bluuebunny/crossref_metadata_2025 huggingface dataset:
Addition of backward walking training to forward walking training improves walking speed in children with cerebral palsy: a systematic review with meta-analysis
Authors: Menezes Kênia K.P. , Avelino Patrick R. , Nascimento Lucas R.
Published: August 2023

The objective was to examine the effects of backward walking training for improving walking speed and balance in children with cerebral palsy. A systematic review of randomized trials was conducted. Trials had to include children with cerebral palsy, with a Gross Motor Function Classification System, between I and III, that delivered backward walking training as a solo intervention or in combination with forward walking training. The outcomes of interest were walking speed and balance. The methodological quality of included trials was assessed by the PEDro scale, and the quality of evidence was assessed according to Grading of Recommendations Assessment, Development and Evaluation. Eight papers, involving 156 participants, were included. Using random-effects meta-analysis, we estimated that backward walking training improved walking speed by 0.10 m/s [95% confidence interval (CI) 0.05–0.16] and by 2 points on the Pediatric Balance Scale (0–56) (95% CI 1.5–2.2) more than forward walking training. We also estimated that the addition of backward walking training increased walking speed by 0.20 m/s (95% CI 0.07–0.34) and reduced the angular excursion of the center of gravity by 0.5 degrees (95% CI −0.7 to −0.3). The quality of the evidence was classified as low to moderate. In conclusion, overall, backward walking training appears to be as effective or slightly superior to forward walking training for improving walking speed in children with CP. The addition of backward walking training statistically significantly and clinically important enhanced benefits on walking speed.
Progressive multifocal leukoencephalopathy in the background of chlorambucil treated chronic lymphocytic leukemia: a case report from Nepal
Authors: Dhakal Bishal , Upadhaya Regmi Binit , Subedi Ram Chandra , Joshi Sushil , Pathak Bishnu Deep , Bogati Kanchan , Baniya Sunil , Neupane Peter , Paudel Raju
Published: August 2023

Introduction:

Progressive multifocal leukoencephalopathy is a rare manifestation in itself. Although many immunosuppressive states are associated with the disease, its occurrence in the setting of chronic lymphocytic leukaemia treated with chemotherapy is seldom reported to date.

Case presentation:

A 67-year-old woman with known chronic lymphocytic leukaemia who was previously receiving chlorambucil treatment was identified as having progressive multifocal leukoencephalopathy; her prognosis is currently good.

Clinical discussion:

Although a rare disease in an immunocompromised setting, progressive multifocal leukoencephalopathy often leads to a grave outcome. However, the authors describe a case with a good prognosis to date.

Conclusion:

Progressive multifocal leukoencephalopathy should be in differentials in immunocompromised patients with dementia. Given that the later prognosis of the disease is unpredictable, an earlier diagnosis would be better for immunological reconstitution.
Weight Self-Efficacy and Recovery Among African-Americans With Serious Mental Illness and High Body Weight
Authors: Corrigan Patrick W. , Nieweglowski Katherine , Qin Sang , Sheehan Lindsay , Puhl Rebecca , Talluri Sai Snigdha
Published: August 2023

Many African-Americans with serious mental illness fail to engage in evidence-based programs that positively affect weight management. We examined how having a weight-related physical illness correlated with self-efficacy, recovery, and quality of life by contrasting illnesses with symptoms that are obviously perceived (e.g., sleep apnea and pain related to weight) versus those that are not (e.g., hypertension). African-Americans with serious mental illness who were overweight (body mass index ≥25) completed the Weight Efficacy Lifestyle Questionnaire, Recovery Assessment Scale, and Quality of Life Scale in this study assessing the impact of a program on weight and health. Silent weight-related physical disorders were not found to correlate with quality of life, recovery, or weight self-efficacy. Differences in recovery were found in people with versus without sleep apnea and weight-related pain. Findings suggest future directions for affirming approaches to promote engagement among African-Americans with serious mental illness in weight management programs.
Integration of Person-Centered Narratives Into the Electronic Health Record
Authors: Coats Heather , Shive Nadia , Adrian Bonnie , Doorenbos Ardith Z. , Schmiege Sarah J.
Published: August 2023

Background

Care delivery that is not person-centered has been called discordant care. There has been a shift to incorporate more of a person’s narrative into their individual healthcare treatment plan to reduce discordant care. Aligning with this shift in healthcare delivery, we developed a person-centered narrative intervention (PCNI) to address existing gaps in delivery of person-centered care.

Objectives

This study aimed to evaluate the feasibility of conducting a randomized study and describe the outcomes of PCNI to usual care on the following person (patient)-reported outcomes: perceptions of the quality of communication with their nurses and their psychosocial and existential well-being.

Methods

This study’s design was an Obesity-Related Behavioral Intervention Trials model Phase II proof-of-concept randomized study. The participants were people admitted to an acute care hospital diagnosed with heart failure and/or end-stage renal disease.

Results

Despite COVID-19 challenges, the PCNI was feasible in an acute care setting; it showed a moderate positive difference between conditions in the person’s perception of their quality of communication and a small positive difference in their perception of feeling heard and understood. For our secondary outcomes of anxiety, depression, and psychosocial illness effect, there were small or no effects in the acute care setting.

