-cell signatures within a lab-on-a-chip approach along with machine learning could be used as a fast, affordable, non-invasive macrophage phenotyping tool to supersede resource-intensive cell labelling.
Testing the protein-leverage hypothesis using population surveillance data
Authors: Senior Alistair M. , Raubenheimer David , Simpson Stephen J.
Published: September 2022

It is hypothesized that humans exhibit ‘protein leverage’ (PL), whereby regulation of absolute protein intake results in the over-consumption of non-protein food on low percentage protein diets. Testing for PL using dietary surveillance data involves seeking evidence for a negative association between total energy intake and percentage energy from protein. However, it is unclear whether such an association might emerge without PL due to the structure of intake data (protein and non-protein intakes have different means and variances and covary). We derive a set of models that describe the association between the expected estimate of PL and the distributions of protein and non-protein intake. Models were validated via simulation. Patterns consistent with PL will not emerge simply because protein intake has a lower mean and/or variance than non-protein. Rather, evidence of PL is observed where protein has a lower index of dispersion (variance/mean) than non-protein intake. Reciprocally, the stronger PL is the lower the index of dispersion for protein intake becomes. Disentangling causality is ultimately beyond the power of observational data alone. However, we show that one can correct for confounders (e.g. age) in generating signals of PL, and describe independent measures that can anchor inferences around the role of PL.
Native species exhibit physiological habituation to invaders: a reason for hope
Authors: Santicchia Francesca , Wauters Lucas Armand , Dantzer Ben , Palme Rupert , Tranquillo Claudia , Preatoni Damiano , Martinoli Adriano
Published: September 2022

Animals cope with environmental perturbations through the stress response, a set of behavioural and physiological responses aimed to maintain and/or return to homeostasis and enhance fitness. Vertebrate neuroendocrine axis activation in response to environmental stressors can result in the secretion of glucocorticoids (GCs), whose acute increases may be adaptive, while chronic elevation may be detrimental. Invasive grey squirrels (
Sciurus carolinensis
) act as a stressor eliciting elevation of GCs in native red squirrels (
Sciurus vulgaris
). Here we used 6-year data of variation in faecal glucocorticoid metabolite (FGM) concentrations following invasion by grey squirrels in three red squirrel populations, to identify if red squirrels showed physiological habituation to this stressor. The decrease in FGMs over time was more pronounced shortly after invasion and at high densities of grey squirrels while it decreased less strongly and was no longer influenced by the invader density as time since invasion elapsed. At the individual level, FGMs also decreased more markedly as each red squirrel experienced prolonged contact with the invader. Our study provides compelling new data suggesting that native species in the wild can habituate to prolonged contact with invasive species, showing that they may avoid the potentially harmful effects of chronic elevations in GCs.
Risk factors for stereotypic behaviour in captive ungulates
Authors: Lewis Kate , Parker Matthew O. , Proops Leanne , McBride Sebastian D.
Published: September 2022

Behavioural needs are highly motivated actions critical to a species survival and reproduction. Prolonged restriction of these behaviours can lead to stereotypic behaviours (SB) in captive animals, and this is particularly common in ungulate species. While risk factors for SB have been suggested for some ungulates, no study has integrated these findings to identify which aspects of ungulates’ wild behavioural biology and captive husbandry are potential drivers for SB across this clade. We collated SB data from 15 236 individuals across 38 ungulate species from 95 sources, and determined species wild/free-ranging behaviour from 559 additional studies. Bayesian-phylogenetic statistical methods showed that ungulate behavioural needs relating to foraging and mating are particularly affected by captive environments, with promiscuous and browsing species showing the greatest prevalence of SB. Concentrate-only diets and lack of
ad libitum
feed substrates were also associated with high SB prevalence. This study identifies which ungulates are better suited to captive environments and which species require targeted husbandry, enrichment and breeding protocols in order to meet their behavioural needs. Our approach of applying Bayesian-phylogenetic inference to factors influencing SB within a clade can be used to identify other intrinsic and extrinsic risk factors of reduced animal health and welfare.
Fossil basicranium clarifies the origin of the avian central nervous system and inner ear
Authors: Chiappe Luis M. , Navalón Guillermo , Martinelli Agustín G. , Nava William , Field Daniel J.
Published: September 2022

