bluuebunny/crossref_metadata_2025 huggingface dataset:
The Effects of Adipose-Derived Mesenchymal Stem Cells and Adipose-Derived Mesenchymal Stem Cell–Originating Exosomes on Nerve Allograft Regeneration
Authors: Koplay Tugba Gun , Yildiran Gokce , Dursunoglu Duygu , Aktan Murad , Duman Selcuk , Akdag Osman , Karamese Mehtap , Tosun Zekeriya
Published: February 2023

Introduction

Nerve regeneration has been the subject of many studies because of its complex mechanism and functional outcome. Mesenchymal stem cells and exosomes are promising factors in regeneration in many areas. Reconstruction of nerve defects is a controversial issue, and nerve allografts are promising alternatives with many advantages. In this study, it is aimed to evaluate the nerve regeneration in cellularized and decellularized nerve allografts and whether it is possible to accelerate this process with adipose-derived mesenchymal stem cells (ad MSC) or ad MSC–originating exosomes.

Method

This study was performed with 36 Lewis and 18 Brown Norway isogenic male rats aged 10 to 12 weeks and weighing 300 to 350 g. The Lewis rats were divided into 6 groups. Nerve allografts at a length of 12 mm that were obtained from the Brown Norway rats' proximal portion of both sciatic nerve branching points were coapted as cellularized in group A and decellularized in group B to the sciatic nerve defects of the Lewis rats. Group A received oral tacrolimus (0.2 mg/kg) for 30 days. Perineural saline (A1-B1), ad MSC (A2-B2), or ad MSC–originating exosomes (A3-B3) were applied to these groups. Walking track analysis, pinch-prick test and electromyelography were applied at the 8th and 16th weeks following surgery. Nerves were examined histopathologically at the 16th week.

Results

Between cellularized groups, better results were shown in A3 about axon-myelin regeneration/organization (P = 0.001), endoneural connective tissue (P = 0.005), and inflammation (P = 0.004). Better results were shown in the B2 and B3 groups electromyelographicaly about latency period (P = 0.033) and action potential (P = 0.008) at late period, and histomorphologicaly at vascularization (P = 0.012).

Discussion

It is argued that regeneration is accelerated with decellularization of nerve allografts by removing the chondroidin sulfate proteoglycans. The positive effects of stem cells are derived by exosomes without the cell-related disadvantages. In this study, better results were obtained by decellularization and perineural application of ad MSC and/or ad MSC exosome.
Timing of Unplanned Reoperation After Lower Extremity Free Flap Reconstruction
Authors: Elmer Nicholas A. , Araya Sthefano , Panichella Juliet , Egleston Brian , Deng Mengying , Patel Sameer A.
Published: February 2023

Background

Advancements in lower extremity (LE) microsurgery have allowed for the expansion of indications for LE reconstructions. This project aims to better understand the temporal pattern and risk factors associated with LE free flap failure based on the clinical indication.

Materials and Methods

We analyzed all patients undergoing LE free flap reconstruction from the American College of Surgeons National Surgical Quality Improvement Program 2012–2019 prospectively collected data to determine rates and timing of reoperation. Free flaps were stratified by indication, type, and timing of reoperation. Weibull survival models were used to compare rates of takebacks among time intervals. Multivariable logistic regression was used to identify independent predictors for unplanned reoperation.

Results

Four hundred seven of LE free flaps were analyzed. There was a 14.5% rate (59/407) of unplanned reoperation within the first 30 postoperative days (PODs) after surgery. When stratified by the indication necessitating reoperation, patients with an underlying vascular indication had the highest rate of reoperation (40.9%). The reoperation rates were significantly different between indications (P < 0.05) The mean daily proportion of patients experiencing reoperation was highest during POD 0 to 2 (1.47% reoperations per day), which dropped significantly during POD 3 to 10 (0.55% per day) and again during POD 11 to 30 (0.28% per day, P < 0.05). African American race as well as malignant, prosthetic/implant, and wound/infectious indications were significant independent predictors for unplanned reoperation.

Conclusions

Lower extremity reconstruction is an important reconstructive option for the coverage of a myriad of defects. Understanding the differences between postoperative reoperation timelines among indication subtypes is important for updated flap monitoring protocols, optimizing ERAS pathways, and beginning dangle protocols.
Ram pressure in astronomy and engineering
Authors: Dowling Timothy E. , Bradley Mary E.
Published: February 2023

The ram pressure of a moving fluid,

P
r

, is the rise in pressure at a stagnation point relative to the upstream pressure. In astronomy, it is used to calculate the interaction of stellar winds with planets and to quantify the effects of ram pressure stripping. On aeroplanes and in wind tunnels, it is measured with a pitot-static tube, an inexpensive device with no moving parts that was invented in 1732. Up through the mid-1960s, across both astronomy and engineering the ram pressure of a moving gas and its momentum flux,

ρ

u
2

, where

ρ

and

u

are the upstream mass density and flow speed, were properly treated as related but distinct quantities. This relationship may be expressed as

P
r

=

Sp

 
ρ

u
2

, where

Sp

is the dimensionless Spreiter number, which ranges between 0.5 and 0.88 for a monatomic gas, depending on the upstream Mach number,

Ma

. Unfortunately, by the early 1970s, in astronomy ram pressure was
defined
to be the momentum flux and

