bluuebunny/crossref_metadata_2025 huggingface dataset:
Fatores relacionados a alta incidência da sífilis em gestantes no Brasil: uma revisão integrativa
Authors: Gonçalves Ana Luiza Sardinha , Oliveira Giovana da Silva , Melo Vitória Alves , Toledo Eduardo Henrique Oliveira , Soares Deyze Alencar
Published: March 2022

Objetivo: Analisar os fatores relacionados a alta incidência da sífilis gestacional e congênita, no Brasil. Metodologia: Foi realizada uma revisão integrativa de estudos publicados entre os anos de 2016 à 2021, através das bases de dados LILACS, MEDLINE, PubMed e SciELO. Resultados: Foram identificados como principais fatores relacionados à alta incidência da sífilis gestacional e congênita, falha nos métodos diagnósticos, subnotificação, não adesão de métodos preventivos e de controle, bem como a não associação do tratamento concomitante das gestantes e seus parceiros. Além disso, nota-se uma escassez da matéria prima de penicilina benzatina, fármaco de primeira linha para o tratamento, e deficiência na qualificação dos profissionais de saúde que atuam diante da infecção treponêmica em gestantes e recém-nascidos. Conclusão: A falha no tratamento e o aumento da incidência da sífilis gestacional e congênita está diretamente relacionado a falta de capacitação dos profissionais de saúde, ao não tratamento do parceiro e o início tardio do pré-natal.
Implications of the COVID-19 Pandemic on the Management of Inflammatory Bowel Disease in the Low Resource Countries of Asia
Authors: Pal Partha , Yan Mak Joyce Wing , Ng Siew C , Banerjee Rupa
Published: March 2022

The COVID-19 pandemic has overwhelmed the already limited healthcare systems of low resource Asian countries. It has had a profound impact on inflammatory bowel disease (IBD) patient care in this region, where the disease is emerging. Fear of increased risk of COVID-19 due to disease or drugs, lack of access to medications, laboratory testing, endoscopy, surgery, infusion centres, and even remote medical consultation have made the lives of patients with IBD in this region more difficult than before. Similarly, physicians faced challenges due to limited testing facilities and therapeutic armamentarium for IBD management in the face of the COVID-19 pandemic. There was also the fear of potential spread of COVID-19 during colonoscopy or physical consultation, with the shortage of protective equipment, and unfamiliarity with teleconsultation and the remote monitoring of IBD. Most of the healthcare systems in these countries faced similar challenges in disease containment and management due to overwhelmed healthcare facilities in the face of crisis, inadequate vaccination drive in highly populous regions, and the unequal distribution of healthcare facilities centred in urban areas. COVID-19-specific safety norms, proper psychological support, and IBD-focused COVID-19 information can help alleviate patient concerns. Widespread adaptation of telemedicine, being up to date with current evidence, and performing endoscopy in high-priority cases, with precautions, can help physicians treat patients with IBD optimally. Additionally, the restructuring of the public health system, widespread vaccine rollout, and, ultimately, containment of the pandemic, can improve healthcare outcomes of patients with IBD in low resource countries.
‘The People’s Dinosaur’: How Dippy became British Heritage
Authors: Billing Björn
Published: March 2022

In 2015 the Natural History Museum (NHM) in London informed the public that their most beloved exhibit, a Diplodocus replica nicknamed Dippy, was going to be dismounted and removed from the large entrance hall. Protests arose immediately: Facebook groups appeared, the hashtag #SaveDippy was trending and petitions were sent to the authorities. Paleontogists and celebrities debated the decision in the newspapers. When three years the NHM later launched a tour project that will take Dippy around the UK, the dinosaur’s popularity grew to unprecedented heights. Its significance shifted from being a London landmark to becoming a national icon. Although the original fossil was excavated in Wyoming in the late nineteenth century, Dippy has unofficially gained the status of British heritage. This article analyses this transformation by putting recent events into historical contexts, paying particular attention to the presentation of the dinosaur in the NHM in May 1905. The analysis shows how the skeleton cast was articulated with ideological intent in a confluence of museums, science, mass media, politics and popular culture. Throughout its history, Dippy has been appropriated and contested by various actors, and nationalistic ideas have been a recurrent theme in the heritageisation process.
Efektivitas Pengawetan Kayu Gmelina Menggunakan Akar Tuba Terhadap Serangan Rayap Tanah (The Effectiveness Of Preservation Of Gmelina Wood Using Tubal Roots Against Subterranean termites Attacks)
Authors: Hadjar Nurhayati , Pujirahayu Niken , Uslinawaty Zakiah , Hasrudin Hasrudin
Published: March 2022