Among terrestrial vertebrates, only crown birds (Neornithes) rival mammals in terms of relative brain size and behavioural complexity. Relatedly, the anatomy of the avian central nervous system and associated sensory structures, such as the vestibular system of the inner ear, are highly modified with respect to those of other extant reptile lineages. However, a dearth of three-dimensional Mesozoic fossils has limited our knowledge of the origins of the distinctive endocranial structures of crown birds. Traits such as an expanded, flexed brain, a ventral connection between the brain and spinal column, and a modified vestibular system have been regarded as exclusive to Neornithes. Here, we demonstrate all of these ‘advanced’ traits in an undistorted braincase from an Upper Cretaceous enantiornithine bonebed in southeastern Brazil. Our discovery suggests that these crown bird-like endocranial traits may have originated prior to the split between Enantiornithes and the more crownward portion of avian phylogeny over 140 Ma, while coexisting with a remarkably plesiomorphic cranial base and posterior palate region. Altogether, our results support the interpretation that the distinctive endocranial morphologies of crown birds and their Mesozoic relatives are affected by complex trade-offs between spatial constraints during development.
Optimal vaccination at high reproductive numbers: sharp transitions and counterintuitive allocations
Authors: Gavish Nir , Katriel Guy
Published: September 2022

Optimization of vaccine allocations among different segments of a heterogeneous population is important for enhancing the effectiveness of vaccination campaigns in reducing the burden of epidemics. Intuitively, it would seem that allocations designed to minimize infections should prioritize those with the highest risk of being infected and infecting others. This prescription is well supported by vaccination theory, e.g. when the vaccination campaign aims to reach herd immunity. In this work, we show, however, that for vaccines providing partial protection (leaky vaccines) and for sufficiently high values of the basic reproduction number, intuition is overturned: the optimal allocation minimizing the number of infections prioritizes the vaccination of those who are
least
likely to be infected. The work combines numerical investigations, asymptotic analysis for a general model, and complete mathematical analysis in a two-group model. The results point to important considerations in managing vaccination campaigns for infections with high transmissibility.
Cell circuits between leukemic cells and mesenchymal stem cells block lymphopoiesis by activating lymphotoxin-beta receptor signaling
Authors: Feng Xing , Sun Ruifeng , Lee Moonyoung , Chen Xinyue , Guo Shangqin , Geng Huimin , Müschen Markus , Choi Jungmin , Pereira Joao P.
Published: September 2022

Acute lymphoblastic and myeloblastic leukemias (ALL and AML) have been known to modify the bone marrow microenvironment and disrupt non-malignant hematopoiesis. However, the molecular mechanisms driving these alterations remain poorly defined. Here we show that leukemic cells turn-off lymphopoiesis and erythropoiesis shortly after colonizing the bone marrow. ALL and AML cells express lymphotoxin-α1β2 and activate LTβR signaling in mesenchymal stem cells (MSCs), which turns off IL7 production and prevents non-malignant lymphopoiesis. We show that the DNA damage response pathway and CXCR4 signaling promote lymphotoxin-α1β2 expression in leukemic cells. Genetic or pharmacologic disruption of LTβR signaling in MSCs restores lymphopoiesis but not erythropoiesis, reduces leukemic cell growth, and significantly extends the survival of transplant recipients. Similarly, CXCR4 blocking also prevents leukemia-induced IL7 downregulation, and inhibits leukemia growth. These studies demonstrate that acute leukemias exploit physiological mechanisms governing hematopoietic output as a strategy for gaining competitive advantage.

