bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of Genes Related to 5-Fluorouracil Based Chemotherapy for Colorectal Cancer
Authors: Huang Xingxing , Ke Kun , Jin Weiwei , Zhu Qianru , Zhu Qicong , Mei Ruyi , Zhang Ruonan , Yu Shuxian , Shou Lan , Sun Xueni , Feng Jiao , Duan Ting , Mou Yiping , Xie Tian , Wu Qibiao , Sui Xinbing
Published: June 2022

Background

Colorectal cancer (CRC) is one of the most common malignancies and its incidence and mortality are increasing yearly. 5-Fluorouracil (5-FU) has long been used as a standard first-line treatment for CRC patients. Although 5-FU-based chemotherapy is effective for advanced CRC, the consequent resistance remains a key problem and causes the poor prognosis of CRC patients. Thus, there is an urgent need to identify new biomarkers to predict the response to 5-FU-based chemotherapy.

Methods

CRC samples were retrieved from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA). The immune-related genes were retrieved from the ImmPort database. Single-cell sequencing results from colorectal cancer were obtained by the ArrayExpress database. 5-FU resistance-related genes were filtered and validated by R packages. ESTIMATE algorithms were used to assess the tumor microenvironment (TME). KEGG and GO analysis were performed to explore the biological signaling pathway for resistant-response patients and sensitive-response patients in the tumor microenvironment. pRRophetic algorithms were used to predict 5-FU sensitivity. GSEA and GSVA analysis was performed to excavate the biological signaling pathway of the RBP7 gene.

Results

Nine immune-related genes were identified to be associated with 5-FU resistance and poor disease-free survival (DFS) of CRC patients and the signature of these genes was developed in a DFS-prognostic model. Four immune-related genes were determined to be associated with 5-FU resistance and overall survival (OS) of CRC patients. The signature of these genes was developed an OS-prognostic model. ESTIMATE scores showed a significant difference between 5-FU resistant and 5-FU sensitive CRC patients. Resistant-response patients and sensitive-response patients to 5-FU based chemotherapy showed different GO and KEGG enrichment on the tumor microenvironment. RBP7, as a tumor immune microenvironment (TIME) related gene, was found to have the potential of predicting chemotherapy resistance and poor prognosis of CRC patients. GSEA analysis showed multiple signaling differences between the high and low expression of RBP7 in CRC patients. Hypoxia and TNFα signaling via NFκB gene sets were significantly different between chemotherapy resistant (RBP7High) and chemotherapy sensitive (RBP7Low) patients. Single-cell RNA-seq suggested RBP7 was centrally distributed in endothelial stalk cells, endothelial tip cells, and myeloid cells.

Conclusions

Immune-related genes will hopefully be potential prognostic biomarkers to predict chemotherapy resistance for CRC. RBP7 may function as a tumor microenvironment regulator to induce 5-FU resistance, thereby affecting the prognosis of CRC patients.
Analysis of Hepatic Lipid Metabolism and Immune Function During the Development of Collagen-Induced Arthritis
Authors: Shi Yingjie , Shu Jun , Ning Zhangchi , Fan Dancai , Shu Haiyang , Zhao Hanxiao , Li Li , Zhao Ning , Lu Cheng , Lu Aiping , He Xiaojuan
Published: June 2022

The liver is essential for metabolic and immune functions and has been linked to systemic inflammatory diseases. However, the role of the liver is still elusive during the development of rheumatoid arthritis (RA), although there have been indeed some reports. We used label-free quantitative proteomics and experimental verification in this study to reveal the hepatic lipid metabolism and immune function during collagen-induced arthritis (CIA) development. The proteomics results revealed that the role of the liver differs in different phases of CIA rats. In terms of specific performance, hepatic lipid metabolism, which is primarily concerned with cholesterol, triacylglycerol, and phospholipid, was significantly influenced in the CIA induction phase, whereas the immune function, which includes binding of granulocytes, adhesion of immune cells, etc., was affected considerably at the peak phase of CIA rats compared to normal rats. Finally, the hepatic dynamic changes in CIA rats were further confirmed using targeted metabolomics and ELISA. We found that most fatty acids of the liver in the CIA induction phase were significantly decreased, and proteins related to complement activation and migration or adhesion of immune cells including C3, MMP-8, CTSZ, and S100A9 were significantly increased in the liver of CIA rats in the peak phase. Our findings indicated that the lipid metabolism and immune function of the liver were influenced in CIA rats. Thus, the conditions of the liver during RA development should be considered in therapeutic and nutritional interventions.
The Potential of Purinergic Signaling to Thwart Viruses Including SARS-CoV-2
Authors: Ferrari Davide , Rubini Michele , Burns Jorge S.
Published: June 2022

A long-shared evolutionary history is congruent with the multiple roles played by purinergic signaling in viral infection, replication and host responses that can assist or hinder viral functions. An overview of the involvement of purinergic signaling among a range of viruses is compared and contrasted with what is currently understood for SARS-CoV-2. In particular, we focus on the inflammatory and antiviral responses of infected cells mediated by purinergic receptor activation. Although there is considerable variation in a patient’s response to SARS-CoV-2 infection, a principle immediate concern in Coronavirus disease (COVID-19) is the possibility of an aberrant inflammatory activation causing diffuse lung oedema and respiratory failure. We discuss the most promising potential interventions modulating purinergic signaling that may attenuate the more serious repercussions of SARS-CoV-2 infection and aspects of their implementation.
Lighting a Fire: Gasdermin-Mediated Pyroptosis Remodels the Glioma Microenvironment and Promotes Immune Checkpoint Blockade Response
Authors: Cai Yonghua , Li Ke , Lin Jie , Liang Xianqiu , Xu Wei , Zhan Zhengming , Xue Shuaishuai , Zeng Yu , Chai Peng , Mao Yangqi , Song Zibin , Han Lei , Song Ye , Zhang Xian , Wang Hai
Published: June 2022

