bluuebunny/crossref_metadata_2025 huggingface dataset:
PANoptosis: A New Insight Into Oral Infectious Diseases
Authors: Jiang Weiyi , Deng Zilong , Dai Xingzhu , Zhao Wanghong
Published: December 2021

The oral microbiome, one of the most complex and intensive microbial ecosystems in the human body, comprises bacteria, archaea, fungi, protozoa, and viruses. Dysbiosis of the oral microbiome is the initiating factor that leads to oral infectious diseases. Infection is a sophisticated biological process involving interplay between the pathogen and the host, which often leads to activation of programmed cell death. Studies suggest that pyroptosis, apoptosis, and necroptosis are involved in multiple oral infectious diseases. Further understanding of crosstalk between cell death pathways has led to pyroptosis, apoptosis, and necroptosis being integrated into a single term: PANoptosis. PANoptosis is a multifaceted agent of the immune response that has important pathophysiological relevance to infectious diseases, autoimmunity, and cancer. As such, it plays an important role in innate immune cells that detect and eliminate intracellular pathogens. In addition to the classical model of influenza virus-infected and Yersinia-infected macrophages, other studies have expanded the scope of PANoptosis to include other microorganisms, as well as potential roles in cell types other than macrophages. In this review, we will summarize the pathophysiological mechanisms underlying inflammation and tissue destruction caused by oral pathogens. We present an overview of different pathogens that may induce activation of PANoptosis, along with the functional consequences of PANoptosis in the context of oral infectious diseases. To advance our understanding of immunology, we also explore the strategies used by microbes that enable immune evasion and replication within host cells. Improved understanding of the interplay between the host and pathogen through PANoptosis will direct development of therapeutic strategies that target oral infectious diseases.
Macrophage Polarization and Its Role in Liver Disease
Authors: Wang Cheng , Ma Cheng , Gong Lihong , Guo Yuqin , Fu Ke , Zhang Yafang , Zhou Honglin , Li Yunxia
Published: December 2021

Macrophages are important immune cells in innate immunity, and have remarkable heterogeneity and polarization. Under pathological conditions, in addition to the resident macrophages, other macrophages are also recruited to the diseased tissues, and polarize to various phenotypes (mainly M1 and M2) under the stimulation of various factors in the microenvironment, thus playing different roles and functions. Liver diseases are hepatic pathological changes caused by a variety of pathogenic factors (viruses, alcohol, drugs, etc.), including acute liver injury, viral hepatitis, alcoholic liver disease, metabolic-associated fatty liver disease, liver fibrosis, and hepatocellular carcinoma. Recent studies have shown that macrophage polarization plays an important role in the initiation and development of liver diseases. However, because both macrophage polarization and the pathogenesis of liver diseases are complex, the role and mechanism of macrophage polarization in liver diseases need to be further clarified. Therefore, the origin of hepatic macrophages, and the phenotypes and mechanisms of macrophage polarization are reviewed first in this paper. It is found that macrophage polarization involves several molecular mechanisms, mainly including TLR4/NF-κB, JAK/STATs, TGF-β/Smads, PPARγ, Notch, and miRNA signaling pathways. In addition, this paper also expounds the role and mechanism of macrophage polarization in various liver diseases, which aims to provide references for further research of macrophage polarization in liver diseases, contributing to the therapeutic strategy of ameliorating liver diseases by modulating macrophage polarization.
Mini Review: Structure and Function of Nematode Phosphorylcholine-Containing Glycoconjugates
Authors: Buitrago Geraldine , Duncombe-Moore Josephine , Harnett Margaret M. , Harnett William
Published: December 2021

An unusual aspect of the biology of nematodes is the covalent attachment of phosphorylcholine (PC) to carbohydrate in glycoconjugates. Investigation of the structure of these molecules by ever-increasingly sophisticated analytical procedures has revealed that PC is generally in phosphodiester linkage with C6 ofN-acetylglucosamine (GlcNAc) in bothN-type glycans and glycosphingolipids. Up to five PC groups have been detected in the former, being located on both antenna and core GlcNAc. The PC donor for transfer to carbohydrate appears to be phosphatidylcholine but the enzyme responsible for transfer remains to be identified. Work primarily involving the PC-containingAcanthocheilonema viteaesecreted product ES-62, has shown that the PC attached to nematodeN-glycans possesses a range of immunomodulatory properties, subverting for example, pro-inflammatory signalling in various immune system cell-types including lymphocytes, mast cells, dendritic cells and macrophages. This has led to the generation of PC-based ES-62 small molecule analogues (SMAs), which mirror the parent molecule in preventing the initiation or progression of disease in mouse models of a number of human conditions associated with aberrant inflammatory responses. These include rheumatoid arthritis, systemic lupus erythematosus and lung and skin allergy such that the SMAs are considered to have widespread therapeutic potential.
Assessment of Plasmodium falciparum Infection and Fitness of Genetically Modified Anopheles gambiae Aimed at Mosquito Population Replacement
Authors: Tapanelli Sofia , Inghilterra Maria Grazia , Cai Julia , Philpott James , Capriotti Paolo , Windbichler Nikolai , Christophides George K.
Published: December 2021