Discussion

Using a person-centered narrative, such as the PCNI, can help inform delivery of care that incorporates a person’s (patient’s) beliefs, values, and preferences into their healthcare. This study used a pragmatic approach to evaluate the PCNI in real time in an acute care setting to assess patient-reported outcomes. These positive results in a small sample indicate the need for continued testing of the PCNI. These promising effects require further testing in a Phase III efficacy study within a larger randomized controlled clinical trial.
Adverse Childhood Experiences, Preventive Care Utilization, and Patient–Nurse Trust Relationship Among Sexual and Gender Minority Individuals
Authors: Zha Peijia , Qureshi Rubab , Porter Sallie , Zhang Crystal
Published: August 2023

Background

Individuals who identify as sexual and gender minorities often experience high rates of adverse childhood experiences and encounter discrimination and stigma in their interactions with healthcare providers, leading to low utilization of healthcare services. However, the relationship between adverse childhood experiences, preventive care utilization, and trust in nurses among sexual and gender minority individuals remains unclear.

Purpose

This study explored the relationship between adverse childhood experiences and preventive care use and assessed the potential interaction effects of trust in nurses between adverse childhood experiences and preventive care use among individuals from sexual and gender minorities.

Methods

A cross-sectional design was used. A sample of 160 self-reported individuals from sexual and gender minorities completed an electronic online survey. Multiple linear regression and moderation analyses were conducted to examine the association between adverse childhood experiences, preventive care utilization, and nurse trust.

Results

There was a significant negative relationship between adverse childhood experiences and preventive care utilization. There was also a significant positive relationship between trust and preventive care utilization. The results also indicated that trust in nurses moderated the relationship between adverse childhood experiences and preventive care utilization among sexual and gender minority individuals.

Discussion

A significant relationship was found between a high prevalence of adverse childhood experiences and low healthcare service utilization. Strengthening the trust relationship between nurses and sexual and gender minority individuals could serve as a potential intervention point, leading to improved health outcomes for this vulnerable population. Hence, enhancing trust in nurses could be a key factor in increasing healthcare service utilization and overall health outcomes.
Genetic Subtypes of Apert Syndrome Are Associated With Differences in Airway Morphology and Early Upper Airway Obstruction
Authors: Wagner Connor S. , Wietlisbach Larissa E. , Kota Anchith , Villavisanis Dillan F. , Pontell Matthew E. , Barrero Carlos E. , Salinero Lauren K. , Swanson Jordan W. , Taylor Jesse A. , Bartlett Scott P.
Published: August 2023

Background:

Apert syndrome is predominantly caused by 2 paternally inherited gain-of-function mutations in the FGFR2 gene, Pro253Arg, and Ser252Trp. Studies comparing phenotypic features between these 2 mutations have established differences in syndactyly severity and incidence of cleft palate. Obstructive sleep apnea can be debilitating in a subset of patients with Apert syndrome, yet is not well understood. This study aims to determine whether FGFR2 mutations impart differential effects on airway physiology and morphology.

Methods:

Patients with Apert syndrome and confirmatory molecular testing were reviewed for polysomnography, nasal endoscopy, microlaryngoscopy and bronchoscopy, and computed tomography imaging. Obstructive apnea-hypopnea index and oxygen saturation nadir, nasal airway volumes, choanal cross-sectional area, and midfacial cephalometric dimensions were compared across mutation types.

Results:

Twenty-four patients (13 Ser252Trp, 11 Pro253Arg) were included. Severe obstructive sleep apnea (obstructive apnea-hypopnea index>10) occurred in 8 (62%) patients with Ser252Trp mutations compared with 1 (9%) patient with Pro253Arg mutations (P=0.009). Computed tomography imaging at 1 year of age demonstrated that nasopharyngeal airway volumes were 5302±1076 mm3 in the Ser252Trp group and 6832±1414 mm3 in the Pro253Arg group (P=0.041). Maxillary length (anterior nasal spine-posterior nasal spine, P=0.026) and basion-anterior nasal spine (P=0.007) were shorter in patients with Ser252Trp mutations.

Conclusions:

The findings suggest that the Ser252Trp mutation in Apert syndrome is associated with higher severity obstructive sleep apnea and decreased nasopharyngeal airway volume. Heightened clinical awareness of these associations may inform treatment planning and family counseling.
Global Prevalence and Burden of Orofacial Clefts: A Systematic Analysis for the Global Burden of Disease Study 2019
Authors: Kantar Rami S. , Hamdan Usama S. , Muller John N. , Hemal Kshipra , Younan Robert A. , Haddad Mario , Melhem Antonio M. , Don Griot J. Peter W. , Breugem Corstiaan C. , Mokdad Ali H.
Published: August 2023