One Sentence Summary

Leukemias colonize bone marrow niches and disrupt hematopoiesis. However, the cross-talk between leukemia and niche cells remains poorly understood. We show that leukemia activates LTβR in mesenchymal stem cells which suppresses IL7 production and IL7-dependent lymphopoiesis and accelerates leukemia growth.
Device-led versus human-led feedback on chest compressions for cardiopulmonary resuscitation and providers’ experience and preference: a randomised crossover study
Authors: Noor Azhar Muhaimin , Bustam Aida , Poh Khadijah , Chew Keng Sheng , Azman Asraff , Kamarudin Anhar , Zambri Aliyah
Published: September 2022

Background

High cardiopulmonary resuscitation (CPR) quality is associated with better patient survival from cardiac arrest. However, CPR providers may not have an accurate perception of the depth and rate of their chest compressions (CC). Realtime feedback during resuscitation improves CPR quality compared to no feedback. Evidence comparing audio-visual feedback device (AVF) and team leader’s feedback (TLF) in improving CPR performance is limited and conflicting.

Methodology

We performed a randomized crossover study to evaluate CC performance with AVF and TLF. Seventy participants performed CC for 1 minute on a CPR manikin connected to ZOLL R series defibrillator with CPR-sensing capability in a randomised crossover sequence. We interviewed participants to explore their perception and preference with both feedback methods.

Results

Mean CC rate was higher with AVF than with TLF (121.8 min-1 ± 17.7 vs. 117.4 min-1 ± 13.5, p = 0.005). There was no significant difference in proportions of participants performing CC within the recommended rate of 100-120 beats per minute between AVF and TLF (48.6% and 51.4%, p = 0.824). Overall, CC depth was below the recommended target regardless of feedback method with mean CC depth of 4.4 cm ± 0.8 in AVF and 4.3 cm ± 0.9 in TLF respectively (p = 0.479). Most participants felt that TLF was easier to follow, more motivating and preferable compared to AVF. Those who preferred TLF performed CC at rates above the recommended range with AVF compared to TLF (124.1 min-1 ± 19.4 versus 118.2 min-1 ± 14.9, p = 0.004).

Conclusion

A well-trained team leader is as effective as an AVF device in leading high-quality CC. CPR providers’ performance may be influenced by their preferred feedback method.
DISCRIMINATOR: Assigning Cohort-Wide Provisional Pathogenicity Classifications to CNVs
Authors: Wetzel Alyssa S. , Major Heather , Parida Mrutyunjaya , Manak J. Robert , Darbro Benjamin W.
Published: September 2022

The interpretation of clinical chromosomal microarrays (CMAs) has historically relied on the relevance of identified copy number variants (CNVs) to the clinical phenotype. New interpretation guidelines are focused on standardizing pathogenicity classifications based on genomic location, gene content, and previous publications, rather than the immediate clinical relevance. Here we report on DISCRIMINATOR, which was developed to assign provisional pathogenicity classifications based on genomic location by integrating information on putative benign and pathogenic loci in the human genome. However, its application extends beyond that of a simple classifier. The novel utility of DISCRIMINATOR is its ability to operate on a cohort-level and easily integrate updated definitions of benign and pathogenic regions of the human genome. We used DISCRIMINATOR to assign provisional pathogenicity classifications (‘Benign’, ‘Secondary’, ‘Primary’ or ‘Non-Coding’) to 87,808 CNVs in 3,362 cases ascertained through clinical CMA testing. The majority of identified CNVs were provisionally classified as ‘Benign’ or ‘Non-Coding’ and consistent with their prevalence rates, 15q11.2, 16p11.2, and 22q11.2 were the most common ‘Primary’ CNVs detected. Targeted re-analysis led to the identification of several cases where DISCRIMINATOR identified a ‘Primary’ CNV within a case that had a non-Abnormal CMA test result, and several cases where only benign and/or non-coding CNVs were identified in reports with a ‘VUS’ CMA test result. Together these results show the utility of large-scale re-analysis of CMA data and how DISCRIMINATOR addresses this long-standing challenge.
Large scale interrogation of retinal cell functions by 1-photon light-sheet microscopy
Authors: Roy Suva , Wang Depeng , Rudzite Andra M. , Perry Benjamin , Scalabrino Miranda L. , Thapa Mishek , Gong Yiyang , Sher Alexander , Field Greg D.
Published: September 2022

