bluuebunny/crossref_metadata_2025 huggingface dataset:
Immune-related gene signature associates with immune landscape and predicts prognosis accurately in patients with Wilms tumour
Authors: Tian Xiao-Mao , Xiang Bin , Jin Li-Ming , Mi Tao , Wang Jin-Kui , Zhanghuang Chenghao , Zhang Zhao-Xia , Chen Mei-Ling , Shi Qin-Lin , Liu Feng , Lin Tao , Wei Guang-Hui
Published: September 2022

Wilms tumour (WT) is the most common kidney malignancy in children. Chemoresistance is the leading cause of tumour recurrence and poses a substantial therapeutic challenge. Increasing evidence has underscored the role of the tumour immune microenvironment (TIM) in cancers and the potential for immunotherapy to improve prognosis. There remain no reliable molecular markers for reflecting the immune landscape and predicting patient survival in WT. Here, we examine differences in gene expression by high-throughput RNA sequencing, focused on differentially expressed immune-related genes (IRGs) based on the ImmPort database. Via univariate Cox regression analysis and Lasso-penalized Cox regression analysis, IRGs were screened out to establish an immune signature. Kaplan-Meier curves, time-related ROC analysis, univariate and multivariate Cox regression studies, and nomograms were used to evaluate the accuracy and prognostic significance of this signature. Furthermore, we found that the immune signature could reflect the immune status and the immune cell infiltration character played in the tumour microenvironment (TME) and showed significant association with immune checkpoint molecules, suggesting that the poor outcome may be partially explained by its immunosuppressive TME. Remarkably, TIDE, a computational method to model tumour immune evasion mechanisms, showed that this signature holds great potential for predicting immunotherapy responses in the TARGET-wt cohort. To decipher the underlying mechanism, GSEA was applied to explore enriched pathways and biological processes associated with immunophenotyping and Connectivity map (CMap) along with DeSigN analysis for drug exploration. Finally, four candidate immune genes were selected, and their expression levels in WT cell lines were monitored via qRT-PCR. Meanwhile, we validated the function of a critical gene, NRP2. Taken together, we established a novel immune signature that may serve as an effective prognostic signature and predictive biomarker for immunotherapy response in WT patients. This study may give light on therapeutic strategies for WT patients from an immunological viewpoint.
Ligand-based CAR-T cell: Different strategies to drive T cells in future new treatments
Authors: Ramírez-Chacón Alejandro , Betriu-Méndez Sergi , Bartoló-Ibars Ariadna , González Azucena , Martí Mercè , Juan Manel
Published: September 2022

Chimeric antigen receptor (CAR)-based therapies are presented as innovative treatments for multiple malignancies. Despite their clinical success, there is scientific evidence of the limitations of these therapies mainly due to immunogenicity issues, toxicities associated with the infusion of the product, and relapses of the tumor. As a result, novel approaches are appearing aiming to solve and/or mitigate the harmful effects of CAR-T therapies. These include strategies based on the use of ligands as binding moieties or ligand-based CAR-T cells. Several proposals are currently under development, with some undergoing clinical trials to assess their potential benefits. In addition to these, therapies such as chimeric autoantibody receptor (CAAR), B-cell receptor antigen for reverse targeting (BAR), and even chimeric human leukocyte antigen (HLA) antibody receptor (CHAR) have emerged, benefiting from the advantages of antigenic ligands as antibody-binding motifs. This review focuses on the potential role that ligands can play in current and future antitumor treatments and in other types of diseases, such as autoimmune diseases or problems associated with transplantation.
Case report: A persistently expanded T cell response in an exceptional responder to radiation and atezolizumab for metastatic non-small cell lung cancer
Authors: Coffey David G. , Xu Yuexin , Towlerton Andrea M. H. , Kowanetz Marcin , Hegde Priti , Darwish Martine , Yadav Mahesh , Blanchette Craig , Ruppert Shannon M. , Bertino Sarah , Xu Qikai , Ferretti Andrew , Weinheimer Adam , Hellmann Matthew , Qin Angel , Thomas Dafydd , Warren Edus H. , Ramnath Nithya
Published: September 2022

Most patients with advanced non-small cell lung cancer (NSCLC) do not achieve a durable remission after treatment with immune checkpoint inhibitors. Here we report the clinical history of an exceptional responder to radiation and anti-program death-ligand 1 (PD-L1) monoclonal antibody, atezolizumab, for metastatic NSCLC who remains in a complete remission more than 8 years after treatment. Sequencing of the patient’s T cell repertoire from a metastatic lesion and the blood before and after anti-PD-L1 treatment revealed oligoclonal T cell expansion. Characterization of the dominant T cell clone, which comprised 10% of all clones and increased 10-fold in the blood post-treatment, revealed an activated CD8+ phenotype and reactivity against 4 HLA-A2 restricted neopeptides but not viral or wild-type human peptides, suggesting tumor reactivity. We hypothesize that the patient’s exceptional response to anti-PD-L1 therapy may have been achieved by increased tumor immunogenicity promoted by pre-treatment radiation therapy as well as long-term persistence of oligoclonal expanded circulating T cells.
Roles of CD4+ T cells as mediators of antitumor immunity
Authors: Kravtsov Dmitriy S. , Erbe Amy K. , Sondel Paul M. , Rakhmilevich Alexander L.
Published: September 2022