Pyroptosis is a proinflammatory programmed cell death pathway mediated by gasdermins. Exploring the role of pyroptosis can provide new insights into tumor malignancy. The most recent studies on pyroptosis have focused on tumor cells. However, the effects of pyroptosis on the tumor microenvironment (TME), immunotherapeutic responses, and efficacy have been neglected, especially in case of glioma. In this study, four independent glioma cohorts comprising 1,339 samples and a pan-cancer cohort comprising 10,535 tumor samples were analyzed. The relationships among pyroptosis status, prognosis, microenvironment cellular components, and clinical and biological phenotypes were investigated through the identification of pyroptosis subtypes, construction of a gasdermin-related prognostic index (GPI), and evaluation of immunological characteristics in glioma. The Genomics of Drug Sensitivity in Cancer database and “pRRophetic” package in R were used to estimate temozolomide (TMZ) sensitivity. The “Submap” package and external immunotherapy cohorts were used to investigate and confirm the role of GPI in response to and efficacy of immunotherapy in glioma. Finally, potential small-molecule compounds related to GPI were identified using the connectivity map database and mode-of-action analysis. We identified three different pyroptosis subtypes: cluster 1 (C1) characterized by a higher GPI, while cluster 2 (C2) and cluster 3 (C3) characterized by a lower GPI. The high GPI of C1 was associated with glioma progression and worse prognoses, whereas the low GPI of subtype C2 and C3 was associated with better prognoses. However, patients with high GPIs were found to be more sensitive to TMZ and immune checkpoint blockade than those with low GPIs. Furthermore, gasdermin D may be a principal potential biomarker and play key roles in pyroptosis-inducible therapy combined with immunotherapy in glioma. This study provides a clinical, biological, and molecular landscape of pyroptosis and suggests that pyroptosis of glioma cells may perform the dual function of promoting both tumorigenesis and antitumor immunity.
Trophic-Mediated Pelagic Habitat Structuring and Partitioning by Sympatric Elasmobranchs
Authors: Afonso André S. , Macena Bruno C. L. , Mourato Bruno , Bezerra Natalia P. A. , Mendonça Sibele , de Queiroz Joyce D. G. R. , Hazin Fábio H. V.
Published: June 2022

Pelagic elasmobranchs are key elements of oceanic ecosystems and must be preserved if marine trophic networks are to be kept in balance. Yet, they face intense fishing pressure that has been threatening their populations worldwide. Ensuring proper conservation management of these taxa depends on a better understanding of the strategies they use to explore the pelagic realm and their contributions to trophic web structuring across the ocean column. This study aimed at examining relationships between vertical habitat use and trophic attributes among six sympatric pelagic elasmobranchs using satellite transmitting tags in the western equatorial South Atlantic Ocean. The vertical movements of 35 elasmobranch individuals were tracked during an overall total of 1911 days. Clear relationships between species’ feeding habits, maximum diving depths, and proportion of time spent either in epipelagic or in surface waters were evidenced by Bayesian generalized linear mixed models and multivariate analysis. Filter-feeders made most use of deep waters from the mesopelagic and bathypelagic and shifted their diving depths in phase with diel vertical migrations of the deep scattering layer, i.e., shallower during the night and deeper during the day. Specialists exhibited distinct diving patterns in epipelagic and mesopelagic waters across the diel period which are potentially indicative of habitat partitioning, whereas generalists were more surface-oriented but also explored deeper waters compared to specialists. The trophic level also seemed to influence elasmobranch maximum diving depths, which tended to become shallower as species’ trophic level increased. These results corroborate previous evidence of widespread vertical habitat partitioning among sympatric pelagic predators and depict a trophic-mediated structuring of the pelagic environment where top-down control may be exerted at different depths by distinct species. Further research is yet required to understand the role of elasmobranch vertical movements in structuring pelagic habitats as well as to guide ecosystem-based fisheries management aimed at reducing species susceptibility to fishing gear and at preserving the structure and functionality of marine trophic networks.
Sea Ice Microbiota in the Antarctic Peninsula Modulates Cloud-Relevant Sea Spray Aerosol Production
Authors: Dall’Osto Manuel , Vaqué Dolors , Sotomayor-Garcia Ana , Cabrera-Brufau Miguel , Estrada Marta , Buchaca Teresa , Soler Montserrat , Nunes Sdena , Zeppenfeld Sebastian , van Pinxteren Manuela , Herrmann Hartmut , Wex Heike , Rinaldi Matteo , Paglione Marco , Beddows David C. S. , Harrison Roy M. , Berdalet Elisa
Published: June 2022