Abstract: The purpose of this study was to determine the effectiveness of the use of two types of tuba root extract, namely milk sap tuba root and clear sap tuba root in Wood Preservation of Gmelina (G. arborea Roxb) against subterranean termites. The method of testing against subterranean termites is using the burial method for 12 weeks. Wood resistance is calculated from the percentage of weight loss and the degree of termite attack on wood according to SNI 01-7207-2006 concerning the classification of wood resistance to subterranean termite attacks. the results of the study, it was concluded that the use of preservatives for milk sap tuba root and clear sap tuba root with concentrations of 2% and 4% were not considered effective for preserving Gmelina wood from subterranean termites. Keywords: Gmelina wood, preservation, milk sap tuba root, clear sap tuba root, subterranean termites, loss of weight, degree of attack.Abstrak: Tujuan dari penelitian ini adalah untuk mengetahui efektifitas penggunaan dua jenis ekstrak akar tuba yaitu akar tuba getah susu  dan akar tuba getah bening  dalam pengawetan kayu Gmelina (G. arborea Roxb) terhadap Rayap Tanah. Metode pengujian rayap tanah menggunakan metode penguburan selama 12 minggu. Ketahanan kayu dihitung dari persentase kehilangan berat dan derajat serangan rayap pada kayu menurut SNI 01-7207-2006 tentang klasifikasi ketahanan kayu terhadap serangan rayap tanah. Berdasarkan hasil penelitian disimpulkan bahwa penggunaan bahan pengawet akar tuba getah susu dan akar tuba getah bening dengan konsentrasi konsentrasi 2% dan 4%, dinilai belum efektif untuk di jadikan bahan mengawetkan kayu Gmelina dari serangan Rayap Tanah. Kata kunci: Kayu Gmelina, pengawetan, akar tuba getah susu, akar tuba getah bening, rayap tanah, Kehilangan berat, derajat serangan.
NetRank Recovers Known Cancer Hallmark Genes as Universal Biomarker Signature for Cancer Outcome Prediction
Authors: Al-Fatlawi Ali , Afrin Nazia , Ozen Cigdem , Malekian Negin , Schroeder Michael
Published: March 2022

Gene expression can serve as a powerful predictor for disease progression and other phenotypes. Consequently, microarrays, which capture gene expression genome-wide, have been used widely over the past two decades to derive biomarker signatures for tasks such as cancer grading, prognosticating the formation of metastases, survival, and others. Each of these signatures was selected and optimized for a very specific phenotype, tissue type, and experimental set-up. While all of these differences may naturally contribute to very heterogeneous and different biomarker signatures, all cancers share characteristics regardless of particular cell types or tissue as summarized in the hallmarks of cancer. These commonalities could give rise to biomarker signatures, which perform well across different phenotypes, cell and tissue types. Here, we explore this possibility by employing a network-based approach for pan-cancer biomarker discovery. We implement a random surfer model, which integrates interaction, expression, and phenotypic information to rank genes by their suitability for outcome prediction. To evaluate our approach, we assembled 105 high-quality microarray datasets sampled from around 13,000 patients and covering 13 cancer types. We applied our approach (NetRank) to each dataset and aggregated individual signatures into one compact signature of 50 genes. This signature stands out for two reasons. First, in contrast to other signatures of the 105 datasets, it is performant across nearly all cancer types and phenotypes. Second, It is interpretable, as the majority of genes are linked to the hallmarks of cancer in general and proliferation specifically. Many of the identified genes are cancer drivers with a known mutation burden linked to cancer. Overall, our work demonstrates the power of network-based approaches to compose robust, compact, and universal biomarker signatures for cancer outcome prediction.
Parylene C-Based, Breathable Tattoo Electrodes for High-Quality Bio-Potential Measurements
Authors: Spanu Andrea , Mascia Antonello , Baldazzi Giulia , Fenech-Salerno Benji , Torrisi Felice , Viola Graziana , Bonfiglio Annalisa , Cosseddu Piero , Pani Danilo
Published: March 2022

A breathable tattoo electrode for bio-potential recording based on a Parylene C nanofilm is presented in this study. The proposed approach allows for the fabrication of micro-perforated epidermal submicrometer-thick electrodes that conjugate the unobtrusiveness of Parylene C nanofilms and the very important feature of breathability. The electrodes were fully validated for electrocardiography (ECG) measurements showing performance comparable to that of conventional disposable gelled Ag/AgCl electrodes, with no visible negative effect on the skin even many hours after their application. This result introduces interesting perspectives in the field of epidermal electronics, particularly in applications where critical on-body measurements are involved.
Biological Nanoparticles in Vaccine Development
Authors: Curley Stephanie M. , Putnam David
Published: March 2022

Vaccines represent one of the most successful public health initiatives worldwide. However, despite the vast number of highly effective vaccines, some infectious diseases still do not have vaccines available. New technologies are needed to fully realize the potential of vaccine development for both emerging infectious diseases and diseases for which there are currently no vaccines available. As can be seen by the success of the COVID-19 mRNA vaccines, nanoscale platforms are promising delivery vectors for effective and safe vaccines. Synthetic nanoscale platforms, including liposomes and inorganic nanoparticles and microparticles, have many advantages in the vaccine market, but often require multiple doses and addition of artificial adjuvants, such as aluminum hydroxide. Biologically derived nanoparticles, on the other hand, contain native pathogen-associated molecular patterns (PAMPs), which can reduce the need for artificial adjuvants. Biological nanoparticles can be engineered to have many additional useful properties, including biodegradability, biocompatibility, and are often able to self-assemble, thereby allowing simple scale-up from benchtop to large-scale manufacturing. This review summarizes the state of the art in biologically derived nanoparticles and their capabilities as novel vaccine platforms.
Mitophagy and Neurodegeneration: Between the Knowns and the Unknowns
Authors: Jetto Cuckoo Teresa , Nambiar Akshaya , Manjithaya Ravi
Published: March 2022

