bluuebunny/crossref_metadata_2025 huggingface dataset:
Enabling Genome Editing for Enhanced Agricultural Sustainability
Authors: Keiper Felicity , Atanassova Ana
Published: May 2022

Agricultural sustainability encompasses environmental, social, and economic aspects, all of which are continually shifting due changing environmental pressures and societal expectations. A range of strategies are required to address these challenges, and these include the use of innovation and adoption of the best available practices and technologies. Advances in biotechnologies, including genome editing, and their application in plant breeding and research are expected to provide a range of benefits that contribute to all aspects of agricultural sustainability. However, adoption of these technologies needs to be supported by proportionate, coherent, forward-looking, and adaptable policies and regulatory approaches. In this Perspective, we reflect on the regulatory challenges associated with commercialising a transgenic crop, and developments thus far in providing regulatory clarity for genome edited crops. We aim to demonstrate that much remains to be done to shift towards a more proportionate and enabling approach before the potential benefits of genome edited crops can be realised. The implications of precautionary and disproportionate regulation are also discussed.
TGFβ-Associated Signature Predicts Prognosis and Tumor Microenvironment Infiltration Characterization in Gastric Carcinoma
Authors: Liu Siyuan , Li Zhenghao , Li Huihuang , Wen Xueyi , Wang Yu , Chen Qilin , Xu Xundi
Published: May 2022

Background: Gastric carcinoma (GC) is a carcinoma with a high incidence rate, and it is a deadly carcinoma globally. An effective tool, that is, able to predict different survival outcomes for GC patients receiving individualized treatments is deeply needed.

Methods: In total, data from 975 GC patients were collected from TCGA-STAD, GSE15459, and GSE84437. Then, we performed a comprehensive unsupervised clustering analysis based on 54 TGFβ-pathway-related genes and correlated these patterns with tumor microenvironment (TME) cell-infiltrating characteristics. WGCNA was then applied to find the module that had the closest relation with these patterns. The least absolute shrinkage and selection operator (LASSO) algorithm was combined with cross validation to narrow down variables and random survival forest (RSF) was used to create a risk score.

Results: We identified two different TGFβ regulation patterns and named them as TGFβ Cluster 1 and Cluster 2. TGFβ Cluster 1 was linked to significantly poorer survival outcomes and represented an inflamed TME subtype of GC. Using WGCNA, a module (magenta) with the closest association with the TGFβ clusters was identified. After narrowing down the gene list by univariate Cox regression analysis, the LASSO algorithm and cross validation, four of the 243 genes in the magenta module were applied to build a risk score. The group with a higher risk score exhibited a considerably poorer survival outcome with high predictive accuracy. The risk score remained an independent risk factor in multivariate Cox analysis. Moreover, we validated this risk score using GSE15459 and GSE84437. Furthermore, we found that the group with a higher risk score represented an inflamed TME according to the evidence that the risk score was remarkably correlated with several steps of cancer immunity cycles and a majority of the infiltrating immune cells. Consistently, the risk score was significantly related to immune checkpoint genes and T cell–inflamed gene expression profiles (GEPs), indicating the value of predicting immunotherapy.

Conclusions: We have developed and validated a TGFβ-associated signature, that is, capable of predicting the survival outcome as well as depicting the TME immune characteristics of GC. In summary, this signature may contribute to precision medicine for GC.
A Potent Neutralizing Nanobody Targeting the Spike Receptor-Binding Domain of SARS-CoV-2 and the Structural Basis of Its Intimate Binding
Authors: Yang Jing , Lin Sheng , Sun Honglu , Chen Zimin , Yang Fanli , Lin Xi , Guo Liyan , Wang Lingling , Wen Ao , Zhang Xindan , Dai Yushan , He Bin , Cao Yu , Dong Haohao , Liu Xianbo , Chen Bo , Li Jian , Zhao Qi , Lu Guangwen
Published: May 2022

The continuous spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) around the world has raised unprecedented challenges to the human society. Antibodies and nanobodies possessing neutralization activity represent promising drug candidates. In this study, we report the identification and characterization of a potent SARS-CoV-2 neutralizing nanobody that targets the viral spike receptor-binding domain (S-RBD). The nanobody, termed as Nb-007, engages SARS-CoV-2 S-RBD with the two-digit picomolar binding affinity and shows outstanding virus entry-inhibition activity. The complex structure of Nb-007 bound to SARS-CoV-2 S-RBD reveals an epitope that is partially overlapping with the binding site for the human receptor of angiotensin-converting enzyme 2 (ACE2). The nanobody therefore exerts neutralization by competing with ACE2 for S-RBD binding, which is further ascertained by our in-vitro biochemical analyses. Finally, we also show that Nb-007 reserves promising, though compromised, neutralization activity against the currently-circulating Delta variant and that fusion of the nanobody with Fc dramatically increases its entry-inhibition capacity. Taken together, these data have paved the way of developing Nb-007 as a drug-reserve for potential treatment of SARS-CoV-2 related diseases.
CD18 Mediates Neutrophil Imperviousness to the Aggregatibacter actinomycetemcomitans JP2 Clone in Molar-Incisor Pattern Periodontitis
Authors: Hashai Koren , Chapple Ian L. , Shapira Lior , Assadi Walaa , Dadon Stav , Polak David
Published: May 2022

Introduction

Molar-incisor pattern periodontitis (MIPP) in the absence of significant local risk factors or systemic disease, is a rare, early onset periodontal disease phenotype, with 0.5% to 2.5% global prevalence. The condition is characterized by impaired neutrophil function and persistent Aggregatibacter actinomycetemcomitans (JP2 clone) infection. The aim of this study was to characterize neutrophil functional responses to JP2 and to investigate the neutrophil receptors involved.

