bluuebunny/crossref_metadata_2025 huggingface dataset:
XBP-1s Promotes B Cell Pathogenicity in Chronic GVHD by Restraining the Activity of Regulated IRE-1α-Dependent Decay
Authors: Choi Hee-Jin , Tang Chih-Hang Anthony , Tian Linlu , Wu Yongxia , Sofi M. Hanief , Ticer Taylor , Schutt Steven D. , Hu Chih-Chi Andrew , Yu Xue-Zhong
Published: October 2021

Allogeneic hematopoietic cell transplantation (allo-HCT) is an effective therapeutic procedure to treat hematological malignancies. However, the benefit of allo-HCT is limited by a major complication, chronic graft-versus-host disease (cGVHD). Since transmembrane and secretory proteins are generated and modified in the endoplasmic reticulum (ER), the ER stress response is of great importance to secretory cells including B cells. By using conditional knock-out (KO) of XBP-1, IRE-1α or both specifically on B cells, we demonstrated that the IRE-1α/XBP-1 pathway, one of the major ER stress response mediators, plays a critical role in B cell pathogenicity on the induction of cGVHD in murine models of allo-HCT. Endoribonuclease activity of IRE-1α activates XBP-1 signaling by converting unspliced XBP-1 (XBP-1u) mRNA into spliced XBP-1 (XBP-1s) mRNA but also cleaves other ER-associated mRNAs through regulated IRE-1α-dependent decay (RIDD). Further, ablation of XBP-1s production leads to unleashed activation of RIDD. Therefore, we hypothesized that RIDD plays an important role in B cells during cGVHD development. In this study, we found that the reduced pathogenicity of XBP-1 deficient B cells in cGVHD was reversed by RIDD restriction in IRE-1α kinase domain KO mice. Restraining RIDD activity per se in B cells resulted in an increased severity of cGVHD. Besides, inhibition of RIDD activity compromised B cell differentiation and led to dysregulated expression of MHC II and costimulatory molecules such as CD86, CD40, and ICOSL in B cells. Furthermore, restraining the RIDD activity without affecting XBP-1 splicing increased B cell ability to induce cGVHD after allo-HCT. These results suggest that RIDD is an important mediator for reducing cGVHD pathogenesis through targeting XBP-1s.
Eosinophils Suppress the Migration of T Cells Into the Brain of Plasmodium berghei-Infected Ifnar1-/- Mice and Protect Them From Experimental Cerebral Malaria
Authors: Scheunemann Johanna F. , Reichwald Julia J. , Korir Patricia Jebett , Kuehlwein Janina M. , Jenster Lea-Marie , Hammerschmidt-Kamper Christiane , Lewis Matthew D. , Klocke Katrin , Borsche Max , Schwendt Kim E. , Soun Camille , Thiebes Stephanie , Limmer Andreas , Engel Daniel R. , Mueller Ann-Kristin , Hoerauf Achim , Hübner Marc P. , Schumak Beatrix
Published: September 2021

Cerebral malaria is a potentially lethal disease, which is caused by excessive inflammatory responses toPlasmodiumparasites. Here we use a newly developed transgenicPlasmodium bergheiANKA (PbAAma1OVA) parasite that can be used to study parasite-specific T cell responses. Our present study demonstrates thatIfnar1-/-mice, which lack type I interferon receptor-dependent signaling, are protected from experimental cerebral malaria (ECM) when infected with this novel parasite. Although CD8+T cell responses generated in the spleen are essential for the development of ECM, we measured comparable parasite-specific cytotoxic T cell responses in ECM-protectedIfnar1-/-mice and wild type mice suffering from ECM. Importantly, CD8+T cells were increased in the spleens of ECM-protectedIfnar1-/-mice and the blood-brain-barrier remained intact. This was associated with elevated splenic levels of CCL5, a T cell and eosinophil chemotactic chemokine, which was mainly produced by eosinophils, and an increase in eosinophil numbers. Depletion of eosinophils enhanced CD8+T cell infiltration into the brain and increased ECM induction inPbAAma1OVA-infectedIfnar1-/-mice. However, eosinophil-depletion did not reduce the CD8+T cell population in the spleen or reduce splenic CCL5 concentrations. Our study demonstrates that eosinophils impact CD8+T cell migration and proliferation duringPbAAma1OVA-infection inIfnar1-/-mice and thereby are contributing to the protection from ECM.
Microdissection of the Bulk Transcriptome at Single-Cell Resolution Reveals Clinical Significance and Myeloid Cells Heterogeneity in Lung Adenocarcinoma
Authors: Wu Hao , Qin Jiale , Zhao Qiang , Lu Lu , Li Chen
Published: October 2021

Background

Tumor infiltrating myeloid (TIM) cells constitute a vital element of the tumor microenvironment. The cell-type heterogeneity of TIM has yet to be fully investigated.

Methods

We used a time saving approach to generate a single-cell reference matrix, allowing quantification of cell-type proportions and cell-type-specific gene abundances in bulk RNA-seq data.

Results

Two distinct clusters, MSC1 and MSC2 (MSC subtype) were newly identified in lung adenocarcinoma (LUAD) patients, both significantly associated with overall survival and immune blockade therapy responses. Twenty myeloid cell types were detected. Thirteen of these had distinct enrichment patterns between MSC1 and MSC2. LAMP3+ dendritic cells, being a mature and transportable subtype of dendritic cell that may migrate to lymph nodes, were noted as associated with non-responsiveness to immunotargeted therapy. High infiltration level of IFIT3+ neutrophils was strongly related to the response to immune-targeted therapy and was seen to activate CD8+ T cells, partly through inflammasome activation. The infiltration levels of TIMP1+ macrophages and S100A8+ neutrophils were both significantly associated with poor prognosis. TIMP1+ macrophages were noted to recruit S100A8+ neutrophils via the CXCL5–CXCR2 axes and promote LUAD progression.