Sea spray aerosol (SSA) formation plays a major role in the climate system. The Antarctic Peninsula (AP) is affected by the greatest warming occurring in the Southern Ocean; changes in cryospheric and biological processes are being observed. Whilst there is some evidence that organic material produced by ice algae and/or phytoplankton in the high Arctic contributes to SSA, less is known about Antarctic Sea ice (sympagic) regions. To gain insight into the influence of Antarctic Sea ice biology and biogeochemistry on atmospheric aerosol, we report simultaneous water-air measurements made by means of in situ aerosol chamber experiments. For the first time, we present a methodology showing that the controlled plunging jet aerosol chamber settings do not cause major cell disruption on the studied sea ice ecosystems. Larger sea ice phytoplankton cells (>20 µm; mainly diatoms) tend to sediment at the bottom of the chamber (during the 24h experiment) and likely have a minor role on SSA production. When comparing four chamber experiments - we find that the two producing more SSA are the ones with highest abundance of nanophytoplankton cells (<20 µm; mainly nanoflagellates) as well as viruses. Our marine biogeochemical data show two broad groups of dissolved organic carbon: one rich in carbohydrates and proteic material and one rich in humic-like substances; the latter enhancing SSA production. This work provides unique insights into sea ice productivity that modulates SSA production, with potentially significant climate impacts. Further studies of these types are advised in order to see how microbiology impacts the biogeochemical cycling of elements and how aerosols are formed and processed in cold regions.
The Irrawaddy River Jet in the Andaman Sea During the Summer Monsoon
Authors: Pargaonkar Shrikant M. , Vinayachandran P. N.
Published: June 2022

The Irrawaddy (IR) is the largest river discharging into the Andaman Sea and plays an important role in the salinity distribution and the mixed layer physics of the Andaman Sea. This study presents the first report of the IR plume pathways in the Andaman Sea during the summer monsoon and the mechanisms behind them. An ocean circulation model is employed to conduct idealized experiments in which the freshwater forcing, due to rivers other than IR as well as precipitation, are ignored. Our simulations reveal that, during the summer monsoon, the discharge from Irrawaddy spreads as a freshwater jet oriented towards southeast and accumulates over the shelf at the eastern coast of the Andaman Sea. Climatology of Chlorophyll-a concentration measured by satellite and surface currents from global ocean model reanalysis indicates the presence of the Irrawaddy freshwater jet during the summer monsoon. The evolution of surface salinity and currents along the jet suggests that the IR freshwater traps momentum imparted by winds. The momentum balance in the Irrawaddy jet is between Coriolis and wind friction term, indicating that the freshwater jet is completely driven by winds during the summer monsoon. Surface distribution of wind friction term also shows that the northwest-southeast orientation of the Irrawaddy jet is due to the southwesterly orientation of the summer monsoon winds. Further experiments with three different wind forcing scenarios (no winds, winds over the equator only, and winds over the Bay of Bengal only) reveal that the flow of Irrawaddy jet during the summer monsoon is completely controlled by the local winds.
Trophic Niche Partitioning of Five Sciaenidae Species Sampled in Zhoushan Archipelago Waters via Stable Isotope Analysis
Authors: Wang Jing , Jiang Ri-Jin , Xiao Yi , Yin Rui , Chen Feng , Zhou Yong-dong , Xu Han-Xiang
Published: June 2022

Sciaenid fishes are usually associated with large freshwater inputs and are the most important economic fish on the coastal shelf off mainland China. To compare the differences in ecological niche and resource sharing among different populations of Sciaenidae species, we collected samples of Larimichthys polyactis, Collichthys lucidus, Johnius belangerii, Nibea albiflora, and Miichthys miiuy from Zhoushan Archipelago waters from 2019 to 2021 and investigated the carbon and nitrogen isotopic values in muscle tissues, the contribution of each food resource, and trophic niche widths and overlaps. Significant differences were observed in both isotopes in the muscles of the five Sciaenid species. Zooplankton was a key food resource for all Sciaenid species. In addition to zooplankton, J. belangerii, N. albiflora, and M. miiuy also fed on benthos organisms. C. lucidus presented a wide trophic niche width and had extensive habitat use. The trophic niche occupied by N. albiflora and M. miiuy was narrow; they presented a high trophic level, with a high degree of trophic niche overlap. This study showed that sciaenid fishes have overlapping trophic niches due to their common feeding on zooplankton, and differences in body size, migration, habitat, and feeding choices led to the reasonable sharing of resources among the five sciaenid fishes, allowing the coexistence of these species.
Investigation of Storm Tides Induced by Super Typhoon in Macro-Tidal Hangzhou Bay
Authors: Li Li , Li Zixuan , He Zhiguo , Yu Zhuzhu , Ren Yihan
Published: June 2022