Visual processing in the retina depends on the collective activity of large ensembles of neurons organized in different layers. Current techniques for measuring activity of layer-specific neural ensembles rely on expensive pulsed infrared lasers to drive 2-photon activation of calcium-dependent fluorescent reporters. Here, we present a 1-photon light-sheet imaging system that can measure the activity in hundreds of ex vivo retinal neurons over a large field of view while simultaneously presenting visual stimuli. This allowed for a reliable functional classification of different retinal ganglion cell types. We also demonstrate that the system has sufficient resolution to image calcium entry at individual synaptic release sites across the axon terminals of dozens of simultaneously imaged bipolar cells. The simple design, a large field of view, and fast image acquisition, make this a powerful system for high-throughput and high-resolution measurements of retinal processing at a fraction of the cost of alternative approaches.
Profound immunomodulatory effects of 225Ac-NM600 drive enhanced anti-tumor response in prostate cancer
Authors: Ferreira Carolina A. , Potluri Hemanth K. , Massey Christopher , Grudzinski Joseph J. , Carston Amanda , Clemons Nathan , Thickens Anna , Rosenkrans Zachary , Choi Cynthia , Pinchuk Anatoly , Kwon Ohyun , Jeffery Justin J. , Bednarz Bryan , Morris Zachary , Weichert Jamey , McNeel Douglas G. , Hernandez Reinier
Published: September 2022

An immunosuppressive tumor microenvironment has hampered the efficacy of immunotherapy in prostate cancer. However, radiation-induced immunological effects can partly mediate anti-tumor effects by promoting a pro-inflammatory environment potentially responsive to immunotherapy. Herein, we examined the immunomodulatory properties of a radiopharmaceutical therapy (RPT) with NM600 radiolabeled with either a beta or alpha emitter in two prostate cancer models. 225Ac-NM600, but not 177Lu-NM600, promoted significant anti-tumor effects and improved overall survival. Immunomodulatory effects were dose, radionuclide, and tumor type-dependent. 225Ac-NM600 elicited an array of immunomodulatory effects such as increased CD8/Treg ratio, activation of effector and memory T cells, abrogation of infiltrating suppressor cells (e.g., Tregs and MDSCs), and increased levels of Th1 cytokine and pro-inflammatory chemokines. Importantly, we demonstrate the need to carefully characterize the immune responses elicited by RPT both pre-clinically and clinically to maximize tumor control and avoid potential counterproductive immunosuppressive effects.

Teaser

Targeted alpha therapy can create a pro-inflammatory tumor micro-environment that partly explains stronger anti-tumor responses in prostate cancer
Molecular diagnostics for early detection of invasion of malaria vector Anopheles stephensi
Authors: Singh Om P. , Kaur Taranjeet , Sharma Gunjan , Prasad Kona M. , Kapoor Neera , Mallick Prashant K.
Published: September 2022

There are increasing reports of the expansion of the Asian malaria vector Anopheles stephensi in new geographical areas posing a threat to the elimination of urban malaria. Efficient surveillance of this vector in affected areas and early detection in new geographical areas is key for the containment and control of this species. To overcome the practical difficulties associated with the morphological identification of immature stages and adults of An. stephensi, a species-specific PCR and a Real-Time PCR assay were developed for their identification targeting a unique segment of ITS2 lacking homology to any other organism. Both PCRs can be used to identify An. stephensi individually or in pooled samples of mixed species, including when present in extremely low proportion. This study also reports a method for selective amplification and sequencing of An. stephensi for their confirmation in pooled samples of mixed species.
Model-based whole-brain perturbational landscape of neurodegenerative diseases
Authors: Perl Yonatan Sanz , Fittipaldi Sol , González Campo Cecilia , Moguilner Sebastián , Cruzat Josephine , Herzog Rubén , Kringelbach Morten , Deco Gustavo , Prado Pavel , Ibañez Agustín , Tagliazucchi Enzo
Published: September 2022