Conclusion

Altogether, we performed virtual microdissection of the bulk transcriptome at single-cell resolution and provided a promising TIM infiltration landscape that may shed new light on the development of immune therapy.
Monocyte Chemotactic Protein-Induced Protein 1 (MCPIP-1): A Key Player of Host Defense and Immune Regulation
Authors: Jin Zhuqing , Zheng En , Sareli Candice , Kolattukudy Pappachan E. , Niu Jianli
Published: October 2021

Inflammatory response is a host-protective mechanism against tissue injury or infections, but also has the potential to cause extensive immunopathology and tissue damage, as seen in many diseases, such as cardiovascular diseases, neurodegenerative diseases, metabolic syndrome and many other infectious diseases with public health concerns, such as Coronavirus Disease 2019 (COVID-19), if failure to resolve in a timely manner. Recent studies have uncovered a superfamily of endogenous chemical molecules that tend to resolve inflammatory responses and re-establish homeostasis without causing excessive damage to healthy cells and tissues. Among these, the monocyte chemoattractant protein-induced protein (MCPIP) family consisting of four members (MCPIP-1, -2, -3, and -4) has emerged as a group of evolutionarily conserved molecules participating in the resolution of inflammation. The focus of this review highlights the biological functions of MCPIP-1 (also known as Regnase-1), the best-studied member of this family, in the resolution of inflammatory response. As outlined in this review, MCPIP-1 acts on specific signaling pathways, in particular NFκB, to blunt production of inflammatory mediators, while also acts as an endonuclease controlling the stability of mRNA and microRNA (miRNA), leading to the resolution of inflammation, clearance of virus and dead cells, and promotion of tissue regeneration via its pleiotropic effects. Evidence from transgenic and knock-out mouse models revealed an involvement of MCPIP-1 expression in immune functions and in the physiology of the cardiovascular system, indicating that MCPIP-1 is a key endogenous molecule that governs normal resolution of acute inflammation and infection. In this review, we also discuss the current evidence underlying the roles of other members of the MCPIP family in the regulation of inflammatory processes. Further understanding of the proteins from this family will provide new insights into the identification of novel targets for both host effectors and microbial factors and will lead to new therapeutic treatments for infections and other inflammatory diseases.
Semen-Derived Exosomes Mediate Immune Escape and Transmission of Reticuloendotheliosis Virus
Authors: Su Qi , Zhang Yawen , Cui Zhizhong , Chang Shuang , Zhao Peng
Published: October 2021

Reticuloendotheliosis virus (REV) causes immune-suppression disease in poultry, leading to a significant economic burden worldwide. Recent evidence demonstrated that the REV can enter the semen and then induce artificial insemination, but how the virus gets into semen was little known. Accumulating studies indicated that exosomes serve as vehicles for virus transmission, but the role of exosomes in viral shedding through the semen remains unclear. In this study, exosomes purified from the REV-positive semen were shown with reverse transcription-PCR and mass spectrometry to contain viral genomic RNA and viral proteins, which could also establish productive infections bothin vivoandin vitroand escape from the REV-specific neutralizing antibodies. More importantly, compared with the infection caused by free virions, the exosome is more efficient for the virus to ensure effective infection and replication, which can also help the REV compromise the efficacy of the host immune response. In summary, this study demonstrated that semen-derived exosomes can medicate the transmission and immune escape of REV, implicating a novel mechanism for REV entering the semen and leading to vertical transmission.
Acute-Phase Levels of CXCL8 as Risk Factor for Chronic Arthralgia Following Chikungunya Virus Infection
Authors: Jacob-Nascimento Leile Camila , Carvalho Caroline Xavier , Silva Monaíse Madalena Oliveira , Kikuti Mariana , Anjos Rosângela Oliveira , Fradico Jordana Rodrigues Barbosa , Campi-Azevedo Ana Carolina , Tauro Laura Beatriz , Campos Gúbio Soares , Moreira Patricia Sousa dos Santos , Portilho Moyra Machado , Martins-Filho Olindo Assis , Ribeiro Guilherme Sousa , Reis Mitermayer Galvão
Published: October 2021

The immunopathogenesis of chikungunya virus (CHIKV) infection and the role of acute-phase immune response on joint pain persistence is not fully understood. We investigated the profile of serum chemokine and cytokine in CHIKV-infected patients with acute disease, compared the levels of these biomarkers to those of patients with other acute febrile diseases (OAFD) and healthy controls (HC), and evaluated their role as predictors of chronic arthralgia development. Chemokines and cytokines were measured by flow Cytometric Bead Array. Patients with CHIKV infection were further categorized according to duration of arthralgia (≤ 3 months vs >3 months), presence of anti-CHIKV IgM at acute-phase sample, and number of days of symptoms at sample collection (1 vs 2-3 vs ≥4). Patients with acute CHIKV infection had significantly higher levels of CXCL8, CCL2, CXCL9, CCL5, CXCL10, IL-1β, IL-6, IL-12, and IL-10 as compared to HC. CCL2, CCL5, and CXCL10 levels were also significantly higher in patients with CHIKV infection compared to patients with OAFD. Patients whose arthralgia lasted > 3 months had increased CXCL8 levels compared to patients whose arthralgia did not (p<0.05). Multivariable analyses further indicated that high levels of CXCL8 and female sex were associated with arthralgia lasting >3 months. Patients with chikungunya and OAFD had similar cytokine kinetics for IL-1β, IL-12, TNF, IFN-γ, IL-2, and IL-4, although the levels were lower for CHIKV patients. This study suggests that chemokines may have an important role in the immunopathogenesis of chronic chikungunya-related arthralgia.
Siglec-7 Mediates Immunomodulation by Colorectal Cancer-Associated Fusobacterium nucleatum ssp. animalis
Authors: Lamprinaki Dimitra , Garcia-Vello Pilar , Marchetti Roberta , Hellmich Charlotte , McCord Kelli A. , Bowles Kristian M. , Macauley Matthew S. , Silipo Alba , De Castro Cristina , Crocker Paul R. , Juge Nathalie
Published: October 2021

