bluuebunny/crossref_metadata_2025 huggingface dataset:
Unique Reciprocal Association Seen Between Latent Tuberculosis Infection and Diabetes Is Due to Immunoendocrine Modulation (DM-LTB-1)
Authors: Aravindhan Vivekanandhan , Bobhate Anup , Sathishkumar Kuppan , Patil Aruna , Kumpatla Satyavani , Viswanathan Vijay
Published: June 2022

Aim

The prevalence of latent tuberculosis infection (LTBI) among diabetes patients is poorly studied. In the present study, the prevalence of LTBI among pre-diabetes and diabetes patients was studied, along with immunoendocrine biomarkers (n = 804).

Methods

LTBI was screened by Quantiferon TB gold in Normal glucose tolerance [(NGT); n = 170, [Pre-diabetes (PDM; n = 209), Newly diagnosed diabetes (NDM; n = 165) and Known diabetes (KDM; n = 260) subjects. CRP, TNF-α, IL-6, IL-1β, IFN-β, IL-12, IFN-γ, IL-2, insulin, leptin, and adiponectin levels in serum and IFN-γ levels in quantiferon supernatants were quantified by ELISA. The expression of T-bet was quantified using qRT-PCR. Serum TBARS and nitrite levels were quantified by colorimetry.

Results

The LTBI prevalence was 32% in NGT, 23% in PDM, 24% in NDM, and 32% in KDM groups, with an adjusted OR of 0.61 (p < 0.05). Downregulation of CRP, TNF-α, and nitrites and upregulation of adiponectin could be responsible for LTBI mediated protection against insulin resistance (IR), while the high levels of IL-1β, IL-12, and leptin could be responsible for IR mediated anti-TB immunity. The defective antigen-specific IFN-γ response, as seen in the KDM group, could be responsible for the low detection rate of LTBI and high probability of endogenous reactivation.

Conclusion

There appears to be a biphasic relationship between diabetes-latent tuberculosis: At the early stages of diabetes it is reciprocal, while at a late stage it is synergistic, this important phenomenon obviously needs further research.
IS6110 Copy Number in Multi-Host Mycobacterium bovis Strains Circulating in Bovine Tuberculosis Endemic French Regions
Authors: Charles Ciriac , Conde Cyril , Biet Franck , Boschiroli Maria Laura , Michelet Lorraine
Published: June 2022

IS6110 is an insertion sequence found in the Mycobacterium tuberculosis complex, to which Mycobacterium bovis belongs, which can play a role in genome plasticity and in bacterial evolution. In this study, the abundance and location of IS6110 on M. bovis genomic data of French animal field strains were studied. A first analysis was performed on a panel of 81 strains that reflect the national M. bovis population’s genetic diversity. The results show that more than one-third of them are IS6110 multicopy and that 10% have IS6110 in a high copy number (more than 6 copies). Multicopy strains are those circulating in the regions where prevalence was above the national average. Further study of 93 such strains, with an IS6110 copy number of 10-12, showed stability of IS6110 copy number and genome location over time and between host species. The correlation between M. bovis multicopy strains and high bovine tuberculosis (bTB) prevalence leads us to consider whether their epidemiological success could be partly due to genetic changes originated by IS6110 transposition.
Biospeleothems Formed by Fungal Activity During the Early Holocene in the “Salar de Uyuni”
Authors: Anglés Angélica , He Qitao , Sánchez García Laura , Carrizo Daniel , Rodriguez Nuria , Huang Ting , Shen Yan , Amils Ricardo , Fernández-Remolar David C.
Published: June 2022

The Chiquini and Galaxias caves contain speleothems that are templated by long fungal structures. They have been associated with the carbonate lacustrine deposits in the margins of the Coipasa and Uyuni Salar basins. During a wetter episode, such carbonates formed at the end of the last glaciation raising the lake level to more than 100 m in the Tauca events (15–12 ky). Such an event flooded the caves that eventually became a cryptic habitat in the lake. The caves show bizarre speleothems framed by large (>1 m) fungal buildings covering the older algal mineralized structures. Although the origin of the caves is not fully understood, the occurrence of two carbonatic units with very distinctive fabric suggests that they formed in two separated humid events. In this regard, the mineralized algal structures, showing the same features as the lacustrine carbonates, likely formed during the Tauca flooding events in the terminal Pleistocene that inundated older caves. The different caves were exposed to the atmosphere after a drop in the lake level that promoted alluvial erosion by <12–10 ky (Ticaña episode) under arid conditions. A last humid episode rising the lake surface 10 m above the Salar level, which was not enough to inundate the caves a second time, drove the formation of the biospeleothems by fungi biomineralization. The abundance and size of the preserved fungal structures suggest that they were sustained by a stable hydrological activity plus a constant organic supply. While nutrients could have been primarily sourced from the vegetal communities that occupied the exhumated lake margins, they might have also been released from the lacustrine carbonatic unit. The combination of hydrology and biological activities were likely determinants for a fast rock dissolution and mineralization ending in the construction of the fungal biospeleothems.
Rewiring of Gene Expression in Pseudomonas aeruginosa During Diauxic Growth Reveals an Indirect Regulation of the MexGHI-OpmD Efflux Pump by Hfq
Authors: Rozner Marlena , Nukarinen Ella , Wolfinger Michael T. , Amman Fabian , Weckwerth Wolfram , Bläsi Udo , Sonnleitner Elisabeth
Published: June 2022

