bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterization of human epithelial resident memory regulatory T cells
Authors: Sato Takuya , Ogawa Youichi , Yokoi Kazunori , Nagasaka Yuka , Ishikawa Aoha , Shiokawa Ichiro , Kinoshita Manao , Watanabe Rei , Shimada Shinji , Tanaka Atsushi , Momosawa Akira , Kawamura Tatsuyoshi
Published: August 2022

Human resident memory regulatory T cells (Tregs) exist in the normal, noninflamed skin. Except one, all previous studies analyzed skin Tregs using full-thickness human skin. Considering that thick dermis contains more Tregs than thin epidermis, the current understanding of skin Tregs might be biased toward dermal Tregs. Therefore, we sought to determine the phenotype and function of human epidermal and epithelial Tregs. Human epidermis and epithelium were allowed to float on a medium without adding any exogenous cytokines and stimulations for two days and then emigrants from the explants were analyzed. Foxp3 was selectively expressed in CD4+CD103− T cells in the various human epithelia, as it is highly demethylated. CD4+CD103−Foxp3+ cells suppressed proliferation of other resident memory T cells. The generation and maintenance of epithelial Tregs were independent of hair density and Langerhans cells. Collectively, immune-suppressive CD4+CD103−Foxp3+ Tregs are present in the normal, noninflamed human epidermis and mucosal epithelia.
Identification of necroptosis-related subtypes and prognosis model in triple negative breast cancer
Authors: Pu Shengyu , Zhou Yudong , Xie Peiling , Gao Xiaoqian , Liu Yang , Ren Yu , He Jianjun , Hao Na
Published: August 2022

Background

Necroptosis is considered to be a new form of programmed necrotic cell death, which is associated with metastasis, progression and prognosis of various types of tumors. However, the potential role of necroptosis-related genes (NRGs) in the triple negative breast cancer (TNBC) is unclear.

Methods

We extracted the gene expression and relevant clinicopathological data of TNBC from The Cancer Genome Atlas (TCGA) databases and the Gene Expression Omnibus (GEO) databases. We analyzed the expression, somatic mutation, and copy number variation (CNV) of 67 NRGs in TNBC, and then observed their interaction, biological functions, and prognosis value. By performing Lasso and COX regression analysis, a NRGs-related risk model for predicting overall survival (OS) was constructed and its predictive capabilities were verified. Finally, the relationship between risk_score and immune cell infiltration, tumor microenvironment (TME), immune checkpoint, and tumor mutation burden (TMB), cancer stem cell (CSC) index, and drug sensitivity were analyzed.

Results

A total 67 NRGs were identified in our analysis. A small number of genes (23.81%) detected somatic mutation, most genes appeared to have a high frequency of CNV, and there was a close interaction between them. These genes were remarkably enriched in immune-related process. A seven-gene risk_score was generated, containing TPSG1, KRT6A, GPR19, EIF4EBP1, TLE1, SLC4A7, ESPN. The low-risk group has a better OS, higher immune score, TMB and CSC index, and lower IC50 value of common therapeutic agents in TNBC. To improve clinical practicability, we added age, stage_T and stage_N to the risk_score and construct a more comprehensive nomogram for predicting OS. It was verified that nomogram had good predictive capability, the AUC values for 1-, 3-, and 5-year OS were 0.847, 0.908, and 0.942.

Conclusion

Our research identified the significant impact of NRGs on immunity and prognosis in TNBC. These findings were expected to provide a new strategy for personalize the treatment of TNBC and improve its clinical benefit.
Efficacy and safety of CD19-specific CAR-T cell-based therapy in secondary central nervous system lymphoma
Authors: Zhang Huanxin , Yan Zhiling , Wang Ying , Qi Yuekun , Hu Yongxian , Li Ping , Cao Jiang , Zhang Meng , Xiao Xia , Shi Ming , Xia Jieyun , Ma Sha , Qiao Jianlin , Li Hujun , Pan Bin , Qi Kunming , Cheng Hai , Sun Haiying , Zhu Feng , Sang Wei , Li Depeng , Li Zhenyu , Zheng Junnian , Zhao Mingfeng , Liang Aibin , Huang He , Xu Kailin
Published: August 2022

Encouraging response has been achieved in relapsed/refractory (R/R) B-cell lymphoma treated by chimeric antigen receptor T (CAR-T) cells. The efficacy and safety of CAR-T cells in central nervous system lymphoma (CNSL) are still elusive. Here, we retrospectively analyzed 15 patients with R/R secondary CNSL receiving CD19-specific CAR-T cell-based therapy. The patients were infused with CD19, CD19/CD20 or CD19/CD22 CAR-T cells following a conditioning regimen of cyclophosphamide and fludarabine. The overall response rate was 73.3% (11/15), including 9 (60%) with complete remission (CR) and 2 (13.3%) with partial remission (PR). During a median follow-up of 12 months, the median progression-free survival (PFS) was 4 months, and the median overall survival (OS) was 9 months. Of 12 patients with systemic tumor infiltration, 7 (58.3%) achieved CR in CNS, and 5 (41.7%) achieved CR both systemically and in CNS. Median DOR for CNS and systemic disease were 8 and 4 months, respectively. At the end point of observation, of the 7 patients achieved CNS disease CR, one was still alive with sustained CR of CNS disease and systemic disease. The other 6 died of systemic progression. Of the 15 patients, 11 (73.3%) experienced grades 1-2 CRS, and no patient had grades 3-4 CRS. Immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 3 (20%) patients, including 1 (6.6%) with grade 4 ICANS. All the CRS or ICANS were manageable. The CD19-specific CAR-T cell-based therapy appeared to be a promising therapeutic approach in secondary CNSL, based on its antitumor effects and an acceptable side effect profile, meanwhile more strategies are needed to maintain the response.
Differential proteome response to H5N1 highly pathogenic avian influenza (HPAI) viruses infection in duck
Authors: Ye Yu , Fan Huiying , Li Qi , Zhang Zhen , Miao Peisi , Zhu Jun , Liu Jie , Zhang Jie , Liao Ming
Published: August 2022