Genetically modified (GM) mosquitoes expressing anti-plasmodial effectors propagating through wild mosquito populations by means of gene drive is a promising tool to support current malaria control strategies. The process of generating GM mosquitoes involves genetic transformation of mosquitoes from a laboratory colony and, often, interbreeding with other GM lines to cross in auxiliary traits. These mosquito colonies and GM lines thus often have different genetic backgrounds and GM lines are invariably highly inbred, which in conjunction with their independent rearing in the laboratory may translate to differences in their susceptibility to malaria parasite infection and life history traits. Here, we show that laboratory Anopheles gambiae colonies and GM lines expressing Cas9 and Cre recombinase vary greatly in their susceptibility to Plasmodium falciparum NF54 infection. Therefore, the choice of mosquitoes to be used as a reference when conducting infection or life history trait assays requires careful consideration. To address these issues, we established an experimental pipeline involving genetic crosses and genotyping of mosquitoes reared in shared containers throughout their lifecycle. We used this protocol to examine whether GM lines expressing the antimicrobial peptide (AMP) Scorpine in the mosquito midgut interfere with parasite infection and mosquito survival. We demonstrate that Scorpine expression in the Peritrophin 1 (Aper1) genomic locus reduces both P. falciparum sporozoite prevalence and mosquito lifespan; both these phenotypes are likely to be associated with the disturbance of the midgut microbiota homeostasis. These data lead us to conclude that the Aper1-Sco GM line could be used in proof-of-concept experiments aimed at mosquito population replacement, although the impact of its reduced fitness on the spread of the transgene through wild populations requires further investigation.
Testing the Influence of Seascape Connectivity on Marine-Based Species Distribution Models
Authors: Cecino Giorgia , Valavi Roozbeh , Treml Eric A.
Published: December 2021

Species distribution models (SDMs) are commonly used in ecology to predict species occurrence probability and how species are geographically distributed. Here, we propose innovative predictive factors to efficiently integrate information on connectivity into SDMs, a key element of population dynamics strongly influencing how species are distributed across seascapes. We also quantify the influence of species-specific connectivity estimates (i.e., larval dispersal vs. adult movement) on the marine-based SDMs outcomes. For illustration, seascape connectivity was modeled for two common, yet contrasting, marine species occurring in southeast Australian waters, the purple sea urchin, Heliocidaris erythrogramma, and the Australasian snapper, Chrysophrys auratus. Our models illustrate how different species-specific larval dispersal and adult movement can be efficiently accommodated. We used network-based centrality metrics to compute patch-level importance values and include these metrics in the group of predictors of correlative SDMs. We employed boosted regression trees (BRT) to fit our models, calculating the predictive performance, comparing spatial predictions and evaluating the relative influence of connectivity-based metrics among other predictors. Network-based metrics provide a flexible tool to quantify seascape connectivity that can be efficiently incorporated into SDMs. Connectivity across larval and adult stages was found to contribute to SDMs predictions and model performance was not negatively influenced from including these connectivity measures. Degree centrality, quantifying incoming and outgoing connections with habitat patches, was the most influential centrality metric. Pairwise interactions between predictors revealed that the species were predominantly found around hubs of connectivity and in warm, high-oxygenated, shallow waters. Additional research is needed to quantify the complex role that habitat network structure and temporal dynamics may have on SDM spatial predictions and explanatory power.
Integrating Biophysical, Socio-Economic and Governance Principles Into Marine Reserve Design and Management in Mexico: From Theory to Practice
Authors: Précoma-de la Mora Magdalena , Bennett Nathan J. , Fulton Stuart , Munguia-Vega Adrian , Lasch-Thaler Cristina , Walther-Mendoza Mariana , Zepeda-Domínguez José Alberto , Finkbeiner Elena Marie , Green Alison L. , Suárez Alvin , Weaver Amy Hudson , Figueroa Carranza Ana Luisa R. , Vega Velázquez Armando , Zepeda Calina , Montes Celerino , Fuentes Montalvo David Antonio , Micheli Fiorenza , Reyes-Bonilla Héctor , Chollett Iliana , Lopez-Ercilla Ines , Torres Origel Juan Francisco , Vázquez-Vera Leonardo , García-Rivas María del Carmen , Mancha-Cisneros María del Mar , Espinosa-Romero María José , Martín Ruíz Mirian , Arafeh-Dalmau Nur , González-Cuellar Ollin T. , Huchim Oswaldo , Rodríguez Van Dyck Salvador
Published: December 2021

Marine conservation design and fisheries management are increasingly integrating biophysical, socio-economic and governance considerations. Integrative approaches are adopted to achieve more effective, equitable, inclusive, and robust marine policies and practices. This paper describes a participatory process to co-produce biophysical, socio-economic, and governance principles to guide the design and management of marine reserves in three regions of Mexico: the Pacific region of the Baja California Peninsula, the Gulf of California, and the Mexican Caribbean. The process of co-producing the principles included convening a coordination team, reviewing the science, convening multi-stakeholder workshops, developing and communicating the principles with key practitioners and policy makers, and supporting uptake and application to policy and practice. Biophysical principles were related to: habitat representation and risk spreading; protecting critical, special and unique areas; incorporating connectivity; allowing time for recovery; adapting to changes in climate and ocean chemistry; and considering threats and opportunities. Socio-economic principles focused on: integrating the social context, local aspirations, and human-environment interactions; considering economic and non-economic uses, promoting an equitable distribution of costs and benefits, and respecting and maintaining cultural identity and diversity. Governance principles prioritized establishing and ensuring legitimacy and institutional continuity; implementing collaborative and adaptive management; and, promoting effective management. The paper also examines early efforts to implement the principles, next steps to promote further uptake and application in Mexico, and lessons learned from the process. Thus it provides insights into a practical process and a set of principles that are valuable to inform marine conservation and fisheries management processes elsewhere.
The Second Wave of COVID-19 in South and Southeast Asia and the Effects of Vaccination
Authors: Song Haitao , Fan Guihong , Liu Yuan , Wang Xueying , He Daihai
Published: December 2021

Background: By February 2021, the overall impact of coronavirus disease 2019 (COVID-19) in South and Southeast Asia was relatively mild. Surprisingly, in early April 2021, the second wave significantly impacted the population and garnered widespread international attention.