In Pseudomonas aeruginosa, the RNA chaperone Hfq and the catabolite repression protein Crc act in concert to regulate numerous genes during carbon catabolite repression (CCR). After alleviation of CCR, the RNA CrcZ sequesters Hfq/Crc, which leads to a rewiring of gene expression to ensure the consumption of less preferred carbon and nitrogen sources. Here, we performed a multiomics approach by assessing the transcriptome, translatome, and proteome in parallel in P. aeruginosa strain O1 during and after relief of CCR. As Hfq function is impeded by the RNA CrcZ upon relief of CCR, and Hfq is known to impact antibiotic susceptibility in P. aeruginosa, emphasis was laid on links between CCR and antibiotic susceptibility. To this end, we show that the mexGHI-opmD operon encoding an efflux pump for the antibiotic norfloxacin and the virulence factor 5-Methyl-phenazine is upregulated after alleviation of CCR, resulting in a decreased susceptibility to the antibiotic norfloxacin. A model for indirect regulation of the mexGHI-opmD operon by Hfq is presented.
Dual RNA Sequencing Analysis of Bacillus amyloliquefaciens and Sclerotinia sclerotiorum During Infection of Soybean Seedlings by S. sclerotiorum Unveils Antagonistic Interactions
Authors: Cheng Yunqing , Gao Xin , He Hongli , Zhang Xingzheng , Wang Ran , Liu Jianfeng
Published: June 2022

Soybean Sclerotinia stem rot is caused by Sclerotinia sclerotiorum infection, which causes extensive and severe damage to soybean production. Here, we isolated and patented a Bacillus amyloliquefaciens strain, and used it to verify the antagonistic effect of B. amyloliquefaciens on S. sclerotiorum and to explore the possible underlying mechanism. First, we conducted a plate confrontation experiment using the two microbes. Then, inoculation of soybean (Glycine max) seedlings with S. sclerotiorum (Gm-Ss), B. amyloliquefaciens (Gm-Ba), and their combination (Gm-Ba-Ss) was performed, followed by dual RNA sequencing analysis. Plate confrontation and inoculation experiments showed that B. amyloliquefaciens significantly antagonized S. sclerotiorum growth. The average number of fragments per kilobase of transcript per million fragments mapped of S. sclerotiorum transcripts in Gm-Ss and Gm-Ba-Ss inoculation treatments were 117.82 and 50.79, respectively, indicating that B. amyloliquefaciens strongly inhibited gene expression of S. sclerotiorum. In contrast, the average number of fragments per kilobase of transcript per million fragments mapped of B. amyloliquefaciens transcripts in Gm-Ba and Gm-Ba-Ss inoculation treatments were 479.56 and 579.66, respectively, indicating that S. sclerotiorum promoted overall gene expression in B. amyloliquefaciens. For S. sclerotiorum, 507 upregulated and 4,950 downregulated genes were identified among 8,975 genes in the paired comparison Gm-Ba-Ss vs. Gm-Ss. These differentially expressed genes (DEGs) were significantly enriched in the ribosome (ko03010) KEGG pathway. Additionally, for B. amyloliquefaciens, 294 upregulated and 178 downregulated genes were identified among all 3,154 genes in the paired comparison Gm-Ba-Ss vs. Gm-Ba, and these DEGs were mainly and significantly enriched in metabolism-related KEGG pathways, including the citrate cycle (ko00020) and carbon metabolism (ko01200). We concluded that B. amyloliquefaciens inhibits the expression of genes encoding the ribosomal subunit of S. sclerotiorum, resulting in protein synthesis inhibition in S. sclerotiorum, and thus had a strong antagonistic effect on the fungus. This study provides a scientific basis for the biological control of S. sclerotiorum by B. amyloliquefaciens.
Deletion of the Loop Linking Two Domains of Exo-Inulinase InuAMN8 Diminished the Enzymatic Thermo-Halo-Alcohol Tolerance
Authors: Cen Xiaolong , Zhang Rui , He Limei , Tang Xianghua , Wu Qian , Zhou Junpei , Huang Zunxi
Published: June 2022

Inulin is the rich water-soluble storage polysaccharide after starch in nature, and utilization of inulin through hydrolysis of exo-inulinases has attracted much attention. Thermo-halo-alcohol tolerance is essential for exo-inulinase applications, while no report reveals the molecular basis involved in halo-alcohol tolerance of exo-inulinases via experimental data. In this study, two loops of exo-inulinase InuAMN8, including the loop built with 360GHVRLGPQP368 linking domains of Glyco_hydro_32N and Glyco_hydro_32C and another loop built with 169GGAG172 in the catalytic domain, were deleted to generate mutants MutG360Δ9 and MutG169Δ4, respectively. After heterologous expression, purification, and dialysis, InuAMN8, MutG169Δ4, and MutG360Δ9 showed half-lives of 144, 151, and 7 min at 50°C, respectively. InuAMN8 and MutG169Δ4 were very stable, while MutG360Δ9 showed a half-life of approximately 60 min in 5.0% (w/v) NaCl, and they showed half-lives of approximately 60 min in 25.0, 25.0, and 5.0% (w/v) ethanol, respectively. Structural analysis indicated that two cation-π bonds, which contributed to thermal properties of InuAMN8 at high temperatures, broke in MutG360Δ9. Four basic amino acid residues were exposed to the structural surface of MutG360Δ9 and formed positive and neutral electrostatic potential that caused detrimental effects on halo-alcohol tolerance. The study may provide a better understanding of the loop-function relationships that are involved in thermo-halo-alcohol adaptation of enzymes in extreme environment.
SsAGM1-Mediated Uridine Diphosphate-N-Acetylglucosamine Synthesis Is Essential for Development, Stress Response, and Pathogenicity of Sclerotinia sclerotiorum
Authors: Zhang Junting , Xiao Kunqin , Li Maoxiang , Hu Hanlong , Zhang Xianghui , Liu Jinliang , Pan Hongyu , Zhang Yanhua
Published: June 2022