The treatment of neurodegenerative diseases is hindered by lack of interventions capable of steering multimodal whole-brain dynamics towards patterns indicative of preserved brain health. To address this problem, we combined deep learning with a model capable of reproducing whole-brain functional connectivity in patients diagnosed with Alzheimer’s disease (AD) and behavioral variant frontotemporal dementia (bvFTD). These models included disease-specific atrophy maps as priors to modulate local parameters, revealing increased stability of hippocampal and insular dynamics as signatures of brain atrophy in AD and bvFTD, respectively. Using variational autoencoders, we visualized different pathologies and their severity as the evolution of trajectories in a low-dimensional latent space. Finally, we perturbed the model to reveal key AD− and bvFTD-specific regions to induce transitions from pathological to healthy brain states. Overall, we obtained novel insights on disease progression and control by means of external stimulation, while identifying dynamical mechanisms that underlie functional alterations in neurodegeneration.
Cerebral Small Vessel Disease Burden is Associated with Decreased Abundance of Gut Barnesiella intestinihominis Bacterium in the Framingham Heart Study
Authors: Fongang Bernard , Satizabal Claudia L. , Kautz Tiffany F. , Ngouongo Yannick W. , SherraeMuhammad Jazmyn A. , Vasquez Erin , Mathews Julia , Goss Monica , Saklad Amy R. , Himali Jayandra , Beiser Alexa , Cavazos Jose E. , Mahaney Michael C. , Maestre Gladys , DeCarli Charles , Shipp Eric L. , Vasan Ramachandran S. , Seshadri Sudha
Published: September 2022

A bidirectional communication exists between the brain and the gut, in which the gut microbiota influences cognitive function and vice-versa. Gut dysbiosis has been linked to several diseases, including Alzheimer’s disease and related dementias (ADRD). However, the relationship between gut dysbiosis and markers of cerebral small vessel disease (cSVD), a major contributor to ADRD, is unknown. In this cross-sectional study, we examined the connection between the gut microbiome, cognitive, and neuroimaging markers of cSVD in the Framingham Heart Study (FHS). Markers of cSVD included white matter hyperintensities (WMH), peak width of skeletonized mean diffusivity (PSMD), and executive function (EF), estimated as the difference between the trail-making tests B and A. We included 972 FHS participants with MRI scans, neurocognitive measures, and stool samples and quantified the gut microbiota composition using 16S rRNA sequencing. We used multivariable association and differential abundance analyses adjusting for age, sex, BMI, and education level to estimate the association between gut microbiota and WMH, PSMD, and EF measures. Our results suggest an increased abundance ofPseudobutyrivibrioandRuminococcusgenera was associated with lower WMH and PSMD (p-values < 0.001), as well as better executive function (p-values < 0.01). In addition, in both differential and multivariable analyses, we found that the gram-negative bacteriumBarnesiella intestinihominiswas strongly associated with markers indicating a higher cSVD burden. Finally, functional analyses usingPICRUStimplicated various KEGG pathways, including microbial quorum sensing, AMP/GMP-activated protein kinase, phenylpyruvate, and β-hydroxybutyrate production previously associated with cognitive performance and dementia. Our study provides important insights into the association between the gut microbiome and cSVD, but further studies are needed to replicate the findings.
Murine breast cancers disorganize the liver transcriptome in zonated manners
Authors: Vandenbon Alexis , Mizuno Rin , Konishi Riyo , Onishi Masaya , Masuda Kyoko , Kobayashi Yuka , Kawamoto Hiroshi , Suzuki Ayako , Shimizu Masahito , Tanaka Yasuhito , Suzuki Yutaka , Kawaoka Shinpei
Published: September 2022

