bluuebunny/crossref_metadata_2025 huggingface dataset:
An Fc-Competent Anti-Human TIGIT Blocking Antibody Ociperlimab (BGB-A1217) Elicits Strong Immune Responses and Potent Anti-Tumor Efficacy in Pre-Clinical Models
Authors: Chen Xin , Xue Liu , Ding Xiao , Zhang Jing , Jiang Lei , Liu Sha , Hou Hongjia , Jiang Bin , Cheng Liang , Zhu Qing , Zhang Lijie , Zhou Xiaosui , Ma Jie , Liu Qi , Li Yucheng , Ren Zhiying , Jiang Beibei , Song Xiaomin , Song Jing , Jin Wei , Wei Min , Shen Zhirong , Liu Xuesong , Wang Lai , Li Kang , Zhang Tong
Published: February 2022

TIGIT (T-cell immunoglobulin and ITIM domain) has emerged as a promising target in cancer immunotherapy. It is an immune “checkpoint” inhibitor primarily expressed on activated T cells, NK cells and Tregs. Engagement of TIGIT to its ligands PVR and PVR-L2 leads to inhibitory signaling in T cells, promoting functional exhaustion of tumor-infiltrating T lymphocytes. Here, we described the pre-clinical characterization of Ociperlimab (BGB-A1217), a novel humanized IgG1 anti-TIGIT antibody (mAb), and systemically evaluated the contribution of Fc functions in the TIGIT mAb-mediated anti-tumor activities. BGB-A1217 binds to the extracellular domain of human TIGIT with high affinity (KD = 0.135 nM) and specificity, and efficiently blocks the interaction between TIGIT and its ligands PVR or PVR-L2. Cell-based assays show that BGB-A1217 significantly enhances T-cell functions. In addition, BGB-A1217 induces antibody dependent cellular cytotoxicity (ADCC) against Treg cells, activates NK cells and monocytes, and removes TIGIT from T cell surfaces in an Fc-dependent manner, In vivo, BGB-A1217, either alone or in combination with an anti-PD-1 mAb elicits strong immune responses and potent anti-tumor efficacy in pre-clinical models. Moreover, the Fc effector function is critical for the anti-tumor activity of BGB-A1217 in a syngeneic human TIGIT-knock-in mouse model. The observed anti-tumor efficacy is associated with a pharmacodynamic change of TIGIT down-regulation and Treg reduction. These data support the selection of BGB-A1217 with an effector function competent Fc region for clinical development for the treatment of human cancers.
Interplay Between the Immune and Endocrine Systems in the Lung: Implications for TB Susceptibility
Authors: Webber Tariq , Ronacher Katharina , Conradie-Smit Marli , Kleynhans Léanie
Published: February 2022

The role of the endocrine system on the immune response, especially in the lung, remains poorly understood. Hormones play a crucial role in the development, homeostasis, metabolism, and response to the environment of cells and tissues. Major infectious and metabolic diseases, such as tuberculosis and diabetes, continue to converge, necessitating the development of a clearer understanding of the immune and endocrine interactions that occur in the lung. Research in bacterial respiratory infections is at a critical point, where the limitations in identifying and developing antibiotics is becoming more profound. Hormone receptors on alveolar and immune cells may provide a plethora of targets for host-directed therapy. This review discusses the interactions between the immune and endocrine systems in the lung. We describe hormone receptors currently identified in the lungs, focusing on the effect hormones have on the pulmonary immune response. Altered endocrine responses in the lung affect the balance between pro- and anti-inflammatory immune responses and play a role in the response to infection in the lung. While some hormones, such as leptin, resistin and lipocalin-2 promote pro-inflammatory responses and immune cell infiltration, others including adiponectin and ghrelin reduce inflammation and promote anti-inflammatory cell responses. Furthermore, type 2 diabetes as a major endocrine disease presents with altered immune responses leading to susceptibility to lung infections, such as tuberculosis. A better understanding of these interactions will expand our knowledge of the mechanisms at play in susceptibility to infectious diseases and may reveal opportunities for the development of host-directed therapies.
Inborn Errors of Immunity Associated With Type 2 Inflammation in the USIDNET Registry
Authors: Smith Kelsey L. , Dai Darlene , Modi Bhavi P. , Sara Rahnuma , Garabedian Elizabeth , Marsh Rebecca A. , Puck Jennifer , Secord Elizabeth , Sullivan Kathleen E. , Turvey Stuart E. , Biggs Catherine M. ,   the USIDNET Consortium
Published: February 2022

Background

Monogenic conditions that disrupt proper development and/or function of the immune system are termed inborn errors of immunity (IEIs), also known as primary immunodeficiencies. Patients with IEIs often suffer from other manifestations in addition to infection, and allergic inflammation is an increasingly recognized feature of these conditions.

Methods

We performed a retrospective analysis of IEIs presenting with allergic inflammation as reported in the USIDNET registry. Our inclusion criteria comprised of patients with a reported monogenic cause for IEI where reported lab eosinophil and/or IgE values were available for the patient prior to them receiving potentially curative therapy. Patients were excluded if we were unable to determine the defective gene underlying their IEI. Patients were classified as having eosinophilia or elevated IgE when their record included at least 1 eosinophil count or IgE value that was greater than the age stratified upper limit of normal. We compared the proportion of patients with eosinophilia or elevated IgE with the proportion of samples in a reference population that fall above the upper limit of normal (2.5%).