The necrotrophic fungus Sclerotinia sclerotiorum is a devastating pathogen. S. sclerotiorum can cause Sclerotinia stem rot in more than 600 species of plants, which results in serious economic losses every year. Chitin is one of the most important polysaccharides in fungal cell walls. Chitin and β-Glucan form a scaffold that wraps around the cell and determines the vegetative growth and pathogenicity of pathogens. UDP-GlcNAc is a direct precursor of chitin synthesis. During the synthesis of UDP-GlcNAc, the conversion of GlcNAc-6P to GlcNAc-1P that is catalyzed by AGM1 (N-acetylglucosamine-phosphate mutase) is a key step. However, the significance and role of AGM1 in phytopathogenic fungus are unclear. We identified a cytoplasm-localized SsAGM1 in S. sclerotiorum, which is homologous to AGM1 of Saccharomyces cerevisiae. We utilized RNA interference (RNAi) and overexpression to characterize the function of SsAGM1 in S. sclerotiorum. After reducing the expression of SsAGM1, the contents of chitin and UDP-GlcNAc decreased significantly. Concomitantly, the gene-silenced transformants of SsAGM1 slowed vegetative growth and, importantly, lost the ability to produce sclerotia and infection cushion; it also lost virulence, even on wounded leaves. In addition, SsAGM1 was also involved in the response to osmotic stress and inhibitors of cell wall synthesis. Our results revealed the function of SsAGM1 in the growth, development, stress response, and pathogenicity in S. sclerotiorum.
Development and Application of Transcription Terminators for Polyhydroxylkanoates Production in Halophilic Halomonas bluephagenesis TD01
Authors: Xu Mengmeng , Chang Yue , Zhang Yuyan , Wang Weizhe , Hong Jingyi , Zhao Jiping , Lu Xiaoyun , Tan Dan
Published: June 2022

Halomonas bluephagenesis TD01 is one of the ideal chassis for low-cost industrial production based on “Next Generation Industrial Biotechnology,” yet the limited genetically regulatory parts such as transcriptional terminators, which are crucial for tuned regulations on gene expression, have hampered the engineering and applications of the strain. In this study, a series of intrinsic Rho-independent terminators were developed by either genome mining or rational design, and seven of them proved to exhibit higher efficiencies than the canonical strong T7 terminator, among which three terminators displayed high efficiencies over 90%. A preliminary modeling on the sequence-efficiency relationship of the terminators suggested that the poly U sequence regularity, the length and GC content of the stem, and the number and the size of hairpin loops remarkably affected the termination efficiency (TE). The rational and de novo designs of novel synthetic terminators based on the sequence-efficiency relationship and the “main contributor” engineering strategy proved to be effective, and fine-tuned polyhydroxylkanoates production was also achieved by the regulation of these native or synthetic terminators with different efficiencies. Furthermore, a perfectly positive correlation between the promoter activity and the TE was revealed in our study. The study enriches our knowledge of transcriptional termination via its sequence–strength relationship and enables the precise regulation of gene expression and PHA synthesis by intrinsic terminators, contributing to the extensive applications of H. bluephagenesis TD01 in the low-cost production of various chemicals.
Toll-Like Receptor Signaling in Severe Acute Respiratory Syndrome Coronavirus 2-Induced Innate Immune Responses and the Potential Application Value of Toll-Like Receptor Immunomodulators in Patients With Coronavirus Disease 2019
Authors: Dai Jiayu , Wang Yibo , Wang Hongrui , Gao Ziyuan , Wang Ying , Fang Mingli , Shi Shuyou , Zhang Peng , Wang Hua , Su Yingying , Yang Ming
Published: June 2022

Toll-like receptors (TLRs) are key sensors that recognize the pathogen-associated molecular patterns (PAMPs) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to activate innate immune response to clear the invading virus. However, dysregulated immune responses may elicit the overproduction of proinflammatory cytokines and chemokines, resulting in the enhancement of immune-mediated pathology. Therefore, a proper understanding of the interaction between SARS-CoV-2 and TLR-induced immune responses is very important for the development of effective preventive and therapeutic strategies. In this review, we discuss the recognition of SARS-CoV-2 components by TLRs and the downstream signaling pathways that are activated, as well as the dual role of TLRs in regulating antiviral effects and excessive inflammatory responses in patients with coronavirus disease 2019 (COVID-19). In addition, this article describes recent progress in the development of TLR immunomodulators including the agonists and antagonists, as vaccine adjuvants or agents used to treat hyperinflammatory responses during SARS-CoV-2 infection.
Epigenetics in Alzheimer’s Disease
Authors: Gao Xiaodie , Chen Qiang , Yao Hua , Tan Jie , Liu Zheng , Zhou Yan , Zou Zhenyou
Published: June 2022

Alzheimer’s disease (AD) is a neurodegenerative disease with unknown pathogenesis and complex pathological manifestations. At present, a large number of studies on targeted drugs for the typical pathological phenomenon of AD (Aβ) have ended in failure. Although there are some drugs on the market that indirectly act on AD, their efficacy is very low and the side effects are substantial, so there is an urgent need to develop a new strategy for the treatment of AD. An increasing number of studies have confirmed epigenetic changes in AD. Although it is not clear whether these epigenetic changes are the cause or result of AD, they provide a new avenue of treatment for medical researchers worldwide. This article summarizes various epigenetic changes in AD, including DNA methylation, histone modification and miRNA, and concludes that epigenetics has great potential as a new target for the treatment of AD.
Photo-Oxygenation as a New Therapeutic Strategy for Neurodegenerative Proteinopathies by Enhancing the Clearance of Amyloid Proteins
Authors: Tomizawa Ikumi , Nakagawa Hanako , Sohma Youhei , Kanai Motomu , Hori Yukiko , Tomita Taisuke
Published: June 2022