Ducks and wild aquatic birds are the natural reservoirs of avian influenza viruses. However, the host proteome response that causes disease in vivo by the H5N1 HPAI virus is still unclear. This study presented a comprehensive analysis of the proteome response in Muscovy duck lung tissue during 3 days of infection with either a highly virulent DK383 or an avirulent DK212. An unbiased strategy- isobaric tags for relative and absolute quantitation (iTRAQ) in conjunction with high-performance liquid chromatography with tandem mass spectrometry (HPLC-MS/MS) was utilized to investigate the infection mechanism. Pathways derived from analysis of 292 significantly altered proteins may contribute to the high pathogenic nature and disease progression of H5N1 viruses. Global proteome profiles indicated improved correlation with the virus titers and gene expression patterns between the two strains of the H5N1 virus. DK383 replicated more efficiently and induced a stronger response specific to severe disease. While proteins involved in the immune response of neutrophils were increased markedly by DK383, DK212 evoked a distinct response characterized by an increase in proteins involved in the maturation of dendritic cells, adhesion of phagocytes, and immune response of macrophages. The differentially activated Akt/mTOR/p70S6K pathway might involve in the host response to H5N1 viruses. Therefore, systematically integrated with datasets from primary genomic and virus titer results, proteomic analyses may help reveal the potential pathogenesis.
Endoplasmic reticulum stress promoted acinar cell necroptosis in acute pancreatitis through cathepsinB-mediated AP-1 activation
Authors: Han Xiao , Li Bin , Bao Jingpiao , Wu Zengkai , Chen Congying , Ni Jianbo , Shen Jie , Song Pengli , Peng Qi , Wan Rong , Wang Xingpeng , Wu Jianghong , Hu Guoyong
Published: August 2022

Acinar cell death and inflammatory response are two important events which determine the severity of acute pancreatitis (AP). Endoplasmic reticulum (ER) stress and necroptosis are involved in this process, but the relationships between them remain unknown. Here, we analyzed the interaction between ER stress and necroptosis and the underlying mechanisms during AP. Experimental pancreatitis was induced in Balb/C mice by caerulein (Cae) and lipopolysaccharide (LPS) or L-arginine (L-Arg) in vivo, and pancreatic acinar cells were also used to follow cellular mechanisms during cholecystokinin (CCK) stimulation in vitro. AP severity was assessed by serum amylase, lipase levels and histological examination. Changes in ER stress, trypsinogen activation and necroptosis levels were analyzed by western blotting, enzyme-linked immunosorbent assay (ELISA), adenosine triphosphate (ATP) analysis or lactate dehydrogenase (LDH) assay. The protein kinase C (PKC)α -mitogen-activated protein kinase (MAPK) -cJun pathway and cathepsin B (CTSB) activation were evaluated by western blotting. Activating protein 1 (AP-1) binding activity was detected by electrophoretic mobility shift assay (EMSA). We found that ER stress is initiated before necroptosis in CCK-stimulated acinar cells in vitro. Inhibition of ER stress by 4-phenylbutyrate (4-PBA) can significantly alleviate AP severity both in two AP models in vivo. 4-PBA markedly inhibited ER stress and necroptosis of pancreatic acinar cells both in vitro and in vivo. Mechanistically, we found that 4-PBA significantly reduced CTSB maturation and PKCα-JNK-cJun pathway -mediated AP-1 activation during AP. Besides, CTSB inhibitor CA074Me markedly blocked PKCα-JNK-cJun pathway -mediated AP-1 activation and necroptosis in AP. However, pharmacologic inhibition of trypsin activity with benzamidine hydrochloride had no effect on PKCα-JNK-cJun pathway and necroptosis in CCK-stimulated pancreatic acinar cells. Furthermore, SR11302, the inhibitor of AP-1, significantly lowered tumor necrosis factor (TNF) α levels, and its subsequent receptor interacting protein kinases (RIP)3 and phosphorylated mixed lineagekinase domain-like (pMLKL) levels, ATP depletion and LDH release rate in CCK-stimulated pancreatic acinar cells. To sum up, all the results indicated that during AP, ER stress promoted pancreatic acinar cell necroptosis through CTSB maturation, thus induced AP-1 activation and TNFα secretion via PKCα-JNK-cJun pathway, not related with trypsin activity. These findings provided potential therapeutic target and treatment strategies for AP or other cell death-related diseases.
Time-resolved characterization of the innate immune response in the respiratory epithelium of human, porcine, and bovine during influenza virus infection
Authors: Laloli Laura , Licheri Manon Flore , Probst Lukas , Licheri Matthias , Gultom Mitra , Holwerda Melle , V’kovski Philip , Dijkman Ronald
Published: August 2022