Methods: This study focused on the nine countries with the highest cumulative deaths from the disease as of August 17, 2021. We look at COVID-19 transmission dynamics in South and Southeast Asia using the reported death data, which fits a mathematical model with a time-varying transmission rate.

Results: We estimated the transmission rate, infection fatality rate (IFR), infection attack rate (IAR), and the effects of vaccination in the nine countries in South and Southeast Asia. Our study suggested that the IAR is still low in most countries, and increased vaccination is required to prevent future waves.

Conclusion: Implementing non-pharmacological interventions (NPIs) could have helped South and Southeast Asia keep COVID-19 under control in 2020, as demonstrated in our estimated low-transmission rate. We believe that the emergence of the new Delta variant, social unrest, and migrant workers could have triggered the second wave of COVID-19.
Early Transcriptional Changes in Rabies Virus-Infected Neurons and Their Impact on Neuronal Functions
Authors: Kim Seonhee , Larrous Florence , Varet Hugo , Legendre Rachel , Feige Lena , Dumas Guillaume , Matsas Rebecca , Kouroupi Georgia , Grailhe Regis , Bourhy Hervé
Published: December 2021

Rabies is a zoonotic disease caused by rabies virus (RABV). As rabies advances, patients develop a variety of severe neurological symptoms that inevitably lead to coma and death. Unlike other neurotropic viruses that can induce symptoms of a similar range, RABV-infected post-mortem brains do not show significant signs of inflammation nor the structural damages on neurons. This suggests that the observed neurological symptoms possibly originate from dysfunctions of neurons. However, many aspects of neuronal dysfunctions in the context of RABV infection are only partially understood, and therefore require further investigation. In this study, we used differentiated neurons to characterize the RABV-induced transcriptomic changes at the early time-points of infection. We found that the genes modulated in response to the infection are particularly involved in cell cycle, gene expression, immune response, and neuronal function-associated processes. Comparing a wild-type RABV to a mutant virus harboring altered matrix proteins, we found that the RABV matrix protein plays an important role in the early down-regulation of host genes, of which a significant number is involved in neuronal functions. The kinetics of differentially expressed genes (DEGs) are also different between the wild type and mutant virus datasets. The number of modulated genes remained constant upon wild-type RABV infection up to 24 h post-infection, but dramatically increased in the mutant condition. This result suggests that the intact viral matrix protein is important to control the size of host gene modulation. We then examined the signaling pathways previously studied in relation to the innate immune responses against RABV, and found that these pathways contribute to the changes in neuronal function-associated processes. We further examined a set of regulated genes that could impact neuronal functions collectively, and demonstrated in calcium imaging that indeed the spontaneous activity of neurons is influenced by RABV infection. Overall, our findings suggest that neuronal function-associated genes are modulated by RABV early on, potentially through the viral matrix protein-interacting signaling molecules and their downstream pathways.
In vitro Bactericidal Activities of Combination Antibiotic Therapies Against Carbapenem-Resistant Klebsiella pneumoniae With Different Carbapenemases and Sequence Types
Authors: Teo Jocelyn Qi-Min , Fauzi Nazira , Ho Jayden Jun-Yuan , Tan Si Hui , Lee Shannon Jing-Yi , Lim Tze Peng , Cai Yiying , Chang Hong Yi , Mohamed Yusoff Nurhayati , Sim James Heng-Chiak , Tan Thuan Tong , Ong Rick Twee-Hee , Kwa Andrea Lay-Hoon
Published: December 2021

Carbapenem-resistant Klebsiella pneumoniae (CRKP) is becoming increasingly problematic due to the limited effectiveness of new antimicrobials or other factors such as treatment cost. Thus, combination therapy remains a suitable treatment option. We aimed to evaluate the in vitro bactericidal activity of various antibiotic combinations against CRKP with different carbapenemase genotypes and sequence types (STs). Thirty-seven CRKP with various STs and carbapenemases were exposed to 11 antibiotic combinations (polymyxin B or tigecycline in combination with β-lactams including aztreonam, cefepime, piperacillin/tazobactam, doripenem, meropenem, and polymyxin B with tigecycline) in static time-kill studies (TKS) using clinically achievable concentrations. Out of the 407 isolate-combination pairs, only 146 (35.8%) were bactericidal (≥3 log10CFU/mL decrease from initial inoculum). Polymyxin B in combination with doripenem, meropenem, or cefepime was the most active, each demonstrating bactericidal activity in 27, 24, and 24 out of 37 isolates, respectively. Tigecycline in combination with β-lactams was rarely bactericidal. Aside from the lower frequency of bactericidal activity in the dual-carbapenemase producers, there was no apparent difference in combination activity among the strains with other carbapenemase types. In addition, bactericidal combinations were varied even in strains with similar STs, carbapenemases, and other genomic characteristics. Our findings demonstrate that the bactericidal activity of antibiotic combinations is highly strain-specific likely owing to the complex interplay of carbapenem-resistance mechanisms, i.e., carbapenemase genotype alone cannot predict in vitro bactericidal activity. The availability of WGS information can help rationalize the activity of certain combinations. Further studies should explore the use of genomic markers with phenotypic information to predict combination activity.
Taxonomic Structure of Rhizosphere Bacterial Communities and Its Association With the Accumulation of Alkaloidal Metabolites in Sophora flavescens
Authors: Chen Jie , Li Na , Chang Jiayu , Ren Kaida , Zhou Jiangtao , Yang Guan’e
Published: December 2021