Alzheimer disease (AD) is associated with the aggregation of two amyloid proteins: tau and amyloid-β (Aβ). The results of immunotherapies have shown that enhancing the clearance and suppressing the aggregation of these two proteins are effective therapeutic strategies for AD. We have developed photocatalysts that attach oxygen atoms to Aβ and tau aggregates via light irradiation. Photo-oxygenation of these amyloid aggregates reduced their neurotoxicity by suppressing their aggregation both in vitro and in vivo. Furthermore, photo-oxygenation enhanced the clearance of Aβ in the brain and microglial cells. Here, we describe the effects of photo-oxygenation on tau and Aβ aggregation, and the potential of photo-oxygenation as a therapeutic strategy for AD, acting via microglial clearance.
Associations of Circulating Insulin-Growth Factor-1 With Cognitive Functions and Quality of Life Domains in Ambulatory Young Adults With Cerebral Palsy: A Pilot Study
Authors: Ng Ted Kheng Siang , Heyn Patricia C. , Tagawa Alex , Coughlan Christina , Carollo James J.
Published: June 2022

Objective

Adults with cerebral palsy (CP) often have impaired cognitive functions. CP also has deteriorations in multiple quality-of-life (QoL) domains. The bio-psycho-social health psychology model posits that biological factor interacts with social and psychological functions. However, the biological determinant of psycho-social and functional outcomes in CP has been scarcely examined. Circulating Insulin-like growth factor-1 (IGF-1) is associated with cognitive deficits in older adults, we thus aimed to examine the associations of circulating IGF-1 with: (1) objectively measured cognitive functions, (2) self-reported cognitive functions, and (3) QoL measures in adults diagnosed with CP.

Methods

Seventy-two adults with CP and varying degrees of cognitive functions were recruited from an accredited clinical motion analysis laboratory at a regional Children's Hospital. Circulating IGF-1 was measured using post-fasting serum. The Wechsler Adult Intelligence Scale (WAIS) tests were administered to assess multiple cognitive functions, whereas the Patient-Reported Outcomes Measurement Information System (PROMIS) was used to measure multiple domains of self-reported health, including cognitive complaints and eight QoL domains.

Results

Sixty-eight participants had complete data [mean age = 25 (SD = 5.3), female = 52.8%]. Controlling for covariates, circulating IGF-1 was associated with multiple cognitive domains, including positively with declarative memory and executive function and inversely with visual-spatial and motor skills, and processing speed, while no association with subjective memory complaint was detected. Circulating IGF-1 was also inversely associated with four QoL domains, including depressive symptoms, executive function, physical function, and social roles and activities.

Conclusions

In CP, circulating IGF-1 might be a useful biological determinant of objective cognitive functions and several quality-of-life domains commonly impaired in CP.
Predictors of the Efficacy for Daytime Sleepiness in Patients With Obstructive Sleep Apnea With Continual Positive Airway Pressure Therapy: A Meta-Analysis of Randomized Controlled Trials
Authors: Li Zhiqiang , Cai Sijie , Wang Jing , Chen Rui
Published: June 2022

Objective

The main aim of this meta-analysis was to evaluate the predictors of the efficacy of continuous positive airway pressure (CPAP) in ameliorating excessive daytime sleepiness (EDS) in patients with obstructive sleep apnea (OSA).

Methods

Randomized controlled trials (RCTs) published between January 1994 and October 2021 were searched in the PubMed, EMBASE, and Cochrane Library databases. The weighted mean differences (WMDs) for the Epworth Sleepiness Scale (ESS) scores, the Multiple Sleep Latency Test (MSLT), and the Maintenance of Wakefulness Test (MWT) were pooled in STATA.

Results

A total of 41 RCTs involving 7,332 patients were included. CPAP therapy was found to be significantly associated with changes in ESS (WMD = −2.14, P < 0.001), MSLT (WMD = 1.23, P < 0.001), and MWT (WMD = 1.6, P < 0.001). Meta-regression analysis and subgroup analysis indicated that in mild OSA, the efficacy of CPAP therapy for subjective EDS was limited to patients <50 years of age, with a baseline body mass index (BMI) of ≥30 kg/m2, baseline ESS score of ≥11, therapy adherence for ≥3 h/night, and treatment duration of ≥2 months. In moderate OSA, significant differences were observed in the changes in ESS among groups stratified by baseline ESS score (P = 0.005), adherence (P < 0.001), treatment duration (P = 0.009), and trial design type (P = 0.001). In severe OSA, this difference was observed among groups stratified by baseline BMI (P = 0.028), baseline ESS score (P = 0.001), and adherence (P = 0.047). Patients with moderate-severe OSA but not mild OSA showed significant improvements in MSLT. Patients with the age <50 years or BMI ≥33 kg/m2 had a more significant increase in MWT.