Viral cross-species transmission is recognized to be a major threat to both human and animal health, however detailed information on determinants underlying virus host tropism and susceptibility is missing. Influenza C and D viruses (ICV, IDV) are two respiratory viruses that share up to 50% genetic similarity, and both employ 9-O-acetylated sialic acids to enter a host cell. While ICV infections are mainly restricted to humans, IDV possesses a much broader host tropism and has shown to have a zoonotic potential. This suggests that additional virus–host interactions play an important role in the distinct host spectrum of ICV and IDV. In this study, we aimed to characterize the innate immune response of the respiratory epithelium of biologically relevant host species during influenza virus infection to identify possible determinants involved in viral cross-species transmission. To this end, we performed a detailed characterization of ICV and IDV infection in primary airway epithelial cell (AEC) cultures from human, porcine, and bovine origin. We monitored virus replication kinetics, cellular and host tropism, as well as the host transcriptional response over time at distinct ambient temperatures. We observed that both ICV and IDV predominantly infect ciliated cells, independently from host and temperature. Interestingly, temperature had a profound influence on ICV replication in both porcine and bovine AEC cultures, while IDV replicated efficiently irrespective of temperature and host. Detailed time-resolved transcriptome analysis revealed both species-specific and species uniform host responses and highlighted 34 innate immune-related genes with clear virus-specific and temperature-dependent profiles. These data provide the first comprehensive insights into important common and species-specific virus-host dynamics underlying the distinct host tropism of ICV and IDV, as well as possible determinants involved in viral cross-species transmission.
Stimulator of interferon genes defends against bacterial infection via IKKβ-mediated Relish activation in shrimp
Authors: Li Haoyang , Li Qinyao , Wang Sheng , He Jianguo , Li Chaozheng
Published: August 2022

Stimulator of interferon genes (STING) is crucial for the innate immune to defend against pathogenic infections. Our previous study showed that a STING homolog from Litopenaeus vannamei (LvSTING) was involved in antibacterial response via regulating antimicrobial peptides (AMPs). Nevertheless, how LvSTING induces AMPs expression to inhibit bacterial infection remains unknown. Herein, we revealed that the existence of a STING–IKKβ–Relish–AMPs axis in shrimp that was essential for opposing to Vibrio parahaemolyticus invasion. We observed that LvRelish was essential for host defense against V. parahaemolyticus infection via inducing several AMPs, such as LvALF1, LvCRU1, LvLYZ1 and LvPEN4. Knockdown of LvSTING or LvIKKβ in vivo led to the attenuated phosphorylation and diminished nuclear translocation of LvRelish, as well as the impaired expression levels of LvRelish-regulated AMPs. Accordingly, shrimps with knockdown of LvSTING or LvIKKβ or both were vulnerable to V. parahaemolyticus infection. Finally, LvSTING could recruit LvRelish and LvIKKβ to form a complex, which synergistically induced the promoter activity of several AMPs in vitro. Taken together, our results demonstrated that the shrimp STING–IKKβ–Relish–AMPs axis played a critical role in the defense against bacterial infection, and provided some insights into the development of disease prevention strategies in shrimp culture.
Palmitic acid induces intestinal lipid metabolism disorder, endoplasmic reticulum stress and inflammation by affecting phosphatidylethanolamine content in large yellow croaker Larimichthys crocea
Authors: Fang Wei , Liu Yongtao , Chen Qiuchi , Xu Dan , Liu Qiangde , Cao Xiufei , Hao Tingting , Zhang Lu , Mai Kangsen , Ai Qinghui
Published: August 2022

In the 21st century, intestinal homeostatic imbalance has emerged as a growing health challenge worldwide. Accumulating evidence reveals that excessive intake of saturated fatty acid (SFA) induces intestinal homeostatic imbalance. However, the potential molecular mechanism is still unclear. In the present study, we found that palm oil or palmitic acid (PA) treatment disturbed lipid metabolism homeostasis and triggered endoplasmic reticulum (ER) stress and inflammation in the intestine or intestinal cells of large yellow croaker (Larimichthys crocea). Interestingly, PA treatment significantly decreased phosphatidylethanolamine (PE) content in the intestinal cells. PE supplementation decreased triglyceride content in the intestinal cells induced by PA treatment by inhibiting fatty acid uptake and lipogenesis. PE supplementation suppressed ER stress. Meanwhile, PE supplementation alleviated inflammatory response through p38 MAPK-p65 pathway, reducing the damage of intestinal cells caused by PA treatment to some extent. Our work revealed that intestinal homeostatic imbalance caused by PA treatment was partly due to the decrease of PE content. PE consumption might be a nutritional strategy to regulate intestinal homeostasis in fish and even human beings.
Molecular subtypes of osteosarcoma classified by cancer stem cell related genes define immunological cell infiltration and patient survival
Authors: Guo Lei , Yan Taiqiang , Guo Wei , Niu Jianfang , Wang Wei , Ren Tingting , Huang Yi , Xu Jiuhui , Wang Boyang
Published: August 2022

Recent studies have shown that tumor stemness has biological significance in tumorigenicity and tumor progression. However, the characteristics of TME immune infiltration in osteosarcoma mediated by the combined effects of multiple cancer stem cell-related genes remain unknown.

Methods

In this study, we identified different cancer stem cell-associated subtypes in osteosarcoma based on 25 cancer stem cell-associated genes by consensus clustering analysis, and we comprehensively evaluated the association between these subtypes and immunocytes infiltration in the TME. The cancer stem cell (CSC) score was constructed to quantify the stemness of individual tumors.