Results

The query submitted to the USIDNET registry identified 1409 patients meeting inclusion criteria with a monogenic cause for their IEI diagnosis, of which 975 had eosinophil counts and 645 had IgE levels obtained prior to transplantation or gene therapy that were available for analysis. Overall, 18.8% (183/975) of the patients evaluated from the USIDNET registry had eosinophilia and 20.9% (135/645) had an elevated IgE. IEIs caused by defects in 32 genes were found to be significantly associated with eosinophilia and/or an elevated IgE level, spanning 7 of the 10 IEI categories according to the International Union of Immunological Societies classification.

Conclusion

Type 2 inflammation manifesting as eosinophilia or elevated IgE is found in a broad range of IEIs in the USIDNET registry. Our findings suggest that allergic immune dysregulation may be more widespread in IEIs than previously reported.
Transcriptomic, Proteomic, and Functional Assays Underline the Dual Role of Extrapallial Hemocytes in Immunity and Biomineralization in the Hard Clam Mercenaria mercenaria
Authors: Schwaner Caroline , Farhat Sarah , Haley John , Pales Espinosa Emmanuelle , Allam Bassem
Published: February 2022

Circulating hemocytes in the hemolymph represent the backbone of innate immunity in bivalves. Hemocytes are also found in the extrapallial fluid (EPF), the space delimited between the shell and the mantle, which is the site of shell biomineralization. This study investigated the transcriptome, proteome, and function of EPF and hemolymph in the hard clam Mercenaria mercenaria. Total and differential hemocyte counts were similar between EPF and hemolymph. Overexpressed genes in the EPF were found to have domains previously identified as being part of the “biomineralization toolkit” and involved in bivalve shell formation. Biomineralization related genes included chitin-metabolism genes, carbonic anhydrase, perlucin, and insoluble shell matrix protein genes. Overexpressed genes in the EPF encoded proteins present at higher abundances in the EPF proteome, specifically those related to shell formation such as carbonic anhydrase and insoluble shell matrix proteins. Genes coding for bicarbonate and ion transporters were also overexpressed, suggesting that EPF hemocytes are involved in regulating the availability of ions critical for biomineralization. Functional assays also showed that Ca2+ content of hemocytes in the EPF were significantly higher than those in hemolymph, supporting the idea that hemocytes serve as a source of Ca2+ during biomineralization. Overexpressed genes and proteins also contained domains such as C1q that have dual functions in biomineralization and immune response. The percent of phagocytic granulocytes was not significantly different between EPF and hemolymph. Together, these findings suggest that hemocytes in EPF play a central role in both biomineralization and immunity.
CPT1A-Mediated Fatty Acid Oxidation Promotes Precursor Osteoclast Fusion in Rheumatoid Arthritis
Authors: Huang Zhaoyang , Luo Rong , Yang Liu , Chen Haiqi , Zhang Xinyao , Han Jiawen , Wang Hongxia , Zhou Zhongyang , Wang Zhao , Shao Lan
Published: February 2022

The overproduction of osteoclasts, leading to bone destruction in patients with rheumatoid arthritis (RA), is well established. However, little is known about the metabolic dysfunction of osteoclast precursors (OCPs) in RA. Herein, we show that increasing fatty acid oxidation (FAO) induces OCP fusion. Carnitine palmitoyltransferase IA (CPT1A), which is important for carnitine transportation and is involved in FAO in the mitochondria, is upregulated in RA patients. This metabolic change further increases the expression of clathrin heavy chain (CLTC) and clathrin light chain A (CLTA) by enhancing the binding of the transcription factor CCAAT/enhancer binding protein β (C/EBPβ) to the promoters of CLTA and CLTC. This drives clathrin-dependent endocytosis pathway, which attenuates fusion receptors in the cellular membrane and contributes to increased podosome structure formation. This study reveals a new mechanism through which FAO metabolism participates in joint destruction in RA and provides a novel therapeutic direction for the development of drugs against bone destruction in patients with RA.
CD226 and TIGIT Cooperate in the Differentiation and Maturation of Human Tfh Cells
Authors: Yasutomi Motoko , Christiaansen Allison F. , Imai Naoko , Martin-Orozco Natalia , Forst Christian V. , Chen Gang , Ueno Hideki
Published: February 2022

Costimulation pathways play an essential role in T cell activation, differentiation, and regulation. CD155 expressed on antigen-presenting cells (APCs) interacts with TIGIT, an inhibitory costimulatory molecule, and CD226, an activating costimulatory molecule, on T cells. TIGIT and CD226 are expressed at varying levels depending on the T cell subset and activation state. T follicular helper cells in germinal centers (GC-Tfh) in human tonsils express high TIGIT and low CD226. However, the biological role of the CD155/TIGIT/CD226 axis in human Tfh cell biology has not been elucidated. To address this, we analyzed tonsillar CD4+T cell subsets cultured with artificial APCs constitutively expressing CD155. Here we show that CD226 signals promote the early phase of Tfh cell differentiation in humans. CD155 signals promoted the proliferation of naïve CD4+T cells and Tfh precursors (pre-Tfh) isolated from human tonsils and upregulated multiple Tfh molecules and decreased IL-2, a cytokine detrimental for Tfh cell differentiation. Blocking CD226 potently inhibited their proliferation and expression of Tfh markers. By contrast, while CD155 signals promoted the proliferation of tonsillar GC-Tfh cells, their proliferation required only weak CD226 signals. Furthermore, attenuating CD226 signals rather increased the expression of CXCR5, ICOS, and IL-21 by CD155-stimulated GC-Tfh cells. Thus, the importance of CD226 signals changes according to the differentiation stage of human Tfh cells and wanes in mature GC-Tfh cells. High TIGIT expression on GC-Tfh may play a role in attenuating the detrimental CD226 signals post GC-Tfh cell maturation.
Molecular Characteristics, Clinical Significance, and Cancer Immune Interactions of Angiogenesis-Associated Genes in Gastric Cancer
Authors: Qing Xin , Xu Wenjing , Liu Shengli , Chen Zhencheng , Ye Chunping , Zhang Yewei
Published: February 2022