Typhoon-induced storm tides can cause serious coastal disasters and considerable economic losses. Understanding the mechanisms controlling storm surges helps the prevention of coastal disasters. Hangzhou Bay (HZB), a typical macro-tidal estuary, is located on the east coast of China, where typhoons frequently occur. The funnel-shaped topography makes this macro-tidal bay even more sensitive to storm tides. Super Typhoon Chan-hom was used as an example to study the characteristics and dynamic mechanisms of storm surges using a well-validated numerical model. The model considers the two-way coupling of waves and tides. The wind strength for the model was reconstructed using multi-source wind data and was refined by considering different rotating and moving wind fields. The Holland–Miyazaki model was used to reconstruct the local wind-field data with a good performance. The model results show that the total water level of HZB during typhoon Chan-hom was mainly dominated by tides, and the storm surge was closely related to the wind field. Surface flow was mostly influenced by winds, followed by tides. The spatial and temporal distributions of the significant wave height were controlled by the wind and local terrain. Wind stress was the largest contributor to storm surges (91%), followed by the pressure effect (15%) and the wave effect (5%). Both wind and wave-induced surges occurred during low slack waters. The tide-surge interaction changes (enhance or suppress) the surge by approximately 0.5 m during the typhoon, comprising approximately 50% of the total surge. Tides interacted with surges through various mechanisms, from the bay mouth (local acceleration and friction) to the bay head (friction and advection). The Coriolis force had a relatively minor effect. The findings of this study provide useful information for studies on sediment dynamics and coastal structures under extreme weather conditions.
H3K4me3 CUT&Tag and Transcriptome Analysis Reveal the Epigenetic Regulatory Landscape in Gill Tissue of Large Yellow Croaker (Larimichthys crocea) Under Low Salinity Stress
Authors: Yang Jian , Liu Minhai , Shen Weiliang , Zhou Tingting , Wu Xiongfei , Li Qi , Lin Zhihua
Published: June 2022

H3K4me3 is an important histone modification that could influence DNA replication and RNA translation in response to abiotic stress. Here, RNA-seq analyses were conducted in gill tissues of large yellow croaker to identify the function of H3K4me3 under low salinity stress. Additionally, CUT&Tag analyses were performed to identify the genome-wide dynamic changes in H3K4me3 and explore the mechanisms by which H3K4me3 regulates gene expression. A total of 201 differentially expressed genes (DEGs) were identified between the 5‰ low salinity group (S-group) and 25‰ normal salinity group (C-group), among which 23 DEGs (11 up-regulated H3K4me3 targets and 12 down-regulated targets) were directly regulated by H3K4me3. Our findings thus describe the epigenetic regulatory landscape of H3K4me3 in gill of large yellow croaker during low salinity stress, and provide novel insights into the regulation mechanisms of H3K4me3 mediating the responses of aquatic animals to abiotic stress.
Surface Mo or Ni-Enrichment Applied to Granulated Self-Lubricating Composites: Microstructural and Tribological Evaluation
Authors: Damin Keli Vanessa Salvador , Tasior Gabriel da Rosa , Hammes Gisele , Klein Aloisio Nelmo , de Mello José Daniel Biasoli , Bendo Tatiana , Binder Cristiano
Published: June 2022

Sintered self-lubricating components may present inappropriate mechanical properties despite their excellent tribological properties. In general, alloying elements are used to improve these properties, but with a cost increase. As an alternative, surface enrichment (or surface alloying) with alloying elements may be applied. This study developed and characterized sintered composite materials surface-enriched with nickel or molybdenum. The results showed that the surface enrichment process is useful for increasing the tribomechanical properties. The Mo-enriched samples presented superior tribological results. Compared with the reference samples (not enriched), the Mo-enriched specimens showed an increase of 4,954% in scuffing resistance, lower friction coefficient (0.09), and reduced wear rate (68% and 96% lower for the specimen and the counter body). These results were mainly attributed to microstructural modification.
Type-1 Grade 2 Multi-Focal Gastric Neuroendocrine Tumors Secondary to Chronic Autoimmune Gastritis
Authors: Yu Ziqi , Wang Aiyao , Hu Chong , Yu Tao , Chen Jianyong
Published: June 2022

Background

Chronic autoimmune gastritis (CAG) refers to chronic atrophic gastritis due to autoimmunity. Loss of gastric glands in CAG results in hypergastrinemia and achlorhydria leading to Vitamin B12 deficiency and hyperplasia of G cells and enterochromaffin-like (ECL) cells. Vitamin B12 deficiency could cause pernicious anemia and subacute combined degeneration, while G cells and ECL cells hyperplasia might develop gastric neuroendocrine tumor (G-NET).

Case Presentation

A 35-year-old Chinese female presented with multi-focal type-1 Grade 2 (G2) NETs with a 14-year history of pernicious anemia and subacute combined degeneration.

Conclusion

Here, we report a rare case of a Chinese patient presenting G-NET combined with pernicious anemia and subacute combined degeneration, which are secondary to chronic autoimmune gastritis. This case also illustrates the importance of routine gastroscopy in patients with Vitamin B12 deficiency.
Prediction of Fluid Responsiveness by the Effect of the Lung Recruitment Maneuver on the Perfusion Index in Mechanically Ventilated Patients During Surgery
Authors: Morakul Sunthiti , Prachanpanich Naruemol , Permsakmesub Pattarada , Pinsem Pimwatana , Mongkolpun Wasineenart , Trongtrakul Konlawij
Published: June 2022

Introduction

Excessive or inadequate fluid administration during perioperative period affects outcomes. Adjustment of volume expansion (VE) by performing fluid responsiveness (FR) test plays an important role in optimizing fluid infusion. Since changes in stroke volume (SV) during lung recruitment maneuver (LRM) can predict FR, and peripheral perfusion index (PI) is related to SV; therefore, we hypothesized that the changes in PI during LRM (ΔPILRM) could predict FR during perioperative period.