It has been well established that CD8+ T cells serve as effector cells of the adaptive immune response against tumors, whereas CD4+ T cells either help or suppress the generation of CD8+ cytotoxic T cells. However, in several experimental models as well as in cancer patients, it has been shown that CD4+ T cells can also mediate antitumor immunity either directly by killing tumor cells or indirectly by activating innate immune cells or by reducing tumor angiogenesis. In this review, we discuss the growing evidence of this underappreciated role of CD4+ T cells as mediators of antitumor immunity.
Vascular homeostasis in atherosclerosis: A holistic overview
Authors: Xu Suowen , Lyu Qing Rex , Ilyas Iqra , Tian Xiao-Yu , Weng Jianping
Published: September 2022

Atherosclerosis refers to the deposition of lipids and the co-existence of inflammation and impaired inflammation resolution in pan-vasculature, which causes lumen narrowing, hardening, plaque formation, and the manifestation of acute cardiovascular events. Emerging evidence has suggested that vascular circulation can be viewed as a complex homeostatic system analogous to a mini-ecosystem which consists of the vascular microenvironment (niche) and the crosstalk among phenotypically and functionally diverse vascular cell types. Here, we elucidate how cell components in the vascular wall affect vascular homeostasis, structure, function, and atherosclerosis in a holistic perspective. Finally, we discuss the potential role of vascular-stabilizing strategies including pharmacotherapies, natural substances and lifestyle modifications, in preventing cardiovascular diseases by preserving vascular integrity and homeostasis.
PLAAT1 inhibits type I interferon response via degradation of IRF3 and IRF7 in Zebrafish
Authors: Zhao Xin , Huang Wenji , Shi Yanjie , Guo Jiahong , Xiao Hehe , Ji Ning , Feng Jianhua , Dang Huifeng , Zou Jun
Published: September 2022

PLAAT1 is a member of the PLAAT protein family and plays important roles in tumor suppression, transglutaminase activation and peroxisomal biogenesis. Recently, PLAAT1 has been shown to promote degradation of p53 protein and cellular organelles such as mitochondria, endoplasmic reticulum and lysosome. In this study, we show that PLAAT1 inhibits the production of type I interferon and promotes virus replication in zebrafish. Overexpression of Plaat1 in zebrafish cells suppresses antiviral responses and promotes virus replication. Mechanistically, PLAAT1 interacts with IRF3 and IRF7 to initiate degradation of IRF3 and IRF7, which can be attenuated by 3-methyladenine, an inhibitor of autophagosome. Our study provides novel insights into the functions of PLAAT1 in host immune response to viral infection.
Role of N-Glycosylation in FcγRIIIa interaction with IgG
Authors: Van Coillie Julie , Schulz Morten A. , Bentlage Arthur E. H. , de Haan Noortje , Ye Zilu , Geerdes Dionne M. , van Esch Wim J. E. , Hafkenscheid Lise , Miller Rebecca L. , Narimatsu Yoshiki , Vakhrushev Sergey Y. , Yang Zhang , Vidarsson Gestur , Clausen Henrik
Published: September 2022

Immunoglobulins G (IgG) and their Fc gamma receptors (FcγRs) play important roles in our immune system. The conservedN-glycan in the Fc region of IgG1 impacts interaction of IgG with FcγRs and the resulting effector functions, which has led to the design of antibody therapeutics with greatly improved antibody-dependent cell cytotoxicity (ADCC) activities. Studies have suggested that alsoN-glycosylation of the FcγRIII affects receptor interactions with IgG, but detailed studies of the interaction of IgG1 and FcγRIIIa with distinctN-glycans have been hindered by the natural heterogeneity inN-glycosylation. In this study, we employed comprehensive genetic engineering of theN-glycosylation capacities in mammalian cell lines to express IgG1 and FcγRIIIa with differentN-glycan structures to more generally explore the role ofN-glycosylation in IgG1:FcγRIIIa binding interactions. We included FcγRIIIa variants of both the 158F and 158V allotypes and investigated the keyN-glycan features that affected binding affinity. Our study confirms that afucosylated IgG1 has the highest binding affinity to oligomannose FcγRIIIa, a glycan structure commonly found on Asn162 on FcγRIIIa expressed by NK cells but not monocytes or recombinantly expressed FcγRIIIa.
Intranasal administration of a single dose of MVA-based vaccine candidates against COVID-19 induced local and systemic immune responses and protects mice from a lethal SARS-CoV-2 infection
Authors: Pérez Patricia , Astorgano David , Albericio Guillermo , Flores Sara , Sánchez-Cordón Pedro J. , Luczkowiak Joanna , Delgado Rafael , Casasnovas José M. , Esteban Mariano , García-Arriaza Juan
Published: September 2022