Conclusion

Continuous positive airway pressure therapy improved subjective and objective sleepiness in patients with OSA. Age, baseline BMI, baseline ESS score, adherence, and duration of treatment may predict the effects of CPAP on EDS in patients with OSA. Notably, the baseline ESS scores and adherence were stable predictors regardless of OSA severity.
EEG-Based Brain Network Analysis of Chronic Stroke Patients After BCI Rehabilitation Training
Authors: Zhan Gege , Chen Shugeng , Ji Yanyun , Xu Ying , Song Zuoting , Wang Junkongshuai , Niu Lan , Bin Jianxiong , Kang Xiaoyang , Jia Jie
Published: June 2022

Traditional rehabilitation strategies become difficult in the chronic phase stage of stroke prognosis. Brain–computer interface (BCI) combined with external devices may improve motor function in chronic stroke patients, but it lacks comprehensive assessments of neurological changes regarding functional rehabilitation. This study aimed to comprehensively and quantitatively investigate the changes in brain activity induced by BCI–FES training in patients with chronic stroke. We analyzed the EEG of two groups of patients with chronic stroke, one group received functional electrical stimulation (FES) rehabilitation training (FES group) and the other group received BCI combined with FES training (BCI–FES group). We constructed functional networks in both groups of patients based on direct directed transfer function (dDTF) and assessed the changes in brain activity using graph theory analysis. The results of this study can be summarized as follows: (i) after rehabilitation training, the Fugl–Meyer assessment scale (FMA) score was significantly improved in the BCI–FES group (p < 0.05), and there was no significant difference in the FES group. (ii) Both the global and local graph theory measures of the brain network of patients with chronic stroke in the BCI–FES group were improved after rehabilitation training. (iii) The node strength in the contralesional hemisphere and central region of patients in the BCI–FES group was significantly higher than that in the FES group after the intervention (p < 0.05), and a significant increase in the node strength of C4 in the contralesional sensorimotor cortex region could be observed in the BCI–FES group (p < 0.05). These results suggest that BCI–FES rehabilitation training can induce clinically significant improvements in motor function of patients with chronic stroke. It can improve the functional integration and functional separation of brain networks and boost compensatory activity in the contralesional hemisphere to a certain extent. The findings of our study may provide new insights into understanding the plastic changes of brain activity in patients with chronic stroke induced by BCI–FES rehabilitation training.
Alteration of Degree Centrality in Adolescents With Early Blindness
Authors: Wen Zhi , Kang Yan , Zhang Yu , Yang Huaguang , Xie Baojun
Published: June 2022

Congenital nystagmus in infants and young children can lead to early blindness (EB). Previous neuroimaging studies have demonstrated that EB is accompanied by alterations in brain structure and function. However, the effects of visual impairment and critical developmental periods on brain functional connectivity at rest have been unclear. Here, we used the voxel-wise degree centrality (DC) method to explore the underlying functional network brain activity in adolescents with EB. Twenty-one patients with EBs and 21 sighted controls (SCs) underwent magnetic resonance imaging. Differences between the two groups were assessed using the DC method. Moreover, the support vector machine (SVM) method was used to differentiate patients with EB patients from the SCs according to DC values. Compared with the SCs, the patients with EB had increased DC values in the bilateral cerebellum_6, cerebellum vermis_4_5, bilateral supplementary motor areas (SMA), and left fusiform gyrus; the patients with EB had decreased DC values in the bilateral rectal gyrus and left medial orbital frontal gyrus. The SVM classification of the DC values achieved an overall accuracy of 70.45% and an area under the curve of 0.86 in distinguishing between the patients with EB and the SCs. Our study may reveal the neuromechanism of neuroplasticity in EB; the findings provide an imaging basis for future development of restorative visual therapies and sensory substitution devices, and future assessments of visual rehabilitation efficacy.
Modernizing the NEURON Simulator for Sustainability, Portability, and Performance
Authors: Awile Omar , Kumbhar Pramod , Cornu Nicolas , Dura-Bernal Salvador , King James Gonzalo , Lupton Olli , Magkanaris Ioannis , McDougal Robert A. , Newton Adam J. H. , Pereira Fernando , Săvulescu Alexandru , Carnevale Nicholas T. , Lytton William W. , Hines Michael L. , Schürmann Felix
Published: June 2022

The need for reproducible, credible, multiscale biological modeling has led to the development of standardized simulation platforms, such as the widely-used NEURON environment for computational neuroscience. Developing and maintaining NEURON over several decades has required attention to the competing needs of backwards compatibility, evolving computer architectures, the addition of new scales and physical processes, accessibility to new users, and efficiency and flexibility for specialists. In order to meet these challenges, we have now substantially modernized NEURON, providing continuous integration, an improved build system and release workflow, and better documentation. With the help of a new source-to-source compiler of the NMODL domain-specific language we have enhanced NEURON's ability to run efficiently, via the CoreNEURON simulation engine, on a variety of hardware platforms, including GPUs. Through the implementation of an optimized in-memory transfer mechanism this performance optimized backend is made easily accessible to users, providing training and model-development paths from laptop to workstation to supercomputer and cloud platform. Similarly, we have been able to accelerate NEURON's reaction-diffusion simulation performance through the use of just-in-time compilation. We show that these efforts have led to a growing developer base, a simpler and more robust software distribution, a wider range of supported computer architectures, a better integration of NEURON with other scientific workflows, and substantially improved performance for the simulation of biophysical and biochemical models.
Converging Mechanisms of Epileptogenesis and Their Insight in Glioblastoma
Authors: Hills Kate E. , Kostarelos Kostas , Wykes Robert C.
Published: June 2022