Fusobacterium nucleatum is involved in the development of colorectal cancer (CRC) through innate immune cell modulation. However, the receptors of the interaction between F. nucleatum ssp. and immune cells remain largely undetermined. Here, we showed that F. nucleatum ssp. animalis interacts with Siglecs (sialic acid–binding immunoglobulin-like lectins) expressed on innate immune cells with highest binding to Siglec-7. Binding to Siglec-7 was also observed using F. nucleatum-derived outer membrane vesicles (OMVs) and lipopolysaccharide (LPS). F. nucleatum and its derived OMVs or LPS induced a pro-inflammatory profile in human monocyte-derived dendritic cells (moDCs) and a tumour associated profile in human monocyte-derived macrophages (moMϕs). Siglec-7 silencing in moDCs or CRISPR-cas9 Siglec-7-depletion of U-937 macrophage cells altered F. nucleatum induced cytokine but not marker expression. The molecular interaction between Siglec-7 and the LPS O-antigen purified from F. nucleatum ssp. animalis was further characterised by saturation transfer difference (STD) NMR spectroscopy, revealing novel ligands for Siglec-7. Together, these data support a new role for Siglec-7 in mediating immune modulation by F. nucleatum strains and their OMVs through recognition of LPS on the bacterial cell surface. This opens a new dimension in our understanding of how F. nucleatum promotes CRC progression through the generation of a pro-inflammatory environment and provides a molecular lead for the development of novel cancer therapeutic approaches targeting F. nucleatum-Siglec-7 interaction.
Global-Local-Comparison Approach: Understanding Marine Mammal Spatial Behavior by Applying Spatial Statistics and Hypothesis Testing to Passive Acoustic Data
Authors: Kates Varghese Hilary , Lowell Kim , Miksis-Olds Jennifer
Published: October 2021

Technological innovation in underwater acoustics has progressed research in marine mammal behavior by providing the ability to collect data on various marine mammal biological and behavioral attributes across time and space. But with this comes the need for an approach to distill the large amounts of data collected. Though disparate general statistical and modeling approaches exist, here, a holistic quantitative approach specifically motivated by the need to analyze different aspects of marine mammal behavior within a Before-After Control-Impact framework using spatial observations is introduced: the Global-Local-Comparison (GLC) approach. This approach capitalizes on the use of data sets from large-scale, hydrophone arrays and combines established spatial autocorrelation statistics of (Global) Moran’s I and (Local) Getis-Ord Gi∗(Gi∗) with (Comparison) statistical hypothesis testing to provide a detailed understanding of array-wide, local, and order-of-magnitude changes in spatial observations. This approach was demonstrated using beaked whale foraging behavior (using foraging-specific clicks as a proxy) during acoustic exposure events as an exemplar. The demonstration revealed that the Moran’s I analysis was effective at showing whether an array-wide change in behavior had occurred, i.e., clustered to random distribution, or vice-versa. The Gi∗analysis identified where hot or cold spots of foraging activity occurred and how those spots varied spatially from one analysis period to the next. Since neither spatial statistic could be used to directly compare the magnitude of change between analysis periods, a statistical hypothesis test, using the Kruskal-Wallis test, was used to directly compare the number of foraging events among analysis periods. When all three components of the GLC approach were used together, a comprehensive assessment of group level spatial foraging activity was obtained. This spatial approach is demonstrated on marine mammal behavior, but it can be applied to a broad range of spatial observations over a wide variety of species.
Elasmobranch Responses to Experimental Warming, Acidification, and Oxygen Loss—A Meta-Analysis
Authors: Santos Catarina Pereira , Sampaio Eduardo , Pereira Beatriz P. , Pegado Maria Rita , Borges Francisco O. , Wheeler Carolyn R. , Bouyoucos Ian A. , Rummer Jodie L. , Frazão Santos Catarina , Rosa Rui
Published: October 2021