The spatially organized gene expression program within the liver specifies hepatocyte functions according to their relative distances to the bloodstream (i.e., zonation), contributing to liver homeostasis. Despite the knowledge that solid cancers remotely disrupt liver homeostasis, it remains unexplored whether solid cancers affect liver zonation. Here, using spatial transcriptomics, we thoroughly investigate the abundance and zonation of hepatic genes in cancer-bearing mice. We find that breast cancers affect liver zonation in various distinct manners depending on biological pathways. Aspartate metabolism and triglyceride catabolic processes retain relatively intact zonation patterns, but the zonation of xenobiotic catabolic process genes exhibits a strong disruption. The acute phase response is induced in zonated manners. Furthermore, we demonstrate that breast cancers activate innate immune cells in particular neutrophils in distinct zonated manners, rather than in a uniform fashion within the liver. Collectively, breast cancers disorganize hepatic transcriptomes in zonated manners, thereby disrupting zonated functions of the liver.
Classic and dissociative psychedelics induce similar hyper-synchronous states in the cognitive-limbic cortex-basal ganglia system
Authors: Brys Ivani , Barrientos Sebastian , Ward Jon Ezra , Wallander Jonathan , Petersson Per , Halje Pär
Published: September 2022

The neurophysiological mechanisms behind the profound changes in perception and cognition induced by psychedelic drugs are not well understood. To identify neuronal activity specific to the psychedelic state, we here investigated the effects of classic psychedelics (LSD, DOI) and dissociative psychedelics (ketamine, PCP) on neuronal firing rates and local field potentials in several brain structures involved in cognitive processing in freely moving rats.

The classic psychedelics had a net inhibitory effect on firing rates of putative interneurons and principal cells in all recorded regions. The dissociative psychedelics had a similar inhibitory effect on principal cells, but an opposite excitatory effect on interneurons in most regions. However, the inhibitory effect on principal cells was not specific to the psychedelic state, as similar inhibition occurred with a non-psychedelic psychotropic control (amphetamine).

In contrast, both types of psychedelics dramatically increased the prevalence of high-frequency oscillations (HFOs) in local field potentials, while the non-psychedelic control did not. Further analysis revealed strong HFO phase locking between structures and very small phase differences corresponding to <1 ms delays. Such standing-wave behavior suggests local generation of HFOs in multiple regions and weak, fast coupling between structures.

The observed HFO hypersynchrony is likely to have major effects on processes that rely on integration of information across neuronal systems, and it might be an important mechanism behind the changes in perception and cognition during psychedelic drug use. Potentially, similar mechanisms could induce hallucinations and delusions in psychotic disorders and would constitute promising targets for new antipsychotic treatments.
A Genome Scale Transcriptional Regulatory Model of the Human Placenta
Authors: Paquette Alison , Ahuna Kylia , Hwang Yeon Mi , Pearl Jocelynn , Liao Hanna , Shannon Paul , Kadam Leena , Lapehn Samantha , Bucher Matthew , Roper Ryan , Funk Cory , MacDonald James , Bammler Theo , Baloni Priyanka , Brockway Heather , Mason W. Alex , Bush Nicole , Lewinn Kaja Z , Karr Catherine J , Stamatoyannopoulos John , Muglia Louis J , Jones Helen , Sadovsky Yoel , Myatt Leslie , Sathyanarayana Sheela , Price Nathan D.
Published: September 2022

Gene regulation is essential to placental function and fetal development. We report a genome-scale transcriptional regulatory network (TRN) of the human placenta built using digital genomic footprinting and transcriptomic data. We integrated 475 transcriptomes and 12 DNase hypersensitivity datasets from placental samples to globally and quantitatively map transcription factor (TF)-target gene interactions. In an independent dataset, the TRN model predicted target gene expression with an out of sample R2value greater than 0.25 for 74% of target genes. We performed siRNA knockdowns of 4 TFs and achieved concordance between the predicted gene targets in our TRN and differences in expression of knockdowns with an accuracy of >0.7 for 3 of the 4 TFs. Our final model contained 113,158 interactions across 391 TFs and 7,712 target genes and is publicly available. We identified six TFs which were significantly enriched as regulators for genes previously associated with preterm birth.
Disruption of Tonic Endocannabinoid Signaling Triggers the Generation of a Stress Response
Authors: Petrie Gavin N. , Balsevich Georgia , Füzesi Tamás , Aukema Robert J. , Driever Wouter P. F. , van der Stelt Mario , Bainsand Jaideep S. , Hill Matthew N.
Published: September 2022