Orofacial clefts, in particular cleft lip and cleft palate, are among the most common congenital anomalies. Despite guidelines recommending early surgical correction, a global backlog of untreated patients persists. This has made orofacial clefts an attractive target for global cleft care initiatives. The most recent global burden of orofacial clefts was estimated to be 529,758.92 disability-adjusted life years (95% uncertainty interval: 362,492.88–798,419.69 disability-adjusted life years), whereas the global prevalence of orofacial clefts was estimated to be 4.6 million (95% uncertainty interval: 3.8–5.7 million). An inverse relationship exists between the Sociodemographic Index and the burden of orofacial clefts. Sub-Saharan Africa, Middle East/North Africa, and South Asia are the regions carrying the most significant burden of orofacial clefts. This manuscript provides updated estimates of the global burden and prevalence of orofacial clefts, acting as a guide to direct future investments, resources, and initiatives from individuals and organizations engaged in global cleft care delivery with the goal of building sustainable cleft care capacity where it is needed the most.
Outcomes of Apert Syndrome Hand Reconstruction With Tilapia Skin: A prospective study
Authors: Monte Thais Miguel , Lima Júnior Edmar Maciel , de Moraes Filho Manoel Odorico , Koscky Paier Carlos Roberto , Rocha Rodrigues Felipe Augusto , Nunes Alves Ana Paula Negreiros , Mathor Mônica Beatriz , Raposo-Amaral Cassio Eduardo
Published: August 2023

Background:

Tilapia skin has already been used in various medical scenarios, but there are no studies showing the use of tilapia skin for hand reconstruction in Apert syndrome. The objective of this study is to determine whether the use of tilapia skin during graft bed preparation for children with Apert syndrome can shorten wound reepithelialization intervals, reduce the number of dressing changes, and decrease patient discomfort.

Methods:

This is a prospective study on consecutive patients with Apert syndrome who underwent hand reconstruction at our Hospital. Patients were divided into 2 groups: (1) a control group consisting of patients who underwent conventional digit separation hand reconstruction surgery (2) an experimental group consisting of patients who underwent similar digit separation hand reconstruction surgery that commenced with the placement of a thin layer of tilapia skin at the raw commissures during a first operation, which was subsequently replaced by an autologous skin graft during a second operation staged 10 days postoperatively. Pain assessment was performed using the Visual Analog Scale. The number of dressing changes was also assessed. A T test compared the total number of dressings changes and pain data.

Results:

Experimental group patients (n = 8) required an average of 9.4 days of daily dressing changes, and control group patients (n = 5) required an average of 20.8 days of daily dressing changes (P < 0.05) and tended to experience significantly less pain when compared with patients in the control group (P = 0.079).

Conclusion:

Tilapia skin can shorten wound reepithelialization intervals by reducing the total number of dressing changes.
A Scarless Method for Correcting Tanzer Group IIB-Constricted Ear Without Cartilage Grafting
Authors: Chen Guocheng
Published: August 2023

Tanzer group IIB-constricted ear is described as a deformity of the helix, antihelix, or scapha. Deficiency of the auricular skin and cartilage is a key point in the reconstruction of the cartilaginous framework. Traditionally, the treatment of a constricted ear mainly includes 2 aspects: correction of cartilage deformity and restoration of skin volume deficiency. By mimicking the suspension principle of a cable bridge, our technique only requires adjustment of the spatial directions and mechanical forces between the 2 flaps to achieve an aesthetic effect. The authors were able to avoid harvesting the costal cartilage. The desired ear shape was obtained immediately postoperatively. Therefore, Vaseline gauze was not applied and was modeled along the scapha and antihelix. Expansion of the ear was remarkable in both horizontal and vertical lengths. Our technique causes less damage, less scarring, shorter operation time, fewer complications, faster rehabilitation, and no delays.
The Curious Case of Alagille Syndrome
Authors: Arora Anjali , George Mini
Published: August 2023

Alagille syndrome is a rare and complex pleiotropic multisystem disorder caused by an autosomal dominant genetic mutation of JAG1 (90%) and NOTCH2 (1%–2%) genes located on the short arm of chromosome 20. This case is reported as per the CAse REports (CARE) guidelines (2013). A 14-year-old boy who is a known case of chronic cholestatic liver disease of neonatal onset, was diagnosed with Alagille syndrome as evident from a NOTCH 2 mutation in genetic analysis and paucity of intrahepatic bile ducts on biopsy. He presented with portal hypertension, growth failure, and persistent hyperbilirubinemia. This case highlights the gamut of multisystem dysfunctions faced by this child. He is currently on conservative management and worked up for liver transplantation. The condition is often rare and challenging due to the multisystem pathogenesis. Thus, the nursing care is also multifaceted. This case study identified relevant North American Nursing Diagnosis Association (NANDA) Classification, Nursing Interventions Classification (NIC), and Nursing Outcomes Classification (NOC) concepts to describe care of children with Alagille syndrome based on actual patient data.
The tight attachment achieved by the male discoidal setae is possibly a counter-adaptation to the grease layer on female integument surfaces in green dock beetles
Authors: Matsumura Yoko , Gorb Elena V. , Gorb Stanislav N.
Published: August 2023

Green dock beetles
Gastrophysa viridula
exhibit sexual dimorphism in tarsal attachment setae: females have only pointed, lanceolate and spatula-like setae, while males additionally possess discoidal ones. The sexual dimorphism is probably attributed to the necessity of male discoidal setae to adhere to the smooth back of the female during copulation. We aimed to understand its possible mechanism of attachment with
G. viridula
. Pull-off forces of both females and males were measured on (i) alive females, (ii) dead and dried females, and (iii) resin replicas of fresh females. The attachment ability tended to increase on dead and replicated female surfaces in both sexes, which indicates that the epicuticular grease layer on the integument of alive intact beetles decreases the attachment. This tendency was prominent in females. The present study clearly showed that in
G. viridula
discoidal setae enable the males to adhere stronger to female surfaces. The divergent performance found between the sexes differing in their setal composition is probably caused by the stiffness difference between the setae types and by the specific shape of the setal tips. A peculiar reproductive biology in
G. viridula
is probably attributed to this remarkable divergence of labour in their attachment pads between the sexes.
Boundary bypass activity in theabdominal-Bregion of theDrosophilabithorax complex is position dependent and regulated
Authors: Kyrchanova Olga , Ibragimov Airat , Postika Nikolay , Georgiev Pavel , Schedl Paul
Published: August 2023