Current coronavirus disease-19 (COVID-19) vaccines are administered by the intramuscular route, but this vaccine administration failed to prevent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus infection in the upper respiratory tract, mainly due to the absence of virus-specific mucosal immune responses. It is hypothesized that intranasal (IN) vaccination could induce both mucosal and systemic immune responses that blocked SARS-CoV-2 transmission and COVID-19 progression. Here, we evaluated in mice IN administration of three modified vaccinia virus Ankara (MVA)-based vaccine candidates expressing the SARS-CoV-2 spike (S) protein, either the full-length native S or a prefusion-stabilized [S(3P)] protein; SARS-CoV-2-specific immune responses and efficacy were determined after a single IN vaccine application. Results showed that in C57BL/6 mice, MVA-based vaccine candidates elicited S-specific IgG and IgA antibodies in serum and bronchoalveolar lavages, respectively, and neutralizing antibodies against parental and SARS-CoV-2 variants of concern (VoC), with MVA-S(3P) being the most immunogenic vaccine candidate. IN vaccine administration also induced polyfunctional S-specific Th1-skewed CD4+ and cytotoxic CD8+ T-cell immune responses locally (in lungs and bronchoalveolar lymph nodes) or systemically (in spleen). Remarkably, a single IN vaccine dose protected susceptible K18-hACE2 transgenic mice from morbidity and mortality caused by SARS-CoV-2 infection, with MVA-S(3P) being the most effective candidate. Infectious SARS-CoV-2 viruses were undetectable in lungs and nasal washes, correlating with high titers of S-specific IgGs and neutralizing antibodies against parental SARS-CoV-2 and several VoC. Moreover, low histopathological lung lesions and low levels of pro-inflammatory cytokines in lungs and nasal washes were detected in vaccinated animals. These results demonstrated that a single IN inoculation of our MVA-based vaccine candidates induced potent immune responses, either locally or systemically, and protected animal models from COVID-19. These results also identified an effective vaccine administration route to induce mucosal immunity that should prevent SARS-CoV-2 host-to-host transmission.
The monocyte-to-osteoclast transition in rheumatoid arthritis: Recent findings
Authors: Iwamoto Naoki , Kawakami Atsushi
Published: September 2022

Rheumatoid arthritis (RA) is an autoimmune disease characterized by joint inflammation leading to joint destruction and deformity. The crucial role of osteoclasts in the bone erosion in RA has been demonstrated. Deregulated osteoclastogenesis which is affected by environmental factors including the inflammatory state, as well as genetic and epigenetic factors, is one of hallmarks of RA pathogenesis. An enhanced-monocyte-to-osteoclast transition plays an important role in osteoclast upregulation in RA because under specific stimuli, circulating monocytes might migrate to a specific location in the bones and fuse with each other to become mature multinucleated osteoclasts. To understand the mechanism of bone damage in RA and to develop novel treatments targeting osteoclast upregulation, it is important to clarify our understanding of the monocyte-to-osteoclast transition in RA. Several potential targets which inhibit both inflammation and osteoclastogenesis, as well as regulators that affect the monocyte-to-osteoclast transition have been revealed by recent studies. Here, we review the factors affecting osteoclastogenesis in RA, summarize the anti-osteoclastogenic effects of current RA treatments, and identify promising therapeutic targets relating to both inflammation and osteoclastogenesis.
Estimating ecological carrying capacity for stock enhancement in marine ranching ecosystems of Northern China
Authors: Wang Zhaoguo , Feng Jie , Lozano-Montes Hector M. , Loneragan Neil R. , Zhang Xiumei , Tian Tao , Wu Zhongxin
Published: September 2022

Marine ranching has been proposed as a promising solution to manage the depleted coastal fishery ecosystem in recent decades across China. Marine ranching integrates the practices of artificial habitat-based with aquaculture-based enhancement. Assessing the ecological carrying capacity of target species for enhancement is a precondition for determining the optimal numbers for release, particularly for those species whose habitat restrictions have been eliminated through the construction of artificial habitats in the marine ranch. A responsible approach to stock enhancement aims not only to increase total yield and stock abundance but also to consider any potential effects on ecosystem structure and function. A time-dynamic, ecosystem model was constructed using Ecopath with Ecosim for the Laizhou Bay (Bohai Sea) marine ranching ecosystem in the nearshore waters of northern China. Two sedentary target species with potential for stock enhancement, i.e., the carnivorous red snail Rapana venosa and the detritivorous sea cucumber Apostichopus japonicus, were selected to simulate and estimate their ecological carrying capacities and project their overall effects on the ecosystem. Ecological carrying capacity was defined as the maximum standing stocks of the target species that would not cause “unacceptable” impacts on the ecosystem function and resilience, i.e., not cause any other group’s biomass to fall below 10% of its original biomass. The ecological carrying capacities estimated for R. venosa and A. japonicus were 623.46 and 200.57 t·km−2, respectively, corresponding to 7.8 and 5.0 times higher than their current standing stocks. Simulations of R. venosa enhancement showed distinct effects of increased target species abundance on other functional groups and ecosystem properties. An increase in red snail biomass caused negative impacts on the biomass of most other functional groups and ecosystem indicators, such as Finn’s cycling index, transfer efficiency, and Kempton’s Q index. In contrast, the simulated A. japonicus enhancement had relatively few impacts, and the biomasses of most other functional groups and ecosystem indicators did not change or changed very slightly (<5%). The current model framework provides a means of estimating the ecological carrying capacity in commercial-scale stock enhancement practices and avoiding potential ecological risks for marine ranching in northern China.
Deciphering organic matter distribution by source-specific biomarkers in the shallow Taiwan Strait from a source-to-sink perspective
Authors: Tao Shuqin , Liu James T. , Wang Aijun , Blattmann Thomas M. , Yang Rick J. , Lee Jay , Xu Jimmy J. , Li Li , Ye Xiang , Yin Xijie , Wang Liang
Published: September 2022