Despite the long evolutionary history of this group, the challenges brought by the Anthropocene have been inflicting an extensive pressure over sharks and their relatives. Overexploitation has been driving a worldwide decline in elasmobranch populations, and rapid environmental change, triggered by anthropogenic activities, may further test this group's resilience. In this context, we searched the literature for peer-reviewed studies featuring a sustained (>24 h) and controlled exposure of elasmobranch species to warming, acidification, and/or deoxygenation: three of the most pressing symptoms of change in the ocean. In a standardized comparative framework, we conducted an array of mixed-model meta-analyses (based on 368 control-treatment contrasts from 53 studies) to evaluate the effects of these factors and their combination as experimental treatments. We further compared these effects across different attributes (lineages, climates, lifestyles, reproductive modes, and life stages) and assessed the direction of impact over a comprehensive set of biological responses (survival, development, growth, aerobic metabolism, anaerobic metabolism, oxygen transport, feeding, behavior, acid-base status, thermal tolerance, hypoxia tolerance, and cell stress). Based on the present findings, warming appears as the most influential factor, with clear directional effects, namely decreasing development time and increasing aerobic metabolism, feeding, and thermal tolerance. While warming influence was pervasive across attributes, acidification effects appear to be more context-specific, with no perceivable directional trends across biological responses apart from the necessary to achieve acid-base balance. Meanwhile, despite its potential for steep impacts, deoxygenation has been the most neglected factor, with data paucity ultimately precluding sound conclusions. Likewise, the implementation of multi-factor treatments has been mostly restricted to the combination of warming and acidification, with effects approximately matching those of warming. Despite considerable progress over recent years, research regarding the impact of these drivers on elasmobranchs lags behind other taxa, with more research required to disentangle many of the observed effects. Given the current levels of extinction risk and the quick pace of global change, it is further crucial that we integrate the knowledge accumulated through different scientific approaches into a holistic perspective to better understand how this group may fare in a changing ocean.
Fluorescence Characteristics of Chromophoric Dissolved Organic Matter in the Eastern Indian Ocean: A Case Study of Three Subregions
Authors: Liu Yang , Sun Jun , Wang Xingzhou , Liu Xiaofang , Wu Xi , Chen Zhuo , Gu Ting , Wang Weiqiang , Yu Linghui , Guo Yu , Wen Yujian , Zhang Guodong , Zhang Guicheng
Published: October 2021

Comprising one of the major carbon pools on Earth, marine dissolved organic matter (DOM) plays an essential role in global carbon dynamics. The objective of this study was to better characterize DOM in the eastern Indian Ocean. To better understand the underlying mechanisms, seawater samples were collected in October and November of 2020 from sampling stations in three subregions: the mouth of the Bay of Bengal, Southern Sri Lanka, and Western Sumatra. We calculated and evaluated different hydrological parameters and organic carbon concentrations. In addition, we used excitation emission matrix (EEM) spectroscopy combined with parallel factor analysis (PARAFAC) to analyze the natural water samples directly. Parameters associated with chromophoric DOM did not behave conservatively in the study areas as a result of biogeochemical processes. We further evaluated the sources and processing of DOM in the eastern Indian Ocean by determining four fluorescence indices (the fluorescence index, the biological index, the humification index, and the freshness index β/α). Based on EEM-PARAFAC, we identified six components (five fluorophores) using the peak picking technique. Commonly occurring fluorophores were present within the sample set: peak A (humic-like), peak B (protein-like), peak C (humic-like), and peak T (tryptophan-like). The fluorescence intensity levels of the protein-like components (peaks B and T) were highest in the surface ocean and decreased with depth. In contrast, the ratio of the two humic-like components (peaks A and C) remained in a relatively narrow range in the bathypelagic layer compared to the surface layer, which indicates a relatively constant composition of humic-like fluorophores in the deep layer.
DNA Repair and Immune Response Pathways Are Deregulated in Melanocyte-Keratinocyte Co-cultures Derived From the Healthy Skin of Familial Melanoma Patients
Authors: Potrony Miriam , Haddad Tariq Sami , Tell-Martí Gemma , Gimenez-Xavier Pol , Leon Carlos , Pevida Marta , Mateu Judit , Badenas Celia , Carrera Cristina , Malvehy Josep , Aguilera Paula , Llames Sara , Escámez Maria José , Puig-Butillé Joan A. , del Río Marcela , Puig Susana
Published: October 2021

Familial melanoma accounts for 10% of cases, being CDKN2A the main high-risk gene. However, the mechanisms underlying melanomagenesis in these cases remain poorly understood. Our aim was to analyze the transcriptome of melanocyte-keratinocyte co-cultures derived from healthy skin from familial melanoma patients vs. controls, to unveil pathways involved in melanoma development in at-risk individuals. Accordingly, primary melanocyte-keratinocyte co-cultures were established from the healthy skin biopsies of 16 unrelated familial melanoma patients (8 CDKN2A mutant, 8 CDKN2A wild-type) and 7 healthy controls. Whole transcriptome was captured using the SurePrint G3 Human Microarray. Transcriptome analyses included: differential gene expression, functional enrichment, and protein-protein interaction (PPI) networks. We identified a gene profile associated with familial melanoma independently of CDKN2A germline status. Functional enrichment analysis of this profile showed a downregulation of pathways related to DNA repair and immune response in familial melanoma (P < 0.05). In addition, the PPI network analysis revealed a network that consisted of double-stranded DNA repair genes (including BRCA1, BRCA2, BRIP1, and FANCA), immune response genes, and regulation of chromosome segregation. The hub gene was BRCA1. In conclusion, the constitutive deregulation of BRCA1 pathway genes and the immune response in healthy skin could be a mechanism related to melanoma risk.
Association of Myopia With Microvascular Alterations in Patients With Type 2 Diabetes: An Optical Coherence Tomography Angiography Study
Authors: Wen Xin , Li Zijing , Xiao Jianhui , Liu Xuane , Zhang Yichi , Lan Yuqing
Published: October 2021

Purpose: To determine the association of myopia with peripapillary and macular microvasculature in eyes with type 2 diabetes using optical coherence tomography angiography (OCTA).

Methods: Diabetic patients with and without diabetic retinopathy (DR) were recruited and grouped according to myopic status in this cross-sectional study. Axial length, refractive error, and OCTA parameters were measured. OCTA parameters were analyzed with adjustment of confounding factors and further Bonferroni analysis was performed to determine the differences in multiple group comparisons.