Methods

Patients who were scheduled for elective non-laparoscopic surgery under general anesthesia with a mechanical ventilator and who required VE (250 mL of crystalloid solution infusion over 10 min) were included. Before VE, LRM was performed by a continuous positive airway pressure of 30 cm H2O for 30 sec; hemodynamic variables with their changes (PI, obtained by pulse oximetry; and ΔPILRM, calculated by using [(PI before LRM—PI after LRM)/PI before LRM]*100) were obtained before and after LRM. After SV (measured by esophageal doppler) and PI had returned to the baseline values, VE was infused, and the values of these variables were recorded again, before and after VE. Fluid responders (Fluid-Res) were defined by an increase in SV ≥10% after VE. Receiver operating characteristic curves of the baseline values and ΔPILRM were constructed and reported as areas under the curve (AUC) with 95% confidence intervals, to predict FR.

Results

Of 32 mechanically ventilated adult patients included, 13 (41%) were in the Fluid-Res group. Before VE and LRM, there were no differences in the mean arterial pressure (MAP), heart rate, SV, and PI between patients in the Fluid-Res and fluid non-responders (Fluid-NonRes) groups. After LRM, SV, MAP, and, PI decreased in both groups, ΔPILRM was greater in the Fluid-Res group than in Fluid-NonRes group (55.2 ± 17.8% vs. 35.3 ± 17.3%, p < 0.001, respectively). After VE, only SV and cardiac index increased in the Fluid-Res group. ΔPILRM had the highest AUC [0.81 (0.66–0.97)] to predict FR with a cut-off value of 40% (sensitivity 92.3%, specificity 73.7%).

Conclusions

ΔPILRM can be applied to predict FR in mechanical ventilated patients during the perioperative period.
Case Report: A Rare Heterozygous ATP8B1 Mutation in a BRIC1 Patient: Haploinsufficiency?
Authors: Bing Hao , Li Yi-Ling , Li Dan , Zhang Chen , Chang Bing
Published: June 2022

Benign recurrent intrahepatic cholestasis (BRIC) is an autosomal recessive disorder characterized by recurrent cholestasis. ATPase class I, type 8B, member 1 (ATP8B1) encodes familial intrahepatic cholestasis 1 (FIC1), which acts as a phosphatidylserine reversing enzyme in the tubule membrane of hepatocytes to mediate the inward translocation of phosphatidylserine (PS). At present, dozens of ATP8B1 pathogenic mutations have been identified that mainly cause BRIC1 and progressive familial intrahepatic cholestasis 1 (PFIC1). The diagnosis of BRIC1 is based on symptoms, laboratory tests, imaging, liver histology, and genetic testing. BRIC1 treatment seeks to prevent recurrence and reduce disease severity. At present, the main treatment methods include ursodeoxycholic acid (UDCA), rifampin, cholestyramine and haemofiltration, and endoscopic nasobiliary drainage (ENBD). Here, we report a 17-year-old patient with cholestasis who has a rare heterozygous ATP8B1 gene mutation (p.T888K). The patient was treated with UDCA, glucocorticoids and haemofiltration, after which bilirubin levels gradually returned to normal. This case was thought to be caused by an ATP8B1 heterozygous mutation, which may be related to haploinsufficiency (HI).
Peptidase Regulation in Trichophyton rubrum Is Mediated by the Synergism Between Alternative Splicing and StuA-Dependent Transcriptional Mechanisms
Authors: Martins-Santana Leonardo , Petrucelli Monise Fazolin , Sanches Pablo R. , Martinez-Rossi Nilce M. , Rossi Antonio
Published: June 2022

Trichophyton rubrum is the most common causative agent of dermatophytosis worldwide and uses keratinized substrates such as skin and nails as its main source of nutrition during infection. Its pathogenic character relies on colonization and viability maintenance at the target host sites. Since fungal physiology must adapt and respond to host conditions for the successful establishment of infection, biological mechanisms are constantly being triggered by T. rubrum to guarantee its survival in the host environment. The ability of this fungus to sense and modulate the secretion of specific proteases according to environmental pH signaling is considered as a pivotal virulence factor for effective invasion and persistence of infection in the host. Transcriptional regulation of genes encoding specific proteases, such as peptidases, is a key biological process that drives physiological modulation to meet fungal requirements. It accomplishes a robust balance among transcript isoforms that can be directed to perform distinct cellular functions. Thus, alternative splicing mechanisms are suitable for fungal cells to establish a balance toward reprogramming protein translation to impair or boost physiological conditions. In this study, we investigated the role of alternative splicing, especially intron retention events, in generating isoforms of virulence factors in T. rubrum mediated by transcriptional coordination of the protein StuA, a recently described transcription factor in this fungus. By analyzing the previous gene expression data provided by RNA-sequencing and after validation by reverse transcriptase quantitative polymerase chain reaction (RT-qPCR), we observed that two peptidase-coding genes (TERG_00734 and TERG_04614) could be direct targets of alternative splicing in the presence of keratin. Furthermore, protease isoforms generated by alternative splicing in T. rubrum were also detected in a co-culture with human keratinocytes, highlighting the role of these proteins in keratin deconstruction. Our results strongly suggest the influence of StuA on the regulation of virulence factors in T. rubrum and dermatophyte infections by triggering the transcription of the peptidase genes mentioned above in an alternative splicing-independent balance. The results elucidate how fungal cells drive alternate splicing to promote physiological adaptations and show that transcriptional regulation and virulence traits are robust elements required for dermatophyte infection.
Endogenous Sterol Synthesis Is Dispensable for Trypanosoma cruzi Epimastigote Growth but Not Stress Tolerance
Authors: Dumoulin Peter C. , Vollrath Joshua , Won Madalyn M. , Wang Jennifer X. , Burleigh Barbara A.
Published: June 2022