Sedimentary organic matter (OM) in coastal systems is inherently diverse, often with multiple particulate sources and transport histories. The Taiwan Strait (TS) is a typical shallow conduit region, linking the East and South China Seas. Strong ocean currents, coastal upwellings, distal large rivers, and proximal small mountainous rivers all influence the distribution of OM in the TS. We investigated the covarying patterns in the distribution of gain size classes of sand, silt, and clay; terrestrial-sourced biomarkers (n-C27+29+31 alkanes, n-C26+28+30 fatty acids (FAs), and n-C28+30+32 alkanols); marine-sourced biomarkers (phytoplankton-derived alkenones, brassicasterol, dinosterol, and zooplankton-derived cholesterol) in sea floor sediment; indicator satellite-derived primary production (Chl-a); and water-mass indicator (sea surface temperature, SST). We used an empirical orthogonal/eigen function (EOF) analysis to distinguish the influence of four hypothetical sources that entered the TS through the north, south, west, and east boundaries. Results show that input sources from the south-bound ZMCC (Zhejiang-Fujian Coastal Current) and north-bound SCSWC (South China Sea Warm Current) had the dominant influence on the OM distributions buried in the TS. Input sources via river plumes on lateral boundaries and upwellings in the TS were the secondary factors that affected the sedimentary OM distribution. Within this source-to-sink system of multiple sources and transport processes, silt and clay were the major carriers of the OM signals. Terrestrial biomarkers and primary production (Chl-a) were associated with the two major current systems and river plumes along the edge of TS. Marine biomarkers were associated with upwellings in the interior of the TS. Our finding points out that the physical systems of ocean currents, river plumes, and upwelling not only determine the distributions of biomarkers in the TS but also determine the diversity of OM in the TS.
Transcriptome analysis provides insight into adaptive mechanisms of scallops under environmental stress
Authors: Mao Junxia , Huang Xiaofang , Sun Hongyan , Jin Xin , Guan Wenjuan , Xie Jiahui , Wang Yiying , Wang Xubo , Yin Donghong , Hao Zhenlin , Tian Ying , Song Jian , Ding Jun , Chang Yaqing
Published: September 2022

High temperature and hypoxia greatly threaten marine life and aquaculture. Scallops, a diverse and ecologically important group of high economic value, mostly thrive in fluctuating environments, and are vulnerable to environmental stress. In the present study, the molecular response mechanism of scallops to a combination of environmental stressors was investigated via transcriptome analysis of the gill tissues in three scallop species, the Yesso scallop (Patinopecten yessoensis), Zhikong scallop (Chlamys farreri) and bay scallop (Argopecten irradians) that were exposed to transient heat, hypoxia and a combination thereof. The Yesso scallop had the most differentially expressed genes (DEGs) compared with the other two scallop species, indicating the highest sensitivity of the Yesso scallop to environmental stress. With increased temperature and decreased dissolved oxygen, the number of DEGs was greatly increased in the three scallop species, indicative of the enhancement in gene expression regulation in scallops in response to severe environmental changes. Heat and hypoxia had a synergistic effect on scallops. GO and KEGG enrichment analysis of DEGs under different stressors revealed overlapping molecular mechanisms of response in scallops following exposure to heat and hypoxia. Several immune and apoptosis-related pathways were highly enriched in the upregulated DEGs of the three scallops, suggesting that immune system activation and apoptosis promotion occurred in scallops in response to environmental stress. Heat shock proteins (HSPs) were significantly upregulated under heat and hypoxia, which likely assisted in correct protein folding to facilitate the adaption of the scallops to the altered environment. Additionally, the HIF-1 signaling pathway—the key pathway associated with hypoxia response—was triggered by extremely acute environmental changes. Comparative transcriptome analysis revealed 239 positively selected genes among the different scallops, including those involved in immune system and environmental adaptation, suggesting a long-term mechanism of environmental adaptation. The present study provides new insights into the molecular response mechanism in scallops to multiple environmental stressors and improves our understanding of the adaptive mechanisms of marine organisms under changing global climate conditions.
Acidification and high-temperature impacts on energetics and shell production of the edible clam Ameghinomya antiqua
Authors: Martel Sebastián I. , Fernández Carolina , Lagos Nelson A. , Labra Fabio A. , Duarte Cristián , Vivanco Juan F. , García-Herrera Claudio , Lardies Marco A.
Published: September 2022

Warming and ocean acidification are currently critical global change drivers for marine ecosystems due to their complex and irreversible effects on the ecology and evolution of marine communities. Changes in the chemistry and the temperature of the ocean impact the biological performance of marine resources by affecting their energy budget and thus imposing energetic restrictions and trade-offs on their survival, growth, and reproduction. In this study, we evaluated the interplaying effects of increased pCO2 levels and temperature on the economically relevant clam Ameghinomya antiqua, an infaunal bivalve inhabiting a wide distributional range along the coast of Chile. Juvenile clams collected from southern Chile were exposed to a 90-day experimental set-up emulating the current and a future scenario projeced to the end of the current century for both high pCO2/low-pH and temperature (10 and 15°C) projected for the Chilean coast. Clams showed physiological plasticity to different projected environmental scenarios without mortality. In addition, our results showed that the specimens under low-pH conditions were not able to meet the energetic requirements when increased temperature imposed high maintenance costs, consequently showing metabolic depression. Indeed, although the calcification rate was negative in the high-pCO2 scenario, it was the temperature that determined the amount of shell loss. These results indicate that the studied clam can face environmental changes for short-term periods modifying energetic allocation on maintenance and growth processes, but with possible long-term population costs, endangering the sustainability of an important benthic artisanal fisheries resource.
Should China access to the convention on the protection of underwater cultural heritage? — A SWOT analysis
Authors: Yuan Wei
Published: September 2022