Plant secondary metabolites (SMs) play a crucial role in plant defense against pathogens and adaptation to environmental stresses, some of which are produced from medicinal plants and are the material basis of clinical efficacy and vital indicators for quality evaluation of corresponding medicinal materials. The influence of plant microbiota on plant nutrient uptake, production, and stress tolerance has been revealed, but the associations between plant microbiota and the accumulation of SMs in medicinal plants remain largely unknown. Plant SMs can vary among individuals, which could be partly ascribed to the shift in microbial community associated with the plant host. In the present study, we sampled fine roots and rhizosphere soils of Sophora flavescens grown in four well-separated cities/counties in China and determined the taxonomic composition of rhizosphere bacterial communities using Illumina 16S amplicon sequencing. In addition, the association of the rhizosphere bacterial microbiota with the accumulation of alkaloids in the roots of S. flavescens was analyzed. The results showed that S. flavescens hosted distinct bacterial communities in the rhizosphere across geographic locations and plant ages, also indicating that geographic location was a larger source of variation than plant age. Moreover, redundancy analysis revealed that spatial, climatic (mean annual temperature and precipitation), and edaphic factors (pH and available N and P) were the key drivers that shape the rhizosphere bacterial communities. Furthermore, the results of the Mantel test demonstrated that the rhizosphere bacterial microbiota was remarkably correlated with the contents of oxymatrine, sophoridine, and matrine + oxymatrine in roots. Specific taxa belonging to Actinobacteria and Chloroflexi were identified as potential beneficial bacteria associated with the total accumulation of matrine and oxymatrine by a random forest machine learning algorithm. Finally, the structural equation modeling indicated that the Actinobacteria phylum had a direct effect on the total accumulation of matrine and oxymatrine. The present study addresses the association between the rhizosphere bacterial communities and the accumulation of alkaloids in the medicinal plant S. flavescens. Our findings may provide a basis for the quality improvement and sustainable utilization of this medicinal plant thorough rhizosphere microbiota manipulation.
Probiotic Potential Analysis and Safety Evaluation of Enterococcus durans A8-1 Isolated From a Healthy Chinese Infant
Authors: Zhou Yi , Shi Lu , Wang Juan , Yuan Jia , Liu Jin , Liu Lijuan , Da Rong , Cheng Yue , Han Bei
Published: December 2021

To evaluate the probiotic characteristics and safety of Enterococcus durans isolate A8-1 from a fecal sample of a healthy Chinese infant, we determined the tolerance to low pH, survival in bile salts and NaCl, adhesion ability, biofilm formation, antimicrobial activity, toxin gene distribution, hemolysis, gelatinase activity, antibiotic resistance, and virulence to Galleria mellonella and interpreted the characters by genome resequencing. Phenotypically, E. durans A8-1 survived at pH 5.0 in 7.0% NaCl and 3% bile salt under aerobic and anaerobic condition. The bacterium had higher adhesion ability toward mucin, collagen, and Bovine Serum Albumin (BSA) in vitro and showed high hydrophobicity (79.2% in chloroform, 49.2% in xylene), auto-aggregation activity (51.7%), and could co-aggregate (66.2%) with Salmonella typhimurium. It had adhesion capability to intestinal epithelial Caco-2 cells (38.74%) with moderate biofilm production and antimicrobial activity against several Gram-positive pathogenic bacteria. A8-1 can antagonize the adhesion of S. typhimurium ATCC14028 on Caco-2 cells to protect the integrity of the cell membrane by detection of lactate dehydrogenase (LDH) and AKP activities. A8-1 also helps the cell relieve the inflammation induced by lipopolysaccharide by reducing the expression of cytokine IL-8 (P = 0.002) and TNF-α (P > 0.05), and increasing the IL-10 (P < 0.001). For the safety evaluation, A8-1 showed no hemolytic activity, no gelatinase activity, and had only asa1 positive in the seven detected virulence genes in polymerase chain reaction (PCR), whereas it was not predicted in the genome sequence. It was susceptible to benzylpenicillin, ampicillin, ciprofloxacin, levofloxacin, moxifloxacin, tigecycline, nitrofurantoin, linezolid, vancomycin, erythromycin, and quinupristin/dalofopine except clindamycin, which was verified by the predicted lasA, lmrB, lmrC, and lmrD genes contributing to the clindamycin resistance. The virulence test of G. mellonella showed that it had toxicity lower than 10% at 1 × 107 CFU. According to the results of these evaluated attributes, E. durans strain A8-1 could be a promising probiotic candidate for applications.
Exercise Reduces H3K9me3 and Regulates Brain Derived Neurotrophic Factor and GABRA2 in an Age Dependent Manner
Authors: Ionescu-Tucker Andra , Butler Christopher W. , Berchtold Nicole C. , Matheos Dina P. , Wood Marcelo A. , Cotman Carl W.
Published: December 2021