Background

Immunotherapy has evolved as a critical option to treat diverse cancers. The active response to immunotherapy relies on the unique interaction between cancer and the tumor microenvironment (TME). Angiogenesis is one of the hallmarks of cancer. However, the association between angiogenesis and clinical outcome, immune cell infiltration, and immunotherapy remains unknown in gastric cancer (GC).

Methods

We systematically assessed 36 angiogenesis-associated genes (AAGs) and comprehensively identified the correlation between angiogenesis and transcriptional patterns, prognosis, and immune cell infiltration. The AAG_score was applied to quantify the angiogenesis subtypes of each patient. We then evaluated their values in prognostic prediction and therapeutic responses in GC.

Results

We discussed the mutations of AAGs in GC specimens from genetic levels and identified their expression patterns from TCGA and GEO cohorts. We determined two different molecular subtypes and observed that AAG mutations were related to patients’ clinicopathological characteristics, prognosis, and infiltrating TME. Next, an AAG_score for predicting overall survival (OS) was established and its reliable predictive ability in GC patients was confirmed. Furthermore, we created a highly reliable nomogram to facilitate the clinical viability of the AAG_score. A low AAG_score, characterized by elevated microsatellite instability-high, mutation burden, and immune activation, demonstrated a superior OS. Additionally, the AAG_score was remarkedly correlated with the cancer stem cell index and drug susceptibility.

Conclusion

Collectively, we identified a prognostic AAG signature for GC patients. This signature may contribute to clarifying the characteristics of TME and enable the exploration of more potent immunotherapy strategies.
Effects of Early Sea-Ice Reduction on Zooplankton and Copepod Population Structure in the Northern Bering Sea During the Summers of 2017 and 2018
Authors: Kimura Fumihiko , Matsuno Kohei , Abe Yoshiyuki , Yamaguchi Atsushi
Published: February 2022

A remarkable early sea-ice reduction event was observed in the northern Bering Sea during 2018. In turn, this unusual hydrographic phenomenon affected several marine trophic levels, resulting in delayed phytoplankton blooms, phytoplankton community changes, and a northward shift of fish stocks. However, the response of the zooplankton community remains uncharacterized. Therefore, our study sought to investigate the zooplankton community shifts in the northern Bering Sea during the summers of 2017 and 2018 and evaluate the effects of early sea-ice melt events on the zooplankton community, population structure of large copepods, and copepod production. Five zooplankton communities were identified based on cluster analysis. Further, annual changes in the zooplankton community were identified in the Chirikov Basin. In 2017, the zooplankton community included abundant Pacific copepods transported by the Anadyr water. In 2018, however, the zooplankton community was dominated by small copepods and younger stages of large copepods (Calanus glacialis/marshallaeandMetridia pacifica), which was likely caused by reproduction delays resulting from the early sea-ice reduction event. These environmental abnormalities increased copepod production; however, this higher zooplankton productivity did not efficiently reach the higher trophic levels. Taken together, our findings demonstrated that zooplankton community structure and production are highly sensitive to the environmental changes associated with early sea-ice reduction (e.g., warm temperatures and food availability).
A Dendrophyllia ramea Population in the Ionian Sea (Central Mediterranean Sea) Threatened by Anthropogenic Impacts
Authors: Angiolillo Michela , Giusti Michela , Rossi Lorenzo , Tunesi Leonardo
Published: February 2022

This study reports the first attempt to quantitatively describe a Dendrophyllia ramea population on the Apollo bank (Ionian Sea), revealed in summer 2021 through a remotely operated vehicle (ROV) survey. The habitat description, bathymetric distribution, population density, and structure of the species were assessed by image analysis. A well-developed population of D. ramea, located on boulders on a sedimentary plateau at 70–80 m depth, was observed. The density ranged on average between 0.17 ± 0.04 and 0.8 ± 2.4 colonies m–2 with dense patches up to 8 colonies m–2. The population consisted primarily of many isolated single corallites and colonies of various sizes, some of which reached a maximum height of more than 40 cm. Deepwater fishing activities, primarily longline fishing, negatively affected this species. The newly collected data add knowledge about this vulnerable scleractinian coral. The documented negative effect of fishing activities on vulnerable marine ecosystem (VME) species further highlights the need for urgent conservation measures.
Dispersal and Deposition of Detritus From Kelp Cultivation
Authors: Broch Ole Jacob , Hancke Kasper , Ellingsen Ingrid Helene
Published: February 2022