In recent years, with China’s marine strength having enhanced, the discussion on whether to access to the ‘Convention on the Protection of Underwater Cultural Heritage’ has become increasingly prominent. A growing number of experts and scholars believe that the current domestic laws cannot meet the needs of development; thus accession to the ‘Convention’ may after all be accepted as a solution. Given the current development in China, it cannot be generalized whether it is appropriate to access to the ‘Convention’. Indeed, based on the analysis of comparison between status quo of domestic legislation and international marine development, there is no necessity for China to eagerly access to the ‘Convention’, in that for many issues, the domestic laws in China have many differences with international law, and still need further development and improvement.
Multiple linear-crossing metamaterials for directional refraction
Authors: Guo Zhiwei , Jian Yiran , Wu Xian , Deng Fusheng , Dong Lijuan , Chen Hong
Published: September 2022

Recently, linear-crossing metamaterials (LCMMs) in the hyperbolic topological transition of iso-frequency contour, have attracted people’s great attention. Due to the novel linear dispersion, LCMM provides a new platform to control and enhance the light-matter interactions, such as all-angle negative refraction, filters, super-lens, etc. However, the narrow-band working frequency is currently the major limitation in LCMMs. In this work, we propose two methods to realize multiple linear-crossing metamaterials (MLCMMs), including a basic Drude-Lorenz model and an actual step-like multilayer structure. Especially, in order to identify the designed two kinds of MLCMMs, we numerically demonstrate the unique beam splitting and directional refraction of MLCMM at different frequencies. Our findings may not only provide a new platform for the fundamental study of LCMM, but also facilitate some broadband applications.
Factors associated with the recurrence of choroidal neovascularization in pathologic myopia
Authors: Jing Ruixia , Bo Yuxia , Gao Lei , Wang Zhen
Published: September 2022

Purpose

To investigate the factors associated with the recurrence of pathologic myopia choroidal neovascularization (PM-CNV).

Methods

Forty-eight eyes of 48 patients with PM-CNV treated with conbercept at least 6 months of follow-up were included. Appearance of ellipsoid zone (EZ) and retinal pigment epithelium (RPE) observed on optical coherence tomography (OCT). Hyperreflective foci (HRF) height measured on OCT. Observation of CNV shape on OCT-angiography (OCTA). PM-CNV area measured on OCTA. To observe relationship between these factors and best corrected visual acuity (BCVA) and PM-CNV recurrence.

Results

The 48 patients (48 eyes) with PM-CNV were divided into two groups: yielding a group of 20 eyes with type 1 and a group of 28 eyes with type 2. The BCVA of type 1 was better than type 2 before and after treatment (P < 0.005). Smaller HRF height (P < 0.001) and CNV area (P < 0.001) for type 1 than type 2. The appearance of EZ and RPE were intact (P < 0.001). Spearman correlation analysis found that final BCVA was significantly associated with baseline BCVA, HRF height, and appearance of EZ (P < 0.05). Binary logistics regression analysis revealed that PM-CNV recurrence was significantly correlated not only HRF height and CNV area, but also with appearance of EZ, and RPE (P < 0.05).

Conclusion

PM-CNV had a higher recurrence ratio. Baseline BCVA and clinical features play an important role for vision prognosis. Factors associated with PM-CNV recurrence include HRF height, CNV area, and changes in EZ and RPE structure.
Awake prone positioning for patients with COVID-19 pneumonia in intensive care unit: A systematic review and meta-analysis
Authors: Huang Hui-Bin , Yao Yan , Zhu Yi-Bing , Du Bin
Published: September 2022

Background

Awake prone positioning (APP) has been widely used in non-intubated COVID-19 patients during the pandemic. However, high-quality evidence to support its use in severe COVID-19 patients in an intensive care unit (ICU) is inadequate. Therefore, we aimed to assess the efficacy and safety of APP for intubation requirements and other important outcomes in this patient population.

Methods

We searched for potentially relevant articles in PubMed, Embase, and the Cochrane database from inception to May 25, 2022. Studies focusing on COVID-19 adults in ICU who received APP compared to controls were included. The primary outcome was the intubation requirement. Secondary outcomes were mortality, ICU stay, and adverse events. Study quality was independently assessed, and we also conducted subgroup analysis, sensitivity analysis, and publication bias to explore the potential influence factors.

Results

Ten randomized controlled trials with 1,686 patients were eligible. The quality of the included studies was low to moderate. Overall, the intubation rate was 35.2% in the included patients. The mean daily APP duration ranged from <6 to 9 h, with poor adherence to APP protocols. When pooling, APP significantly reduced intubation requirement (risk ratio [RR] 0.84; 95%CI, 0.74–0.95; I2 = 0%, P = 0.007). Subgroup analyses confirmed the reduced intubation rates in patients who were older (≥60 years), obese, came from a high mortality risk population (>20%), received HFNC/NIV, had lower SpO2/FiO2 (<150 mmHg), or undergone longer duration of APP (≥8 h). However, APP showed no beneficial effect on mortality (RR 0.92 [95% CI 0.77–1.10; I2 = 0%, P = 0.37] and length of ICU stay (mean difference = −0.58 days; 95% CI, −2.49 to 1.32; I2 = 63%; P = 0.55).