Sp

was fixed to be unity and forgotten as a parameter. This article seeks to raise awareness of this issue, and to review the determination of

Sp

for subsonic and supersonic flow.
Characterizing the use of the ICD-10 Code for Long COVID in 3 US Healthcare Systems
Authors: Zhang Harrison G , Honerlaw Jacqueline P , Maripuri Monika , Samayamuthu Malarkodi Jebathilagam , Beaulieu-Jones Brendin R , Baig Huma S , L’Yi Sehi , Ho Yuk-Lam , Morris Michele , Panickan Vidul Ayakulangara , Wang Xuan , Hong Chuan , Weber Griffin M , Liao Katherine P , Visweswaran Shyam , Tan Bryce W.Q. , Yuan William , Gehlenborg Nils , Muralidhar Sumitra , Ramoni Rachel B ,   The Consortium for Clinical Characterization of COVID-19 by EHR (4CE), Kohane Isaac S , Xia Zongqi , Cho Kelly , Cai Tianxi , Brat Gabriel A
Published: February 2023

The International Classification of Diseases (ICD)-10 code (U09.9) for post-acute sequelae of COVID-19 (PASC) was introduced in October of 2021. As researchers seek to leverage this billing code for research purposes in large scale real-world studies of PASC, it is of utmost importance to understand the functional use of the code by healthcare providers and the clinical characteristics of patients who have been assigned this code. To this end, we operationalized clinical case definitions of PASC using World Health Organization and Centers for Disease Control guidelines. We then chart reviewed 300 patients with COVID-19 from three participating healthcare systems of the 4CE Consortium who were assigned the U09.9 code. Chart review results showed the average positive predictive value (PPV) of the U09.9 code ranged from 40.2% to 65.4% depending on which definition of PASC was used in the evaluation. The PPV of the U09.9 code also fluctuated significantly between calendar time periods. We demonstrated the potential utility of textual data extracted from natural language processing techniques to more comprehensively capture symptoms associated with PASC from electronic health records data. Finally, we investigated the utilization of long COVID clinics in the cohort of patients. We observed that only an average of 24.0% of patients with the U09.9 code visited a long COVID clinic. Among patients who met the WHO PASC definition, only an average of 35.6% visited a long COVID clinic.
Early Treatment, Inflammation and Post-COVID Conditions
Authors: Gebo Kelly A. , Heath Sonya L. , Fukuta Yuriko , Zhu Xianming , Baksh Sheriza , Abraham Alison G. , Habtehyimer Feben , Shade David , Ruff Jessica , Ram Malathi , Laeyendecker Oliver , Fernandez Reinaldo E. , Patel Eshan U. , Baker Owen R. , Shoham Shmuel , Cachay Edward R. , Currier Judith S. , Gerber Jonathan M. , Meisenberg Barry , Forthal Donald N. , Hammitt Laura L. , Huaman Moises A. , Levine Adam , Mosnaim Giselle S. , Patel Bela , Paxton James H. , Raval Jay S. , Sutcliffe Catherine G. , Anjan Shweta , Gniadek Thomas , Kassaye Seble , Blair Janis E. , Lane Karen , McBee Nichol A. , Gawad Amy L. , Das Piyali , Klein Sabra L. , Pekosz Andrew , Casadevall Arturo , Bloch Evan M. , Hanley Daniel , Tobian Aaron A.R. , Sullivan David J.
Published: February 2023

Background

Post-COVID conditions (PCC) are common and have significant morbidity. Risk factors for PCC include advancing age, female sex, obesity, and diabetes mellitus. Little is known about early treatment, inflammation, and PCC.

Methods

Among 883 individuals with confirmed SARS-CoV-2 infection participating in a randomized trial of CCP vs. control plasma with available biospecimens and symptom data, the association between early COVID treatment, cytokine levels and PCC was evaluated. Cytokine and chemokine levels were assessed at baseline, day 14 and day 90 using a multiplexed sandwich immuosassay (Mesoscale Discovery). Presence of any self-reported PCC symptoms was assessed at day 90. Associations between COVID treatment, cytokine levels and PCC were examined using multivariate logistic regression models.

Results

One-third of the 882 participants had day 90 PCC symptoms, with fatigue (14.5%) and loss of smell (14.5%) being most common. Cytokine levels decreased from baseline to day 90. In a multivariable analysis including diabetes, body mass index, race, and vaccine status, female sex (adjusted odds ratio[AOR]=2.70[1.93-3.81]), older age (AOR=1.32[1.17-1.50]), and elevated baseline levels of IL-6 (AOR=1.59[1.02-2.47]) were associated with development of PCC. There was a trend for decreased PCC in those with early CCP treatment (<5 days after symptom onset) compared to late CCP treatment.

Conclusion

Increased IL-6 levels were associated with the development of PCC and there was a trend for decreased PCC with early CCP treatment in this predominately unvaccinated population. Future treatment studies should evaluate the effect of early treatment and anti-IL-6 therapies on PCC development.