A high resolution coastal and ocean hydrodynamic model system was used to investigate the transport and deposition patterns of Particulate Organic Matter (POM) from kelp farmed at three locations of different properties: a sheltered location, an exposed location, and an offshore location. Published values on the sinking speeds of organic particles from kelp were used, spanning several orders of magnitude. Recent work on quantifying the release of particulate organic matter from farmed kelp was used to link the release of carbon to possible cultivation volumes and scenarios, and finally to link this to the potential for carbon loading on the ocean floor. The results are presented in terms of loading and distribution per unit harvested kelp, and the loading estimates are compared with estimates of natural (background) primary production. According to the simulation results, organic matter may be transported anything from a few (hundred) meters up to a hundred km away from the release site, depending on the sinking rates, time of release, and the location. The depth at which the matter settles on the sea floor likewise depends on the properties of the matter and the sites. The time until settlement varied from minutes to several hundred hours. The results underscore the importance of constraining the dispersal and deposition of detritus from kelp cultivation in order to better understand and quantify associated environmental risks posed by organic loading, and the potential for seafloor carbon sequestration by kelp farming as a nature based climate solution.
Effect of CO2 on the Hydration of Aluminate Cement Under Conditions of Burning Reservoir in Heavy Oil Thermal Recovery
Authors: Wu Guangai , Wu Zhiqiang , Xing Xuesong , Cai Jingxuan , Cheng Xiaowei
Published: February 2022

Under conditions of heavy oil thermal recovery, cement sheaths often suffer high-temperature performance degradation and CO2 corrosion. The performance of Class G oil well cement commonly used for cementing, deteriorates significantly at high temperatures and in CO2 environments, which can easily cause accidents. By contrast aluminate cement (CAC), at the same time, has good high-temperature resistance and corrosion resistance. Therefore, this study explored the mechanical properties and permeability of CAC with a high-temperature stabiliser cement slurry system (C1), pure CAC slurry system (C2) and Portland cement with sand cement slurry system (C3) before and after corrosion at 50, 300, 400, 500, and 600°C. The micromorphology, hydration products and pore structure of the cement paste before and after corrosion were analyzed using scanning electron microscopy, X-ray diffraction, thermogravimetry and nitrogen adsorption specific surface area and pore diameter analysis; additionally, the hydration mechanism of CAC under high temperatures and in CO2 environments was explored. The results show that the degree of degradation of the mechanical properties of C1 cement slurry system at high temperatures and under CO2 corrosive environments is significantly lower than that of the C3 cement slurry system. At a curing high temperature of 400°C, the maximum strength of the C1 cement paste reached 36.39 ± 0.37 MPa. The addition of a high-temperature stabiliser improved the mechanical properties of CAC at low temperatures, reduced the formation of C3ASH4 in the cement paste at high temperatures, and improved the strength of the cement paste after high-temperature curing. Compared with the C3 cement slurry system, the C1 cement slurry system had better high-temperature resistance and corrosion resistance and was more suitable for application under conditions of a burning reservoir in heavy oil thermal recovery.
Supramaximal Horizontal Rectus Recession–Resection Surgery for Complete Unilateral Abducens Nerve Palsy
Authors: Wang Zhonghao , Fu Licheng , Shen Tao , Qiu Xuan , Yu Xinping , Shen Huangxuan , Yan Jianhua
Published: February 2022

Purpose

To review the surgical procedures and outcomes of supramaximal horizontal rectus recession–resection surgery for abduction deficiency and esotropia resulting from complete unilateral abducens nerve palsy.

Methods

A total of 36 consecutive cases diagnosed as complete abducens nerve palsy, receiving supramaximal medial rectus recession (8.5 ± 1.4 mm, range: 6–10) combined with a supramaximal lateral rectus resection (11.1 ± 1.7 mm, range: 8–14) as performed over the period from 2017 to 2020, were reviewed retrospectively. All surgeries were performed by a single surgeon. Pre- and post-operative ocular motility, ocular alignment, forced duction test, binocular vision, abnormal head posture, and surgical complications were assessed.

Results

Of these 36 cases, 23 (63.8%) were followed up for greater than 2 months (Mean ± SD = 8.4 ± 6.0, range: 2–24) after surgery and the collected data was presented. Mean ± SD age of these patients was 41.7 ± 14.4 (range: 12–67) years with 73.9% being female. Trauma (52.2%, 12/23) and cerebral lesions (21.7%, 5/23) were the primary etiologies for this condition. Esodeviation in primary position improved from 55.5 ± 27.2 prism diopters (PD) (range: +25 to +123) to 0.04 ± 7.3 PD (range: −18 to +12) as assessed on their last visit. Pre-operative abduction deficits of −5.6 ± 1.0 (range: −8 to −4) reduced to −2.4 ± 1.4 (range: −4 to 0) post-operatively. The mean dose-effect coefficient of 2.80 ± 1.20 PD/mm (range: 1.07–6.05) was positively correlated with pre-operative esodeviation. Rates of overcorrection and ortho were 69.6 and 26.1%, respectively, on the first day after surgery, while on their last visit the respective levels were 4.3 and 82.6%.

Conclusion

Supramaximal horizontal rectus recession–resection surgery is an effective treatment method for complete abduction deficiency. The dose-effect was positively correlated with pre-operative esodeviation. Overcorrection on the first day post-operatively is required for a long-term satisfactory surgical outcome.
A Randomized Placebo-Controlled Trial of Combination Therapy With Post-triple-antibiotic-therapy Fecal Microbiota Transplantation and Alginate for Ulcerative Colitis: Protocol
Authors: Ishikawa Dai , Zhang Xiaochen , Nomura Kei , Seki Natsumi , Haraikawa Mayuko , Haga Keiichi , Shibuya Tomoyoshi , Kim Yun-Gi , Nagahara Akihito
Published: February 2022

Background

Fecal microbiota transplantation (FMT) has been widely performed for ulcerative colitis (UC) treatment at the clinical trial stage. Previous reports have used multiple FMT methods to enhance the colonization of healthy donor microbiota in the recipient's intestines. FMT following triple antibiotic therapy with amoxicillin, fosfomycin, and metronidazole (A-FMT) is not only effective but also requires only one FMT, which improves dysbiosis caused by reduced Bacteroidetes diversity in patients with UC. Alginate and its derivatives have the potential to induce the growth of intestinal bacteria including Bacteroides members and produce short-chain fatty acids (SCFAs), which are beneficial in regulating overactive autoimmunity. Our trial aims to investigate whether post-intervention with alginate, which can improve the intestinal environment, will enhance the therapeutic effect of A-FMT in UC and increase the long-term remission rate.