Results: Compared with the diabetic eyes without myopia, those with myopia had lower rate of DR (21.82 vs. 35.90%, χ2 = 6.190, P = 0.013), longer axial lengths (24.94 ± 0.75 vs. 23.16 ± 0.64, F = 311.055, P < 0.001) and reduced whole vessel density (VD) of optic nerve head (ONH) (45.89 ± 5.76 vs. 49.14 ± 4.33, F = 19.052, P < 0.001), peripapillary VD (48.75 ± 6.56 vs. 50.76 ± 4.51, F = 7.600, P = 0.006), and reduced thickness of the retinal nerve fiber layer (RNFL) (95.50 ± 12.35 vs. 100.67 ± 13.68, F = 5.020, P = 0.026). In eyes without myopia, the superficial vessel density (SVD) (46.58 ± 4.90 vs. 43.01 ± 4.25; 95% CI, 1.80–4.61; P < 0.001), deep vessel density (DVD) (45.64 ± 6.34 vs. 42.15 ± 6.31; 95% CI, 1.07–5.00; P < 0.001), and FD300 area density (50.31 ± 5.74 vs. 44.95 ± 6.96; 95% CI, 2.88–7.27; P < 0.001) were significant reduced in eyes with DR(DR eyes) comparing to those without DR (NoDR eyes). In eyes with myopia, only SVD were significantly reduced in DR eyes comparing to NoDR eyes (41.68 ± 3.34 vs. 45.99 ± 4.17; 95% CI, 1.10–7.22; P = 0.002). In NoDR eyes, both whole VD of ONH and Peripapillary VD demonstrated a significant decrease in eyes with myopia comparing to those without myopia (49.91 ± 4.36 vs. 45.61 ± 6.32; 95% CI, 1.95–6.27; P < 0.001 and 51.36 ± 4.24 vs. 48.52 ± 6.99; 95% CI, 0.56–5.11; P = 0.006, respectively).

Conclusions: In diabetic patients, myopic eyes exhibited lower prevalence of DR and thinner thickness of RNFL. The refractive status could possibly impact the retinal microvascular changes from NoDR to DR stage.
Reduced Serum Levels of Bone Formation Marker P1NP in Psoriasis
Authors: Mentzel Julia , Kynast Tabea , Kohlmann Johannes , Kirsten Holger , Blüher Matthias , Simon Jan C. , Kunz Manfred , Saalbach Anja
Published: October 2021

Psoriasis is a chronic inflammatory disease of the skin and joints. More recent data emphasize an association with dysregulated glucose and fatty acid metabolism, obesity, elevated blood pressure and cardiac disease, summarized as metabolic syndrome. TNF-α and IL-17, central players in the pathogenesis of psoriasis, are known to impair bone formation. Therefore, the relation between psoriasis and bone metabolism parameters was investigated. Two serum markers of either bone formation—N-terminal propeptide of type I procollagen (P1NP) or bone resorption—C-terminal telopeptide of type I collagen (CTX-I)—were analyzed in a cohort of patients with psoriasis vulgaris. In patients with psoriasis, P1NP serum levels were reduced compared to gender-, age-, and body mass index-matched healthy controls. CTX-I levels were indistinguishable between patients with psoriasis and controls. Consistently, induction of psoriasis-like skin inflammation in mice decreases bone volume and activity of osteoblasts. Moreover, efficient anti-psoriatic treatment improved psoriasis severity, but did not reverse decreased P1NP level suggesting that independent of efficient skin treatment psoriasis did affect bone metabolism and might favor the development of osteoporosis. Taken together, evidence is provided that bone metabolism might be affected by psoriatic inflammation, which may have consequences for future patient counseling and disease monitoring.
Latent Myofascial Trigger Points Injection Reduced the Severity of Persistent, Moderate to Severe Allergic Rhinitis: A Randomized Controlled Trial
Authors: Liu Yu , Yang Yan , Hu Qiya , Badughaish Ahmed , Zhang Hanbing , Qi Feng , Hou Yuedong
Published: October 2021

Background: Myofascial trigger points (MTrPs) injection has been effectively used for the management of chronic painful diseases. Latent MTrPs can induce autonomic nerve phenomena. In our clinic, we observed that allergic rhinitis (AR) symptoms significantly improved when latent MTrPs injection was performed for migraine.

Objective: To compare the efficacy and safety between latent MTrPs injection and sublingual immunotherapy (SLIT) in patients with persistent, moderate to severe AR.

Methods: This randomized controlled trial was conducted with 112 patients with AR. Patients were randomized to receive SLIT (n = 56) or latent MTrPs injection. Total nasal symptom score (TNSS, n = 56), nasal symptoms, medication days, and adverse events were evaluated during the 9 months follow-up period after treatment in both groups.

Results: Latent MTrPs injection significantly reduced TNSS to a greater level from baseline (from 8.36 ± 1.96 to 4.43 ± 2.18) than SLIT (from 8.66 ± 2.31 to 7.80 ± 2.47) at week 1 (P < 0.001), and sustained the improvement in symptoms throughout to month 9. Latent MTrPs showed statistically significant differences vs. SLIT for the TNSS reduction both at month 2 (6.59 ± 2.37 vs. 2.64 ± 2.38; p < 0.001) and month 3 (4.59 ± 2.77 vs. 2.62 ± 2.43; p <0.001). Latent MTrPs also showed a better improvement in the onset time of efficacy compared with SLIT. Adverse reactions were few and non-serious in both treatment groups.

Conclusions: Latent MTrPs injection significantly improved symptoms and decreased symptom-relieving medication use in patients with AR and was well tolerated.