Conclusion

APP significantly reduced intubation requirements in ICU patients with COVID-19 pneumonia without affecting the outcomes of mortality and ICU stay. Further studies with better APP protocol adherence will be needed to define the subgroup of patients most likely to benefit from this strategy.
Epidemiological characteristics and molecular evolution mechanisms of carbapenem-resistant hypervirulent Klebsiella pneumoniae
Authors: Han Yu-Ling , Wen Xu-Hui , Zhao Wen , Cao Xi-Shan , Wen Jian-Xun , Wang Jun-Rui , Hu Zhi-De , Zheng Wen-Qi
Published: September 2022

Carbapenem-resistant hypervirulent Klebsiella pneumoniae (CR-hvKP), a type of Klebsiella pneumoniae (KP) that exhibits hypervirulence and carbapenem resistance phenotypes, can cause severe infections, both hospital- and community-acquired infections. CR-hvKP has brought great challenges to global public health and is associated with significant morbidity and mortality. There are many mechanisms responsible for the evolution of the hypervirulence and carbapenem resistance phenotypes, such as the horizontal transfer of the plasmid carrying the carbapenem resistance gene to hypervirulent Klebsiella pneumoniae (hvKP) or carbapenemase-producing Klebsiella pneumoniae (CRKP) acquiring a hypervirulence plasmid carrying a virulence-encoding gene. Notably, KP can evolve into CR-hvKP by acquiring a hybrid plasmid carrying both the carbapenem resistance and hypervirulence genes. In this review, we summarize the evolutionary mechanisms of resistance and plasmid-borne virulence as well as the prevalence of CR-hvKP.
Allosteric regulation of substrate channeling: Salmonella typhimurium tryptophan synthase
Authors: Ghosh Rittik K. , Hilario Eduardo , Chang Chia-en A. , Mueller Leonard J. , Dunn Michael F.
Published: September 2022

The regulation of the synthesis of L-tryptophan (L-Trp) in enteric bacteria begins at the level of gene expression where the cellular concentration of L-Trp tightly controls expression of the five enzymes of the Trp operon responsible for the synthesis of L-Trp. Two of these enzymes, trpA and trpB, form an αββα bienzyme complex, designated as tryptophan synthase (TS). TS carries out the last two enzymatic processes comprising the synthesis of L-Trp. The TS α-subunits catalyze the cleavage of 3-indole D-glyceraldehyde 3′-phosphate to indole and D-glyceraldehyde 3-phosphate; the pyridoxal phosphate-requiring β-subunits catalyze a nine-step reaction sequence to replace the L-Ser hydroxyl by indole giving L-Trp and a water molecule. Within αβ dimeric units of the αββα bienzyme complex, the common intermediate indole is channeled from the α site to the β site via an interconnecting 25 Å-long tunnel. The TS system provides an unusual example of allosteric control wherein the structures of the nine different covalent intermediates along the β-reaction catalytic path and substrate binding to the α-site provide the allosteric triggers for switching the αββα system between the open (T) and closed (R) allosteric states. This triggering provides a linkage that couples the allosteric conformational coordinate to the covalent chemical reaction coordinates at the α- and β-sites. This coupling drives the α- and β-sites between T and R conformations to achieve regulation of substrate binding and/or product release, modulation of the α- and β-site catalytic activities, prevention of indole escape from the confines of the active sites and the interconnecting tunnel, and synchronization of the α- and β-site catalytic activities. Here we review recent advances in the understanding of the relationships between structure, function, and allosteric regulation of the complex found in Salmonella typhimurium.
Mathematical characterization of population dynamics in breast cancer cells treated with doxorubicin
Authors: Yang Emily Y. , Howard Grant R. , Brock Amy , Yankeelov Thomas E. , Lorenzo Guillermo
Published: September 2022

The development of chemoresistance remains a significant cause of treatment failure in breast cancer. We posit that a mathematical understanding of chemoresistance could assist in developing successful treatment strategies. Towards that end, we have developed a model that describes the cytotoxic effects of the standard chemotherapeutic drug doxorubicin on the MCF-7 breast cancer cell line. We assume that treatment with doxorubicin induces a compartmentalization of the breast cancer cell population into surviving cells, which continue proliferating after treatment, and irreversibly damaged cells, which gradually transition from proliferating to treatment-induced death. The model is fit to experimental data including variations in drug concentration, inter-treatment interval, and number of doses. Our model recapitulates tumor cell dynamics in all these scenarios (as quantified by the concordance correlation coefficient, CCC > 0.95). In particular, superior tumor control is observed with higher doxorubicin concentrations, shorter inter-treatment intervals, and a higher number of doses (p < 0.05). Longer inter-treatment intervals require adapting the model parameterization after each doxorubicin dose, suggesting the promotion of chemoresistance. Additionally, we propose promising empirical formulas to describe the variation of model parameters as functions of doxorubicin concentration (CCC > 0.78). Thus, we conclude that our mathematical model could deepen our understanding of the cytotoxic effects of doxorubicin and could be used to explore practical drug regimens achieving optimal tumor control.
Release of protein N-glycans by effectors of a Hofmann carboxamide rearrangement
Authors: Kasim Mumtaz , Schulz Malissa , Griebel Anja , Malhotra Akshay , Müller Barbara , von Horsten Hans Henning
Published: September 2022

Background: Chemical methods for glycan release have gained traction because of their cost efficiency, accelerated reaction time and ability to release glycans not amenable to enzymatic cleavage. Oxidative chemical glycan release via hypochlorite treatment has been shown to be a convenient and efficient method that yields N-glycans similar to classical PNGase F digestion. We observed that the initial steps of the suggested mechanism for the oxidative release of glycans from glycoproteins by hypohalites showed similarities to the initiating steps of the classical Hofmann rearrangement of carboxamides. Therefore, we investigated the ability of different stable effectors of a Hofmann-type carboxamide rearrangement to efficiently and selectively release N-glycans from glycoproteins.