Expression ofAbdominal-B(Abd-B) in abdominal segments A5–A8 is controlled by four regulatory domains,iab-5–iab-8. Each domain has an initiator element (which sets the activity state), elements that maintain this state and tissue-specific enhancers. To ensure their functional autonomy, each domain is bracketed by boundary elements (Mcp,Fab-7,Fab-7andFab-8). In addition to blocking crosstalk between adjacent regulatory domains, theFabboundaries must also have bypass activity so the relevant regulatory domains can ‘jump over’ intervening boundaries and activate theAbd-Bpromoter. In the studies reported here we have investigated the parameters governing bypass activity. We find that the bypass elements in theFab-7andFab-8boundaries must be located in the regulatory domain that is responsible for drivingAbd-Bexpression. We suggest that bypass activity may also be subject to regulation.
A man with culture sterile cavitating lung lesions: molecular techniques can provide the key to diagnosis.
Authors: Cheema Ranvir S P , Kler Prabhjoyt K , Madu Alpha , Macve Joanna , MacDuff Andrew
Published: August 2023

A 20-year-old male presented to the Emergency Department with pyrexia, dyspnoea, chest pain and haemoptysis. Cavitating lung lesions were noted on chest x-ray and the patient was admitted to the intensive care unit where he was intubated and ventilated. Routine investigations including serial cultures did not provide an aetiological diagnosis. As such, a CT-guided lung biopsy lung biopsy was carried out and 16S rDNA PCR was undertaken on the sample. This identified Fusobacterium necrophorum as the causative organism. The patient was treated for Lemierre’s syndrome and successfully discharged from hospital. This case highlights how DNA tissue typing on a lung biopsy sample can be the key to successful diagnosis in an atypical pneumonia and raises the question as to whether this infrequently used approach should be added to forthcoming community acquired pneumonia guidelines.
LOX-1 and MMP-9 inhibition attenuates the detrimental effects of delayed rt-PA therapy and improves outcomes after acute ischemic stroke
Authors: Arkelius Kajsa , Wendt Trevor S , Andersson Henrik , Arnou Anaële , Gottschalk Michael , Gonzales Rayna J , Ansar Saema
Published: August 2023

Background

Acute ischemic stroke triggers endothelial activation that disrupts vascular integrity and increases hemorrhagic transformation leading to worsened stroke outcomes. Recombinant-tissue plasminogen activator (rt-PA) is an effective treatment; however, its use is limited due to a restricted time window and high risk for hemorrhagic transformation, which in part may involve activation of metalloproteinases (MMPs) mediated through lectin-like oxidized LDL receptor 1 (LOX-1). This study’s overall aim was to evaluate the therapeutic potential of novel MMP-9 and LOX-1 inhibitors in combination with rt-PA to improve stroke outcomes.

Methods

Thromboembolic rat stroke model was utilized to investigate the impact of rt-PA delivered 4h post-stroke onset as well as selective LOX-1 (BI-0115) and/or MMP-9 (JNJ0966) inhibitors given prior to rt-PA administration. Infarct size, perfusion, and hemorrhagic transformation were evaluated by MRI. Neurological function was assessed using sensorimotor functioning testing. Using anin vitro, human brain microvascular endothelial cell (HBMEC) model, cells were exposed to hypoxia plus glucose deprivation (3h)/reperfusion (12h) (HGD/R) and treated with rt-PA ± an MMP-9 and LOX-1 inhibition cocktail. MMP-9 activity was determined with zymography, and endothelial barrier marker gene expression and LOX-1 levels were evaluated via qRT-PCR and western blot respectively.

Results

Rt-PA treatment increased edema, hemorrhage, and worsened neurological outcomes post stroke. LOX-1 inhibition significantly improved neurological function and reduced edema after delayed rt-PA treatment. Hemorrhagic transformation, edema, and increased MMP-9 activity were attenuated by the MMP-9 inhibitor. Stroke induced increases in cerebrovascular LOX-1 expression correlated with increased MMP-9 activity and elevated activity correlated with increased edema, infarct volume, and decreased neurological function. In cultured HBMECs, LOX-1/MMP-9 inhibition differentially attenuated rt-PA-mediated increases in endothelial derived MMP-9 levels and activity, inflammation, and activation following HGD/R.