Methods and Analysis

This trial is a double-blinded, randomized, placebo-controlled, parallel assignment trial. Patients with UC and fecal donation candidates will undergo strict screening before being involved in the trial. Eligible patients are randomly divided into two groups: one group will drink one bottle of alginate twice a day for 8 consecutive weeks after A-FMT, while the other group will take a placebo instead of the alginate drink. The primary endpoints are the changes in the Total Mayo Score at 8 weeks after study initiation and A-FMT from baseline. The secondary endpoint is the comparison of clinical features, microbiota, and metabolomic analysis before and after 8 weeks of study food intake. Changes at 6, 12, 18, and 24 months after A-FMT will be assessed. Finally, a subpopulation analysis of the relationship between patients and donors is an exploratory endpoint.

Discussion

The FMT post-treatment used in this study is an oral alginate drink that is easily accepted by patients. If the regimen achieves the desired results, it can further improve the A-FMT regimen and provide evidence for clinical practice guidelines for UC.

Clinical Trial Registration

https://jrct.niph.go.jp/latest-detail/jRCTs031200103, identifier: jRCTs031200103.
Correlation Between CT Features of Active Tuberculosis and Residual Metabolic Activity on End-of-Treatment FDG PET/CT in Patients Treated for Pulmonary Tuberculosis
Authors: Lawal Ismaheel O. , Mokoala Kgomotso M. G. , Mathebula Matsontso , Moagi Ingrid , Popoola Gbenga O. , Moeketsi Nontando , Nchabeleng Maphoshane , Hikuam Chris , Ellner Jerrold J. , Hatherill Mark , Fourie Bernard P. , Sathekge Mike M.
Published: February 2022

Patients who complete a standard course of anti-tuberculous treatment (ATT) for pulmonary tuberculosis and are declared cured according to the current standard of care commonly have residual metabolic activity (RMA) in their lungs on fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (FDG PER/CT) imaging. RMA seen in this setting has been shown to be associated with relapse of tuberculosis. The routine clinical use of FDG PET/CT imaging for treatment response assessment in tuberculosis is hindered by cost and availability. CT is a more readily available imaging modality. We sought to determine the association between CT features suggestive of active tuberculosis and RMA on FDG PET/CT obtained in patients who completed a standard course of ATT for pulmonary tuberculosis. We prospectively recruited patients who completed a standard course of ATT and declared cured based on negative sputum culture. All patients had FDG PET/CT within 2 weeks of completing ATT. We determined the presence of RMA on FDG PET images. Among the various lung changes seen on CT, we considered the presence of lung nodule, consolidation, micronodules in tree-in-bud pattern, FDG-avid chest nodes, and pleural effusion as suggestive of active tuberculosis. We determine the association between the presence of RMA on FDG PET and the CT features of active tuberculosis. We include 75 patients with a mean age of 36.09 ± 10.49 years. Forty-one patients (54.67%) had RMA on their FDG PET/CT while 34 patients (45.33%) achieved complete metabolic response to ATT. There was a significant association between four of the five CT features of active disease, p < 0.05 in all cases. Pleural effusion (seen in two patients) was the only CT feature of active disease without a significant association with the presence of RMA. This suggests that CT may be used in lieu of FDG PET/CT for treatment response assessment of pulmonary tuberculosis.
Nano-Antibacterials Using Medicinal Plant Components: An Overview
Authors: Ghosh Sourav , Nandi Susmita , Basu Tarakdas
Published: February 2022

Gradual emergence of new bacterial strains, resistant to one or more antibiotics, necessitates development of new antibacterials to prevent us from newly evolved disease-causing, drug-resistant, pathogenic bacteria. Different inorganic and organic compounds have been synthesized as antibacterials, but with the problem of toxicity. Other alternatives of using green products, i.e., the medicinal plant extracts with biocompatible and potent antibacterial characteristics, also had limitation because of their low aqueous solubility and therefore less bioavailability. Use of nanotechnological strategy appears to be a savior, where phytochemicals are nanonized through encapsulation or entrapment within inorganic or organic hydrophilic capping agents. Nanonization of such products not only makes them water soluble but also helps to attain high surface to volume ratio and therefore high reaction area of the nanonized products with better therapeutic potential, over that of the equivalent amount of raw bulk products. Medicinal plant extracts, whose prime components are flavonoids, alkaloids, terpenoids, polyphenolic compounds, and essential oils, are in one hand nanonized (capped and stabilized) by polymers, lipids, or clay materials for developing nanodrugs; on the other hand, high antioxidant activity of those plant extracts is also used to reduce various metal salts to produce metallic nanoparticles. In this review, five medicinal plants, viz., tulsi (Ocimum sanctum), turmeric (Curcuma longa), aloe vera (Aloe vera), oregano (Oregano vulgare), and eucalyptus (Eucalyptus globulus), with promising antibacterial potential and the nanoformulations associated with the plants’ crude extracts and their respective major components (eugenol, curcumin, anthraquinone, carvacrol, eucalyptus oil) have been discussed with respect to their antibacterial potency.
Lactobacillus crispatus Strain KT-11 S-Layer Protein Inhibits Rotavirus Infection
Authors: Kawahara Takeshi , Shimizu Issei , Tanaka Yuuki , Tobita Keisuke , Tomokiyo Mikado , Watanabe Itsuki
Published: February 2022