In addition to scavenging exogenous cholesterol, the parasitic kinetoplastid Trypanosoma cruzi can endogenously synthesize sterols. Similar to fungal species, T. cruzi synthesizes ergostane type sterols and is sensitive to a class of azole inhibitors of ergosterol biosynthesis that target the enzyme lanosterol 14α-demethylase (CYP51). In the related kinetoplastid parasite Leishmania donovani, CYP51 is essential, yet in Leishmania major, the cognate enzyme is dispensable for growth; but not heat resistance. The essentiality of CYP51 and the specific role of ergostane-type sterol products in T. cruzi has not been established. To better understand the importance of this pathway, we have disrupted the CYP51 gene in T. cruzi epimastigotes (ΔCYP51). Disruption of CYP51 leads to accumulation of 14-methylated sterols and a concurrent absence of the final sterol product ergosterol. While ΔCYP51 epimastigotes have slowed proliferation compared to wild type parasites, the enzyme is not required for growth; however, ΔCYP51 epimastigotes exhibit sensitivity to elevated temperature, an elevated mitochondrial membrane potential and fail to establish growth as intracellular amastigotes in vitro. Further genetic disruption of squalene epoxidase (ΔSQLE) results in the absence of all endogenous sterols and sterol auxotrophy, yet failed to rescue tolerance to stress in ΔCYP51 parasites, suggesting the loss of ergosterol and not accumulation of 14-methylated sterols modulates stress tolerance.
The Instrumental Activities of Daily Living in Parkinson’s Disease Patients Treated by Subthalamic Deep Brain Stimulation
Authors: Bezdicek Ondrej , Mana Josef , Růžička Filip , Havlik Filip , Fečíková Anna , Uhrová Tereza , Růžička Evžen , Urgošík Dušan , Jech Robert
Published: June 2022

Background

Everyday functioning and instrumental activities of daily living (IADL) play a vital role in preserving the quality of life in patients with Parkinson’s disease (PD) after deep brain stimulation of the subthalamic nucleus (STN-DBS).

Objective

The main goal of the current study was to examine IADL change in pre-and post-surgery of the STN-DBS. We also analyzed the influence of the levodopa equivalent daily dose (LEDD) and global cognitive performance (Dementia Rating Scale; DRS-2) as covariates in relation to IADL.

Methods

Thirty-two non-demented PD patients were administered before and after STN-DBS neurosurgery the Penn Parkinson’s Daily Activities Questionnaire (PDAQ; self-report), the DRS-2 and Beck Depression Inventory (BDI-II) to assess IADL change, global cognition, and depression.

Results

We found a positive effect of STN-DBS on IADL in the post-surgery phase. Moreover, lower global cognition and lower LEDD are predictive of lower IADL in both pre-surgery and post-surgery examinations.

Summary/Conclusion

STN-DBS in PD is a safe method for improvement of everyday functioning and IADL. In the post-surgery phase, we show a relation of IADL to the severity of cognitive impairment in PD and to LEDD.
A Multi-User Transradial Functional-Test Socket for Validation of New Myoelectric Prosthetic Control Strategies
Authors: Hansen Taylor C. , Citterman Abigail R. , Stone Eric S. , Tully Troy N. , Baschuk Christopher M. , Duncan Christopher C. , George Jacob A.
Published: June 2022

The validation of myoelectric prosthetic control strategies for individuals experiencing upper-limb loss is hindered by the time and cost affiliated with traditional custom-fabricated sockets. Consequently, researchers often rely upon virtual reality or robotic arms to validate novel control strategies, which limits end-user involvement. Prosthetists fabricate diagnostic check sockets to assess and refine socket fit, but these clinical techniques are not readily available to researchers and are not intended to assess functionality for control strategies. Here we present a multi-user, low-cost, transradial, functional-test socket for short-term research use that can be custom-fit and donned rapidly, used in conjunction with various electromyography configurations, and adapted for use with various residual limbs and terminal devices. In this study, participants with upper-limb amputation completed functional tasks in physical and virtual environments both with and without the socket, and they reported on their perceived comfort level over time. The functional-test socket was fabricated prior to participants' arrival, iteratively fitted by the researchers within 10 mins, and donned in under 1 min (excluding electrode placement, which will vary for different use cases). It accommodated multiple individuals and terminal devices and had a total cost of materials under $10 USD. Across all participants, the socket did not significantly impede functional task performance or reduce the electromyography signal-to-noise ratio. The socket was rated as comfortable enough for at least 2 h of use, though it was expectedly perceived as less comfortable than a clinically-prescribed daily-use socket. The development of this multi-user, transradial, functional-test socket constitutes an important step toward increased end-user participation in advanced myoelectric prosthetic research. The socket design has been open-sourced and is available for other researchers.
Nicotinamide Promotes Formation of Retinal Organoids From Human Pluripotent Stem Cells via Enhanced Neural Cell Fate Commitment
Authors: Regent Florian , Batz Zachary , Kelley Ryan A. , Gieser Linn , Swaroop Anand , Chen Holly Y. , Li Tiansen
Published: June 2022