Conclusion

Here, we conclude that MMP-9/LOX-1 inhibition attenuates negative aspects of delayed rt-PA therapy leading to improved neurological function.
Parental effects provide an opportunity for coral resilience following major bleaching events
Authors: Lenz Elizabeth A. , Donahue Megan J. , Gates Ruth D. , Putnam Hollie M. , van der Steeg Eveline , Padilla-Gamiño Jacqueline L.
Published: August 2023

Identifying processes that promote coral reef recovery and resilience is crucial as ocean warming becomes more frequent and severe. Sexual reproduction is essential for the replenishment of coral populations and maintenance of genetic diversity; however, the ability for corals to reproduce may be impaired by marine heatwaves that cause coral bleaching. In 2014 and 2015, the Hawaiian Islands experienced coral bleaching with differential bleaching susceptibility in the speciesMontipora capitata, a dominant reef-building coral in the region. We tested the hypothesis that coral bleaching resistance enhances reproductive capacity and offspring performance by examining the reproductive biology of colonies that bleached and recovered (B) and colonies that did not bleach (NB) in 2015 in the subsequent spawning seasons. The proportion of colonies that spawned was higher in 2016 than in 2017. Regardless of parental bleaching history, we found eggs with higher abnormality and bundles with fewer eggs in 2016 than 2017. While reproductive output was similar between B and NB colonies in 2016, survivorship of offspring that year were significantly influenced by the parental bleaching history (egg donor × sperm donor: B × B, B × NB, NB × B, and NB × NB). Offspring produced by NB egg donors had the highest survivorship, while offspring from previously bleached colonies had the lowest survivorship, highlighting the negative effects of bleaching on parental investment and offspring performance. While sexual reproduction continues inM. capitatapost-bleaching, gametes are differentially impacted by recovery time following a bleaching event and by parental bleaching resistance. Our results demonstrate the importance of identifying bleaching resistant individuals during and after heating events. This study further highlights the significance of maternal effects through potential egg provisioning for offspring survivorship and provides a baseline for human-assisted intervention (i.e., selective breeding) to mitigate the effects of climate change on coral reefs.
Identification of inter- and intra-tumoral molecular phenotypes steering temozolomide resistance in patient-derived glioblastoma cells
Authors: Fabro Federica , Kers Trisha V. , Feller Kate J. , Beerens Cecile , Ntafoulis Ioannis , Idbaih Ahmed , Verreault Maite , Connor Kate , Biswas Archita , Salvucci Manuela , Prehn Jochen H.M. , Byrne Annette T. , O’Farrell Alice C. , Lambrechts Diether , Dilcan Gonca , Lodi Francesca , Arijs Ingrid , Kremer Andreas , Tching Chi Yen Romain , Chien Miao-Ping , Lamfers Martine L. M. , Leenstra Sieger
Published: August 2023

Background

Radiation therapy and chemotherapy using Temozolomide are the standard adjuvant treatments for patients with glioblastoma. Despite maximal treatment prognosis is still poor largely due to the emergence of Temozolomide resistance. This resistance is closely linked to the widely recognized inter- and intra-tumoral heterogeneity in glioblastoma, although the underlying mechanisms are not yet fully understood. This study aims to investigate the diverse molecular mechanisms involved in temozolomide resistance.

Methods

To induce temozolomide resistance, we subjected 21 patient-derived glioblastoma cell cultures to Temozolomide treatment for a period of up to 90 days. Prior to treatment, the cells’ molecular characteristics were analyzed using bulk RNA sequencing. Additionally, we performed single-cell sequencing on four of the cell cultures to track the evolution of temozolomide resistance.

Results

The induced temozolomide resistance was associated with two distinct phenotypic behaviors, classified as “adaptive” (ADA) or “non-adaptive” (N-ADA) to temozolomide. The ADA phenotype displayed neurodevelopmental and metabolic gene signatures, whereas the N-ADA phenotype expressed genes related to cell cycle regulation, DNA repair, and protein synthesis. Single-cell RNA sequencing revealed that in ADA cell cultures, one or more subpopulations emerged as dominant in the resistant samples, whereas N-ADA cell cultures remained relatively stable.

Conclusions

The adaptability and heterogeneity of glioblastoma cells play pivotal roles in temozolomide treatment and contribute to the tumor’s ability to survive. Depending on the tumor’s adaptability potential, subpopulations with acquired resistance mechanisms may arise. Further research is necessary to deepen our understanding of these mechanisms and develop strategies to overcome them.
Effects of nicotine compared to placebo gum on sensitivity to pain and mediating effects of peak alpha frequency
Authors: Millard Samantha K. , Chiang Alan K. I. , Humburg Peter , Chowdhury Nahian , Rehan Raafay , Furman Andrew J. , Mazaheri Ali , Schabrun Siobhan M. , Seminowicz David A.
Published: August 2023

Abstract

Recent research has linked individual peak alpha frequency (PAF) to pain sensitivity, but whether PAF alterations can influence pain remains unclear. Our study investigated the effects of nicotine on pain sensitivity and whether pain changes are mediated by PAF changes. In a randomised, double-blind, placebo-controlled experiment, 62 healthy adults (18–44 years) received either 4 mg nicotine gum (n=29) or placebo (n=33). Resting state EEG and pain ratings during prolonged heat and pressure models were collected before and after nicotine intake. The nicotine group had a decrease in heat pain ratings compared to the placebo group and increased PAF speed across the scalp from pre to post-gum, driven by changes at central-parietal and right-frontal regions. However, mediation analysis did not support the notion that PAF changes mediate nicotine’s effects on pain sensitivity. While a growing body of literature supports a link between PAF and both acute and chronic pain, further work is needed to understand the mechanisms of this link.
Nutritional insensitivity to mating in male fruit flies
Authors: Sydney Mabel C , Chapman Tracey , Perry Jennifer C
Published: August 2023