Methods: Released glycans obtained from different experimental chemical release approaches were analyzed by HILIC-FLD, BHZ-FACE and ESI-MS and evaluated with respect to electrophoretic mobility, retention time and integrated peak area for resolved glycans.

Results: We show that the known Hoffmann catalysts 1,3-dichloro-5,5-dimethylhydantoin, the hypervalent organoiodine (III) compound diacetoxy-iodobenzene as well as in-situ hypobromite generation using Oxone® and potassium bromide are all capable of releasing protein-bound N-glycans in good yield. Among the compounds investigated, diacetoxy-iodobenzene was capable of releasing glycans in the absence of alkali. Detailed investigations of the bromide/Oxone® method revealed a dependence of N-glycan release efficiency from the temporal order of bromide addition to the reaction mix as well as from a molar excess of bromide over Oxone®. Conclusions. These findings suggest that the oxidative release of N-glycans occurs via the initiating steps of a Hofmann carboxamide rearrangement. Hypervalent organoiodine compounds hold the promise of releasing glycans in the absence of alkali. The in-situ generation of hypobromite by bromide/Oxone® produces a consistent defined amount of reagent for rapid N-glycan release for both analytical and preparative purposes.
Effect of the ACTN-3 gene polymorphism on functional fitness and executive function of elderly
Authors: Henrique Jessica Salles , Braga Pedro Luiz Garcia , Almeida Sandro Soares de , Nunes Nathalia Santanna Petraconi , Benfato Izabelle Dias , Arida Ricardo Mario , de Oliveira Camila Aparecida Machado , Gomes da Silva Sérgio
Published: September 2022

During aging, physical integrity and cognitive abilities, especially executive function, become compromised, directly influencing the quality of life of the elderly. One good strategy to ensure healthy aging is the practice of physical exercise. Activities to improve aerobic capacity and muscle strength are extremely important in old age. However, some genetic factors can interfere both positively and negatively with these gains. In this context, the polymorphism rs1815739 (R577X) of the α-actinin 3 gene (ACTN-3) is commonly studied and related to muscle phenotype. Thus, the present study aimed to investigate the effect of the ACTN-3 gene polymorphism on the functional fitness (measured by the Senior Fit test) and cognitive capacity (evaluated by the Stroop test) of the elderly (n = 347), both men and women. We did not find the effect of genotype on functional fitness, but we did observed a positive effect of the ACTN-3 gene polymorphism on executive function. The presence of the X allele of the ACTN3 gene in the elderly was related to a better performance in the Stroop test (shorter answer time). Our results showed that ACTN-3 gene polymorphism affects the executive function of the elderly but not their functional fitness.
Associations between abdominal obesity and the risk of stroke in Chinese older patients with obstructive sleep apnea: Is there an obesity paradox?
Authors: Su Xiaofeng , Li Kailiang , Yang Ling , Yang Yang , Gao Yinghui , Gao Yan , Guo JingJing , Lin Junling , Chen Kaibing , Han Jiming , Liu Lin
Published: September 2022

Background and purpose

Abdominal obesity (AO) is a well-known independent risk factor for stroke in the general population although it remains unclear in the case of the elderly, especially in Chinese older patients with obstructive sleep apnea (OSA), considering the obesity paradox. This study aimed to investigate the association between AO and stroke among Chinese older patients with OSA.

Methods

Data were collected from January 2015 to October 2017, and 1,290 older patients (age 60–96 years) with OSA (apnea–hypopnea index ≥ 5 events/h on polysomnography) were consecutively enrolled from sleep centers at six hospitals, evaluated for AO defined as waist circumference (WC) using the standardized criteria for the Chinese population, and followed up prospectively for a median period of 42 months. Logistic regression and Cox regression analyses were used to determine the cross-sectional and longitudinal associations between AO and stroke risk in these participants and different groups of the severity of OSA.

Results

Participants with AO had a higher prevalence of stroke at baseline. A higher incidence of stroke during a median follow-up period of 42 months in participants with AO than in participants without AO (12.4% vs. 6.8% and 8.3% vs. 2.4%, respectively; both P < 0.05) was predicted. Cross-sectional analysis revealed an association between AO and stroke (odds ratio [OR]1.96, 95% confidence interval [CI] 1.31–2.91), which was stronger among participants with moderate OSA only (OR 2.16, 95%CI 1.05–4.43). Cox regression analysis showed that, compared to participants without AO, participants with AO had a higher cumulative incidence of stroke (hazard ratio [HR] 2.16, 95% CI 1.12–4.04) during a median follow-up of 42 months, and this association was observed in patients with severe OSA only (HR 3.67, 95% CI 1.41–9.87) but not for individuals with mild OSA (HR = 1.84, 95% CI 0.43–6.23) and moderate OSA (HR = 1.98, 95% CI 0.73–6.45).