Retinal organoids (ROs) derived from human pluripotent stem cells (hPSCs) recapitulate key features of retinogenesis and provide a promising platform to study retinal development and disease in a human context. Although multiple protocols are currently in use, hPSCs exhibit tremendous variability in differentiation efficiency, with some cell lines consistently yielding few or even no ROs, limiting their utility in research. We report here that early nicotinamide (NAM) treatment significantly improves RO yield across 8 hPSC lines from different donors, including some that would otherwise fail to generate a meaningful number of ROs. NAM treatment promotes neural commitment of hPSCs at the expense of non-neural ectodermal cell fate, which in turn increases eye field progenitor generation. Further analysis suggests that this effect is partially mediated through inhibition of BMP signaling. Our data encourage a broader use of human ROs for disease modeling applications that require the use of multiple patient-specific cell lines.
Alzheimer’s Amyloid-β Accelerates Human Neuronal Cell Senescence Which Could Be Rescued by Sirtuin-1 and Aspirin
Authors: Li Yi , Lu Juan , Hou Yujun , Huang Shichao , Pei Gang
Published: June 2022

Cellular senescence is a major biological process related to aging. Neuronal cell senescence contributes to the pathogenesis of many aging-related neurodegenerative diseases including Alzheimer’s disease (AD). In this study, we showed that amyloid-β42 oligomers (Aβ), one of the core pathological players of AD, significantly upregulated the expression of senescence markers, p21, plasminogen activator inhibitor-1 (PAI-1), and SA-β-gal (senescence-associated β-galactosidase) in multiple human neuronal cells, including SK-N-SH cells, SH-SY5Y cells, and neural stem cell (NSC)-derived neuronal cells. Moreover, it was consistently observed among the cells that Aβ promoted senescence-associated DNA damage as the levels of 8-OHdG staining, histone variant H2AX phosphorylation (γ-H2AX), and genomic DNA lesion increased. Mechanism study revealed that the exposure of Aβ markedly suppressed the expression of sirtuin-1 (SIRT1), a critical regulator of aging, and the exogenous expression of SIRT1 alleviated Aβ-induced cell senescence phenotypes. To our surprise, a widely used cardiovascular drug aspirin considerably rescued Aβ-induced cellular senescence at least partially through its regulation of SIRT1. In conclusion, our findings clearly demonstrate that exposure of Aβ alone is sufficient to accelerate the senescence of human neuronal cells through the downregulation of SIRT1.
Association Between A-Waves and Outcome in Pediatric Guillain-Barré Syndrome
Authors: Jin Mei , Liu Jing , Zhao Ziwei , Geng Wenjin , Sun Suzhen
Published: June 2022

Introduction

To examine the importance of abundant A-waves in electrophysiological classification and prognosis of pediatric Guillain-Barré Syndrome (GBS).

Methods

A single-center and retrospective study enrolling 65 children-patients, aged 16 years and younger, with clinically diagnosed GBS between 2013 to 2020. Hughes grade was used to assess functional disability at nadir, 1 month, and 6 months after symptom onset. Patients were divided into 2 groups according to the presence of abundant A-waves. Clinical features and prognosis between the 2 groups were compared.

Results

The distal motor latency of the median nerve in patients with GBS with A-waves (9.18 ms) was more prolonged than that of patients with GBS without A-waves (4.1 ms). An electrophysiological variant of these two groups was also statistically different (p = 0.006). The short-term prognosis of patients with AIDP with A-waves was worse than patients with AIDP without A-waves (χ2 = 5.022, p = 0.025), and univariable logistic regression analysis showed statistically significant (OR: 5.844, 95% CI 1.118–30.553; p = 0.036).

Conclusion

A-waves were strongly associated with demyelination and poor short-term prognosis of AIDP in children. We proposed an electrophysiological marker for early prediction of outcome in the AIDP subtype of GBS, applicable for clinical practice and future treatment administration.
Abnormal Functional Hierarchies of EEG Networks in Familial and Sporadic Prodromal Alzheimer's Disease During Visual Short-Term Memory Binding
Authors: Smith Keith M. , Starr John M. , Escudero Javier , Ibañez Agustin , Parra Mario A.
Published: June 2022

Alzheimer's Disease (AD) shows both complex alterations of functional dependencies between brain regions and a decreased ability to perform Visual Short-Term Memory Binding (VSTMB) tasks. Recent advances in network neuroscience toward understanding the complexity of hierarchical brain function here enables us to establish a link between these two phenomena. Here, we study data on two types of dementia at Mild Cognitive Impairment (MCI) stage—familial AD patients (E280A mutation of the presenilin-1 gene) and elderly MCI patients at high risk of sporadic AD, both with age-matched controls. We analyzed Electroencephalogram (EEG) signals recorded during the performance of Visual Short-Term Memory (VSTM) tasks by these participants. Functional connectivity was computed using the phase-lag index in Alpha and Beta; and network analysis was employed using network indices of hierarchical spread (degree variance) and complexity. Hierarchical characteristics of EEG functional connectivity networks revealed abnormal patterns in familial MCI VSTMB function and sporadic MCI VSTMB function. The middle-aged familial MCI binding network displayed a larger degree variance in lower Beta compared to healthy controls (p = 0.0051, Cohen's d = 1.0124), while the elderly sporadic MCI binding network displayed greater hierarchical complexity in Alpha (p = 0.0140, Cohen's d = 1.1627). Characteristics in healthy aging were not shown to differ. These results indicate that activity in MCI exhibits cross-frequency network reorganization characterized by increased heterogeneity of node roles in the functional hierarchy. Aging itself is not found to cause VSTM functional hierarchy differences.
Interpersonal Family Dynamics Relate to Hippocampal CA Subfield Structure
Authors: Coughlin Christine , Ben-Asher Eliya , Roome Hannah E. , Varga Nicole L. , Moreau Michelle M. , Schneider Lauren L. , Preston Alison R.
Published: June 2022