S-layer proteins (SLPs), which are present in the external layer of certain strains of lactic acid bacteria isolated from the intestinal tract, are known to recognize and bind to specific proteins and glycan structures and contribute to adsorption to the host intestinal mucosa. The binding properties of certain SLPs are considered to exert a competitive inhibitory effect on infection because similar properties are involved in the infection mechanisms of several viruses. However, little is known regarding whether SLPs directly inhibit viral infection. In the present study, we investigated the effect of an SLP of the Lactobacillus crispatus KT-11 strain, a probiotic strain isolated from a healthy human infant, on human rotavirus infection. The impact of KT-11 lithium chloride extract (KT-11 LE), which contains SLP, on the infection of the P[4] genotype human rotavirus strain DS-1 was evaluated by monitoring the amplification of viral protein 6 (VP6) expression in human intestinal epithelial Caco-2 cells by quantitative reverse transcription-polymerase chain reaction assay after infection. KT-11 LE showed a significant suppressive effect on DS-1 infection in a dose-dependent manner with pre-infection treatment, whereas post-infection treatment was not effective. A 45 KDa protein isolated from KT-11 LE was investigated for homology using the BLAST database and was found to be a novel SLP. KT-11 SLP concentrate (KT-11 SLP) significantly inhibited the proliferative process of the DS-1 strain but not that of the P[8] genotype human rotavirus strain Wa. KT-11 SLP exerted significant inhibitory effect on DS-1 infection by pre-infection treatment even after digestion with gastric juice up to 2 h. Our results provided crucial evidence that SLPs from certain Lactobacillus strains can inhibit human rotavirus infection of intestinal epithelial cells.
iThermo: A Sequence-Based Model for Identifying Thermophilic Proteins Using a Multi-Feature Fusion Strategy
Authors: Ahmed Zahoor , Zulfiqar Hasan , Khan Abdullah Aman , Gul Ijaz , Dao Fu-Ying , Zhang Zhao-Yue , Yu Xiao-Long , Tang Lixia
Published: February 2022

Thermophilic proteins have important application value in biotechnology and industrial processes. The correct identification of thermophilic proteins provides important information for the application of these proteins in engineering. The identification method of thermophilic proteins based on biochemistry is laborious, time-consuming, and high cost. Therefore, there is an urgent need for a fast and accurate method to identify thermophilic proteins. Considering this urgency, we constructed a reliable benchmark dataset containing 1,368 thermophilic and 1,443 non-thermophilic proteins. A multi-layer perceptron (MLP) model based on a multi-feature fusion strategy was proposed to discriminate thermophilic proteins from non-thermophilic proteins. On independent data set, the proposed model could achieve an accuracy of 96.26%, which demonstrates that the model has a good application prospect. In order to use the model conveniently, a user-friendly software package called iThermo was established and can be freely accessed at http://lin-group.cn/server/iThermo/index.html. The high accuracy of the model and the practicability of the developed software package indicate that this study can accelerate the discovery and engineering application of thermally stable proteins.
Assessing the Impact of Diet on the Mucosa-Adhered Microbiome in Piglets Using Comparative Analysis of Rectal Swabs and Colon Content
Authors: Choudhury Raka , Kleerebezem Michiel
Published: February 2022

Previously, we demonstrated that rectal swabs provide a legitimate alternative to faecal sampling for the assessment of the intestinal microbiota in young piglets. However, we also reported that mucosa-adhered microbial populations were more represented in rectal swabs compared to faecal samples, albeit to a degree that varied per swab-sample. Here, we explored the possibility to exploit this variable enrichment of adhered populations in the rectal swabs to assess the impact of diet on mucosa-adhered microbiota in pre-weaning piglets. Paired samples of rectal swabs and colon luminal contents were collected from piglets just before weaning during two independent but similarly designed animal experiments [n = 28 piglets (experiment 1); n = 16 piglets (experiment 2)], with an early feeding treatment (EF) group that had access to customised fibrous feed in addition to sow’s milk and a control (CON) group exclusively reared on sow’s milk. The intestinal microbiome composition in rectal swabs and colon samples collected at 29 days of age were subjected to metataxonomic analysis. The results identified the genera Escherichia-Shigella, Anaerococcus, Peptostreptococcus, Enterococcus, Trueperella, Actinomyces, and Peptoniphilus as discriminative taxa enriched in rectal swabs compared to colon. Apart from Escherichia-Shigella (10–11% average relative abundance), most of these mucosa-adhered microbial genera display relatively low abundance. Rectal swab microbiota was found to be more variable, which is likely due to variable enrichment of mucosa-adhered microbes. Although almost exclusively driven by one of the experiments, the post-weaning diarrhoea-associated taxa Escherichia-Shigella, was enriched in CON compared to the EF group, suggesting that early life feeding may suppress post-weaning-diarrhoea-related problems in piglets. Our findings demonstrate that rectal swabs allow the investigation of the mucosa-adhered microbial populations as a function of dietary treatment in piglets. This offers opportunities to further study dietary approaches that suppress the abundance of the post-weaning diarrhoea associated adherent microbes like Escherichia-Shigella. Furthermore, we demonstrate that the paired swab-colon microbiota information (obtained from a subset of animals) can predict the mucosa-adhered populations or “mucosity factor” in rectal swab samples, facilitating the analysis of the adhered microbiota in large animal cohort studies using readily obtainable rectal swabs.
Insights Into the Species-Specific Microbiota of Greenideinae (Hemiptera: Aphididae) With Evidence of Phylosymbiosis
Authors: Qin Man , Chen Jing , Jiang Liyun , Qiao Gexia
Published: February 2022