Exercise improves cognition in the aging brain and is a key regulator of neuronal plasticity genes such as BDNF. However, the mechanism by which exercise modifies gene expression continues to be explored. The repressive histone modification H3K9me3 has been shown to impair cognition, reduce synaptic density and decrease BDNF in aged but not young mice. Treatment with ETP69, a selective inhibitor of H3K9me3’s catalyzing enzyme (SUV39H1), restores synapses, BDNF and cognitive performance. GABA receptor expression, which modulates BDNF secretion, is also modulated by exercise and H3K9me3. In this study, we examined if exercise and ETP69 regulated neuronal plasticity genes by reducing H3K9me3 at their promoter regions. We further determined the effect of age on H3K9me3 promoter binding and neuronal plasticity gene expression. Exercise and ETP69 decreased H3K9me3 at BDNF promoter VI in aged mice, corresponding with an increase in BDNF VI expression with ETP69. Exercise increased GABRA2 in aged mice while increasing BDNF 1 in young mice, and both exercise and ETP69 reduced GABRA2 in young mice. Overall, H3K9me3 repression at BDNF and GABA receptor promoters decreased with age. Our findings suggest that exercise and SUV39H1 inhibition differentially modulate BDNF and GABRA2 expression in an age dependent manner.
Specificity Protein 1: A Protein With a Two-Sided Role in Ischemic Stroke
Authors: Yu Qinyang , Liu Wangyang , Chen Zhuohui , Zhang Mengqi
Published: December 2021

Stroke is one of the leading causes of death and disability worldwide. However, there is a lack of effective medications to speed up the recovery process. Ischemic stroke, as the result of cerebral infarction or cerebral artery narrowing, is accompanied by hemiplegia or impaired consciousness. There are many transcription factors involved in the development of this condition, whose alterations can influence or signal the prognostic outcomes of ischemic stroke. Among them, the augmented expression of specificity protein 1 (SP1) can participate in the progression of the disease by binding DNA to regulate the transcriptions of many genes. Different studies have provided different answers as to whether SP1 plays a positive or a negative role in ischemic stroke. On the one hand, SP1 can play a cytoprotective role as both an antioxidant and anti-apoptotic agent for neurons and glial cells. On the other hand, it can also damage neuronal cells by promoting inflammation and exacerbating brain edema. In this review, we highlight the roles of SP1 in ischemic stroke and shed light on the underlying mechanism.
Effects of Simulated Microgravity and Hypergravity Conditions on Arm Movements in Normogravity
Authors: Jamšek Marko , Kunavar Tjaša , Blohm Gunnar , Nozaki Daichi , Papaxanthis Charalambos , White Olivier , Babič Jan
Published: December 2021

The human sensorimotor control has evolved in the Earth’s environment where all movement is influenced by the gravitational force. Changes in this environmental force can severely impact the performance of arm movements which can be detrimental in completing certain tasks such as piloting or controlling complex vehicles. For this reason, subjects that are required to perform such tasks undergo extensive training procedures in order to minimize the chances of failure. We investigated whether local gravity simulation of altered gravitational conditions on the arm would lead to changes in kinematic parameters comparable to the full-body experience of microgravity and hypergravity onboard a parabolic flight. To see if this would be a feasible approach for on-ground training of arm reaching movements in altered gravity conditions we developed a robotic device that was able to apply forces at the wrist in order to simulate micro- or hypergravity conditions for the arm while subjects performed pointing movements on a touch screen. We analyzed and compared the results of several kinematic parameters along with muscle activity using this system with data of the same subjects being fully exposed to microgravity and hypergravity conditions on a parabolic flight. Both in our simulation and in-flight, we observed a significant increase in movement durations in microgravity conditions and increased velocities in hypergravity for upward movements. Additionally, we noted a reduced accuracy of pointing both in-flight and in our simulation. These promising results suggest, that locally simulated altered gravity can elicit similar changes in some movement characteristics for arm reaching movements. This could potentially be exploited as a means of developing devices such as exoskeletons to aid in training individuals prior to undertaking tasks in changed gravitational conditions.
Dorsal Bed Nucleus of the Stria Terminalis-Subcortical Output Circuits Encode Positive Bias in Pavlovian Fear and Reward
Authors: Kaouane Nadia , Ada Sibel , Hausleitner Marlene , Haubensak Wulf
Published: December 2021

Opposite emotions like fear and reward states often utilize the same brain regions. The bed nucleus of the stria terminalis (BNST) comprises one hub for processing fear and reward processes. However, it remains unknown how dorsal BNST (dBNST) circuits process these antagonistic behaviors. Here, we exploited a combined Pavlovian fear and reward conditioning task that exposed mice to conditioned tone stimuli (CS)s, either paired with sucrose delivery or footshock unconditioned stimuli (US). Pharmacological inactivation identified the dorsal BNST as a crucial element for both fear and reward behavior. Deep brain calcium imaging revealed opposite roles of two distinct dBNST neuronal output pathways to the periaqueductal gray (PAG) or paraventricular hypothalamus (PVH). dBNST neural activity profiles differentially process valence and Pavlovian behavior components: dBNST-PAG neurons encode fear CS, whereas dBNST-PVH neurons encode reward responding. Optogenetic activation of BNST-PVH neurons increased reward seeking, whereas dBNST-PAG neurons attenuated freezing. Thus, dBNST-PVH or dBNST-PAG circuitry encodes oppositely valenced fear and reward states, while simultaneously triggering an overall positive affective response bias (increased reward seeking while reducing fear responses). We speculate that this mechanism amplifies reward responding and suppresses fear responses linked to BNST dysfunction in stress and addictive behaviors.
Social Outcomes of School Leavers With Cerebral Palsy Living in Victoria
Authors: Imms Christine , Reddihough Dinah , Shepherd Daisy A. , Kavanagh Anne
Published: December 2021

Objective:In Australia, the National Disability Strategy provides a framework to guide actions and investment to achieve equity in social inclusion and economic participation for people with disability. We investigated the social outcomes of school leavers with cerebral palsy (CP) in Victoria, Australia and explored the determinants of desirable outcomes.