Increased IL-6 levels were associated with the development of Post-COVID Conditions (PCC) and there was a trend for decreased PCC with early COVID convalescent plasma treatment in this predominately unvaccinated population.
Pancreatic cancer symptom trajectories from Danish registry data and free text in electronic health records
Authors: Hjaltelin Jessica Xin , Novitski Sif Ingibergsdóttir , Jørgensen Isabella Friis , Johansen Julia Sidenius , Chen Inna M , Siggaard Troels , Vulpius Siri , Jensen Lars Juhl , Brunak Søren
Published: February 2023

Pancreatic cancer is one of the deadliest cancer types with poor treatment options. Better detection of early symptoms and relevant disease correlations could improve pancreatic cancer prognosis. In this retrospective study, we used symptom and disease codes (ICD-10) from the Danish National Patient Registry (NPR) encompassing 8.1 million patients from 1977 to 2018, of whom 22,727 were diagnosed with pancreatic cancer. To complement and compare these diagnosis codes with deeper clinical data, we used a text mining approach to extract symptoms from free text clinical notes in electronic health records (4,418 pancreatic cancer patients and 44,180 controls). We used both data sources to generate and compare symptom disease trajectories to uncover temporal patterns of symptoms prior to pancreatic cancer diagnosis for the same patients. We show that the text mining of the clinical notes was able to capture richer statistically significant symptom patterns, in particular general pain, abdominal pain, and liver-related conditions. We also detected haemorrhages (p-value =4.80·10-08) and headache (p-value =2.12·10-06) to be linked as early symptoms of pancreatic cancer. Chaining symptoms together in trajectories identified patients with jaundice conditions having higher median survival (>90 days) compared to patients following trajectories that included haemorrhage, oedema or anaemia (≤90 days). Additionally, we discovered a group of cardiovascular patients that developed pancreatic cancer with a lower median survival (≤90 days). These results provide an overview of two types of pancreatic cancer symptom trajectories. The two approaches and data types complement each other to provide a fuller picture of the early risk factors for pancreatic cancer.
Spatial transcriptomic analysis of Sonic Hedgehog Medulloblastoma identifies that the loss of heterogeneity and promotion of differentiation underlies the response to CDK4/6 inhibition
Authors: Vo Tuan , Balderson Brad , Jones Kahli , Ni Guiyan , Crawford Joanna , Millar Amanda , Tolson Elissa , Singleton Matthew , Mulay Onkar , Walters Shaun , Kojic Marija , Robertson Thomas , Bhuva Dharmesh D. , Davis Melissa J. , Wainwright Brandon J. , Nguyen Quan , Genovesi Laura A.
Published: February 2023

Background

Medulloblastoma (MB) is a malignant tumour of the cerebellum which can be classified into four major subgroups based on gene expression and genomic features. Single cell transcriptome studies have defined the cellular states underlying each MB subgroup, however the spatial organisation of these diverse cell states and how this impacts response to therapy remains to be determined.

Methods

Here, we used spatially resolved transcriptomics to define the cellular diversity within a sonic hedgehog (SHH) patient-derived model of MB and identify how cells specific to a transcriptional state or spatial location are pivotal in responses to treatment with the CDK4/6 inhibitor, Palbociclib. We integrated spatial gene expression with histological annotation and single cell gene expression data from MB, developing a analysis strategy to spatially map cell type responses within the hybrid system of human and mouse cells and their interface within an intact brain tumour section.

Results

We distinguish neoplastic and non-neoplastic cells within tumours and from the surrounding cerebellar tissue, further refining pathological annotation. We identify a regional response to Palbociclib, with reduced proliferation and induced neuronal differentiation in both treated tumours. Additionally, we resolve at a cellular resolution a distinct tumour interface where the tumour contacts neighbouring mouse brain tissue consisting of abundant astrocytes and microglia and continues to proliferate despite Palbociclib treatment.

Conclusions

Our data highlight the power of using spatial transcriptomics to characterise the response of a tumour to a targeted therapy and provide further insights into the molecular and cellular basis underlying the response and resistance to CDK4/6 inhibitors in SHH MB.
A novel triptolide analog downregulates NF-κB and induces mitochondrial apoptosis pathways in human pancreatic cancer
Authors: Tian Qiaomu , Zhang Peng , Wang Yihan , Si Youhui , Yin Dengping , Weber Christopher R , Fishel Melissa L , Pollok Karen E , Qiu Bo , Xiao Fei , Chong Anita S
Published: February 2023

Background

Pancreatic cancer is the seventh leading cause of cancer-related death worldwide, and despite advancements in disease management, the 5-year survival rates stands at only 9%. Triptolides have potent anti-tumor activity against different types of cancers, including pancreatic cancer, however poor solubility and toxicity limit their translation into clinical use.

Methods

We synthesized a novel pro-drug of triptolide, (E)-19-[(1’-benzoyloxy-1’-phenyl)-methylidene]-Triptolide (CK21), and formulated into an emulsion for in vitro and in vivo testing in rats and mice, and using human pancreatic cancer cell lines and patient-derived pancreatic tumor organoids. A time-course transcriptomic profiling of tumor organoids treated with CK21 in vitro was conducted to define its mechanism of action, as well as transcriptomic profiling at a single time point post-CK21 administration in vivo.