Results

We performed a comprehensive evaluation of 218 osteosarcoma patients based on 25 cancer stem cell-related genes. Three different cancer stem cells related subtypes were identified, which were related to different biological processes and clinical outcomes. The three subtypes have different TME cells infiltrating characteristics, and CSC Cluster A had a higher level of immunocyte infiltration compared to CSC Cluster B and C. We constructed a scoring system, called the CSC score, to assess the stemness of individual patients. Then we found that the prognosis of patients was predicted by CSC score, and patients with low CSC score had prolonged survival. Further analyses showed that low CSC score was correlated with enhanced immune infiltration. CSC score may predict the effect of immunotherapy, and patients with low CSC score may have better immune response and clinical prognosis.

Conclusions

This study demonstrates that there could be three cancer stem cell-associated subtypes in osteosarcoma and that they were associated with different patient prognosis and TME immune infiltration characteristics. CSC score could be used to assess the stemness of individual patients, improve our comprehension of TME characteristics, and direct more effective immune therapy.
Physiological characteristics of phytoplankton in response to different light environments in the Philippine Sea, Northwestern Pacific Ocean
Authors: Lee Chang Hwa , Kang Jae Joong , Min Jun-Oh , Bae Hyeonji , Kim Yejin , Park Sanghoon , Kim Joonmin , Kim Dongseon , Lee Sang Heon
Published: August 2022

The physiological status of phytoplankton, used to determine the quantity and quality of basic food sources in marine ecosystems, can change rapidly due to ambient environmental conditions (e.g., light, temperature, and nutrients). To understand the physiological characteristics of phytoplankton, the phytoplankton community composition, pigment concentration, primary production, and pigment production rate were estimated at 100% and 1% light depths in the Philippine Sea during the summer of 2019. The predominant phytoplankton classes at both light depths were Prochlorococcus and Synechococcus during the study period. Pigment concentrations, except for photoprotective pigment concentrations (i.e., diadinoxanthin and zeaxanthin), were significantly higher (t-test, p<0.05) at 1% light depth to increase the light-harvesting efficiency. The production rates of these pigments had a weak correlation with primary production at 100% light depth, whereas they showed a strong positive relationship at 1% light depth. Moreover, all photosynthetic pigments had a significantly faster turnover rate at 100% light depth compared with 1% light depth to obtain light energy to repair PSII subunits damaged by strong light. This suggests that the phytoplankton community, especially cyanobacteria (Prochlorococcus and Synechococcus), could use light energy absorbed by newly produced photosynthetic pigments for repairing photoinhibition-damaged PSII as well as for production activity. A further study on photosynthetic pigments responding to light conditions must be conducted for a better understanding of the physiological conditions of phytoplankton.
Consistency between the ichthyotoxicity and allelopathy among strains and ribotypes of Margalefidinium polykrikoides suggests that its toxins are allelochemicals
Authors: Yang Huijiao , Gobler Christopher J. , Tang Ying Zhong
Published: August 2022

Harmful algal blooms (HABs) of the ichthytoxic dinoflagellate Margalefidinium polykrikoides have caused mass mortality of marine life around the world. While its toxic effects can impact fish, bivalves, coral, zooplankton, and even other phytoplankton, the toxin(s) and allelochemical(s) eliciting these impacts have yet to be definitely identified, leaving open the question as to whether its toxicity and allelopathic effects are caused by the same chemical agents. In this study, we investigated the ability of 10 strains of M. polykrikoides with different geographic origins and ribotypes to cause mortality in two strains of the dinoflagellate, Akashiwo sanguinea (allelopathy), and the sheepshead minnow, Cyprinodon variegatus (toxicity). Results showed that the potency of allelopathy against both strains of A. sanguinea and toxicity to the fish were significantly correlated across strains of M. polykrikoides (p < 0.001 for all). These results strongly support the notion that the major allelochemicals and toxins of M. polykrikoides are identical chemicals, an ecological strategy that may be more energetically efficient than the separate synthesis of toxins and allelochemicals as has been reported in other HABs. Our results also highlight the vital significance of the definitive identification of allelochemicals and toxins of M. polykrikoides and of the quantitative characterization of these compounds in the field where HABs of M. polykrikoides occur during blooms.
A TMPS-designed personalized mandibular scaffolds with optimized SLA parameters and mechanical properties
Authors: Zheng Xiaoxiao , Duan Feng , Song Zhenyu , Mo Hongbing , Li Zhehao , Song Yihan , Su Yucheng , Wang Xinyu
Published: August 2022

With the rapid development of 3D printing technology, porous titanium scaffolds have provided a new restoration method to repair bone defects. Compared with the traditional body-centered cubic (bcc) dot matrix structure with a simple arrangement and repetitive structure, the topology-driven properties of triply periodic minimal surfaces (TPMS) can offer a continuous surface and smooth curvature, an excellent platform for cell proliferation. In this study, we used reverse engineering techniques to model the mandible. Sheet and solid networks of gyroid structure, the most common type of TPMS, were selected for porous design and then molded using metal 3D printing technology. At the same time, the surface treatment parameters of sandblasted, large-grit, and acid-etched (SLA) were optimized by orthogonal experimental design. Then, the optimized SLA parameter was used to treat the gyroid with 70% porosity. The result showed that reverse engineering reconstructed the TPMS-based mandibular model had good formability. Furthermore, the best surface morphology, wettability, and roughness were obtained for 3D printed Ti6Al4V under the treatment of 80 mesh Al2O3, blasting distances of 4 cm, and a 1:1:2 acid ratio. Moreover, the mechanical properties of Sheet-Gyroid and Solid-Gyroid were significantly different at 70% porosity. The porosity of the scaffolds was close to the design porosity after SLA treatment. However, no significant changes were found in its mechanical properties, all matching the mandible’s mechanical properties to meet the implantation conditions.
Anti-colorectal cancer effects of seaweed-derived bioactive compounds
Authors: Fu Yunhua , Xie Dong , Zhu Yinghao , Zhang Xinyue , Yue Hao , Zhu Kai , Pi Zifeng , Dai Yulin
Published: August 2022