Macroautophagy (henceforth autophagy) an evolutionary conserved intracellular pathway, involves lysosomal degradation of damaged and superfluous cytosolic contents to maintain cellular homeostasis. While autophagy was initially perceived as a bulk degradation process, a surfeit of studies in the last 2 decades has revealed that it can also be selective in choosing intracellular constituents for degradation. In addition to the core autophagy machinery, these selective autophagy pathways comprise of distinct molecular players that are involved in the capture of specific cargoes. The diverse organelles that are degraded by selective autophagy pathways are endoplasmic reticulum (ERphagy), lysosomes (lysophagy), mitochondria (mitophagy), Golgi apparatus (Golgiphagy), peroxisomes (pexophagy) and nucleus (nucleophagy). Among these, the main focus of this review is on the selective autophagic pathway involved in mitochondrial turnover called mitophagy. The mitophagy pathway encompasses diverse mechanisms involving a complex interplay of a multitude of proteins that confers the selective recognition of damaged mitochondria and their targeting to degradationviaautophagy. Mitophagy is triggered by cues that signal the mitochondrial damage such as disturbances in mitochondrial fission-fusion dynamics, mitochondrial membrane depolarisation, enhanced ROS production, mtDNA damage as well as developmental cues such as erythrocyte maturation, removal of paternal mitochondria, cardiomyocyte maturation and somatic cell reprogramming. As research on the mechanistic aspects of this complex pathway is progressing, emerging roles of new players such as the NIPSNAP proteins, Miro proteins and ER-Mitochondria contact sites (ERMES) are being explored. Although diverse aspects of this pathway are being investigated in depth, several outstanding questions such as distinct molecular players of basal mitophagy, selective dominance of a particular mitophagy adapter protein over the other in a given physiological condition, molecular mechanism of how specific disease mutations affect this pathway remain to be addressed. In this review, we aim to give an overview with special emphasis on molecular and signalling pathways of mitophagy and its dysregulation in neurodegenerative disorders.
Nintedanib and Dasatinib Treatments Induce Protective Autophagy as a Potential Resistance Mechanism in MPM Cells
Authors: Hegedüs Luca , Szücs Kata D. , Kudla Matthias , Heidenreich Julian , Jendrossek Verena , Peña-Llopis Samuel , Garay Tamas , Czirok Andras , Aigner Clemens , Plönes Till , Vega-Rubin-de-Celis Silvia , Hegedüs Balazs
Published: March 2022

Malignant pleural mesothelioma (MPM) is a rare type of cancer with a grim prognosis. So far, no targetable oncogenic mutation was identified in MPM and biomarkers with predictive value toward drug sensitivity or resistance are also lacking. Nintedanib (BIBF1120) is a small-molecule tyrosine kinase inhibitor that showed promising efficacy preclinically and in phase II trial in MPM as an angiogenesis inhibitor combined with chemotherapy. However, the extended phase III trial failed. In this study, we investigated the effect of nintedanib on one of its targets, the SRC kinase, in two commercial and six novel MPM cell lines. Surprisingly, nintedanib treatment did not inhibit SRC activation in MPM cells and even increased phosphorylation of SRC in several cell lines. Combination treatment with the SRC inhibitor dasatinib could reverse this effect in all cell lines, however, the cellular response was dependent on the drug sensitivity of the cells. In 2 cell lines, with high sensitivity to both nintedanib and dasatinib, the drug combination had no synergistic effect but cell death was initiated. In 2 cell lines insensitive to nintedanib combination treatment reduced cell viability synergisticaly without cell death. In contrast, in these cells both treatments increased the autophagic flux assessed by degradation of the autophagy substrate p62 and increased presence of LC3B-II, increased number of GFP-LC3 puncta and decreased readings of the HiBiT-LC3 reporter. Additionaly, autophagy was synergistically promoted by the combined treatment. At the transcriptional level, analysis of lysosomal biogenesis regulator Transcription Factor EB (TFEB) showed that in all cell lines treated with nintedanib and to a lesser extent, with dasatinib, it became dephosphorylated and accumulated in the nucleus. Interestingly, the expression of certain known TFEB target genes implicated in autophagy or lysosomal biogenesis were significantly modified only in 1 cell line. Finally, we showed that autophagy induction in our MPM cell lines panel by nintedanib and dasatinib is independent of the AKT/mTOR and the ERK pathways. Our study reveals that autophagy can serve as a cytoprotective mechanism following nintedanib or dasatinib treatments in MPM cells.
Analysis of Half a Billion Datapoints Across Ten Machine-Learning Algorithms Identifies Key Elements Associated With Insulin Transcription in Human Pancreatic Islet Cells
Authors: Wong Wilson K. M. , Thorat Vinod , Joglekar Mugdha V. , Dong Charlotte X. , Lee Hugo , Chew Yi Vee , Bhave Adwait , Hawthorne Wayne J. , Engin Feyza , Pant Aniruddha , Dalgaard Louise T. , Bapat Sharda , Hardikar Anandwardhan A.
Published: March 2022