Findings

Intravenous administration of emulsified CK21 resulted in the stable release of triptolide, and potent anti-proliferative effects on human pancreatic cancer cell lines and patient-derived pancreatic tumor organoidsin vitro,and with minimal toxicityin vivo. Time course transcriptomic profiling of tumor organoids treated with CK21in vitrorevealed <10 differentially expressed genes (DEGs) at 3 h and ∼8,000 DEGs at 12 h. Overall inhibition of general RNA transcription was observed, and Ingenuity pathway analysis together with functional cellular assays confirmed inhibition of the NF-κB pathway, increased oxidative phosphorylation and mitochondrial dysfunction, leading ultimately to increased reactive oxygen species (ROS) production, reduced B-cell-lymphoma protein 2 (BCL2) expression, and mitochondrial-mediated tumor cell apoptosis.

Interpretation

CK21 is a novel pro-drug of triptolide that exerts potent anti-proliferative effects on human pancreatic tumors by inhibiting the NF-κB pathway, leading ultimately to mitochondrial-mediated tumor cell apoptosis.

Funding

The study of the anti-tumor efficacy of CK21 supported in part by a research grant from Cinkate Pharmaceutical Corp; the funders had no role in the study design, interpretation or decision to publish. Patient-derived pancreatic tumor organoids were a generous gift from the Organoid and Primary Culture Research Core at University of Chicago.
Low Gut Microbial Diversity Augments Estrogen-driven Pulmonary Fibrosis in Female-Predominant Interstitial Lung Disease
Authors: Chioma Ozioma S. , Mallott Elizabeth , Shah-Gandhi Binal , Wiggins ZaDarreyal , Langford Madison , Lancaster Andrew William , Gelbard Alexander , Wu Hongmei , Johnson Joyce E. , Lancaster Lisa , Wilfong Erin M. , Crofford Leslie J. , Montgomery Courtney G. , Van Kaer Luc , Bordenstein Seth , Newcomb Dawn C. , Drake Wonder Puryear
Published: February 2023

Although profibrotic cytokines such as IL-17A and TGF-β1 have been implicated in interstitial lung disease (ILD) pathogenesis, interactions between gut dysbiosis, gonadotrophic hormones and molecular mediators of profibrotic cytokine expression, such as phosphorylation of STAT3, have not been defined. Here we show by chromatin immunoprecipitation sequencing (ChIP-seq) analysis of primary human CD4+ T cells that regions within theSTAT3locus are significantly enriched for binding by the transcription factor estrogen receptor alpha (ERa). Using the murine model of bleomycin-induced pulmonary fibrosis, we found significantly increased regulatory T cells compared to Th17 cells in the female lung. Genetic absence ofESR1or ovariectomy in mice significantly increased pSTAT3 and IL-17A expression in pulmonary CD4+ T cells, which was reduced after repletion of female hormones. Remarkably, there was no significant reduction in lung fibrosis under either condition, suggesting that factors outside of ovarian hormones also contribute. Assessment of lung fibrosis among menstruating females in different rearing environments revealed that environments favoring gut dysbiosis augment fibrosis. Furthermore, hormone repletion following ovariectomy further augmented lung fibrosis, suggesting pathologic interactions between gonadal hormones and gut microbiota on lung fibrosis severity. Analysis in female sarcoidosis patients revealed a significant reduction in pSTAT3 and IL-17A levels and a concomitant increase in TGF-β1 levels in CD4+ T cells, compared to male sarcoidosis patients. These studies reveal that estrogen is profibrotic in females and that gut dysbiosis in menstruating females augments lung fibrosis severity, supporting a critical interaction between gonadal hormones and gut flora in lung fibrosis pathogenesis.
Western diet increases brain metabolism and adaptive immune responses in a mouse model of amyloidosis
Authors: Poxleitner Marilena , Hoffmann Sabrina H.L. , Berezhnoy Georgy , Ionescu Tudor , Gonzalez-Menendez Irene , Maier Florian C. , Seyfried Dominik , Ehrlichmann Walter , Quintanilla-Martinez Leticia , Schmid Andreas M. , Reischl Gerald , Trautwein Christoph , Maurer Andreas , Pichler Bernd J. , Herfert Kristina , Beziere Nicolas
Published: February 2023

Diet-induced body weight gain is a growing health problem worldwide, leading to several serious systemic diseases such as diabetes. Because it is often accompanied by a low-grade metabolic inflammation that alters systemic function, dietary changes may also contribute to the progression of neurodegenerative diseases. Here we demonstrate disrupted glucose and fatty acid metabolism and a disrupted plasma metabolome in a mouse model of Alzheimer’s disease following a western diet using a multimodal imaging approach and NMR-based metabolomics. We did not detect glial-dependent neuroinflammation, however using flow cytometry we observed T cell recruitment in the brains of western diet-fed mice. Our study highlights the role of the brain-liver-fat-axis and the adaptive immune system in the disruption of brain homeostasis due to a Western diet.
Muscle Preflex Response to Perturbations in locomotion: In-vitro experiments and simulations with realistic boundary conditions
Authors: Araz Matthew , Weidner Sven , Izzi Fabio , Badri-Spröwitz Alexander , Siebert Tobias , Haeufle Daniel F. B.
Published: February 2023