Seaweeds are classified as Chlorophyta, Rhodophyta, and Phaeophyta. They constitute a number of the most significant repositories of new therapeutic compounds for human use. Seaweed has been proven to possess diverse bioactive properties, which include anticancer properties. The present review focuses on colorectal cancer, which is a primary cause of cancer-related mortality in humans. In addition, it discusses various compounds derived from a series of seaweeds that have been shown to eradicate or slow the progression of cancer. Therapeutic compounds extracted from seaweed have shown activity against colorectal cancer. Furthermore, the mechanisms through which these compounds can induce apoptosis in vitro and in vivo were reviewed. This review emphasizes the potential utility of seaweeds as anticancer agents through the consideration of the capability of compounds present in seaweeds to fight against colorectal cancer.
PRR11 promotes cell proliferation by regulating PTTG1 through interacting with E2F1 transcription factor in pan-cancer
Authors: Zhang Haibo , He Ziqing , Qiu Li , Wei Jinfen , Gong Xiaocheng , Xian Mingjian , Chen Zixi , Cui Ying , Fu Shuying , Zhang Zihao , Hu Bowen , Zhang Xiquan , Lin Shudai , Du Hongli
Published: August 2022

The upregulated proline rich 11 (PRR11) plays a critical role in cancer progression. The relevant biological functions of PRR11 in pan-cancer development are not well understood. In the current study, we found that PRR11 was upregulated in 19 cancer types compared with that of normal tissues and high-expressed PRR11 was a predictor of poor prognosis in 10 cancer types by bioinformatics. Then we showed that interfering PRR11 on three cancer cell lines could greatly inhibit cell proliferation and migration and arrest cells to S phase in vivo. Based on RNA-seq, downregulation of PRR11 expression could extremely suppress the expression of PTTG1 and the cell cycle pathway identified by a differentially expressed gene analysis and an enrichment analysis. The expression of PRR11 and PTTG1 was positively correlated in TCGA and independent GEO data sets. Importantly, we revealed that the PRR11 could express itself in the nucleus and interact with E2F1 on the PTTG1 promoter region to increase the expression of PTTG1. Further results indicated that the expression of PTTG1 was also associated with poor prognosis in 10 cancer types, while downregulation of PTTG1 expression could inhibit cancer cell proliferation and migration. Therefore, we found that PRR11 served as an oncogene in pan-cancer and could influence the cell cycle progression through regulating the expression of PTTG1 by interacting with the transcription factor E2F1.
A structural discovery journey of streptococcal phages adhesion devices by AlphaFold2
Authors: Goulet Adeline , Joos Raphaela , Lavelle Katherine , Van Sinderen Douwe , Mahony Jennifer , Cambillau Christian
Published: August 2022

Successful bacteriophage infection starts with specific recognition and adhesion to the host cell surface. Adhesion devices of siphophages infecting Gram-positive bacteria are very diverse and remain, for the majority, poorly understood. These assemblies often comprise long, flexible, and multi-domain proteins, which limits their structural analyses by experimental approaches such as X-ray crystallography and electron microscopy. However, the protein structure prediction program AlphaFold2 is exquisitely adapted to unveil structural and functional details of such molecular machineries. Here, we present structure predictions of whole adhesion devices of five representative siphophages infecting Streptococcus thermophilus, one of the main lactic acid bacteria used in dairy fermentations. The predictions highlight the mosaic nature of these devices that share functional domains for which active sites and residues could be unambiguously identified. Such AlphaFold2 analyses of phage-encoded host adhesion devices should become a standard method to characterize phage-host interaction machineries and to reliably annotate phage genomes.
Subjective perception of activity level: A prognostic factor for developing chronic dizziness after vestibular schwannoma resection?
Authors: Van Laer Lien , Hallemans Ann , Van Rompaey Vincent , De Valck Claudia , Van de Heyning Paul , Vereeck Luc
Published: August 2022

Introduction

A vestibular schwannoma (VS) resection causes an acute unilateral vestibular deafferentation resulting in acute postoperative symptoms. Despite the expected resolution of most of the symptoms, due to central vestibular compensation, more than one out of four patients develop chronic dizziness. Several predictive factors, such as age and tumor size, have been suggested. Despite its potential effect on the process of central vestibular compensation, the level of physical activity after VS resection was not yet considered. Therefore, the association between the level of physical activity and chronic dizziness after VS resection will be investigated.

Methods

This retrospective cohort study included 66 patients who underwent a retro-sigmoid VS resection between October 2001 and February 2007. Patients were assessed before surgery and at 9 weeks and 6 months postoperatively. At 9 weeks, patients were asked to report their level of physical activity (PA) during the past week by using a visual analogue scale and their balance performance was assessed by four standing balance conditions with eyes closed and the Timed Up and Go test (TUG). Based on the Dizziness Handicap Inventory (DHI) score at 6 months, patients were divided in a chronic dizziness group (DHI > 30) and non-chronic dizziness group (DHI-score ≤ 30). Age, sex, Koos classification, preoperative vestibular function, treatment group, balance performance, and level of PA were compared between both groups and used as independent variables in linear regression analyses with the DHI score at 6 months as dependent variable.