Machine learning (ML)-workflows enable unprejudiced/robust evaluation of complex datasets. Here, we analyzed over 490,000,000 data points to compare 10 different ML-workflows in a large (N=11,652) training dataset of human pancreatic single-cell (sc-)transcriptomes to identify genes associated with the presence or absence of insulin transcript(s). Prediction accuracy/sensitivity of each ML-workflow was tested in a separate validation dataset (N=2,913). Ensemble ML-workflows, in particular Random Forest ML-algorithm delivered high predictive power (AUC=0.83) and sensitivity (0.98), compared to other algorithms. The transcripts identified through these analyses also demonstrated significant correlation with insulin in bulk RNA-seq data from human islets. The top-10 features, (including IAPP, ADCYAP1, LDHA and SST) common to the three Ensemble ML-workflows were significantly dysregulated in scRNA-seq datasets from Ire-1αβ-/- mice that demonstrate dedifferentiation of pancreatic β-cells in a model of type 1 diabetes (T1D) and in pancreatic single cells from individuals with type 2 Diabetes (T2D). Our findings provide direct comparison of ML-workflows in big data analyses, identify key elements associated with insulin transcription and provide workflows for future analyses.
Assessment of Renal Risk Score and Histopathological Classification for Prediction of End-Stage Kidney Disease and Factors Associated With Change in eGFR After ANCA-Glomerulonephritis Diagnosis
Authors: Brilland Benoit , Boud’hors Charlotte , Copin Marie-Christine , Jourdain Pierre , Henry Nicolas , Wacrenier Samuel , Djema Assia , Samoreau Clément , Coindre Jean-Philippe , Cousin Maud , Riou Jeremie , Croue Anne , Saint-André Jean-Paul , Subra Jean-François , Piccoli Giorgina Barbara , Augusto Jean-François
Published: March 2022

Introduction

The “Renal Risk Score” (RRS) and the histopathological classification have been proposed to predict the risk of end-stage kidney disease (ESKD) in ANCA-associated glomerulonephritis (ANCA-GN). Besides, factors associated with kidney function recovery after ANCA-GN onset remain to be more extensively studied. In the present study, we analyzed the value of the RRS and of the histopathological classification for ESKD prediction. Next, we analyzed factors associated with eGFR change within the first 2 years following ANCA-GN diagnosis.

Materials and Methods

We included patients from the Maine–Anjou ANCA-associated vasculitis registry with at least 6 months of follow-up. The values of ANCA-GN, histopathological classification, and RRS, and the factors associated with eGFR variations between ANCA-GN diagnosis and 2 years of follow-up were assessed.

Results

The predictive values of the histopathological classification and RRS were analyzed in 123 patients. After a median follow-up of 42 months, 33.3% patients developed ESKD. The predictive value of RRS for ESKD was greater than that of the histopathological classification. Determinants of eGFR variation were assessed in 80/123 patients with complete eGFR measurement. The median eGFR increased from ANCA-GN diagnosis to month 6 and stabilized thereafter. The only factor associated with eGFR variation in our study was eGFR at ANCA-GN diagnosis, with higher eGFR at diagnosis being associated with eGFR loss (p<0.001).

Conclusion

The RRS has a better predictive value for ESKD than the histopathological classification. The main determinant of eGFR variation at 2 years was eGFR at ANCA-GN diagnosis. Thus, this study suggests that eGFR recovery is poorly predicted by histological damage at ANCA-GN diagnosis.
“The Stakes Are Higher”- Patient and Caregiver Perspectives on Cystic Fibrosis Research and Personalized Medicine
Authors: Knoppers Terese , Cosquer Marie , Hagan Julie , Nguyen Minh Thu , Knoppers Bartha Maria
Published: March 2022

Introduction

Making bench to bedside advances in cystic fibrosis (CF) care requires the sustained engagement and trust of people living with CF. However, there is a scarcity of studies exploring their concerns and priorities regarding research and its end products. The aim of this qualitative study was to generate empirical evidence regarding patient and caregiver perspectives on cystic fibrosis research and personalized medicine to foster developments in translational research in Canada.

Methods

A total of 15 focus groups were conducted, engaging 22 adults with CF and 18 caregivers (e.g., parents, siblings and partners) living in Canada. Inductive thematic analysis relied on an iterative process involving themes derived from both participant meaning-making and existing scientific literature. Participant perspectives were considered along intrapersonal, intracommunity, interpersonal, and structural lines.

Results

Overall, participants described a relationship to CF research inextricable from the lived experience of CF as a lifelong progressive and terminal disease and from the goal of advancing medical science. They were enthusiastic and excited about the emergence of CFTR modulators, although they had some knowledge gaps regarding the associated research. They largely spoke to positive experiences with researcher communication but had feedback regarding informed consent processes and the return of study results. Participants also voiced concerns about structural access barriers to research and to its end products. Extensive histories of research participation, a relatively small and intercommunicative CF community, and structural overlap between research and care settings contributed to their perspectives and priorities.