Clinical Trials Registration: Chinese Clinical Trial Registry, ChiCTR1900020590. Registered 9 January 2019, http://www.chictr.org.cn/index.aspx.
BB0259 Encompasses a Peptidoglycan Lytic Enzyme Function for Proper Assembly of Periplasmic Flagella in Borrelia burgdorferi
Authors: Xu Hui , Hu Bo , Flesher David A. , Liu Jun , Motaleb Md A.
Published: October 2021

Assembly of the bacterial flagellar rod, hook, and filament requires penetration through the peptidoglycan (PG) sacculus and outer membrane. In most β- and γ-proteobacteria, the protein FlgJ has two functional domains that enable PG hydrolyzing activity to create pores, facilitating proper assembly of the flagellar rod. However, two distinct proteins performing the same functions as the dual-domain FlgJ are proposed in δ- and ε-proteobacteria as well as spirochetes. The Lyme disease spirochete Borrelia burgdorferi genome possesses a FlgJ and a PG lytic SLT enzyme protein homolog (BB0259). FlgJ in B. burgdorferi is crucial for flagellar hook and filament assembly but not for the proper rod assembly reported in other bacteria. However, BB0259 has never been characterized. Here, we use cryo-electron tomography to visualize periplasmic flagella in different bb0259 mutant strains and provide evidence that the E580 residue of BB0259 is essential for PG-hydrolyzing activity. Without the enzyme activity, the flagellar hook fails to penetrate through the pores in the cell wall to complete assembly of an intact periplasmic flagellum. Given that FlgJ and BB0259 interact with each other, they likely coordinate the penetration through the PG sacculus and assembly of a functional flagellum in B. burgdorferi and other spirochetes. Because of its role, we renamed BB0259 as flagellar-specific lytic transglycosylase or LTaseBb.
Growth Response and Recovery of Corynebacterium glutamicum Colonies on Single-Cell Level Upon Defined pH Stress Pulses
Authors: Täuber Sarah , Blöbaum Luisa , Wendisch Volker F. , Grünberger Alexander
Published: October 2021

Bacteria respond to pH changes in their environment and use pH homeostasis to keep the intracellular pH as constant as possible and within a small range. A change in intracellular pH influences enzyme activity, protein stability, trace element solubilities and proton motive force. Here, the species Corynebacterium glutamicum was chosen as a neutralophilic and moderately alkali-tolerant bacterium capable of maintaining an internal pH of 7.5 ± 0.5 in environments with external pH values ranging between 5.5 and 9. In recent years, the phenotypic response of C. glutamicum to pH changes has been systematically investigated at the bulk population level. A detailed understanding of the C. glutamicum cell response to defined short-term pH perturbations/pulses is missing. In this study, dynamic microfluidic single-cell cultivation (dMSCC) was applied to analyze the physiological growth response of C. glutamicum to precise pH stress pulses at the single-cell level. Analysis by dMSCC of the growth behavior of colonies exposed to single pH stress pulses (pH = 4, 5, 10, 11) revealed a decrease in viability with increasing stress duration w. Colony regrowth was possible for all tested pH values after increasing lag phases for which stress durations w were increased from 5 min to 9 h. Furthermore, single-cell analyses revealed heterogeneous regrowth of cells after pH stress, which can be categorized into three physiological states. Cells in the first physiological state continued to grow without interruption after pH stress pulse. Cells in the second physiological state rested for several hours after pH stress pulse before they started to grow again after this lag phase, and cells in the third physiological state did not divide after the pH stress pulse. This study provides the first insights into single-cell responses to acidic and alkaline pH stress by C. glutamicum.
PepVAE: Variational Autoencoder Framework for Antimicrobial Peptide Generation and Activity Prediction
Authors: Dean Scott N. , Alvarez Jerome Anthony E. , Zabetakis Dan , Walper Scott A. , Malanoski Anthony P.
Published: September 2021

New methods for antimicrobial design are critical for combating pathogenic bacteria in the post-antibiotic era. Fortunately, competition within complex communities has led to the natural evolution of antimicrobial peptide (AMP) sequences that have promising bactericidal properties. Unfortunately, the identification, characterization, and production of AMPs can prove complex and time consuming. Here, we report a peptide generation framework, PepVAE, based around variational autoencoder (VAE) and antimicrobial activity prediction models for designing novel AMPs using only sequences and experimental minimum inhibitory concentration (MIC) data as input. Sampling from distinct regions of the learned latent space allows for controllable generation of new AMP sequences with minimal input parameters. Extensive analysis of the PepVAE-generated sequences paired with antimicrobial activity prediction models supports this modular design framework as a promising system for development of novel AMPs, demonstrating controlled production of AMPs with experimental validation of predicted antimicrobial activity.
The Microbial Composition of Lower Genital Tract May Affect the Outcome of in vitro Fertilization-Embryo Transfer
Authors: Wang Ruiying , Zhou Guojun , Wu Lukanxuan , Huang Xin , Li Yujing , Luo Bin , Zhu Huili , Huang Wei
Published: October 2021

Objective: This work was conducted in order to study the effect of the lower genital tract (vaginal and cervical canal) microbiota on pregnancy outcomes of reproductive-aged women receiving embryo transfer.

Study design: A total of 150 reproductive-aged patients who received the first fresh in vitro fertilization-embryo transfer (IVF-ET) were included in the study. Samples from the vagina and cervical site of each patient were collected separately using sterile swabs before ET. Genomic DNA was pyrosequenced for the V3–V4 regions of the 16S ribosomal RNA gene. Further bioinformatics analysis was performed using QIIME and R package. Pregnancy outcomes were followed and analyzed to compare differences in microbial composition.