Animals can adjust their consumption of different nutrients to adaptively match their current or expected physiological state. Changes in diet preference can arise from social and sexual experience. For example, in femaleDrosophila melanogasterfruit flies, a single mating triggers a behavioural switch in diet choice towards increased protein intake and total food consumption, which supports offspring production. In contrast, male diet choice appears to be unaffected by a single mating. However, one mating may not fully capture the impact of mating on male feeding behaviour. Males can often mate multiply in natural settings, and the costs of ejaculate production and energetic courtship may be cumulative, such that males might experience increased nutritional demands only after multiple matings. In this study we tested this idea by measuring the effect of multiple matings on the diet choice of maleD. melanogasterfruit flies. Males were assigned to one of three mating treatments – unmated, mated once or mated five times consecutively – and then allowed to feed freely on chemically-defined diets of protein and carbohydrate. In contrast to the prediction, we found that males that mated five times did not alter the amount of food, nor the proportion of protein and carbohydrate consumed, when compared with unmated or once-mated males. This absence of a feeding response occurred despite substantial ejaculate depletion from multiple matings: males sired fewer offspring in each consecutive mating. These results reveal a lack of plasticity in male feeding behaviour according to mating status, despite substantial potential physiological costs, and highlight the remarkably distinct nutritional ecologies of males versus females.
Myelin ensheathment and drug response of oligodendrocytes are modulated by stiffness of artificial axons
Authors: Yang Mingyu , Martin Calliope J.L. , Kowsari Kavin , Jagielska Anna , Van Vliet Krystyn J.
Published: August 2023

Myelination is a key biological process wherein glial cells such as oligodendrocytes wrap myelin around neuronal axons, forming an insulative sheath that accelerates signal propagation down the axon. A major obstacle to understanding myelination is the challenge of visualizing and reproducibly quantifying this inherently three-dimensional processin vitro. To this end, we previously developed Artificial Axons (AAs), a biocompatible platform consisting of 3D-printed hydrogel-based axon mimics designed to more closely recapitulate the micrometer-scale diameter and sub-kilopascal mechanical stiffness of biological axons. First, we present our platform for fabricating AAs with tunable axon diameter, stiffness, and inter-axonal spacing. Second, we demonstrate that increasing the Young’s modulusEor stiffness of polymer comprising the AAs increases the extent of myelin ensheathment by rat oligodendrocytes. Third, we demonstrate that the responses of oligodendrocytes to pro-myelinating compounds are also dependent on axon stiffness, which can affect compounds efficacy and the relative ranking. These results reinforce the importance of studying myelination in mechanically representative environments, and highlight the importance of considering biophysical cues when conducting drug screening studies.
17-Oxime ethers of oxidized ecdysteroid derivatives modulate oxidative stress in human brain endothelial cells and dose-dependently might protect or damage the blood-brain barrier
Authors: Vágvölgyi Máté , Laczkó Dávid , Santa-Maria Ana Raquel , Walter Fruzsina R. , Berkecz Róbert , Deli Mária , Tóth Gábor , Hunyadi Attila
Published: August 2023

20-Hydroxyecdysone and several of its oxidized derivatives exert cytoprotective effect in mammals including ans. Inspired by this bioactivity of ecdysteroids, in the current study it was our aim to prepare a set of sidechainmodified derivatives and to evaluate their potential to protect the blood-brain barrier (BBB) from oxidative stress. Six novel ecdysteroids, including an oxime and five oxime ethers, were obtained through regioselective synthesis from a sidechain-cleaved calonysterone derivative2and fully characterized by comprehensive NMR techniques revealing their complete1H and13C signal assignments. Surprisingly, several compounds sensitized hCMEC/D3 brain microvascular endothelial cells totert-butyl hydroperoxide (tBHP)-induced oxidative damage as recorded by impedance measurements. Compound8, containing a benzyloxime ether moiety in its sidechain, was the only one that exerted a protective effect in a higher, 10 μM dose, while at lower (10 μM – 1 μM) doses it promoted tBHP-induced cellular damage. Based on our results, 17-oxime ethers of oxidized ecdysteroids modulate oxidative stress of the BBB in a way that may point towards unexpected toxicity. Further studies are needed to evaluate any possible risk connected to dietary ecdysteroid consumption and CNS pathologies in which BBB damage plays an important role.
Unveiling the Role of Endoplasmic Reticulum Stress Pathways in Canine Demodicosis
Authors: Kelly Pamela A , McHugo Gillian P. , Scaife Caitriona , Peters Susan , Lynn Stevenson M. , McKay Jennifer S , MacHugh David E. , Saez Irene Lara , Breathnach Rory
Published: August 2023