Conclusion

The risk of stroke is associated with AO among Chinese older patients who have OSA, both at baseline and during follow-up, and the strength of the association varied by OSA severity. Active surveillance for early detection of AO could facilitate the implementation of stroke-preventive interventions in the Chinese older OSA population.
Work hard, play hard: how sexually differentiated microglia work to shape social play and reproductive behavior
Authors: Sullivan Olivia , Ciernia Annie Vogel
Published: September 2022

Microglia are brain-resident immune cells that play a critical role in synaptic pruning and circuit fine-tuning during development. In the adult brain, microglia actively survey their local environment and mobilize inflammatory responses to signs of damage or infection. Sex differences in microglial gene expression and function across the lifespan have been identified, which play a key role in shaping brain function and behavior. The levels of sex hormones such as androgens, estrogens, and progesterone vary in an age-dependent and sex-dependent manner. Microglia respond both directly and indirectly to changes in hormone levels, altering transcriptional gene expression, morphology, and function. Of particular interest is the microglial function in brain regions that are highly sexually differentiated in development such as the amygdala as well as the pre-optic and ventromedial hypothalamic regions. With a focus on hormone-sensitive developmental windows, this review compares male and female microglia in the embryonic, developing, and adult brain with a particular interest in the influence of sex hormones on microglial wiring of social, reproductive, and disordered behavior circuits in the brain.
Ayu-Characterization of healthy aging from neuroimaging data with deep learning and rsfMRI
Authors: Borkar Kushal , Chaturvedi Anusha , Vinod P. K. , Bapi Raju Surampudi
Published: September 2022

Estimating brain age and establishing functional biomarkers that are prescient of cognitive declines resulting from aging and different neurological diseases are still open research problems. Functional measures such as functional connectivity are gaining interest as potentially more subtle markers of neurodegeneration. However, brain functions are also affected by “normal” brain aging. More information is needed on how functional connectivity relates to aging, particularly in the absence of neurodegenerative disorders. Resting-state fMRI enables us to investigate functional brain networks and can potentially help us understand the processes of development as well as aging in terms of how functional connectivity (FC) matures during the early years and declines during the late years. We propose models for estimation of the chronological age of a healthy person from the resting state brain activation (rsfMRI). In this work, we utilized a dataset (N = 638, age-range 20–88) comprising rsfMRI images from the Cambridge Centre for Aging and Neuroscience (Cam-CAN) repository of a healthy population. We propose an age prediction pipeline Ayu which consists of data preprocessing, feature selection, and an attention-based model for deep learning architecture for brain age assessment. We extracted features from the static functional connectivity (sFC) to predict the subject's age and classified them into different age groups (young, middle, middle, and old ages). To the best of our knowledge, a classification accuracy of 72.619 % and a mean absolute error of 6.797, and an r2 of 0.754 reported by our Ayu pipeline establish competitive benchmark results as compared to the state-of-the-art-approach. Furthermore, it is vital to identify how different functional regions of the brain are correlated. We also analyzed how functional regions contribute differently across ages by applying attention-based networks and integrated gradients. We obtained well-known resting-state networks using the attention model, which maps to within the default mode network, visual network, ventral attention network, limbic network, frontoparietal network, and somatosensory network connected to aging. Our analysis of fMRI data in healthy elderly Age groups revealed that dynamic FC tends to slow down and becomes less complex and more random with increasing age.
The pharmacological treatment of acute vestibular syndrome
Authors: Viola Pasquale , Gioacchini Federico Maria , Astorina Alessia , Pisani Davide , Scarpa Alfonso , Marcianò Gianmarco , Casarella Alessandro , Basile Emanuele , Rania Vincenzo , Re Massimo , Chiarella Giuseppe
Published: September 2022

Acute vestibular syndrome (AVS) represents a clinical picture that involves urgent management due to the important procession of symptoms accompanying the event, which can be positively or negatively influenced by therapeutic choices and intervention timing. This forces a differential diagnosis and therapeutic choices to be made in conditions that are not always favorable and often not in the specialist field. In this work, we will examine in detail the pharmacological therapeutic possibilities, correlating them to the differential and, as far as possible, to the etiological diagnosis. In particular, the pharmacological possibilities for the two main conditions we can face will be investigated, namely, vestibular neuritis and posterior circulation stroke.
Potential epigenetic mechanisms in psychotherapy: a pilot study on DNA methylation and mentalization change in borderline personality disorder
Authors: Quevedo Yamil , Booij Linda , Herrera Luisa , Hernández Cristobal , Jiménez Juan Pablo
Published: September 2022

Genetic and early environmental factors are interwoven in the etiology of Borderline Personality Disorder (BPD). Epigenetic mechanisms offer the molecular machinery to adapt to environmental conditions. There are gaps in the knowledge about how epigenetic mechanisms are involved in the effects of early affective environment, development of BPD, and psychotherapy response. We reviewed the available evidence of the effects of psychotherapy on changes in DNA methylation and conducted a pilot study in a sample of 11 female adolescents diagnosed with BPD, exploring for changes in peripheral DNA methylation of FKBP5 gene, which encodes for a stress response protein, in relation to psychotherapy, on symptomatology and underlying psychological processes. For this purpose, measures of early trauma, borderline and depressive symptoms, psychotherapy outcome, mentalization, and emotional regulation were studied. A reduction in the average FKBP5 methylation levels was observed over time. Additionally, the decrease in FKBP5 methylation observed occurred only in those individuals who had early trauma and responded to psychotherapy. The results suggest an effect of psychotherapy on epigenetic mechanisms associated with the stress response. The finding that epigenetic changes were only observed in patients with early trauma suggests a specific molecular mechanism of recovery. The results should be taken with caution given the small sample size. Also, further research is needed to adjust for confounding factors and include endocrinological markers and therapeutic process variables.