Conclusion

Study findings are valuable for researchers and policy-makers in CF and rare or progressive diseases more broadly. Continuing to solicit and listen to the voices of patients and caregivers is crucial for research ethics and the translation of new therapies in the area of personalized medicine.
Emulsion-Based Postbiotic Formulation Is Comparable to Viable Cells in Eliciting a Localized Immune Response in Dairy Cows With Chronic Mastitis
Authors: Mathur Harsh , Linehan Kevin , Flynn James , Byrne Noel , Dillon Pat , Conneely Muireann , Grimaud Ghjuvan , Hill Colin , Stanton Catherine , Ross R. Paul
Published: March 2022

Bovine mastitis is a disease with a multi-etiological nature, defined as an infection and inflammation of the udder. Mastitis represents a significant ongoing concern in the dairy industry, leading to substantial losses in profits and revenue for farmers worldwide. The predominant causes of bovine mastitis include the pathogens Staphylococcus aureus, Streptococcus dysgalactiae, Streptococcus uberis, and Escherichia coli. Antibiotic administration is currently the main treatment option for mastitis. However, there is a pressing need for alternative therapies to treat and prevent the disease, especially with the emergence of antibiotic-resistant, mastitis-causing pathogens, resulting in antibiotic treatment failure. One such example is live bio-therapeutics (also known as probiotics), such as Lactococcus lactis DPC3147. The efficacy of this live bio-therapeutic has been demonstrated in several previous trials by our group. The most recent of these trials showed that an emulsion-based formulation of this strain was as effective as a commercial antibiotic formulation in treating sub-clinical and clinical cases of bovine mastitis. Here, we report the results of a follow-up field trial, in which we sought to gain insight into the mechanism of action of such live bio-therapeutics, focussing on chronic mastitis cases. We treated 28 cows with chronic mastitis with two separate emulsion-based formulations containing either viable L. lactis DPC3147 cells (15 cows) or heat-killed L. lactis DPC3147 cells (13 cows). We then evaluated the efficacies of the two formulations (two treatment groups) in terms of stimulating a localized immune response (quantified by measuring IL-8 concentrations in milk collected from udders affected by mastitis) and efficacies in terms of cure rates (quantified by reductions in somatic cell counts and absence of pathogens). We demonstrate that the presence of heat-inactivated bacteria (a postbiotic) was as effective as the live bio-therapeutic in eliciting a localized immune response in cows with chronic mastitis. The response to heat-killed cells (postbiotic) reported herein could have beneficial implications for farmers with regard to prolonging the shelf life of such emulsion-based formulations containing heat-killed cells of L. lactis DPC3147 for curing cows with mastitis.
Tuftsin: A Natural Molecule Against SARS-CoV-2 Infection
Authors: Huang Jiahao , Wang Jing , Li Yan , Wang Ziyuan , Chu Ming , Wang Yuedan
Published: March 2022

Coronavirus disease 2019 (COVID-19) continuously progresses despite the application of a variety of vaccines. Therefore, it is still imperative to find effective ways for treating COVID-19. Recent studies indicate that NRP1, an important receptor of the natural peptide tuftsin (released from IgG), facilitates SARS-CoV-2 infection. Here, we found 91 overlapping genes between tuftsin targets and COVID-19-associated genes. We have demonstrated that tuftsin could also target ACE2 and exert some immune-related functions. Molecular docking results revealed that tustin could combine with ACE2 and NRP1 in stable structures, and their interacted regions cover the binding surfaces of S1-protein with the two receptors. Using surface plasmon resonance (SPR) analysis, we confirmed that tuftsin can bind ACE2 and NRP1 directly. Importantly, using SPR-based competition assay we have shown here that tuftsin effectively prevented the binding of SARS-CoV-2 S1-protein to ACE2. Collectively, these data suggest that tuftsin is an attractive therapeutic candidate against COVID-19 and can be considered for translational as well as clinical studies.
Glucocerebrosidase Mutations Cause Mitochondrial and Lysosomal Dysfunction in Parkinson’s Disease: Pathogenesis and Therapeutic Implications
Authors: Zheng Wei , Fan Dongsheng
Published: March 2022

Parkinson’s disease (PD) is the second most common neurodegenerative disease and is characterized by multiple motor and non-motor symptoms. Mutations in the glucocerebrosidase (GBA) gene, which encodes the lysosomal enzyme glucocerebrosidase (GCase), which hydrolyzes glucosylceramide (GlcCer) to glucose and ceramide, are the most important and common genetic PD risk factors discovered to date. Homozygous GBA mutations result in the most common lysosomal storage disorder, Gaucher’s disease (GD), which is classified according to the presence (neuronopathic types, type 2 and 3 GD) or absence (non-neuronopathic type, type 1 GD) of neurological symptoms. The clinical manifestations of PD in patients with GBA mutations are indistinguishable from those of sporadic PD at the individual level. However, accumulating data have indicated that GBA-associated PD patients exhibit a younger age of onset and a greater risk for cognitive impairment and psychiatric symptoms. The mechanisms underlying the increased risk of developing PD in GBA mutant carriers are currently unclear. Contributors to GBA-PD pathogenesis may include mitochondrial dysfunction, autophagy-lysosomal dysfunction, altered lipid homeostasis and enhanced α-synuclein aggregation. Therapeutic strategies for PD and GD targeting mutant GCase mainly include enzyme replacement, substrate reduction, gene and pharmacological small-molecule chaperones. Emerging clinical, genetic and pathogenic studies on GBA mutations and PD are making significant contributions to our understanding of PD-associated pathogenetic pathways, and further elucidating the interactions between GCase activity and neurodegeneration may improve therapeutic approaches for slowing PD progression.
A Portable Wearable Inertial System for Rehabilitation Monitoring and Evaluation of Patients With Total Knee Replacement
Authors: Lou Nan , Diao Yanan , Chen Qiangqiang , Ning Yunkun , Li Gaoqiang , Liang Shengyun , Li Guanglin , Zhao Guoru
Published: March 2022