Results

The chronic dizzy patients revealed to have significantly lower levels of PA (p < 0.001) and worse static and dynamic balance performance (p = 0.023 and p = 0.041, respectively) 9 weeks after surgery. After elimination, the multiple regression analysis resulted in a model with two variables (PA level, TUG) which significantly predicted the DHI score (F2,42 = 6.581; R2 = 0.239; p = 0.003).

Conclusion

This study revealed associations between (1) the level of PA and balance performance in the subacute phase and (2) chronic dizziness after VS resection. Assessment of the level of PA and balance performance during the subacute phase, which can be performed in a non-invasive and non-time-consuming way, might therefore provide prognostic information after VS resection.
Altered dynamic spontaneous neural activity in minimal hepatic encephalopathy
Authors: Guo Jie-Ru , Shi Jia-Yan , Dong Qiu-Yi , Cao Yun-Bin , Li Dan , Chen Hua-Jun
Published: August 2022

Background and aims:

Abnormal regional neural activity has been identified by the analysis of the static amplitude of low-frequency fluctuation (ALFF) in the setting of minimal hepatic encephalopathy (MHE). Brain activity is highly dynamic. This work sought to evaluate the temporal variability of ALFF to reveal MHE-related alterations in the dynamics of spontaneous neural activity.

Methods

A total of 29 healthy controls and 49 patients with cirrhosis [including 20 patients with MHE and 29 patients without MHE (NHE)] who underwent resting-state functional magnetic resonance imaging and Psychometric Hepatic Encephalopathy Score (PHES) examination were enrolled in this investigation. Utilizing a sliding-window approach, we calculated the dynamic ALFF (dALFF) variability to reflect the temporal dynamics of regional neural activity. An analysis of the correlation between dALFF variability and PHES was performed, and receiver operating characteristic (ROC) curve analysis to determine the potential of the dALFF variability index in identifying MHE was completed.

Results

The dALFF variability in the bilateral precuneus/posterior cingulate gyrus and left middle frontal gyrus progressively decreased from NHE to MHE group. In cirrhotic patients, the value of dALFF variability in the bilateral precuneus/posterior cingulate gyrus was positively correlated with their neurocognitive performance (r = 0.383 and P = 0.007). The index of dALFF variability in the bilateral precuneus/posterior cingulate gyrus could be used to distinguish NHE and MHE patients, with moderate power (area under the ROC curve = 0.712 and P = 0.012).

Conclusion

Our findings highlight the existence of aberrant dynamic brain function in MHE, which could underlie the neural basis of cognitive impairments and could be associated with the development of the disease. Analyzing dALFF could facilitate new biomarker identification for MHE.
The “hot cross bun sign” in patients with autoimmune cerebellar ataxia: A case report and literature review
Authors: Liu Mange , Ren Haitao , Lin Nan , Tan Ying , Fan Siyuan , Guan Hongzhi
Published: August 2022

Objectives

The “hot cross bun sign” (HCBs) on magnetic resonance imaging (MRI) has been initially considered specific for multiple system atrophy with cerebellar features. However, a number of other conditions have since been described, which may be associated with this imaging sign. We herein describe a patient with anti-Ri and paraneoplastic cerebellar ataxia, and review the association of the HCBs on imaging with various neurological autoimmune conditions.

Methods

We report a 40-year-old woman with anti-Ri-associated paraneoplastic neurological syndrome and breast carcinoma, in whom brain MRI revealed the HCBs late in the disease course. We also reviewed similar cases reported in the literature.

Results

The patient presented with cerebellar ataxia, polyneuropathy, and pyramidal signs. Although brain MRI was initially unremarkable, the HCBs and T2-weighted hyperintensity of the bilateral middle cerebellar peduncles were observed at later follow-up. Anti-Ri was detected in the serum and cerebrospinal fluid. Breast adenocarcinoma was confirmed via an axillary lymph node biopsy. Her symptoms partially resolved after the first corticosteroid pulse. However, subsequent immunotherapy and tumor treatments were ineffective. Four autoimmune cerebellar ataxia cases with the HCBs (two paraneoplastic and two non-paraneoplastic) were identified in the literature.

Discussion

The HCBs can be associated with paraneoplastic and non-paraneoplastic cerebellar ataxia, which may reflect neurodegeneration secondary to autoimmune injury. Thus, the HCBs should not be considered a contraindication for autoimmune cerebellar syndrome.
Major dietary patterns in relation to disease severity, symptoms, and inflammatory markers in patients recovered from COVID-19
Authors: Ebrahimzadeh Armin , Taghizadeh Mohsen , Milajerdi Alireza
Published: August 2022

Background

COVID-19 is a highly transmissible viral infection with high morbidity. Few studies have been done about dietary intakes in patients with COVID-19. This study aimed to evaluate the association between major dietary patterns before COVID-19 diagnosis in recovered patients and the risk of disease severity and symptoms after the disease begins.

Methods

Overall, 250 recovered cases with both genders completed study questionnaires providing data on demographic characteristics, self-reported web-based 168-item food frequency questionnaire (FFQ), and COVID-19 outcomes in Shahid Beheshti Hospital, Kashan. PCR was used to determine a positive diagnosis of COVID-19. We used multivariable logistic regression models to assess the association between major dietary patterns and study outcomes. All statistical analyses were done by SPSS version 16.