Methods:We used the Victorian CP Register to invite all adults with CP aged 18–25 years (n= 649). On-line and/or paper-based surveys explored participation in education, employment, community activities, living situation, relationships and life satisfaction. Functional and health status data were collected. Social outcomes were summarized descriptively and compared between individuals with CP and non-disabled peers aged 18–25 years from the Household Income and Labor Dynamics in Australia dataset. Within the CP cohort we explored whether physical and mental health and level of functioning were associated with social outcomes. In addition, a descriptive comparison was undertaken between the social outcomes of the current CP cohort with that of a previously reported 2007 cohort.

Results:Ninety participants (57% male; mean age 22.4 years (SD: 2.2) in 2020; 61.1% self-reported) provided data for analyses; response rate 16.9%. CP characteristics were similar between respondents and non-respondents. In comparison to similar aged peers, 79.8% had completed secondary school (compared to 83.2%); 32.6% (compared to 75.8%) were in paid work; 87.5% (compared to 48.2%) were living in their parental home; and 3.4% (compared to 31.6%) were married or partnered. Individuals with CP and higher levels of functional capacity and better physical health were more likely to undertake post-secondary education. Higher levels of functional capacity and physical health, as well as lower mental health status were associated with being employed.

Conclusions:While foundational education completion rates were similar to non-disabled peers, significant gaps in social outcomes remain, including residence in the parental home and single status. While addressing these issues is challenging, substantial efforts are needed to reduce these disparities—work that needs to be done in collaboration with people with CP and their families.
Multimodality Characterization of the Clot in Acute Stroke
Authors: LaGrange Daniela Dumitriu , Wanke Isabel , Machi Paolo , Bernava Gianmarco , Vargas Maria , Botta Daniele , Berberat Jatta , Muster Michel , Platon Alexandra , Poletti Pierre-Alexandre , Lövblad Karl-Olof
Published: December 2021

Aim: Current treatment of occluded cerebral vessels can be done by a variety of endovascular techniques. Sometimes, the clot responds in varying degrees to the treatment chosen. The Ex vivo characterization of the clot occluding the arteries in acute ischemic stroke can help in understanding the underlying imaging features obtained from pre-treatment brain scans. For this reason, we explored the potential of microCT when combined with electron microscopy for clot characterization. Results were compared to the clinical CT findings.

Methods: 16 patients (9 males, 8 females, age range 54–93 years) who were referred to our institution for acute stroke underwent dual-source CT.

Results: Clinical CT clots were seen as either iso or hyperdense. This was corroborated with micro-CT, and electron microscopy can show the detailed composition.

Conclusion: MicroCT values can be used as an indicator for red blood cells-rich composition of clots. Meaningful information regarding the clot composition and modalities of embedding along the stent retrievers can be obtained through a combination of microCT and electron microscopy.
Characterizing the Access of Cholinergic Antagonists to Efferent Synapses in the Inner Ear
Authors: Lee Choongheon , Sinha Anjali K. , Henry Kenneth , Walbaum Anqi W. , Crooks Peter A. , Holt Joseph C.
Published: December 2021

Stimulation of cholinergic efferent neurons innervating the inner ear has profound, well-characterized effects on vestibular and auditory physiology, after activating distinct ACh receptors (AChRs) on afferents and hair cells in peripheral endorgans. Efferent-mediated fast and slow excitation of vestibular afferents are mediated by α4β2*-containing nicotinic AChRs (nAChRs) and muscarinic AChRs (mAChRs), respectively. On the auditory side, efferent-mediated suppression of distortion product otoacoustic emissions (DPOAEs) is mediated by α9α10nAChRs. Previous characterization of these synaptic mechanisms utilized cholinergic drugs, that when systemically administered, also reach the CNS, which may limit their utility in probing efferent function without also considering central effects. Use of peripherally-acting cholinergic drugs with local application strategies may be useful, but this approach has remained relatively unexplored. Using multiple administration routes, we performed a combination of vestibular afferent and DPOAE recordings during efferent stimulation in mouse and turtle to determine whether charged mAChR or α9α10nAChR antagonists, with little CNS entry, can still engage efferent synaptic targets in the inner ear. The charged mAChR antagonists glycopyrrolate and methscopolamine blocked efferent-mediated slow excitation of mouse vestibular afferents following intraperitoneal, middle ear, or direct perilymphatic administration. Both mAChR antagonists were effective when delivered to the middle ear, contralateral to the side of afferent recordings, suggesting they gain vascular access after first entering the perilymphatic compartment. In contrast, charged α9α10nAChR antagonists blocked efferent-mediated suppression of DPOAEs only upon direct perilymphatic application, but failed to reach efferent synapses when systemically administered. These data show that efferent mechanisms are viable targets for further characterizing drug access in the inner ear.
A Review of Speech Perception of Mandarin-Speaking Children With Cochlear Implantation
Authors: Gao Qi , Wong Lena L. N. , Chen Fei
Published: December 2021

Objective:This paper reviewed the literature on the development of and factors affecting speech perception of Mandarin-speaking children with cochlear implantation (CI). We also summarized speech outcome measures in standard Mandarin for evaluating auditory and speech perception of children with CI.