Knee osteoarthritis is a degenerative disease, which greatly affects the daily life of patients. Total knee replacement (TKR) is the most common method to treat knee joint disorders and relieve knee pain. Postoperative rehabilitation exercise is the key to restore knee joint function. However, there is a lack of a portable equipment for monitoring knee joint activity and a systematic assessment scheme. We have developed a portable rehabilitation monitoring and evaluation system based on the wearable inertial unit to estimate the knee range of motion (ROM). Ten TKR patients and ten healthy adults are recruited for the experiment, then the system performance is verified by professional rehabilitation equipment Baltimore Therapeutic Equipment (BTE) Primus RS. The average absolute difference between the knee ROM and BTE Primus RS of healthy subjects and patients ranges from 0.16° to 4.94°. In addition, the knee ROM of flexion-extension and gait activity between healthy subjects and patients showed significant differences. The proposed system is reliable and effective in monitoring and evaluating the rehabilitation progress of patients. The system proposed in this work is expected to be used for long-term effective supervision of patients in clinical and dwelling environments.
Structural Connectivity of Human Inferior Colliculus Subdivisions Using in vivo and post mortem Diffusion MRI Tractography
Authors: Sitek Kevin R. , Calabrese Evan , Johnson G. Allan , Ghosh Satrajit S. , Chandrasekaran Bharath
Published: March 2022

Inferior colliculus (IC) is an obligatory station along the ascending auditory pathway that also has a high degree of top-down convergence via efferent pathways, making it a major computational hub. Animal models have attributed critical roles for the IC in in mediating auditory plasticity, egocentric selection, and noise exclusion. IC contains multiple functionally distinct subdivisions. These include a central nucleus that predominantly receives ascending inputs and external and dorsal nuclei that receive more heterogeneous inputs, including descending and multisensory connections. Subdivisions of human IC have been challenging to identify and quantify using standard brain imaging techniques such as MRI, and the connectivity of each of these subnuclei has not been identified in the human brain. In this study, we estimated the connectivity of human IC subdivisions with diffusion MRI (dMRI) tractography, using both anatomical-based seed analysis as well as unsupervised k-means clustering. We demonstrate sensitivity of tractography to overall IC connections in both high resolution post mortem and in vivo datasets. k-Means clustering of the IC streamlines in both the post mortem and in vivo datasets generally segregated streamlines based on their terminus beyond IC, such as brainstem, thalamus, or contralateral IC. Using fine-grained anatomical segmentations of the major IC subdivisions, the post mortem dataset exhibited unique connectivity patterns from each subdivision, including commissural connections through dorsal IC and lateral lemniscal connections to central and external IC. The subdivisions were less distinct in the context of in vivo connectivity, although lateral lemniscal connections were again highest to central and external IC. Overall, the unsupervised and anatomically driven methods provide converging evidence for distinct connectivity profiles for each of the IC subdivisions in both post mortem and in vivo datasets, suggesting that dMRI tractography with high quality data is sensitive to neural pathways involved in auditory processing as well as top-down control of incoming auditory information.
Analysis of Long-Term Cochlear Implantation Outcomes and Correlation With Imaging Characteristics in Patients With Common Cavity Deformity
Authors: Zhang Lifang , Chen Biao , Kong Ying , Liau Natalia , Wei Xingmei , Shi Ying , Chen Jingyuan , Yang Mengge , Dhanasingh Anandhan , Li Yongxin
Published: March 2022

Object

To investigate the long-term development of auditory and speech in patients with common cavity deformity (CCD) after cochlear implantation (CI) and its relationship to imaging characteristics.

Methods

Twenty-three CCD patients and 59 age- and sex-matched CI children with normal inner ear structure were recruited. The auditory and speech development of these two groups were evaluated at 0, 1, 3, 6, 12, and 18 months after CI activation using four parent reports questionnaires [Categories of Auditory Performance (CAP), Speech Intelligibility Rating (SIR), Meaningful Auditory Integration Scale/Infant-Toddler Meaningful Auditory Integration Scale (MAIS/ITMAIS), and Meaningful Use of Speech Scale (MUSS)]. Computed tomography-based 3-dimensional reconstruction of the surgical side of 18 CCD children was performed, the volume and surface area were calculated. Correlation analysis was performed on the imaging performance and post-operative outcomes.

Results

The percentages of MAIS/IT-MAIS scores and CAP scores at different evaluation time points are significantly different (p < 0.05). When comparing SIR results across time points, significant growth was observed in most of the comparisons. In addition, significant differences (p < 0.05) are observed among the percentages of MUSS scores at different time points except the comparison between 0 and 1 month after CI activation. Patients in the CCD group had poorer auditory and speech performances at different stages after CI compared with those in the control group. According to the reconstruction of CCD patients, the volume ranged from 12.21 to 291.96 mm3; the surface area ranged from 27.81 to 284.7 mm2. When the lumen surface area was <190.45 mm2 or the volume was <157.91 mm3, the survival time for CCD children to achieve a CAP score of 4 after CI was significantly shorter.