1

Neuromuscular control loops feature substantial communication delays, but mammals run robustly even in the most adverse conditions. In-vivo experiments and computer simulation results suggest that muscles’ preflex—an immediate mechanical response to a perturbation—could be the critical contributor. Muscle preflexes act within a few milliseconds, an order of magnitude faster than neural reflexes. Their short-lasting activity makes mechanical preflexes hard to quantify in-vivo. Muscle models, on the other hand, require further improvement of their prediction accuracy during the non-standard conditions of perturbed locomotion. Additionally, muscles mechanically adapt by increased damping force. Our study aims to quantify the mechanical preflex work and test its mechanical force adaptation. We performed in-vitro experiments with biological muscle fibers under physiological boundary conditions, which we determined in computer simulations of perturbed hopping. Our findings show that muscles initially resist impacts with a stereotypical stiffness response—identified as short-range stiffness—regardless of the exact perturbation condition. We then observe a velocity adaptation to the force related to the amount of perturbation. The main contributor to the preflex work adaptation is not the force difference but the muscle fiber stretch difference. We find that both muscle stiffness and damping are activity-dependent properties. These results indicate that neural control could tune the preflex properties of muscles in expectation of ground conditions leading to previously inexplicable neuromuscular adaptation speeds.
Efficient gene activation in plants by the MoonTag programmable transcriptional activator
Authors: Casas-Mollano J. Armando , Zinselmeier Matthew , Sychla Adam , Smanski Michael J
Published: February 2023

CRISPR/Cas-based transcriptional activators have been developed to induce gene expression in eukaryotic and prokaryotic organisms. The main advantages of CRISPR-Cas based systems is that they can achieve high levels of transcriptional activation and are very easy to program via pairing between the guide RNA and the DNA target strand. SunTag is a second-generation system that activates transcription by recruiting multiple copies of an activation domain (AD) to its target promoters. SunTag is a strong activator; however, in some species it is difficult to stably express. To overcome this problem, we designed MoonTag, a new activator that worked on the same basic principle as SunTag, but whose components are better tolerated when stably expressed in transgenic plants. We demonstrate that MoonTag is capable of inducing high levels of transcription in all plants tested. In Setaria, MoonTag is capable of inducing high levels of transcription of reporter genes as well as of endogenous genes. More important, MoonTag components are expressed in transgenic plants to high levels without any deleterious effects. MoonTag is also able to efficiently activate genes in eudicotyledonous species such as Arabidopsis and tomato. Finally, we show that MoonTag activation is functional across a range of temperatures, which is promising for potential field applications.
Interictal epileptiform discharges affect memory in an Alzheimer’s Disease mouse model
Authors: Soula Marisol , Maslarova Anna , Harvey Ryan E , Valero Manuel , Brandner Sebastian , Hamer Hajo , Fernández-Ruiz Antonio , Buzsáki György
Published: February 2023

Interictal epileptiform discharges (IEDs) are transient abnormal electrophysiological events commonly observed in epilepsy patients but are also present in other neurological disease, such as Alzheimer’s Disease (AD). Understanding the role IEDs have on the hippocampal circuit is important for our understanding of the cognitive deficits seen in epilepsy and AD. We characterize and compare the IEDs of human epilepsy patients from microwire hippocampal recording with those of AD transgenic mice with implanted multi-layer hippocampal silicon probes. Both the local field potential features and firing patterns of pyramidal cells and interneurons were similar in mouse and human. We found that as IEDs emerged from the CA3-1 circuits, they recruited pyramidal cells and silenced interneurons, followed by post-IED suppression. IEDs suppressed the incidence and altered the properties of physiological sharp-wave ripples (SPW-Rs), altered their physiological properties, and interfered with the replay of place field sequences in a maze. In addition, IEDs in AD mice inversely correlated with daily memory performance. Together, our work implicates that IEDs may present a common and epilepsy-independent phenomenon in neurodegenerative diseases that perturbs hippocampal-cortical communication and interferes with memory.

Significant Statement

Prevalence of neurodegenerative diseases and the number of people with dementia is increasing steadily. Therefore, novel treatment strategies for learning and memory disorders are urgently necessary. IEDs, apart from being a surrogate for epileptic brain regions, have also been linked to cognitive decline. Here we report that IEDs in human epilepsy patients and AD mouse models have similar local field potential characteristics and associated firing patterns of pyramidal cells and interneurons. Mice with more IEDs displayed fewer hippocampal SPW-Rs, poorer replay of spatial trajectories, and decreased memory performance. IED suppression is an unexplored target to treat cognitive dysfunction in neurodegenerative diseases.
Vascular oxidative stress causes neutrophil arrest in brain capillaries, leading to decreased cerebral blood flow and contributing to memory impairment in a mouse model of Alzheimer’s disease
Authors: Ruiz-Uribe Nancy E. , Bracko Oliver , Swallow Madisen , Omurzakov Argen , Dash Sabyasachi , Uchida Hiroki , Xiang David , Haft-Javaherian Mohammad , Falkenhain Kaja , Lamont Michael E. , Ali Muhammad , Njiru Brendah N. , Chang Hsin-Yun , Tan Adrian Y , Xiang Jenny Z , Iadecola Costantino , Park Laibaik , Sanchez Teresa , Nishimura Nozomi , Schaffer Chris B.
Published: February 2023

INTRODUCTION

In this study, we explore the role of oxidative stress produced by NOX2-containing NADPH oxidase as a molecular mechanism causing capillary stalling and cerebral blood flow deficits in the APP/PS1 mouse model of AD.

METHODS

We inhibited NOX2 in APP/PS1 mice by administering a 10 mg/kg dose of the peptide inhibitor gp91-ds-tat i.p., for two weeks. We usedin vivotwo-photon imaging to measure capillary stalling, penetrating arteriole flow, and vascular inflammation. We also characterized short-term memory function and gene expression changes in cerebral microvessels.