Results: The cervical microbiota had a higher Shannon index than the vaginal microbiota, and the microbial composition was different between the two sites. However, the Sorenson index between the two sites within the same individual was 0.370 (0.309–0.400). A total of 89 patients achieved clinical pregnancy after ET, while 61 failed. The Shannon indices and the microbial community of both vaginal and cervical microbiota between pregnant and non-pregnant groups were not significantly different. The relative abundance of Lactobacillus in the vagina and cervical canal did not differ between the two groups. Linear discriminant analysis, random forest analysis, and receiver-operating characteristic curve analysis showed that Bifidobacterium, Prevotella, and Lactobacillus iners in the vagina, as well as Solanum torvum, Fusobacterium, and Streptococcus in the cervix, may be negatively associated with clinical pregnancy after IVF.

Conclusion: The cervical microbiota was more diverse than the vaginal microbiota, but because of anatomical continuity, there was a correlation between the two sites. The microbial composition of the vagina and cervical canal may influence the outcome of IVF-ET, but more samples are needed to verify this conclusion.
Aerobic Composting and Anaerobic Digestion Decrease the Copy Numbers of Antibiotic-Resistant Genes and the Levels of Lactose-Degrading Enterobacteriaceae in Dairy Farms in Hokkaido, Japan
Authors: Katada Satoshi , Fukuda Akira , Nakajima Chie , Suzuki Yasuhiko , Azuma Takashi , Takei Ayaka , Takada Hideshige , Okamoto Eiryu , Kato Toshihide , Tamura Yutaka , Usui Masaru
Published: October 2021

Efficient methods for decreasing the spread of antimicrobial resistance genes (ARGs) and transfer of antimicrobial-resistant bacteria (ARB) from livestock manure to humans are urgently needed. Aerobic composting (AC) or anaerobic digestion (AD) are widely used for manure treatment in Japanese dairy farms. To clarify the effects of AC and AD on antimicrobial resistance, the abundances of antimicrobial (tetracycline and cefazolin)-resistant lactose-degrading Enterobacteriaceae as indicator bacteria, copy numbers of ARGs (tetracycline resistance genes and β-lactamase coding genes), and concentrations of residual antimicrobials in dairy cow manure were determined before and after treatment. The concentration of tetracycline/cefazolin-resistant lactose-degrading Enterobacteriaceae was decreased over 1,000-fold by both AC and AD. ARGs such as tetA, tetB, and blaTEM were frequently detected and their copy numbers were significantly reduced by ∼1,000-fold by AD but not by AC. However, several ARG copies remained even after AD treatment. Although concentrations of the majority of residual antimicrobials were decreased by both AC and AD, oxytetracycline level was not decreased after treatment in most cases. In addition, 16S rRNA gene amplicon-based metagenomic analysis revealed that both treatments changed the bacterial community structure. These results suggest that both AC and AD could suppress the transmission of ARB, and AD could reduce ARG copy numbers in dairy cow manure.
The Possible Transmission and Potential Enterotoxicity of Bacillus cereus on Lettuce Farms in Five Chinese Provinces
Authors: Qu Yang , Wei Chao , Dai Xiaohang , Bai Yalong , Zhao Xin , Lan Qingkuo , Wang Wenbo , Wu Yuanjuan , Gao Min , Tang Weihao , Zhou Changyan , Suo Yujuan
Published: October 2021

Bacillus cereus is a well-characterized human pathogen that produces toxins associated with diarrheal and emetic foodborne diseases. To investigate the possible transmission of B. cereus on lettuce farms in China and determine its enterotoxicity, (I) a total of 524 samples (lettuce: 332, soil: 69, water: 57, manure: 57, pesticide: 9) were collected from 46 lettuce farms in five Chinese provinces, (II) multilocus sequence typing (MLST) was used to classify B. cereus isolates and for trace analysis, and (III) the presence of toxin genes and enterotoxins (Hbl and Nhe) was detected in 68 strains. The results showed that one hundred and sixty-one lettuce samples (48.5%) tested positive for B. cereus at levels ranging from 10 to 5.3 × 104 CFU/g. Among the environmental sample categories surveyed, the highest positive rate was that of the pesticide samples at 55.6%, followed by soil samples at 52.2% and manure samples at 12.3%. Moreover, one hundred isolates of B. cereus yielded 68 different sequence types (STs) and were classified into five phylogenetic clades. Furthermore, Nhe toxin genes (nheA, nheB, nheC) were broadly distributed and identified in all 68 strains (100%), while Hbl toxin genes (hblA, hblC, hblD) were present in 61 strains (89.7%), entFM was detected in 62 strains (91.2%), and cytK was found in 29 strains (42.6%). All strains were negative for ces. As for the enterotoxin, Nhe was observed in all 68 isolates carrying nheB, while Hbl was present in 76.5% (52/68) of the strains harboring hblC. This study is the first report of possible B. cereus transmission and of its potential enterotoxicity on lettuce farms in China. The results showed that soil and pesticides are the main sources of B. cereus on lettuce farms in China, and the possible transmission routes are as follows: soil-lettuce, manure-lettuce, pesticide-lettuce, manure-soil-lettuce, and water-manure-soil-lettuce. Furthermore, the B. cereus isolates, whether from lettuce or the environment, pose a potential risk to health.
Mechanism for the Unfolding of the TOP7 Protein in Steered Molecular Dynamics Simulations as Revealed by Mutual Information Analysis
Authors: Perišić Ognjen , Wriggers Willy
Published: October 2021