Social environments that are extremely enriched or adverse can influence hippocampal volume. Though most individuals experience social environments that fall somewhere in between these extremes, substantially less is known about the influence of normative variation in social environments on hippocampal structure. Here, we examined whether hippocampal volume tracks normative variation in interpersonal family dynamics in 7- to 12-year-olds and adults recruited from the general population. We focused on interpersonal family dynamics as a prominent feature of one’s social world. Given evidence that CA1 and CA2 play a key role in tracking social information, we related individual hippocampal subfield volumes to interpersonal family dynamics. More positive perceptions of interpersonal family dynamics were associated with greater CA1 and CA2/3 volume regardless of age and controlling for socioeconomic status. These data suggest that CA subfields are sensitive to normative variation in social environments and identify interpersonal family dynamics as an impactful environmental feature.
Multimodal Neural Response and Effect Assessment During a BCI-Based Neurofeedback Training After Stroke
Authors: Wang Zhongpeng , Cao Cong , Chen Long , Gu Bin , Liu Shuang , Xu Minpeng , He Feng , Ming Dong
Published: June 2022

Stroke caused by cerebral infarction or hemorrhage can lead to motor dysfunction. The recovery of motor function is vital for patients with stroke in daily activities. Traditional rehabilitation of stroke generally depends on physical practice under passive affected limbs movement. Motor imagery-based brain computer interface (MI-BCI) combined with functional electrical stimulation (FES) is a potential active neural rehabilitation technology for patients with stroke recently, which complements traditional passive rehabilitation methods. As the predecessor of BCI technology, neurofeedback training (NFT) is a psychological process that feeds back neural activities online to users for self-regulation. In this work, BCI-based NFT were proposed to promote the active repair and reconstruction of the whole nerve conduction pathway and motor function. We designed and implemented a multimodal, training type motor NFT system (BCI-NFT-FES) by integrating the visual, auditory, and tactile multisensory pathway feedback mode and using the joint detection of electroencephalography (EEG) and functional near-infrared spectroscopy (fNIRS). The results indicated that after 4 weeks of training, the clinical scale score, event-related desynchronization (ERD) of EEG patterns, and cerebral oxygen response of patients with stroke were enhanced obviously. This study preliminarily verified the clinical effectiveness of the long-term NFT system and the prospect of motor function rehabilitation.
A Non-Canonical Role for IRE1α Links ER and Mitochondria as Key Regulators of Astrocyte Dysfunction: Implications in Methamphetamine use and HIV-Associated Neurocognitive Disorders
Authors: Proulx Jessica , Stacy Satomi , Park In-Woo , Borgmann Kathleen
Published: June 2022

Astrocytes are one of the most numerous glial cells in the central nervous system (CNS) and provide essential support to neurons to ensure CNS health and function. During a neuropathological challenge, such as during human immunodeficiency virus (HIV)-1 infection or (METH)amphetamine exposure, astrocytes shift their neuroprotective functions and can become neurotoxic. Identifying cellular and molecular mechanisms underlying astrocyte dysfunction are of heightened importance to optimize the coupling between astrocytes and neurons and ensure neuronal fitness against CNS pathology, including HIV-1-associated neurocognitive disorders (HAND) and METH use disorder. Mitochondria are essential organelles for regulating metabolic, antioxidant, and inflammatory profiles. Moreover, endoplasmic reticulum (ER)-associated signaling pathways, such as calcium and the unfolded protein response (UPR), are important messengers for cellular fate and function, including inflammation and mitochondrial homeostasis. Increasing evidence supports that the three arms of the UPR are involved in the direct contact and communication between ER and mitochondria through mitochondria-associated ER membranes (MAMs). The current study investigated the effects of HIV-1 infection and chronic METH exposure on astrocyte ER and mitochondrial homeostasis and then examined the three UPR messengers as potential regulators of astrocyte mitochondrial dysfunction. Using primary human astrocytes infected with pseudotyped HIV-1 or exposed to low doses of METH for 7 days, astrocytes had increased mitochondrial oxygen consumption rate (OCR), cytosolic calcium flux and protein expression of UPR mediators. Notably, inositol-requiring protein 1α (IRE1α) was most prominently upregulated following both HIV-1 infection and chronic METH exposure. Moreover, pharmacological inhibition of the three UPR arms highlighted IRE1α as a key regulator of astrocyte metabolic function. To further explore the regulatory role of astrocyte IRE1α, astrocytes were transfected with an IRE1α overexpression vector followed by activation with the proinflammatory cytokine interleukin 1β. Overall, our findings confirm IRE1α modulates astrocyte mitochondrial respiration, glycolytic function, morphological activation, inflammation, and glutamate uptake, highlighting a novel potential target for regulating astrocyte dysfunction. Finally, these findings suggest both canonical and non-canonical UPR mechanisms of astrocyte IRE1α. Thus, additional studies are needed to determine how to best balance astrocyte IRE1α functions to both promote astrocyte neuroprotective properties while preventing neurotoxic properties during CNS pathologies.