Glioblastoma (GBM) is the most common and advanced form of primary malignant tumor occurring in the adult central nervous system, and it is frequently associated with epilepsy, a debilitating comorbidity. Seizures are observed both pre- and post-surgical resection, indicating that several pathophysiological mechanisms are shared but also prompting questions about how the process of epileptogenesis evolves throughout GBM progression. Molecular mutations commonly seen in primary GBM, i.e., in PTEN and p53, and their associated downstream effects are known to influence seizure likelihood. Similarly, various intratumoral mechanisms, such as GBM-induced blood-brain barrier breakdown and glioma-immune cell interactions within the tumor microenvironment are also cited as contributing to network hyperexcitability. Substantial alterations to peri-tumoral glutamate and chloride transporter expressions, as well as widespread dysregulation of GABAergic signaling are known to confer increased epileptogenicity and excitotoxicity. The abnormal characteristics of GBM alter neuronal network function to result in metabolically vulnerable and hyperexcitable peri-tumoral tissue, properties the tumor then exploits to favor its own growth even post-resection. It is evident that there is a complex, dynamic interplay between GBM and epilepsy that promotes the progression of both pathologies. This interaction is only more complicated by the concomitant presence of spreading depolarization (SD). The spontaneous, high-frequency nature of GBM-associated epileptiform activity and SD-associated direct current (DC) shifts require technologies capable of recording brain signals over a wide bandwidth, presenting major challenges for comprehensive electrophysiological investigations. This review will initially provide a detailed examination of the underlying mechanisms that promote network hyperexcitability in GBM. We will then discuss how an investigation of these pathologies from a network level, and utilization of novel electrophysiological tools, will yield a more-effective, clinically-relevant understanding of GBM-related epileptogenesis. Further to this, we will evaluate the clinical relevance of current preclinical research and consider how future therapeutic advancements may impact the bidirectional relationship between GBM, SDs, and seizures.
Targeting Adenylate Cyclase Family: New Concept of Targeted Cancer Therapy
Authors: Guo Rui , Liu Tian , Shasaltaneh Marzieh Dehghan , Wang Xuan , Imani Saber , Wen QingLian
Published: June 2022

The adenylate cyclase (ADCY) superfamily is a group of glycoproteins regulating intracellular signaling. ADCYs act as key regulators in the cyclic adenosine monophosphate (cAMP) signaling pathway and are related to cell sensitivity to chemotherapy and ionizing radiation. Many members of the superfamily are detectable in most chemoresistance cases despite the complexity and unknownness of the specific mechanism underlying the role of ADCYs in the proliferation and invasion of cancer cells. The overactivation of ADCY, as well as its upstream and downstream regulators, is implicated as a major potential target of novel anticancer therapies and markers of exceptional responders to chemotherapy. The present review focuses on the oncogenic functions of the ADCY family and emphasizes the possibility of the mediating roles of deleterious nonsynonymous single nucleotide polymorphisms (nsSNPs) in ADCY as a prognostic therapeutic target in modulating resistance to chemotherapy and immunotherapy. It assesses the mediating roles of ADCY and its counterparts as stress regulators in reprogramming cancer cell metabolism and the tumor microenvironment. Additionally, the well-evaluated inhibitors of ADCY-related signaling, which are under clinical investigation, are highlighted. A better understanding of ADCY-induced signaling and deleterious nsSNPs (p.E1003K and p.R1116C) in ADCY6 provides new opportunities for developing novel therapeutic strategies in personalized oncology and new approaches to enhance chemoimmunotherapy efficacy in treating various cancers.
Surgical Strategies for Siewert Type II Esophagogastric Junction Carcinomas: A Randomized Controlled Trial
Authors: Tao Kai , Dong Jianhong , He Songbing , Xu Yingying , Yang Fan , Han Guolin , Abe Masanobu , Zong Liang
Published: June 2022

Aim

To determine the ideal surgical approach for Siewert type II EGJ carcinomas.

Methods

We conducted the randomized controlled trial (RCT) at Shanxi Cancer Hospital from January 2014 to August 2016. A total of 105 patients with T1-4N1-3M0 Siewert type II EGJ carcinomas were initially recruited. The final follow-up was up to June 30, 2019. Patients were randomized to undergo either a proximal gastrectomy plus jejunal interposition (PG+JI), proximal gastrectomy plus esophagogastrostomy (PG+EG), or total gastrectomy plus Roux-en-Y esophagojejunostomy (TG+RY). The primary endpoint was postoperative complications. Secondary endpoints were 5-year survival and recovery indexes.

Results

Among 105 patients, 100 patients (95.2%; mean age, 56.2 years) with tumors <3cm in size underwent surgery: PG+JI (n=33) vs. PG+EG (n=33) and TG+RY (n=34); 91 patients completed the study. Among the groups, the PG+JI group had the longest reconstruction time: 34.11 ± 6.10 min vs. 21.97 ± 3.30 min (PG+EG) vs. 30.56 ± 4.26 min (TG+RY); p<0.001. There was no postoperative mortality. In the per-protocol analysis, the PG+JI group showed a decreased tendency in complication rate: 6.9% vs. 23.3% (PG+EG) vs. 18.8% (TG+RY), but there was no significant difference. For recovery indexes, the TG+RY group had the lowest values of the amount of single meal, weight loss, hemoglobin, albumin, pepsin, and gastrin among the three groups. There was no significant difference among the three groups in 5-year survival.

Conclusions

Proximal gastrectomy is preferable for T1-4N1-3M0 Siewert type II EGJ carcinomas with tumors <3cm in size because of its better nutrition status under similar postoperative complication to total gastrectomy. Jejunal interposition can be recommended as a optional reconstruction approach after proximal gastrectomy.

Clinical Trial Registration

https://www.chictr.org.cn/, identifier ChiCTR-IIR-16007733.
Deep Learning-Based Multi-Omics Integration Robustly Predicts Relapse in Prostate Cancer
Authors: Wei Ziwei , Han Dunsheng , Zhang Cong , Wang Shiyu , Liu Jinke , Chao Fan , Song Zhenyu , Chen Gang
Published: June 2022

Objective

Post-operative biochemical relapse (BCR) continues to occur in a significant percentage of patients with localized prostate cancer (PCa). Current stratification methods are not adequate to identify high-risk patients. The present study exploits the ability of deep learning (DL) algorithms using the H2O package to combine multi-omics data to resolve this problem.