We employed mutual information (MI) analysis to detect motions affecting the mechanical resistance of the human-engineered protein Top7. The results are based on the MI analysis of pair contact correlations measured in steered molecular dynamics (SMD) trajectories and their statistical dependence on global unfolding. This study is the first application of the MI analysis to SMD forced unfolding, and we furnish specific SMD recommendations for the utility of parameters and options in the TimeScapes package. The MI analysis provided a global overview of the effect of perturbation on the stability of the protein. We also employed a more conventional trajectory analysis for a detailed description of the mechanical resistance of Top7. Specifically, we investigated 1) the hydropathy of the interactions of structural segments, 2) the H2O concentration near residues relevant for unfolding, and 3) the changing hydrogen bonding patterns and main chain dihedral angles. The results show that the application of MI in the study of protein mechanical resistance can be useful for the engineering of more resistant mutants when combined with conventional analysis. We propose a novel mutation design based on the hydropathy of residues that would stabilize the unfolding region by mimicking its more stable symmetry mate. The proposed design process does not involve the introduction of covalent crosslinks, so it has the potential to preserve the conformational space and unfolding pathway of the protein.
Trimethylamine-N-Oxide Pathway: A Potential Target for the Treatment of MAFLD
Authors: Li Xun , Hong Jia , Wang Yao , Pei Maohua , Wang Luwen , Gong Zuojiong
Published: October 2021

Trimethylamine-N-oxide (TMAO) is a molecular metabolite derived from the gut flora, which has recently emerged as a candidate risk factor for metabolic dysfunction-associated fatty liver disease (MAFLD). TMAO is mainly derived from gut, where the gut microbiota converts TMA precursors into TMA, which is absorbed into the bloodstream through the intestinal mucosa, and then transformed into TMAO by hepatic flavin monooxygenases (FMOs) in the liver. High-nutrient diets rich in TMA precursors, such as red meat, eggs, and fish, are the main sources of TMAO. Excessively consuming such diets not only directly affects energy metabolism in liver, but also increases the concentration of TMAO in plasma, which promotes the development of MAFLD by affecting bile acid metabolism, unfolded protein response, and oxidative stress. In this review, we focused on the relationship between TMAO and MAFLD and summarized intervention strategies for reducing circulating TMAO concentration, aiming at providing new targets for the prevention and treatment of MAFLD.
A Key Silencing Histone Mark on Chromatin Is Lost When Colorectal Adenocarcinoma Cells Are Depleted of Methionine by Methionine γ-Lyase
Authors: Raboni Samanta , Montalbano Serena , Stransky Stephanie , Garcia Benjamin A. , Buschini Annamaria , Bettati Stefano , Sidoli Simone , Mozzarelli Andrea
Published: October 2021

Methionine is an essential amino acid used, beyond protein synthesis, for polyamine formation and DNA/RNA/protein methylation. Cancer cells require particularly high methionine supply for their homeostasis. A successful approach for decreasing methionine concentration is based on the systemic delivery of methionine γ-lyase (MGL), with in vitro and in vivo studies demonstrating its efficacy in cancer therapy. However, the mechanisms explaining how cancer cells suffer from the absence of methionine more significantly than non-malignant cells are still unclear. We analyzed the outcome of the human colorectal adenocarcinoma cancer cell line HT29 to the exposure of MGL for up to 72 h by monitoring cell viability, proteome expression, histone post-translational modifications, and presence of spurious transcription. The rationale of this study was to verify whether reduced methionine supply would affect chromatin decondensation by changing the levels of histone methylation and therefore increasing genomic instability. MGL treatment showed a time-dependent cytotoxic effect on HT29 cancer cells, with an IC50 of 30 µg/ml, while Hs27 normal cells were less affected, with an IC50 of >460 µg/ml. Although the levels of total histone methylation were not altered, a loss of the silencing histone mark H3K9me2 was observed, as well as a decrease in H4K20me3. Since H3K9me2/3 decorate repetitive DNA elements, we proved by qRT-PCR that MGL treatment leads to an increased expression of major satellite units. Our data indicate that selected histone methylation marks may play major roles in the mechanism of methionine starvation in cancer cells, proving that MGL treatment directly impacts chromatin homeostasis.
Current Approaches and Molecular Mechanisms for Directly Reprogramming Fibroblasts Into Neurons and Dopamine Neurons
Authors: Han Fabin , Liu Yanming , Huang Jin , Zhang Xiaoping , Wei Chuanfei
Published: October 2021

Parkinson’s disease is mainly caused by specific degeneration of dopaminergic neurons (DA neurons) in the substantia nigra of the middle brain. Over the past two decades, transplantation of neural stem cells (NSCs) from fetal brain-derived neural stem cells (fNSCs), human embryonic stem cells (hESCs), and induced pluripotent stem cells (iPSCs) has been shown to improve the symptoms of motor dysfunction in Parkinson’s disease (PD) animal models and PD patients significantly. However, there are ethical concerns with fNSCs and hESCs and there is an issue of rejection by the immune system, and the iPSCs may involve tumorigenicity caused by the integration of the transgenes. Recent studies have shown that somatic fibroblasts can be directly reprogrammed to NSCs, neurons, and specific dopamine neurons. Directly induced neurons (iN) or induced DA neurons (iDANs) from somatic fibroblasts have several advantages over iPSC cells. The neurons produced by direct transdifferentiation do not pass through a pluripotent state. Therefore, direct reprogramming can generate patient-specific cells, and it can overcome the safety problems of rejection by the immune system and teratoma formation related to hESCs and iPSCs. However, there are some critical issues such as the low efficiency of direct reprogramming, biological functions, and risks from the directly converted neurons, which hinder their clinical applications. Here, the recent progress in methods, mechanisms, and future challenges of directly reprogramming somatic fibroblasts into neurons or dopamine neurons were summarized to speed up the clinical translation of these directly converted neural cells to treat PD and other neurodegenerative diseases.