Endocannabinoid (eCB) signalling gates many aspects of the stress response, including the hypothalamic-pituitary-adrenal (HPA) axis. The HPA axis is controlled by corticotropin releasing hormone (CRH) producing neurons in the paraventricular nucleus of the hypothalamus (PVN). Disruption of eCB signalling increases drive to the HPA axis, but the mechanisms subserving this process are poorly understood. Using an array of cellular, endocrine and behavioral readouts associated with activation of CRH neurons in the PVN, we evaluated the contributions of tonic eCB signaling to the generation of a stress response. The CB1 receptor antagonist/inverse agonist AM251, neutral antagonist NESS243, and NAPE PLD inhibitor LEI401 all uniformly increased c-fos in the PVN, unmasked stress-linked behaviors, such as grooming, and increased circulating CORT, recapitulating the effects of stress. Similar effects were also seen after direct administration of AM251 into the PVN, while optogenetic inhibition of PVN CRH neurons ameliorated stress-like behavioral changes produced by disruption of eCB signaling. These data indicate that under resting conditions, constitutive eCB signaling restricts activation of the HPA axis through local regulation of CRH neurons in the PVN.
Comprehensive Analysis of Peptide-Coding Genes Identifies an LRR-only Microprotein That Regulates Reproductive Organs in Marchantia polymorpha
Authors: Kobayashi Haruaki , Sugano Shigeo S. , Tamura Kentaro , Oka Yoshito , Matsushita Tomonao , Shimada Tomoo
Published: September 2022

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In the past two decades, many plant peptides have been found to play crucial roles in various biological events by mediating cell-to-cell communications. However, a large number of small open reading frames (sORFs) or short genes capable of encoding peptides remain uncharacterized. In this study, we examined several candidate genes for peptides conserved between two model plants: Arabidopsis thaliana and Marchantia polymorpha. We examined the expression pattern in M. polymorpha and subcellular localization using a transient assay with Nicotiana benthamiana. We found that one candidate, MpSGF10B, was expressed in meristems, gemma cups, and male reproductive organs called antheridiophores. MpSGF10B has an N-terminal signal peptide followed by two leucine-rich repeat (LRR) domains and was secreted to the extracellular region in N. benthamiana and M. polymorpha. Compared with the wild type, two independent knockout mutants had an increased number of antheridiophores, which emerged from meristems. It was revealed in gene ontology enrichment analysis that MpSGF10B was significantly co-expressed with genes related to cell cycle and development. These results suggest that MpSGF10B may regulate the reproductive development in M. polymorpha. Our research should shed light on the unknown role of LRR-only proteins in land plants.
Single-cell resolution genetic association analysis of heterogeneous bacterial communities by utilizing droplet digital PCR
Authors: Dutra Lara Ambrosio Leal , Jalasvuori Matti , Franz Ole , Nurminen Kimi , Salmi Pauliina , Tiirola Marja , Penttinen Reetta
Published: September 2022

Microbial communities often respond to various challenges, such as the presence of antibiotics, as a whole. Dissecting these community-level effects into separate acting entities requires the identification of organisms that carry functional genes for the observed feature. However, unculturable microbes abound in various environments, hence making the identification challenging. Here we present a cultivation-free technique that can be utilized to link functional genes with carrying bacterial species at single-cell resolution. The developed protocol is relatively simple to use, utilizes commercially available droplet microfluidics devices, does not require toxic reagents (as compared to some previous methods), eliminates invalid signals emerging from extracellular DNA, and allows simultaneous analysis of community diversity via 16S rRNA gene sequencing. The method can be customized for any given genetic trait to accurately identify its hosting subpopulation from a heterogeneous and potentially uncultivable bacterial community.