RESULTS

We found that after NOX2 inhibition capillary stalling, as well as parenchymal and vascular inflammation, were significantly reduced. In addition, we found a significant increase in penetrating arteriole flow, followed by an improvement in short-term memory, and downregulation of inflammatory gene expression pathways.

DISCUSSION

Oxidative stress is a major mechanism leading to microvascular dysfunction in AD, and represents an important therapeutic target.
Lipid nanoparticle structure and delivery route during pregnancy dictates mRNA potency, immunogenicity, and health in the mother and offspring
Authors: Chaudhary Namit , Newby Alexandra N. , Arral Mariah L. , Yerneni Saigopalakrishna S. , LoPresti Samuel T. , Doerfler Rose , Strelkova Petersen Daria M. , Fox Bethany , Coon Tiffany , Malaney Angela , Sadovsky Yoel , Whitehead Kathryn A.
Published: February 2023

Treating pregnancy-related disorders is exceptionally challenging because many small molecule drugs on the market may cause maternal and fetal toxicity. This potential danger has hindered the development and clinical evaluation of new drugs for several decades. Lipid nanoparticle (LNP)-based RNA therapies with high delivery efficacy, favorable immune response, and minimal transplacental transport can quell maternal-fetal toxicity concerns and propel the development of pregnancy-safe drugs. To this extent, we report potent LNP structures that robustly deliver mRNA to maternal organs and placenta. Using structure-function analysis, we show that LNP efficacy is influenced by the polyamine headgroup, and toxicity is governed by the acrylate tail. Our lead nanoparticle shows robust protein expression via multiple clinically relevant administration routes in pregnant mice. In the placenta, it transfects trophoblasts, endothelial cells, and immune cells. Further, by varying ionizable lipid structure, we demonstrate that LNP immunogenicity affects organ expression and pup health during pregnancy. Immunogenic LNPs show lower efficacy in lymphoid organs in an IL-1β dependent manner in pregnant mice. Further, pro-inflammatory immune responses provoke the infiltration of adaptive immune cells in the placenta and restrict pup growth after birth. Together, our results provide a mechanistic basis for designing safe and potent LNPs that can be administered during pregnancy.
Dual credit assignment processes underlie dopamine signals in a complex spatial environment
Authors: Krausz Timothy A. , Comrie Alison E. , Frank Loren M. , Daw Nathaniel D. , Berke Joshua D.
Published: February 2023

Dopamine in the nucleus accumbens helps motivate behavior based on expectations of future reward (“values”). These values need to be updated by experience: after receiving reward, the choices that led to reward should be assigned greater value. There are multiple theoretical proposals for how this credit assignment could be achieved, but the specific algorithms that generate updated dopamine signals remain uncertain. We monitored accumbens dopamine as freely behaving rats foraged for rewards in a complex, changing environment. We observed brief pulses of dopamine both when rats received reward (scaling with prediction error), and when they encountered novel path opportunities. Furthermore, dopamine ramped up as rats ran towards reward ports, in proportion to the value at each location. By examining the evolution of these dopamine place-value signals, we found evidence for two distinct update processes: progressive propagation along taken paths, as in temporal-difference learning, and inference of value throughout the maze, using internal models. Our results demonstrate that within rich, naturalistic environments dopamine conveys place values that are updated via multiple, complementary learning algorithms.
Development of a human glioblastoma model using humanized DRAG mice for immunotherapy
Authors: Srivastava Rashmi , Labani-Motlagh Alireza , Chen Apeng , Yang Fan , Ansari Danish , Patel Sahil , Ji Honglong , Trasti Scott , Dodda Meghana , Patel Yash , Zou Han , Hu Baoli , Yi Guohua
Published: February 2023

Glioblastoma (GBM) is the most common and lethal primary brain tumor with high mortality rates and a short median survival rate of about 15 months despite intensive multimodal treatment of maximal surgical resection, radiotherapy, and chemotherapy. Although immunotherapies have been successful in the treatment of various cancers, disappointing results from clinical trials for GBM immunotherapy represent our incomplete understanding. The development of alternative humanized mouse models with fully functional human immune cells will potentially accelerate the progress of GBM immunotherapy. In this study, we developed a humanized DRAG (NOD.Rag1KO.IL2RγcKO) mouse model, in which the human hematopoietic stem cells (HSCs) were well-engrafted and subsequently differentiated into a full lineage of immune cells. Using this humanized DRAG mouse model, GBM patient-derived tumorsphere lines were successfully engrafted to form xenografted tumors, which can recapitulate the pathological features and the immune cell composition of human GBM. Importantly, the administration of anti-human PD-1 antibodies in these DRAG mice bearing a GBM patient-derived tumorsphere line resulted in decreasing the major tumor-infiltrating immunosuppressive cell populations, including CD4+PD-1+and CD8+PD-1+T cells, CD11b+CD14+HLA-DR+macrophages, CD11b+CD14+HLA-DR−CD15−and CD11b+CD14−CD15+myeloid-derived suppressor cells, indicating the humanized DRAG mouse model as a useful model to test the efficacy of immune checkpoint inhibitors in GBM immunotherapy. Together, these results suggest that humanized DRAG mouse models are a reliable preclinical platform for brain cancer immunotherapy and beyond.
Structural basis for lysophosphatidylserine recognition by GPR34
Authors: Izume Tamaki , Kawahara Ryo , Uwamizu Akiharu , Chen Luying , Yaginuma Shun , Omi Jumpei , Kawana Hiroki , Sano Fumiya K. , Tanaka Tatsuki , Kobayashi Kazuhiro , Okamoto Hiroyuki H. , Kise Yoshiaki , Ohwada Tomohiko , Aoki Junken , Shihoya Wataru , Nureki Osamu
Published: February 2023