Methods

Five-omics data from 417 PCa patients from The Cancer Genome Atlas (TCGA) were used to construct the DL-based, relapse-sensitive model. Among them, 265 (63.5%) individuals experienced BCR. Five additional independent validation sets were applied to assess its predictive robustness. Bioinformatics analyses of two relapse-associated subgroups were then performed for identification of differentially expressed genes (DEGs), enriched pathway analysis, copy number analysis and immune cell infiltration analysis.

Results

The DL-based model, with a significant difference (P = 6e-9) between two subgroups and good concordance index (C-index = 0.767), were proven to be robust by external validation. 1530 DEGs including 678 up- and 852 down-regulated genes were identified in the high-risk subgroup S2 compared with the low-risk subgroup S1. Enrichment analyses found five hallmark gene sets were up-regulated while 13 were down-regulated. Then, we found that DNA damage repair pathways were significantly enriched in the S2 subgroup. CNV analysis showed that 30.18% of genes were significantly up-regulated and gene amplification on chromosomes 7 and 8 was significantly elevated in the S2 subgroup. Moreover, enrichment analysis revealed that some DEGs and pathways were associated with immunity. Three tumor-infiltrating immune cell (TIIC) groups with a higher proportion in the S2 subgroup (p = 1e-05, p = 8.7e-06, p = 0.00014) and one TIIC group with a higher proportion in the S1 subgroup (P = 1.3e-06) were identified.

Conclusion

We developed a novel, robust classification for understanding PCa relapse. This study validated the effectiveness of deep learning technique in prognosis prediction, and the method may benefit patients and prevent relapse by improving early detection and advancing early intervention.
The Androgen Receptor and Its Crosstalk With the Src Kinase During Castrate-Resistant Prostate Cancer Progression
Authors: Gao Lin , Han Bo , Dong Xuesen
Published: June 2022

While the androgen receptor (AR) signalling is the mainstay therapeutic target for metastatic prostate cancers, these tumours will inevitably develop therapy resistance to AR pathway inhibitors suggesting that prostate tumour cells possess the capability to develop mechanisms to bypass their dependency on androgens and/or AR to survive and progress. In many studies, protein kinases such as Src are reported to promote prostate tumour progression. Specifically, the pro-oncogene tyrosine Src kinase regulates prostate cancer cell proliferation, adhesion, invasion, and metastasis. Not only can Src be activated under androgen depletion, low androgen, and supraphysiological androgen conditions, but also through crosstalk with other oncogenic pathways. Reciprocal activations between Src and AR proteins had also been reported. These findings rationalize Src inhibitors to be used to treat castrate-resistant prostate tumours. Although several Src inhibitors had advanced to clinical trials, the failure to observe patient benefits from these studies suggests that further evaluation of the roles of Src in prostate tumours is required. Here, we summarize the interplay between Src and AR signalling during castrate-resistant prostate cancer progression to provide insights on possible approaches to treat prostate cancer patients.
Explainable Machine Learning Model to Prediction EGFR Mutation in Lung Cancer
Authors: Yang Ruiyuan , Xiong Xingyu , Wang Haoyu , Li Weimin
Published: June 2022

Objectives

The aim of this study is to determine whether the clinical features including blood markers can establish an explainable machine learning model to predict epidermal growth factor receptor (EGFR) mutation in lung cancer.

Methods

We retrospectively analyzed 7,413 patients with lung adenocarcinoma (LA) diagnosed by gene sequencing in West China Hospital of the Sichuan University from April 2015 to June 2019. The machine learning algorithms (MLAs) included logistic regression (LR), random forest (RF), LightGBM, support vector machine (SVM), multi-layer perceptron (MLP), extreme gradient boosting (XGBoost), and decision tree (DT). Demographic characteristics, personal history, and blood markers were taken into. The area under the receiver operating characteristic curve (AUC) and SHapley Additive exPlanation (SHAP) value were used to explain the prediction models.

Results

Of the 7,413 patients with LA (47.6%), 3,527 were identified with EGFR mutation; RF achieved greatest performance in predicting EGFR mutation AUC [0.771, 95% confidence interval (CI): 0.770, 0.772], which was like XGBoost with AUC (0.740, 95% CI: 0.739, 0.741). The five most influential features were smoking consumption, sex, cholesterol, age, and albumin globulin ratio. The SHAP summary and dependence plot have been used to explain the affection of the 12 features to this model and how a single feature influences the output, respectively.

Conclusion

We established EGFR mutation prediction models by MLAs and revealed that the RF was preferred, AUC (0.771, 95% CI: 0.770, 0.772), which was better than the traditional models. Therefore, the artificial intelligence–based MLA predicting model may become a practical tool to guide in diagnosis and therapy of LA.
The Phytochemical Potential for Brain Disease Therapy and the Possible Nanodelivery Solutions for Brain Access
Authors: Liu Yang , Chen Zhouchun , Li Aijie , Liu Runhan , Yang Haoying , Xia Xue
Published: June 2022