Aphids and their symbionts represent an outstanding model for studies of insect–symbiont interactions. The aphid microbiota can be shaped by aphid species, geography and host plants. However, the relative importance of phylogenetic and ecological factors in shaping microbial community structures is not well understood. Using Illumina sequencing of the V3–V4 hypervariable region of the 16S rRNA gene, we characterized the microbial compositions of 215 aphid colonies representing 53 species of the aphid subfamily Greenideinae from different regions and plants in China, Nepal, and Vietnam. The primary endosymbiont Buchnera aphidicola and secondary symbiont Serratia symbiotica dominated the microbiota of Greenideinae. We simultaneously explored the relative contribution of host identity (i.e., aphid genus and aphid species), geography and host plant to the structures of bacterial, symbiont and secondary symbiont communities. Ordination analyses and statistical tests highlighted the strongest impact of aphid species on the microbial flora in Greenideinae. Furthermore, we found a phylosymbiosis pattern in natural Greenideinae populations, in which the aphid phylogeny was positively correlated with microbial community dissimilarities. These findings will advance our knowledge of host-associated microbiota assembly across both host phylogenetic and ecological contexts.
Protection Duration of COVID-19 Vaccines: Waning Effectiveness and Future Perspective
Authors: Zhuang Chunlan , Liu Xiaohui , Chen Qi , Sun Yuxin , Su Yingying , Huang Shoujie , Wu Ting , Xia Ningshao
Published: February 2022

The coronavirus disease 2019 (COVID-19) vaccines have very successfully decreased the disease risk as we know; some key information remains unknown due to the short development history and the lack of long-term follow-up studies in vaccinated populations. One of the unanswered issues is the protection duration conferred after COVID-19 vaccination, which appears to play a pivotal role in the future impact of pathogens and is critical to inform the public health response and policy decisions. Here, we review current information on the long-term effectiveness of different COVID-19 vaccines, persistence of immunogenicity, and gaps in knowledge. Meanwhile, we also discuss the influencing factors and future study prospects on this topic.
Comprehensive Analyses of the Immunological and Prognostic Roles of an IQGAP3AR/let-7c-5p/IQGAP3 Axis in Different Types of Human Cancer
Authors: Yuan Yixiao , Jiang Xiulin , Tang Lin , Yang Hong , Wang Juan , Zhang Dahang , Duan Lincan
Published: February 2022

IQ motif containing GTPase-activating protein 3 (IQGAP3) is a member of the Rho family of guanosine-5′-triphosphatases (GTPases). IQGAP3 plays a crucial part in the development and progression of several types of cancer. However, the prognostic, upstream-regulatory, and immunological roles of IQGAP3 in human cancer types are not known. We found that IQGAP3 expression was increased in different types of human cancer. The high expression of IQGAP3 was correlated with tumor stage, lymph node metastasis, and a poor prognosis in diverse types of human cancer. The DNA methylation of IQGAP3 was highly and negatively correlated with IQGAP3 expression in diverse cancer types. High DNA methylation in IQGAP3 was correlated with better overall survival in human cancer types. High mRNA expression of IQGAP3 was associated with tumor mutational burden, microsatellite instability, immune cell infiltration, and immune modulators. Analyses of signaling pathway enrichment showed that IQGAP3 was involved in the cell cycle. IQGAP3 expression was associated with sensitivity to a wide array of drugs in cancer cells lines. We revealed that polypyrimidine tract–binding protein 1 (PTBP1) and an IQGAP3-associated lncRNA (IQGAP3AR)/let-7c-5p axis were potential regulations for IQGAP3 expression. We provided the first evidence to show that an IQGAP3AR/let-7c-5p/IQGAP3 axis has indispensable roles in the progression and immune response in different types of human cancer.
Peripheral Neutrophils-Derived Matrix Metallopeptidase-9 Induces Postoperative Cognitive Dysfunction in Aged Mice
Authors: Huang Lili , Tian Weitian , Chen Xuemei , Xu Huan , Dai Wanbing , Zhang Yizhe , Wu Xiaodan , Yu Weifeng , Tian Jie , Su Diansan
Published: February 2022

Background

Aging is one of the most important risk factors of postoperative cognitive dysfunction (POCD); however, the mechanisms are still not completely understood. In this study, we explore the roles of matrix metalloproteinase-9 (MMP-9) in aged mice with POCD.

Methods

Appendectomy was performed in 18-month-old C57BL/6 and MMP-9–/–mice under anesthesia to establish the POCD model. Learning and memory were assessed using the Morris water maze (MWM) or Barnes maze. Protein expression of MMP-9 was measured by Western blotting or enzyme-linked immunosorbent assay (ELISA). To explore the role of neutrophils-derived MMP-9 in POCD, we treated mice with anti-Gr-1 monoclonal antibody to deplete peripheral neutrophils. And the percentage of neutrophils and other leukocytes were detected by flow cytometry. We further used sodium fluorescein (NaFlu) to evaluate the blood–brain barrier (BBB) permeability.