GPR34 is a recently identified G-protein coupled receptor, which has an immunomodulatory role and recognizes lysophosphatidylserine (LysoPS) as a putative ligand. Here, we report cryo-electron microscopy structures of human GPR34-Gicomplex bound with either the LysoPS analogue S3E-LysoPS, which contains an ethoxy group at thesn-1 position, or M1, a derivative of S3E-LysoPS in which oleic acid is substituted with a metabolically stable aromatic fatty acid surrogate. In both structures, the ligand-binding pocket is laterally open toward the membrane, allowing lateral entry of lipidic agonists into the cavity. The amine and carboxylate groups of the serine moiety are recognized by the charged residue cluster, and the aromatic fatty acid surrogate of M1 forms stable hydrophobic interactions with the cavity, thus acting as a superagonist. Molecular dynamics simulations further account for the LysoPS-regioselectivity of GPR34. Thus, using a series of structural and physiological experiments, we provide evidence that chemically unstable 2-acyl LysoPS is the physiological ligand for GPR34, suggesting its short signal duration. Overall, we anticipate the present structures will pave the way for development of novel anticancer drugs that specifically target GPR34.
Spatiotemporal cortical dynamics for rapid scene recognition as revealed by EEG decoding
Authors: Orima Taiki , Motoyoshi Isamu
Published: February 2023

The human visual system rapidly recognizes the categories and global properties of complex natural scenes. The present study investigated the spatiotemporal dynamics of neural signals involved in ultra-rapid scene recognition using electroencephalography (EEG) decoding. We recorded visual evoked potentials from 11 human observers for 232 natural scenes, each of which belonged to one of 13 natural scene categories (e.g., a bedroom or open country) and had three global properties (naturalness, openness, and roughness). We trained a deep convolutional classification model of the natural scene categories and global properties using EEGNet. Having confirmed that the model successfully classified natural scene categories and the three global properties, we applied Grad-CAM to the EEGNet model to visualize the EEG channels and time points that contributed to the classification. The analysis showed that EEG signals in the occipital lobes at short latencies (approximately 80∼ ms) contributed to the classifications other than roughness, whereas those in the frontal lobes at relatively long latencies (∼ 164 ms) contributed to the classification of naturalness and the individual scene category. These results suggest that different global properties are encoded in different cortical areas and with different timings, and that the encoding of scene categories shifts from the occipital to the frontal lobe over time.
Fractal model of thermal contact conductance of rough surfaces based on cone asperity
Authors: Sun Xianguang , Xing Wuce
Published: February 2023

Purpose

The purpose of this paper is to propose a fractal model of thermal contact conductance (TCC) of rough surfaces based on cone asperity.

Design/methodology/approach

A detailed numerical study is conducted to examine the effects of contact load, fractal dimensional, fractal roughness and material properties on the TCC of rough surfaces.

Findings

The results indicate that when the fractal dimension D is less than 2.5, the TCC of rough surfaces increases nonlinearly with the increase of the contact load. However, when the fractal dimension D is greater than or equal to 2.5, the TCC of rough surfaces increases linearly with the increase of the contact load; the TCC of the rough surfaces increases with the increase of the fractal dimension D and the decrease of the fractal roughness G; the material parameters also have an influence on the TCC of the rough surfaces, and the extent of the effect on the TCC is related to the fractal dimension D.

Originality/value

A fractal model of TCC of rough surfaces based on cone asperity is established in this paper. Some new results and conclusions are obtained from this work, which provides important theoretical guidance for further study of TCC of rough surfaces.
Emerging technologies in the construction industry: challenges and strategies in Ghana
Authors: Kissi Ernest , Aigbavboa Clinton , Kuoribo Ewald
Published: February 2023

Purpose

The momentous contribution of innovative technologies has made a significant impact in several sectors globally. However, the construction industry is undoubtedly lagging when it comes to technology usage. Thus, this study aims to explore the various emerging technologies in the construction industry while noticing stakeholders’ challenges and strategies in its use.

Design/methodology/approach

The study used a pragmatism research philosophy together with a quantitative research strategy in determining emerging technologies in the construction industry while noticing stakeholder challenges and strategies. Data were obtained from a total of 80 construction stakeholders through a structured questionnaire survey. The analysis was done with descriptive statistics using mean score ranking and a one-samplet-test.

Findings

Each emerging technology challenge was analysed and compared to see how pressing the challenges were as well as the aligned strategies. A key indication of this study is that the familiarity of the various emerging technologies was based on how many occasions one had an encounter with the technology.

Practical implications

The discussion’s findings contribute to a better knowledge to construction stakeholders on the challenges and strategies for rising technology adoption and implementation competencies.