Plant-derived phytochemicals have gifted humans with vast therapeutic potentials. Yet, the unique features of the blood–brain barrier significantly limit their accession to the target tissue and thus clinical translation in brain disease treatment. Herein, we explore the medicinal outcomes of both the rare examples of phytochemicals that can easily translocate across the blood–brain barrier and most of the phytochemicals that were reported with brain therapeutic effects, but a bizarre amount of dosage is required due to their chemical nature. Lastly, we offer the nanodelivery platform that is capable of optimizing the targeted delivery and application of the non-permeable phytochemicals as well as utilizing the permeable phytochemicals for boosting novel applications of nanodelivery toward brain therapies.
CXCL13, CXCL10 and CXCL8 as Indicators of Ocular and Neurological Involvement in Patients With Ocular Syphilis: An Observational Descriptive Study
Authors: van der Merwe Laurie W. , Snyders Candice , Kidd Martin , Chegou Novel N. , Walzl Gerhard , Smit Derrick P.
Published: June 2022

Aim

To investigate the role of the chemokines CXCL13, CXCL10 and CXCL8 in the diagnosis of ocular- and neurosyphilis by examining the serum, aqueous humour (AH) and cerebrospinal fluid (CSF) of patients with ocular syphilis.

Methods

An observational descriptive study was performed prospectively at Tygerberg Academic Hospital in Cape Town, South Africa from 1 February 2018 till 31 January 2021 which enrolled 23 participants. 14 Patients were male and 9 female, 15 patients were HIV positive, and all patients were newly diagnosed with ocular syphilis. Upon diagnosis of ocular syphilis, the HIV status of each patient was determined, and 3 samples (AH, serum and CSF) were collected to measure the levels of CXCL13, CXCL10 and CXCL8 in each. All patients were treated with 14 days of intravenous Penicillin G and topical corticosteroid drops for uveitis.

Results

The mean concentrations of all 3 biomarkers were higher in the AH and CSF than in the serum. The mean concentrations of the 3 measured biomarkers were markedly different when comparing both AH and CSF levels to serum levels. The level of CXCL13 measured in the AH correlated well with the concentrations found in the CSF of patients with neurosyphilis. In patients with neurosyphilis, mean AH levels of CXCL13 and CXCL10 were markedly higher than in serum while mean CSF levels of CXCL10 were also markedly higher than in serum. Also, the AH/serum ratio of CXCL13 and CXCL10, as well as the CSF/serum ratio of CXCL10, was much higher in patients with neurosyphilis than without. In patients with HIV infection, mean AH CXCL13 levels were much higher than in patients without HIV infection.

Conclusion

The levels of CXCL13, CXCL10 and CXCL8 in the AH of patients with neurosyphilis are similar to previously reported levels in the CSF of patients with neurosyphilis and can potentially be an adjunct in the diagnosis of ocular syphilis. Patients with ocular syphilis who tested negative for neurosyphilis with conventional CSF testing showed features of neurosyphilis when analysing the CSF chemokines.
Chilblains-Like Lesions in Pediatric Patients: A Review of Their Epidemiology, Etiology, Outcomes, and Treatment
Authors: Fennell Jessica , Onel Karen
Published: June 2022

Vascular pathologies associated with SARS-CoV-2 infection are poorly understood. Color and sensory changes to the extremities, often referred to as “COVID toes” or chilblains-like lesions, have been widely reported in children and adolescents since the onset of the pandemic, raising the concern that they could be a vasculitis secondary to the infection. However, it is unclear if the lesions are a result of the infection or an epiphenomenon. Most literature focuses on adults, and while there are reports on children and adolescents, many of them are small. This review will help medical care providers better understand the epidemiology, etiology, outcomes, and potential treatments for chilblains-like lesions seen in children and adolescents during the pandemic.
SARS-CoV-2 B.1.1.529 (Omicron) Variant Causes an Unprecedented Surge in Children Hospitalizations and Distinct Clinical Presentation Compared to the SARS-CoV-2 B.1.617.2 (Delta) Variant
Authors: Taytard Jessica , Prevost Blandine , Schnuriger Aurélie , Aubertin Guillaume , Berdah Laura , Bitton Lauren , Dupond-Athenor Audrey , Thouvenin Guillaume , Nathan Nadia , Corvol Harriet
Published: June 2022

Background

In the midst of successive waves of SARS-CoV-2 variants, the B.1.1.529 (omicron) variant has recently caused a surge in pediatric infections and hospitalizations. This study aimed to describe and compare the symptoms, explorations, treatment and evolution of COVID-19 in hospitalized children during the successive B.1.617.2 (delta) and B.1.1.529 (omicron) waves.

Methods

This observational study was performed in the Pediatric Pulmonology Department of a University Hospital in Paris, France. All hospitalized children aged between 0 and 18 years who tested positive for SARS-CoV-2 using reverse transcription polymerase chain reaction (RT-PCR) in nasopharyngeal swabs from July 15th to December 15th 2021 (delta wave), and from December 15th 2021 to February 28th 2022 (omicron wave) were included.

Results

In total, 53 children were included, 14 (26.4%) during the delta wave and 39 (73.6%) during the omicron wave (almost three times as many hospitalizations in half the time during the latter wave). During the omicron wave, hospitalized patients were mostly aged < 5 years (90 vs. 71% of all the children during omicron and delta waves, respectively), and tended to have fewer underlying conditions (56 vs. 79% during omicron and delta waves, respectively, p = 0.20). The omicron variant was also responsible for a different clinical presentation when compared to the delta variant, with significantly higher and often poorly tolerated temperatures (p = 0.03) and increased digestive symptoms (p = 0.01). None of the three patients who were older than 12 years were fully vaccinated.

Conclusion

The dramatic increase in the hospitalization of children with COVID-19 and the modification of the clinical presentation between the latest delta and omicron waves require pediatricians to remain vigilant. It should also encourage caregivers to ensure vaccination in children older than 5 years, for whom the BNT162b2 COVID-19 vaccine has been deemed safe, immunogenic, and effective.