Results

The spatial learning and memory ability was injured, and expression of MMP-9 increased in both plasma and the hippocampus after anesthesia/surgery. However, cognitive dysfunction was alleviated in both MMP-9–/–and peripheral neutrophils-depleted mice. The permeability of BBB was increased after anesthesia/surgery while recused by anti-Gr-1 antibody administration.

Conclusion

These findings suggest that peripheral neutrophils-derived MMP-9 could lead to POCD of aged mice through increasing the BBB permeability.
Enhanced Interplay of Neuronal Coherence and Coupling in the Dying Human Brain
Authors: Vicente Raul , Rizzuto Michael , Sarica Can , Yamamoto Kazuaki , Sadr Mohammed , Khajuria Tarun , Fatehi Mostafa , Moien-Afshari Farzad , Haw Charles S. , Llinas Rodolfo R. , Lozano Andres M. , Neimat Joseph S. , Zemmar Ajmal
Published: February 2022

The neurophysiological footprint of brain activity after cardiac arrest and during near-death experience (NDE) is not well understood. Although a hypoactive state of brain activity has been assumed, experimental animal studies have shown increased activity after cardiac arrest, particularly in the gamma-band, resulting from hypercapnia prior to and cessation of cerebral blood flow after cardiac arrest. No study has yet investigated this matter in humans. Here, we present continuous electroencephalography (EEG) recording from a dying human brain, obtained from an 87-year-old patient undergoing cardiac arrest after traumatic subdural hematoma. An increase of absolute power in gamma activity in the narrow and broad bands and a decrease in theta power is seen after suppression of bilateral hemispheric responses. After cardiac arrest, delta, beta, alpha and gamma power were decreased but a higher percentage of relative gamma power was observed when compared to the interictal interval. Cross-frequency coupling revealed modulation of left-hemispheric gamma activity by alpha and theta rhythms across all windows, even after cessation of cerebral blood flow. The strongest coupling is observed for narrow- and broad-band gamma activity by the alpha waves during left-sided suppression and after cardiac arrest. Albeit the influence of neuronal injury and swelling, our data provide the first evidence from the dying human brain in a non-experimental, real-life acute care clinical setting and advocate that the human brain may possess the capability to generate coordinated activity during the near-death period.
Lack of Vesicular Zinc Does Not Affect the Behavioral Phenotype of Polyinosinic:Polycytidylic Acid-Induced Maternal Immune Activation Mice
Authors: Sandoval Katy Celina , Thackray Sarah E. , Wong Alison , Niewinski Nicole , Chipak Colten , Rehal Suhkjinder , Dyck Richard H.
Published: February 2022

Zinc is important in neural and synaptic development and neuronal transmission. Within the brain, zinc transporter 3 (ZnT3) is essential for zinc uptake into vesicles. Loss of vesicular zinc has been shown to produce neurodevelopmental disorder (NDD)-like behavior, such as decreased social interaction and increased anxiety- and repetitive-like behavior. Maternal immune activation (MIA) has been identified as an environmental factor for NDDs, such as autism spectrum disorders (ASDs) and schizophrenia (SZ), in offspring, which occurs during pregnancy when the mother’s immune system reacts to the exposure to viruses or infectious diseases. In this study, we investigated the interaction effect of a genetic factor [ZnT3 knockout (KO) mice] and an environmental factor (MIA). We induced MIA in pregnant female (dams) mice during mid-gestation, using polyinosinic:polycytidylic acid (polyI:C), which mimics a viral infection. Male and female ZnT3 KO and wild-type (WT) offspring were tested in five behavioral paradigms: Ultrasonic Vocalizations (USVs) at postnatal day 9 (P9), Open Field Test, Marble Burying Test, three-Chamber Social Test, and Pre-pulse Inhibition (PPI) in adulthood (P60–75). Our results indicate that loss of vesicular zinc does not result in enhanced ASD- and SZ-like phenotype compared to WT, nor does it show a more pronounced phenotype in male ZnT3 KO compared to female ZnT3 KO. Finally, MIA offspring demonstrated an ASD- and SZ-like phenotype only in specific behavioral tests: increased calls emitted in USVs and fewer marbles buried. Our results suggest that there is no interaction between the loss of vesicular zinc and MIA induction in the susceptibility to developing an ASD- and SZ-like phenotype.
Prevention of MS Requires Intervention on the Causes of the Disease: Reconciling Genes, Epigenetics, and Epstein Barr Virus
Authors: Kearns Patrick K. A.
Published: February 2022

Prevention of multiple sclerosis requires intervention on modifiable causes of the condition making it necessary to establish what those causes are. MS is often stated to be a polygenic disease, with causal contributions from environmental factors and gene-environment interactions, implying an additive and independent relationship of these factors. Mechanistically there are no independent contributions of genes or environmental factors to traits. This model is unrealistic but still useful and underlies the concept of heritability, a foundational parameter in population genetics. However, it perpetuates a debate on an irreconcilable dichotomy about whether MS is primarily genetic or environmental. In particular, epidemiological evidence now exists for a causal, possibly even necessary, role for Epstein Barr Virus in MS. The additive model makes it unintuitive to reconcile MS as a genetic disease but also independently a viral illness. In this perspective it is argued that starting from a realistic interaction only model, based on broadly accepted biological premises, and working forward to explain why the classical additive model gives useful results, there is actually no paradox. An integrated approach using population genetic studies, immunology and molecular virology offers a particularly promising route to establish the elusive role of EBV in MS pathology, as EBV is a large and complex virus and its latency, dysregulated in most EBV-related pathologies, is hard to study in vivo. This approach may offer a route to prevention of MS altogether.