Canine demodicosis is a prevalent skin disease caused by overpopulation of a commensal species ofDemodexmite, yet its precise cause remains unknown. Research suggests that T cell exhaustion, increased immunosuppressive cytokines, induction of regulatory T cells, and increased expression of immune checkpoint inhibitors may contribute to its pathogenesis. This study aimed to gain a deeper understanding of the molecular changes occurring in canine demodicosis using mass spectrometry and pathway enrichment analysis. The results indicate that endoplasmic reticulum stress is promoting canine demodicosis through regulation of three linked signalling pathways: eIF2, mTOR, and eIF4 and p70S6K. These pathways are involved in the modulation of Toll-like receptors, most notably TLR2, and have been shown to play a role in the pathogenesis of skin diseases in both dogs and humans. Moreover, these pathways are also implicated in the promotion of immunosuppressive M2 phenotype macrophages. Immunohistochemical analysis, utilizing common markers of dendritic cells and macrophages, verified the presence of M2 macrophages in canine demodicosis. The proteomic analysis also identified immunological disease, organismal injury and abnormalities, and inflammatory response as the most significant underlying diseases and disorders associated with canine demodicosis. This study demonstrates thatDemodexmites, through ER stress, unfolded protein response and M2 macrophages contribute to an immunosuppressive microenvironment thereby assisting in their proliferation.
Small molecule nitroalkenes inhibit RAD51-mediated homologous recombination and amplify triple-negative breast cancer cell killing by DNA-directed therapies
Authors: Hong Lisa , Braden Dennis C. , Zhao Yaoning , Skoko John J. , Chang Fei , Woodcock Steven R. , Uvalle Crystall , Casey Allison , Wood Katherine , Salvatore Sonia R. , Asan Alparslan , Harkness Trey , Fagunloye Adeola , Razzaghi Mortezaali , Straub Adam , Spies Maria , Brown Daniel D. , Lee Adrian V. , Schopfer Francisco , Freeman Bruce A. , Neumann Carola A
Published: August 2023

Nitro fatty acids (NO2-FAs) are endogenously generated lipid signaling mediators from metabolic and inflammatory reactions between conjugated diene fatty acids and nitric oxide or nitrite-derived reactive species. NO2-FAs undergo reversible Michael addition with hyperreactive protein cysteine thiolates to induce posttranslational protein modifications that can impact protein function. Herein, we report a novel mechanism of action of natural and non-natural nitroalkenes structurally similar to (E) 10-nitro-octadec-9-enoic acid (CP-6), recently de-risked by preclinical Investigational New Drug-enabling studies and Phase 1 and Phase 2 clinical trials and found to induce DNA damage in a TNBC xenograft by inhibiting homologous-recombination (HR)-mediated repair of DNA double-strand breaks (DSB). CP-6 specifically targets Cys319, essential in RAD51-controlled HR-mediated DNA DSB repair in cells. A nitroalkene library screen identified two structurally different nitroalkenes, a non-natural fatty acid [(E) 8-nitro- nonadec-7-enoic acid (CP-8)] and a dicarboxylate ester [dimethyl (E)nitro-oct-4-enedioate (CP- 23)] superior to CP-6 in TNBC cells killing, synergism with three different inhibitors of the poly ADP-ribose polymerase (PARP) and γ-IR. CP-8 and CP-23 effectively inhibited γ-IR-induced RAD51 foci formation and HR in a GFP-reported assay but did not affect benign human epithelial cells or cell cycle phases. In vivo, CP-8 and CP-23’s efficacies diverged as only CP-8 showed promising anticancer activities alone and combined with the PARP inhibitor talazoparib in an HR-proficient TNBC mouse model. As preliminary preclinical toxicology analysis also suggests CP-8 as safe, our data endorse CP-8 as a novel anticancer molecule for treating cancers sensitive to homologous recombination-mediated DNA repair inhibitors.

Graphical Abstract
An Adaptive H-Refinement Method for the Boundary Element Fast Multipole Method for Quasi-static Electromagnetic Modeling
Authors: Wartman William A , Weise Konstantin , Rachh Manas , Morales Leah , Deng Zhi-De , Nummenmaa Aapo , Makaroff Sergey N
Published: August 2023

Objective

In our recent work pertinent to modeling of brain stimulation and neurophysiological recordings, substantial modeling errors in the computed electric field and potential have sometimes been observed for standard multi-compartment head models. The goal of this study is to quantify those errors and, further, eliminate them through an adaptive mesh refinement (AMR) algorithm. The study concentrates on transcranial magnetic stimulation (TMS), transcranial electrical stimulation (TES), and electroencephalography (EEG) forward problems.

Approach

We propose, describe, and systematically investigate an AMR method using the Boundary Element Method with Fast Multipole Acceleration (BEM-FMM) as the base numerical solver. The goal is to efficiently allocate additional unknowns to critical areas of the model, where they will best improve solution accuracy.

The implemented AMR method’s accuracy improvement is measured on head models constructed from 16 Human Connectome Project subjects under problem classes of TES, TMS, and EEG. Errors are computed between three solutions: an initial non-adaptive solution, a solution found after applying AMR with a conservative refinement rate, and a “silver-standard” solution found by subsequent 4:1 global refinement of the adaptively-refined model.

Main Results

Excellent agreement is shown between the adaptively-refined and silver-standard solutions for standard head models. AMR is found to be vital for accurate modeling of TES and EEG forward problems for standard models: an increase of less than 25% (on average) in number of mesh elements for these problems, efficiently allocated by AMR, exposes electric field/potential errors exceeding 60% (on average) in the solution for the unrefined models.