Method:A comprehensive search of Google Scholar and PubMed was conducted from March to June 2021. Search terms used were speech perception/lexical tone recognition/auditory perception AND cochlear implant AND Mandarin/Chinese.

Conclusion:Unilateral CI recipients demonstrated continuous improvements in auditory and speech perception for several years post-activation. Younger age at implantation and longer duration of CI use contribute to better speech perception. Having undergone a hearing aid trial before implantation and having caregivers whose educational level is higher may lead to better performance. While the findings that support the use of CI to improve speech perception continue to grow, much research is needed to validate the use of unilateral and bilateral implantation. Evidence to date, however, revealed bimodal benefits over CI-only conditions in lexical tone recognition and sentence perception in noise. Due to scarcity of research, conclusions on the benefits of bilateral CIs compared to unilateral CI or bimodal CI use cannot be drawn. Therefore, future research on bimodal and bilateral CIs is needed to guide evidence-based clinical practice.
Therapeutic Potential of Vital Transcription Factors in Alzheimer’s and Parkinson’s Disease With Particular Emphasis on Transcription Factor EB Mediated Autophagy
Authors: Rai Sachchida Nand , Tiwari Neeraj , Singh Payal , Mishra Divya , Singh Anurag Kumar , Hooshmandi Etrat , Vamanu Emanuel , Singh Mohan P.
Published: December 2021

Autophagy is an important cellular self-digestion and recycling pathway that helps in maintaining cellular homeostasis. Dysregulation at various steps of the autophagic and endolysosomal pathway has been reported in several neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington disease (HD) and is cited as a critically important feature for central nervous system (CNS) proteostasis. Recently, another molecular target, namely transcription factor EB (TFEB) has been explored globally to treat neurodegenerative disorders. This TFEB, is a key regulator of autophagy and lysosomal biogenesis pathway. Multiple research studies suggested therapeutic potential by targeting TFEB to treat human diseases involving autophagy-lysosomal dysfunction, especially neurodegenerative disorders. A common observation involving all neurodegenerative disorders is their poor efficacy in clearing and recycle toxic aggregated proteins and damaged cellular organelles due to impairment in the autophagy pathway. This dysfunction in autophagy characterized by the accumulation of toxic protein aggregates leads to a progressive loss in structural integrity/functionality of neurons and may even result in neuronal death. In recent years TFEB, a key regulator of autophagy and lysosomal biogenesis, has received considerable attention. It has emerged as a potential therapeutic target in numerous neurodegenerative disorders like AD and PD. In various neurobiology studies involving animal models, TFEB has been found to ameliorate neurotoxicity and rescue neurodegeneration. Since TFEB is a master transcriptional regulator of autophagy and lysosomal biogenesis pathway and plays a crucial role in defining autophagy activation. Studies have been done to understand the mechanisms for TFEB dysfunction, which may yield insights into how TFEB might be targeted and used for the therapeutic strategy to develop a treatment process with extensive application to neurodegenerative disorders. In this review, we explore the role of different transcription factor-based targeted therapy by some natural compounds for AD and PD with special emphasis on TFEB.
Biomarkers to Evaluate Androgen Deprivation Therapy for Prostate Cancer and Risk of Alzheimer’s Disease and Neurodegeneration: Old Drugs, New Concerns
Authors: Achard Vérane , Ceyzériat Kelly , Tournier Benjamin B. , Frisoni Giovanni B. , Garibotto Valentina , Zilli Thomas
Published: December 2021

Androgen deprivation therapy (ADT) is a standard treatment for prostate cancer patients, routinely used in the palliative or in the curative setting in association with radiotherapy. Among the systemic long-term side effects of ADT, growing data suggest a potentially increased risk of dementia/Alzheimer’s disease in prostate cancer patients treated with hormonal manipulation. While pre-clinical data suggest that androgen ablation may have neurotoxic effects due to Aβ accumulation and increased tau phosphorylation in small animal brains, clinical studies have measured the impact of ADT on long-term cognitive function, with conflicting results, and studies on biological changes after ADT are still lacking. The aim of this review is to report on the current evidence on the association between the ADT use and the risk of cognitive impairment in prostate cancer patients. We will focus on the contribution of Alzheimer’s disease biomarkers, namely through imaging, to investigate potential ADT-induced brain modifications. The evidence from these preliminary studies shows brain changes in gray matter volume, cortical activation and metabolism associated with ADT, however with a large variability in biomarker selection, ADT duration and cognitive outcome. Importantly, no study investigated yet biomarkers of Alzheimer’s disease pathology, namely amyloid and tau. These preliminary data emphasize the need for larger targeted investigations.
An External-Validated Algorithm to Predict Postoperative Pneumonia Among Elderly Patients With Lung Cancer After Video-Assisted Thoracoscopic Surgery
Authors: Song Yanping , Liu Jingjing , Lei Mingxing , Wang Yanfeng , Fu Qiang , Wang Bailin , Guo Yongxin , Mi Weidong , Tong Li
Published: December 2021