Conclusion

Cochlear implantation are less effective in CCD patients than in patients with normal inner ear structures, but they can still achieve significant improvement post-operatively. The morphology and size of the inner ear vary in CCD patients, which reflects the degree of inner ear development influences the outcome after CI surgery.
Blood-Based miRNA Biomarkers as Correlates of Brain-Based miRNA Expression
Authors: Kos Mark Z. , Puppala Sobha , Cruz Dianne , Neary Jennifer L. , Kumar Ashish , Dalan Emma , Li Cun , Nathanielsz Peter , Carless Melanie A.
Published: March 2022

The use of easily accessible peripheral samples, such as blood or saliva, to investigate neurological and neuropsychiatric disorders is well-established in genetic and epigenetic research, but the pathological implications of such biomarkers are not easily discerned. To better understand the relationship between peripheral blood- and brain-based epigenetic activity, we conducted a pilot study on captive baboons (Papio hamadryas) to investigate correlations between miRNA expression in peripheral blood mononuclear cells (PBMCs) and 14 different cortical and subcortical brain regions, represented by two study groups comprised of 4 and 6 animals. Using next-generation sequencing, we identified 362 miRNAs expressed at ≥ 10 read counts in 80% or more of the brain samples analyzed. Nominally significant pairwise correlations (one-sided P < 0.05) between peripheral blood and mean brain expression levels of individual miRNAs were observed for 39 and 44 miRNAs in each group. When miRNA expression levels were averaged for tissue type across animals within the groups, Spearman’s rank correlations between PBMCs and the brain regions are all highly significant (rs = 0.47–0.57; P < 2.2 × 10–16), although pairwise correlations among the brain regions are markedly stronger (rs = 0.86–0.99). Principal component analysis revealed differentiation in miRNA expression between peripheral blood and the brain regions for the first component (accounting for ∼75% of variance). Linear mixed effects modeling attributed most of the variance in expression to differences between miRNAs (>70%), with non-significant 7.5% and 13.1% assigned to differences between blood and brain-based samples in the two study groups. Hierarchical UPGMA clustering revealed a major co-expression branch in both study groups, comprised of miRNAs globally upregulated in blood relative to the brain samples, exhibiting an enrichment of miRNAs expressed in immune cells (CD14+, CD15+, CD19+, CD3+, and CD56 + leukocytes) among the top blood-brain correlates, with the gene MYC, encoding a master transcription factor that regulates angiogenesis and neural stem cell activation, representing the most prevalent miRNA target. Although some differentiation was observed between tissue types, these preliminary findings reveal wider correlated patterns between blood- and brain-expressed miRNAs, suggesting the potential utility of blood-based miRNA profiling for investigating by proxy certain miRNA activity in the brain, with implications for neuroinflammatory and c-Myc-mediated processes.
Early Adversity and Accelerated Brain Aging: A Mini-Review
Authors: Chaudhari Pratik R. , Singla Aastha , Vaidya Vidita A.
Published: March 2022

Early adversity is an important risk factor that influences brain aging. Diverse animal models of early adversity, including gestational stress and postnatal paradigms disrupting dam-pup interactions evoke not only persistent neuroendocrine dysfunction and anxio-depressive behaviors, but also perturb the trajectory of healthy brain aging. The process of brain aging is thought to involve hallmark features such as mitochondrial dysfunction and oxidative stress, evoking impairments in neuronal bioenergetics. Furthermore, brain aging is associated with disrupted proteostasis, progressively defective epigenetic and DNA repair mechanisms, the build-up of neuroinflammatory states, thus cumulatively driving cellular senescence, neuronal and cognitive decline. Early adversity is hypothesized to evoke an “allostatic load” via an influence on several of the key physiological processes that define the trajectory of healthy brain aging. In this review we discuss the evidence that animal models of early adversity impinge on fundamental mechanisms of brain aging, setting up a substratum that can accelerate and compromise the time-line and nature of brain aging, and increase risk for aging-associated neuropathologies.
Glycine Receptor Subtypes and Their Roles in Nociception and Chronic Pain
Authors: San Martín Victoria P. , Sazo Anggelo , Utreras Elías , Moraga-Cid Gustavo , Yévenes Gonzalo E.
Published: March 2022

Disruption of the inhibitory control provided by the glycinergic system is one of the major mechanisms underlying chronic pain. In line with this concept, recent studies have provided robust proof that pharmacological intervention of glycine receptors (GlyRs) restores the inhibitory function and exerts anti-nociceptive effects on preclinical models of chronic pain. A targeted regulation of the glycinergic system requires the identification of the GlyR subtypes involved in chronic pain states. Nevertheless, the roles of individual GlyR subunits in nociception and in chronic pain are yet not well defined. This review aims to provide a systematic outline on the contribution of GlyR subtypes in chronic pain mechanisms, with a particular focus on molecular pathways of spinal glycinergic dis-inhibition mediated by post-translational modifications at the receptor level. The current experimental evidence has shown that phosphorylation of synaptic α1β and α3β GlyRs are involved in processes of spinal glycinergic dis-inhibition triggered by chronic inflammatory pain. On the other hand, the participation of α2-containing GlyRs and of β subunits in pain signaling have been less studied and remain undefined. Although many questions in the field are still unresolved, future progress in GlyR research may soon open new exciting avenues into understanding and controlling chronic pain.
Long-Range GABAergic Projections of Cortical Origin in Brain Function
Authors: Urrutia-Piñones Jocelyn , Morales-Moraga Camila , Sanguinetti-González Nicole , Escobar Angelica P. , Chiu Chiayu Q.
Published: March 2022