Originality/value

The study reckoned stakeholders’ challenges on the emerging technologies in the construction industry context and recommended strategies to balloon the adoption of these emerging technologies in a developing country setting.
Creating public value with municipal Wi-Fi networks: a bottom-up methodology
Authors: van den Velden Jenneke , Sadowski Bert M.
Published: February 2023

Purpose

The purpose of this paper is evaluate the public value of municipal Wi-Fi networks by examining their costs and benefits. Increasing attention has been focused on the digital divide, i.e. inequalities in digital access, use and benefits, to a lesser extent on technologies providing opportunities to overcome these inequalities. Different theoretical traditions have approached the problem of the digital divide, this research represents a synthesis by combining a bottom-up approach to calculating the benefits of municipal Wi-Fi networks with an in-depth analysis of the digital divide in Europe.

Design/methodology/approach

After a systematic literature review, the paper uses a bottom-up methodology to evaluate the public value of a municipal Wi-Fi network by quantifying its potential benefits and costs. In addition, it includes different types of users based on the access opportunities available to them. It develops different scenarios for these users depending on the connection alternatives and the digital skills available across European countries.

Findings

By using data from the euro-28, the paper shows that, in general, the private value of a municipal Wi-Fi network is negative, the public value is positive. However, a greater public value is depending on the extent to which the benefits can be attributed to expectations about the arrival and usage of e-government services.

Research limitations/implications

Based on the quantitative analysis, the authors suggest that municipal Wi-Fi networks can provide the potential to bridge the digital divide. To generate public value, these networks have to be driven by a strong need for e-government services.

Practical implications

However, important factors in the adoption of these services are related to digital skills available in the particular region.

Social implications

In addition, public investment is required to stimulate the growth of broadband infrastructure in a complementary manner to enable public wireless networks.

Originality/value

The paper combines new insights into the cost calculations of municipal Wi-Fi networks with socioeconomic data on digital skills to examine different types of users.
Monitoring methods and student performance in distance education exams
Authors: Rodríguez-Villalobos Martha , Fernandez-Garza Jessica , Heredia-Escorza Yolanda
Published: February 2023

Purpose

The objective of this study was to compare three distinct methods of test monitoring in the context of distance education—non-proctored remote or online tests, traditional face-to-face proctored tests and remotely proctored tests using software—to analyze if the method in which tests are monitored influences the obtained grades.

Design/methodology/approach

The experiment was carried out at the postgraduate level in the Master's Degree in Administration program in the modality of distance education, with a total of 296 students during three terms wherein the monitoring method of the final exam varied, keeping the other variables constant. This study used a quantitative method in which the distribution of grades was analyzed; and the grades from each method were tested. Finally, using a multiple linear regression model with dichotomous variables, the impact on students' academic performance with each method was quantified.

Findings

The results indicated that the remotely proctored online test grades were seven points lower with respect to the traditional method. This result does not mean that the lower scores in the remote proctored condition were due to better adherence to academic honesty, maybe this could be due to test anxiety, technology interference or a number of other factors that would confound the validity of the final test score.

Practical implications

The results indicated that the non-proctored online test favored the grade in four points with respect to the traditional method.

Social implications

The authors conclude to support recommending non-proctored online test, this can be a closer substitute to the traditional method than remote application with software monitoring.

Originality/value

Not exist another paper to compare three distinct methods of test monitoring in the context of distance education.
Mediating role of lean management on the effects of workforce management and value-added time in private hospitals
Authors: Ahmed Selim , Hawarna Shatha , Alqasmi Ibrahim , Ashrafi Dewan Mehrab , Rahman Muhammad Khalilur
Published: February 2023

Purpose

This study aims to investigate the mediating role of lean management on the relationship between workforce management and value-added time in private hospitals. This study also investigates the direct influences of workforce management and lean management on the value-added time of the hospitals.

Design/methodology/approach

This study applied a quantitative approach to obtain data from the private hospitals’ staff in Peninsular Malaysia. A self-administered survey questionnaire was used to collect data from 287 hospital staff using a stratified random sampling method. The partial least squares structural equation modeling (PLS-SEM) approach was used to determine the internal consistency, reliability, validity of the constructs. The PLS-SEM method was also used to test the hypothesised research model via SmartPLS 3.3.4 version.

Findings

The findings of the study indicate that lean management has a direct and significant effect on the value-added time of private hospitals. The findings also revealed that lean management significantly mediates the relationship between workforce management and value-added time in private hospitals. The analysis of the results indicates that both workforce and lean management have a significant impact on the value-added time of the hospitals.

Practical implications

This study provides empirical contributions to enhance the quality of workforce management, lean management and value-added time. The findings of this study provide valuable insights into how effectively managing the workforce and providing guidelines to augment the lean management practices can ensure value-added time in Malaysian hospitals and the overall health-care industry. The lean management framework provides useful insights for the policymakers to understand the significance of workforce management, lean management on ensuring value-added time through reducing waiting times, unnecessary delays, generating a higher degree of patient safety, satisfaction and loyalty.

Originality/value

The research findings provide some essential indications for the health-care service providers to understand how the lean management approach can be implemented to enhance value-added time and how lean management can play a mediating role in creating a link between workforce management and value-added time in hospitals. This study also contributes to the theoretical and practical perspectives. The present study contributes to a better understanding of workforce management and lean management in health-care sectors from theoretical and practical perspectives.