The aim of the study was to develop an algorithm to predict postoperative pneumonia among elderly patients with lung cancer after video-assisted thoracoscopic surgery. We analyzed 3,009 patients from the Thoracic Perioperative Database for Geriatrics in our hospital and finally enrolled 1,585 elderly patients (age≧65 years) with lung cancer treated with video-assisted thoracoscopic surgery. The included patients were randomly divided into a training group (n = 793) and a validation group (n = 792). Patients in the training group were used to develop the algorithm after screening up to 30 potential risk factors, and patients in the validation group were used to internally validate the algorithm. External validation of the algorithm was achieved in the external validation dataset after enrolling 165 elderly patients with lung cancer treated with video-assisted thoracoscopic surgery from two hospitals in China. Of all included patients, 9.15% (145/1,585) of patients suffered from postoperative pneumonia in the Thoracic Perioperative Database for Geriatrics, and 10.30% (17/165) of patients had postoperative pneumonia in the external validation dataset. The algorithm consisted of seven variables, including sex, smoking, history of chronic obstructive pulmonary disease (COPD), surgery duration, leukocyte count, intraoperative injection of colloid, and intraoperative injection of hormone. The C-index from the receiver operating characteristic curve (AUROC) was 0.70 in the training group, 0.67 in the internal validation group, and 0.71 in the external validation dataset, and the corresponding calibration slopes were 0.88 (95% confident interval [CI]: 0.37–1.39), 0.90 (95% CI: 0.46–1.34), and 1.03 (95% CI: 0.24–1.83), respectively. The actual probabilities of postoperative pneumonia were 5.14% (53/1031) in the low-risk group, 15.07% (71/471) in the medium-risk group, and 25.30% (21/83) in the high-risk group (p < 0.001). The algorithm can be a useful prognostic tool to predict the risk of developing postoperative pneumonia among elderly patients with lung cancer after video-assisted thoracoscopic surgery.
Mitochondrial Ndufa4l2 Enhances Deposition of Lipids and Expression of Ca9 in the TRACK Model of Early Clear Cell Renal Cell Carcinoma
Authors: Laursen Kristian B. , Chen Qiuying , Khani Francesca , Attarwala Nabeel , Gross Steve S. , Dow Lukas , Nanus David M. , Gudas Lorraine J.
Published: December 2021

Mitochondrial dysfunction and aberrant glycolysis are hallmarks of human clear cell renal cell carcinoma (ccRCC). Whereas glycolysis is thoroughly studied, little is known about the mitochondrial contribution to the pathology of ccRCC. Mitochondrial Ndufa4l2 is predictive of poor survival of ccRCC patients, and in kidney cancer cell lines the protein supports proliferation and colony formation. Its role in ccRCC, however, remains enigmatic. We utilized our established ccRCC model, termed Transgenic Cancer of the Kidney (TRACK), to generate a novel genetically engineered mouse model in which dox-regulated expression of an shRNA decreases Ndufa4l2 levels specifically in the renal proximal tubules (PT). This targeted knockdown of Ndufa4l2 reduced the accumulation of neutral renal lipid and was associated with decreased levels of the ccRCC markers carbonic anhydrase 9 (CA9) and Enolase 1 (ENO1). These findings suggest a link between mitochondrial dysregulation (i.e. high levels of Ndufa4l2), lipid accumulation, and the expression of ccRCC markers ENO1 and CA9, and demonstrate that lipid accumulation and ccRCC development can potentially be attenuated by inhibiting Ndufa4l2.
Comprehensive Analysis to Identify MAGEA3 Expression Correlated With Immune Infiltrates and Lymph Node Metastasis in Gastric Cancer
Authors: Jin Jinji , Tu Jianxin , Ren Jiahuan , Cai Yiqi , Chen Wenjing , Zhang Lifang , Zhang Qiyu , Zhu Guanbao
Published: December 2021

Gastric cancer (GC) is an aggressive malignant tumor and causes a significant number of deaths every year. With the coming of the age of cancer immunotherapy, search for a new target in gastric cancer may benefit more advanced patients. Melanoma-associated antigen-A3 (MAGEA3), one of the members of the cancer-testis antigen (CTA) family, was considered an important part of cancer immunotherapy. We evaluate the potential role of MAGEA3 in GC through the TCGA database. The result revealed that MAGEA3 is upregulated in GC and linked to poor OS and lymph node metastasis. MAGEA3 was also correlated with immune checkpoints, TMB, and affected the tumor immune microenvironment and the prognosis of GC through CIBERSORT, TIMER, and Kaplan-Meier plotter database analysis. In addition, GSEA-identified MAGEA3 is involved in the immune regulation of GC. Moreover, the protein-protein interaction (PPI) networks of MAGEA3 were constructed through STRING database and MAGEA3-correlated miRNAs were screened based on the joint analysis of multiple databases. In terms of experimental verification, we constructed pET21a (+)/MAGEA3 restructuring plasmids and transformed to Escherichia coli Rosetta. MAGEA3 protein was used as an antigen after being expressed and purified and can effectively detect the specific IgG in 93 GC patients’ serum specimens with 44.08% sensitivity and 92.54% specificity. Through further analysis, the positive rate of MAGEA3 was related to the stage and transfer number of lymph nodes. These results indicated that MAGEA3 is a novel biomarker and correlated with lymph node metastasis and immune infiltrates in GC, which could be a new target for immunotherapy.