Results

We identified three major dietary patterns—unhealthy, traditional, and healthy dietary patterns. Serum levels of C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) were significantly higher in patients with unhealthy and traditional dietary patterns and lower in those with healthy dietary patterns. There was a significant direct relationship between unhealthy and traditional patterns with risk of severe COVID-19 and hospitalization duration and a significant direct association between an unhealthy pattern and the odds ratio (OR) of convalescence duration. A significant inverse relationship was found between healthy pattern and risk of severe COVID-19 and OR of convalescence duration. We found a significant direct association between unhealthy pattern and OR of cough, fever, chilling, weakness, myalgia, nausea and vomiting, and sore throat and between traditional pattern and OR of cough, fever, and chilling. In contrast, a significant inverse association was seen between healthy pattern and OR of dyspnea, weakness, and sore throat.

Conclusion

This study showed that high adherence to an healthy pattern was associated with lower CRP and ESR levels and lower risk of severe COVID-19, hospitalization, and convalescence duration in patients who recovered from COVID-19. More adherence to unhealthy or traditional dietary patterns was associated with higher CRP and ESR levels and a higher risk of severe COVID-19 and hospitalization duration. A direct association was found between unhealthy and traditional patterns and the risk of some COVID-19 symptoms, while an inverse association was found for a healthy dietary pattern.
Safety and immunogenicity of the COVID-19 vaccine BNT162b2 for patients with breast and gynecological cancer on active anticancer therapy: Results of a prospective observational study
Authors: De Placido Pietro , Pietroluongo Erica , De Angelis Carmine , Tafuro Margherita , Barraco Chiara , Giannatiempo Rosa , Buonaiuto Roberto , Schettini Francesco , Iervolino Anna , Vozzella Emilia Anna , Giuliano Mario , Bianco Roberto , Arpino Grazia
Published: August 2022

Background

Vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are highly effective. Nevertheless, immunocompromised participants were excluded from randomized controlled clinical trials. This study evaluates the efficacy and safety of the Pfizer/BioNTech BNT162b2 (BNT162b2) vaccine in patients with breast and gynecological cancer treated with active anticancer therapy versus a control cohort of healthy participants.

Methods

Immune responses to the BNT162b2 vaccine in patients with breast cancer (n = 44) or a gynecological malignancy (n = 6) on active anticancer therapy (28 on chemotherapy, mostly anthracycline- or taxane-based, and 22 on target therapy) and in a control cohort of participants without cancer (n = 67) were investigated by SARS-CoV-2 neutralizing antibody titers measured by S1-binding immunoglobulin G (IgG) concentrations assessed using the LIAISON XL tools (DiaSorin S.p.A.). Response was assessed after a second dose of the BNT162b2 vaccine administered before and at least 3 weeks after the vaccine dose.

Results

Overall, 43/50 (86%) patients of the cancer cohort (74% in the breast cancer group and 100% in the gynecological malignancy group) developed IgG antibodies after the second dose of the BNT162b2 vaccine. There were no statistically significant differences in responder rates between patients treated with chemotherapy and those on target therapy. The majority of patients who received chemotherapy with or without target therapy, 21/28 (75%), developed a reliable antibody titer after a vaccine. All seven non-responder patients were undergoing an anthracycline-based regimen. Based on IgG levels (0–400 AU/ml), patients were classified as negative (‘non-responders’), weakly positive, or strongly positive (‘responders’). No delay in cancer therapy schedule or reported side effects were recorded after BNT162b2 vaccine administration. All healthy participants were strongly positive. Responder rates differed significantly between the two study cohorts (p < 0.001).

Conclusions

Most patients develop antibody titers after the second immunization. However, given the persistence of non-responders or weak responders, additional immunization booster seems to be required, along with proactive planning in the vaccination schedule, with vaccine administration spaced out over time with respect to chemotherapy.
Modified blink dynamic index predicts activity and severity in patient with facial nerve palsy
Authors: Kim Yuri , Lew Helen
Published: August 2022

Purpose

We analyzed the dynamics of blink and defined the blink index in facial nerve palsy (FNP) patients using an ocular surface interferometer associated with clinical characteristics and clinical progress.

Methods

In total, 49 patients were enrolled this study. All patients were tested using an ocular surface interferometer which is used to measure blink patterns (total blink (TB), partial blink rate (PBR)) and blink dynamics (blink time (BT), lid closing time (LCT), closure time (CT), lid opening time (LOT), interblink time (IBT), closing speed (CS), and opening speed (OS)) using 600 frames recorded over 20 s. The distance of lagophthalmos and modified interpalpebral fissure (IPF), which was defined as the actual moving distance of the upper eyelid, subtracting the distance of lagophthalmos from IPF, was measured using the ImageJ program. The types of FNP were “idiopathic” (Bell’s palsy) and “surgical” (following the neurosurgery). Patients were classified into “acute” and “chronic” based on the duration of 6 months from the onset time of FNP. The clinical characteristics were classified into mild or severe according to the severe degree of exposure keratopathy—as “severe” if treatment such as tarsorrhaphy and gold plate insertion was required.

Results

Reduced MRD1, brow height, and modified IPF and increased lagophthalmos were noted in the palsy side. LCT was longer and CS, modified CS, and modified OS were shorter in the palsy side. The LCT was longer and the modified CS was shorter in idiopathic patients with acute onset and with clinically severe. IBT was increased in idiopathic patients with clinically severe.