The study of long-range GABAergic projections has traditionally been focused on those with subcortical origin. In the last few years, cortical GABAergic neurons have been shown to not only mediate local inhibition, but also extend long-range axons to remote cortical and subcortical areas. In this review, we delineate the different types of long-range GABAergic neurons (LRGNs) that have been reported to arise from the hippocampus and neocortex, paying attention to the anatomical and functional circuits they form to understand their role in behavior. Although cortical LRGNs are similar to their interneuron and subcortical counterparts, they comprise distinct populations that show specific patterns of cortico-cortical and cortico-fugal connectivity. Functionally, cortical LRGNs likely induce timed disinhibition in target regions to synchronize network activity. Thus, LRGNs are emerging as a new element of cortical output, acting in concert with long-range excitatory projections to shape brain function in health and disease.
Preoperative Prediction of Central Cervical Lymph Node Metastasis in Fine-Needle Aspiration Reporting Suspicious Papillary Thyroid Cancer or Papillary Thyroid Cancer Without Lateral Neck Metastasis
Authors: Zhang Kai , Qian Lang , Chen Jieying , Zhu Qian , Chang Cai
Published: March 2022

Purpose

No non-invasive method can accurately determine the presence of central cervical lymph node (CCLN) metastasis in papillary thyroid cancer (PTC) until now. This study aimed to investigate factors significantly associated with CCLN metastasis and then develop a model to preoperatively predict CCLN metastasis in fine-needle aspiration (FNA) reporting suspicious papillary thyroid cancer (PTC) or PTC without lateral neck metastasis.

Patients and Methods

Consecutive inpatients who were diagnosed as suspicious PTC or PTC in FNA and underwent partial or total thyroidectomy and CCLN dissection between May 1st, 2016 and June 30th, 2018 were included. The total eligible patients were randomly divided into a training set and an internal validation set with the ratio of 7:3. Univariate analysis and multivariate analysis were conducted in the training set to investigate factors associated with CCLN metastasis. The predicting model was built with factors significantly correlated with CCLN metastasis and validated in the validation set.

Results

A total of 770 patients were eligible in this study. Among them, 268 patients had histologically confirmed CCLN metastasis, while the remaining patients did not. Factors including age, BRAF mutation, multifocality, size, and capsule involvement were found to be significantly correlated with the CCLN metastasis in univariate and multivariate analysis. A model used to predict the presence CCLN metastasis based on these factors and US CCLN status yielded AUC, sensitivity, specificity and accuracy of 0.933 (95%CI: 0.905-0.960, p < 0.001), 0.816, 0.966 and 0.914 in the training set and 0.967 (95%CI: 0.943-0.991, p < 0.001), 0.897, 0.959 and 0.936 in the internal validation set.

Conclusion

Age, BRAF mutation, multifocality, size, and capsule involvement were independent predictors of CCLN metastasis in FNA reporting suspicious PTC or PTC without lateral neck metastasis. A simple model was successfully built and showed excellent discrimination to distinguish patients with or without CCLN metastasis.
ERBB2 Mutations as Potential Predictors for Recurrence in Colorectal Serrated Polyps by Targeted Next-Generation Sequencing
Authors: Wang Qi-Wen , Wang Xin-Yuan , Zhang Qing-Wei , Chen Jin-Nan , Zhou Yu-Jie , Tang Zhao-Rong , Wang Rui-Lan , Chen Haoyan , Chen Huimin , Li Xiao-Bo
Published: March 2022

Background

Follow-up guidelines for serrated polyps (SPs) are mainly based on factors such as histology and size with limited evidence. The underlying genomic mechanism of SPs in relation to recurrence risks is utterly unknown.

Methods

We applied targeted next-generation sequencing (NGS) approach on two groups of SPs [polyp-relapsed SPs (PRSPs) vs. polyp-free SPs (PFSPs)] based on the surveillance outcomes to compare differences of DNA variants in 71 colorectal cancer-associated genes. A multicenter validation cohort was established longitudinally from 2016 to 2019 to confirm the relevant results.

Results

Among the 96 NGS samples, at least one mutant after filtration was detected in 90 samples (94%). Molecular profiling presented BRAF, KRAS, and APC as top 3 mutated genes. FBXW7, MSH2, and ERBB2 might be recurrence-relevant, while DMD, BRCA1, and BRCA2 might be negatively correlated with recurrence. Notably, ERBB2 mutants (R678Q and V842I) (n = 5) had higher risks of polyp recurrence than the wild types (n = 85), with a median polyp-free interval of 15 months compared to 26 months [P < 0.001; hazard ratio (HR) = 4.9; 95% confidence interval (CI) = 1.9–12.8]. Furthermore, a multicenter cohort composed by 321 SPs verified that ERBB2-mutated SPs had increased risks of polyp recurrence (P < 0.001; HR = 3.7; 95% CI = 2.3–6.0) and advanced neoplastic lesion (ANL) recurrence (P < 0.001; HR = 10.0; 95% CI = 2.7–36.9) compared with wild-type SPs, respectively.

Conclusions

Our results are emphasizing that SP individuals with ERBB2 mutants are at higher risks of subsequent colorectal neoplasms. ERBB2 mutants might work as facilitated markers for prediction of high-risk SPs and might implicate a potential mechanism in the serrated pathway to colorectal carcinoma (CRC).