Significance

This error has especially important implications for TES dosing prediction – where the stimula t ion strength plays a central role – and for EEG lead fields. Though the specific form of the AMR method described here is implemented for the BEM-FMM, we expect that AMR is applicable and even required for accurate electromagnetic simulations by other numerical modeling packages as well.
A simplified and rapid in situ hybridization protocol for planarians
Authors: Gaetano Andrew J. , King Ryan S.
Published: August 2023

Whole mount in situ hybridization is a critical technique for analyzing gene expression in planarians. While robust in situ protocols have been developed, these protocols are laborious, making them challenging to incorporate in an academic setting, reducing throughput, and increasing time to results. We systematically tested modifications to all phases of the protocol with the goal of eliminating steps and reducing time without impacting quality. Our modified protocol allows for whole mount colorimetric in situ hybridization and multicolor fluorescence in situ hybridization to be completed in two days with a significant reduction in steps and hands on processing time.

Method summary

A planarian in situ hybridization protocol was optimized for time and simplicity. Modifications to the fixation, bleaching, and blocking solutions were tested to identify conditions that reduced time and number of steps without impacting staining quality.
DARTsort: A modular drift tracking spike sorter for high-density multi-electrode probes
Authors: Boussard Julien , Windolf Charlie , Hurwitz Cole , Lee Hyun Dong , Yu Han , Winter Olivier , Paninski Liam
Published: August 2023

With the advent of high-density, multi-electrode probes, there has been a renewed interest in developing robust and scalable algorithms for spike sorting. Current spike sorting approaches, however, struggle to deal with noisy recordings and probe motion (drift). Here we introduce a modular and interpretable spike sorting pipeline,DARTsort (DriftAwareRegistration andTracking), that builds upon recent advances in denoising, spike localization, and drift estimation. DARTsort integrates a precise estimate of probe drift over time into a model of the spiking signal. This allows our method to be robust to drift across a variety of probe geometries. We show that our spike sorting algorithm outperforms a current state-of-the-art spike sorting algorithm, Kilosort 2.5, on simulated datasets with different drift types and noise levels. Open-source code can be found athttps://github.com/cwindolf/dartsort.
Volumetric imaging of an intact organism by a distributed molecular network
Authors: Qian Nianchao , Weinstein Joshua A.
Published: August 2023

Lymphatic, nervous, and tumoral tissues, among others, exhibit physiology that emerges from three-dimensional interactions between genetically unique cells. A technology capable of volumetrically imaging transcriptomes, genotypes, and morphologies in a single de novo measurement would therefore provide a critical view into the biological complexity of living systems. Here we achieve this by extending DNA microscopy, an imaging modality that encodes a spatio-genetic map of a specimen via a massive distributed network of DNA molecules inside it, to three dimensions and multiple length scales in developing zebrafish embryos.
Linking reduced prefrontal microcircuit inhibition in schizophrenia to EEG biomarkers in silico
Authors: Rosanally Sana , Mazza Frank , Yao Heng Kang , Hay Etay
Published: August 2023

Reduced cortical inhibition by parvalbumin-expressing (PV) interneurons has been associated with impaired cortical processing in the prefrontal cortex (PFC) and altered EEG signals such as oddball mismatch negativity (MMN) in schizophrenia. However, establishing the link between reduced PV interneuron inhibition and reduced MMN experimentally in humans is currently not possible. To overcome these challenges, we used detailed computational models of human PFC microcircuits, and modeled schizophrenia microcircuits by integrating gene-expression data from schizophrenia patients indicating reduced PV interneuron inhibition output and NMDA input. We simulated spiking activity and EEG in microcircuits with different levels of reduced PV interneuron mechanisms and showed that a double effect of the reduction indicated by gene-expression led to a reduced MMN amplitude within the range seen in Schizophrenia patients, whereas a single effect resulted in a smaller decrease in MMN that matched the magnitude seen in patients at high-risk of schizophrenia. In addition, we showed that simulated resting EEG of schizophrenia microcircuits exhibited a right shift from alpha to beta frequencies. Our study thus links the level of reduced PV interneuron inhibition to distinct EEG biomarkers that can serve to better stratify different severities of schizophrenia and improve the early detection using non-invasive brain signals.
Correlation of two different devices for the evaluation of primary implant stability depending on dental implant length and bone density: an in vitro study
Authors: Lee Jungwon , Lim Young-Jun , Ahn Jin-Soo , Kim Bongju , Baek Yeon-Wha , Lim Bumsoon
Published: August 2023

Non-invasive objective implant stability measurements are needed to determine the appropriate timing of prosthetic fitting after implant placement. We compared the early implant stability results obtained using resonance frequency analysis (RFA) and damping capacity analysis (DCA) depending on the implant length and bone density. Total 60, 4.0 mm diameter implants of various lengths (7.3 mm, 10 mm, and 13 mm) were used. Group I and Group II had implants placed in an artificial bone model with a uniform density of 15 PCF (0.24 g/cm3) and 30 PCF (0.48 g/cm3), respectively. RFA was performed using an Osstell® Beacon+; DCA was performed using Anycheck®. Measurements were repeated five times for each implant. Statistical significance was set atP<0.05. In Group I, bone density and primary implant stability were positively correlated, while implant length and primary implant stability were positively correlated. In Group II, the implant stability quotient (ISQ) and implant stability test (IST) values in did not change significantly above a certain length. Primary implant stability was positively correlated with bone density and improved with increasing implant length at low bone densities. Compared with the Osstell® Beacon+, the simplicity of Anycheck® was easy to use and accessible.