Conclusion

Analyzing the blink patterns and blink dynamics, this study suggests meaningful indicators among blink profiles and dynamics, LCT, and modified CS based on modified IPF. It was more associated in the idiopathic type than in the surgical type of FNP patients. The modified CS can be a useful tool for evaluating the activity and severity indicator of FNP.
TLR4 signaling modulates extracellular matrix production in the lamina cribrosa
Authors: Geiduschek Emma K. , Milne Paige D. , Mzyk Philip , Mavlyutov Timur A. , McDowell Colleen M.
Published: August 2022

The optic nerve head (ONH) is a place of vulnerability during glaucoma progression due to increased intraocular pressure damaging the retinal ganglion cell axons. The molecular signaling pathways involved in generating glaucomatous ONH damage has not been fully elucidated. There is a great deal of evidence that pro-fibrotic TGFβ2 signaling is involved in modulating the ECM environment within the lamina cribrosa (LC) region of the ONH. Here we investigated the role of signaling crosstalk between the TGFβ2 pathway and the toll-like receptor 4 (TLR4) pathway within the LC. ECM deposition was examined between healthy and glaucomatous human ONH sections, finding increases in fibronectin and fibronectin extra domain A (FN-EDA) an isoform of fibronectin known to be a damage associated molecular pattern (DAMP) that can activate TLR4 signaling. In human LC cell cultures derived from healthy donor eyes, inhibition of TLR4 signaling blocked TGFβ2 induced FN and FN-EDA expression. Activation of TLR4 by cellular FN (cFN) containing the EDA isoform increased both total FN production and Collagen-1 production and this effect was dependent on TLR4 signaling. These studies identify TGFβ2-TLR4 signaling crosstalk in LC cells of the ONH as a novel pathway regulating ECM and DAMP production.
Multidimensional pain phenotypes after Traumatic Brain Injury
Authors: Robayo Linda E. , Govind Varan , Vastano Roberta , Felix Elizabeth R. , Fleming Loriann , Cherup Nicholas P. , Widerström-Noga Eva
Published: August 2022

More than 50% of individuals develop chronic pain following traumatic brain injury (TBI). Research suggests that a significant portion of post-TBI chronic pain conditions is neuropathic in nature, yet the relationship between neuropathic pain, psychological distress, and somatosensory function following TBI is not fully understood. This study evaluated neuropathic pain symptoms, psychological and somatosensory function, and psychosocial factors in individuals with TBI (TBI, N = 38). A two-step cluster analysis was used to identify phenotypes based on the Neuropathic Pain Symptom Inventory and Beck's Anxiety Inventory scores. Phenotypes were then compared on pain characteristics, psychological and somatosensory function, and psychosocial factors. Our analyses resulted in two different neuropathic pain phenotypes: (1) Moderate neuropathic pain severity and anxiety scores (MNP-AS, N = 11); and (2) mild or no neuropathic pain symptoms and anxiety scores (LNP-AS, N = 27). Furthermore, the MNP-AS group exhibited greater depression, PTSD, pain severity, and affective distress scores than the LNP-AS group. In addition, thermal somatosensory function (difference between thermal pain and perception thresholds) was significantly lower in the MNP-AS compared to the LNP-AS group. Our findings suggest that neuropathic pain symptoms are relatively common after TBI and are not only associated with greater psychosocial distress but also with abnormal function of central pain processing pathways.
Influenza: Toward understanding the immune response in the young
Authors: Sakleshpur Sonia , Steed Ashley L.
Published: August 2022

Annually influenza causes a global epidemic resulting in 290,000 to 650,000 deaths and extracts a massive toll on healthcare and the economy. Infants and children are more susceptible to infection and have more severe symptoms than adults likely mitigated by differences in their innate and adaptive immune responses. While it is unclear the exact mechanisms with which the young combat influenza, it is increasingly understood that their immune responses differ from adults. Specifically, underproduction of IFN-γ and IL-12 by the innate immune system likely hampers viral clearance while upregulation of IL-6 may create excessive damaging inflammation. The infant's adaptive immune system preferentially utilizes the Th-2 response that has been tied to γδ T cells and their production of IL-17, which may be less advantageous than the adult Th-1 response for antiviral immunity. This differential immune response of the young is considered to serve as a unique evolutionary adaptation such that they preferentially respond to infection broadly rather than a pathogen-specific one generated by adults. This unique function of the young immune system is temporally, and possibly mechanistically, tied to the microbiota, as they both develop in coordination early in life. Additional research into the relationship between the developing microbiota and the immune system is needed to develop therapies effective at combating influenza in the youngest and most vulnerable of our population.
Therapeutic targets by traditional Chinese medicine for ischemia-reperfusion injury induced apoptosis on cardiovascular and cerebrovascular diseases
Authors: Cheng Xiuli , Hu Jin , Liu Xiaofeng , Tibenda Jonnea Japhet , Wang Xiaobo , Zhao Qipeng
Published: August 2022

Traditional Chinese medicine (TCM) has a significant role in treating and preventing human diseases. Ischemic heart and cerebrovascular injuries are two types of diseases with different clinical manifestations with high prevalence and incidence. In recent years, it has been reported that many TCM has beneficial effects on ischemic diseases through the inhibition of apoptosis, which is the key target to treat myocardial and cerebral ischemia. This review provides a comprehensive summary of the mechanisms of various TCMs in treating ischemic cardiovascular and cerebrovascular diseases through anti-apoptotic targets and pathways. However, clinical investigations into elucidating the pharmacodynamic ingredients of TCM are still lacking, which should be further demystified in the future. Overall, the inhibition of apoptosis by TCM may be an effective strategy for treating ischemic cardio-cerebrovascular diseases.