Materials and Methods

Neutrophils were obtained from whole blood samples of periodontally healthy and MIPP subjects and incubated with the JP2 clone or a non-JP2 clone of A. actinomycetemcomitans. Bacterial survival was tested by blood agar culture; neutrophil death was tested with propidium iodide and flow cytometry; Reactive oxygen production (ROS) was measured with 2′,7′-dichlorofluorescein diacetate and a fluorescence plate reader; the cytokinome was analysed using an array profiler, ELISA and RT-PCR. Receptors binding to JP2 were isolated using a novel immunoprecipitation assay and validated functionally using specific blocking antibodies.

Results

JP2 and non-JP2 survival was comparable between all the neutrophil groups. Resistance to neutrophil necrosis following exposure to JP2 was significantly lower in the MIPP group, than in all the other groups (p<0.0001). Conversely, MIPP neutrophils showed lower levels of ROS production in response to JP2 infection compared with that of healthy neutrophils (p<0.001). Furthermore, significantly lower levels of cytokines, such as IL8, IL10 and TNFα, were observed during JP2 incubation with MIPP neutrophils than upon incubation with periodontally healthy neutrophils. Various proteins expressed on neutrophils bind to JP2. Of these, CD18 was found to mediate neutrophil necrosis. The CD18 receptor on MIPP neutrophils acts differently from that on periodontally healthy patients neutrophils, and appears to reflect differential neutrophil reactions to JP2.

Conclusion

This study portrays a fundamental difference in neutrophil response to JP2 infection between periodontally healthy and MIPP patients. This was evident in the resistance to necrosis, and lower ROS and cytokine production, despite the persistent presence of viable JP2. Whilst in periodontally healthy neutrophils, JP2 binds to CD18 on cell surfaces, this is not the case in MIPP neutrophils, suggesting a potential role for CD18 in the periodontal susceptibility of MIPP patients.
Functions of IFNλs in Anti-Bacterial Immunity at Mucosal Barriers
Authors: Alphonse Noémie , Dickenson Ruth E. , Alrehaili Abrar , Odendall Charlotte
Published: May 2022

Type III interferons (IFNs), or IFNλs, are cytokines produced in response to microbial ligands. They signal through the IFNλ receptor complex (IFNLR), which is located on epithelial cells and select immune cells at barrier sites. As well as being induced during bacterial or viral infection, type III IFNs are produced in response to the microbiota in the lung and intestinal epithelium where they cultivate a resting antiviral state. While the multiple anti-viral activities of IFNλs have been extensively studied, their roles in immunity against bacteria are only recently emerging. Type III IFNs increase epithelial barrier integrity and protect from infection in the intestine but were shown to increase susceptibility to bacterial superinfections in the respiratory tract. Therefore, the effects of IFNλ can be beneficial or detrimental to the host during bacterial infections, depending on timing and biological contexts. This duality will affect the potential benefits of IFNλs as therapeutic agents. In this review, we summarize the current knowledge on IFNλ induction and signaling, as well as their roles at different barrier sites in the context of anti-bacterial immunity.
Custom CARs: Leveraging the Adaptability of Allogeneic CAR Therapies to Address Current Challenges in Relapsed/Refractory DLBCL
Authors: Jeyakumar Nikeshan , Smith Melody
Published: May 2022

Cellular therapies have transformed the treatment of relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL), which typically does not respond well to salvage chemotherapy. Recently, approximately 40% of r/r DLBCL patients across three different trials achieved a complete remission at 1 year after receiving treatment with autologous chimeric antigen receptor (CAR) T cells (auto-CARs). These successes have prompted studies of auto-CARs in second-line settings, in which axicabtagene ciloleucel and lisocabtagene maraleucel both showed improved event-free survival over autologous hematopoietic cell transplantation (AHCT). While encouraging, this data also highlights that 60% of patients relapse or progress following treatment with auto-CARs. Individual disease characteristics and logistical challenges of cell engineering also limit patients’ eligibility for auto-CARs. Allogeneic CAR T cells (allo-CARs) may address some of these limitations as they may mitigate delays associated with auto-CARs, thereby reducing the need for bridging chemotherapies and increasing availability of cellular products for patients with aggressive lymphomas. By being sourced from healthy donors who have never been exposed to cytotoxic chemotherapy, allo-CARs can be created from T cells with better fitness. Allo-CARs made from specific cellular subsets (e.g., stem cell memory or naïve/early memory T cells) may also have increased efficacy and long-term persistence. Additionally, allo-CARs have been successfully created from other cell types, including natural killer cells, gamma-delta T-cells and induced pluripotent stem cells. These cell types can be engineered to target viral antigens, enabling precision targeting of virally driven DLBCL. As allogeneic donor cells can be banked and cryopreserved in batches, they can be made more readily available, potentially reducing logistical hurdles and costs compared to engineering auto-CARs. This may ultimately create a more sustainable platform for cell therapies. Challenges with allo-CARs that will need to be addressed include graft versus host disease, alloimmunization, potentially decreased persistence relative to auto-CARs, and antigen escape. In short, the adaptability of allo-CARs makes them ideal for treating patients with r/r DLBCL who have progressed through standard chemotherapy, AHCT, or auto-CARs. Here, we review the published literature on patients with r/r DLBCL treated with allogeneic CAR products manufactured from various cell types as well as forthcoming allogeneic CAR technologies.
Noncanonical PD-1/PD-L1 Axis in Relation to the Efficacy of Anti-PD Therapy
Authors: Long Yiru , Yu Xiaolu , Chen Runqiu , Tong Yongliang , Gong Likun
Published: May 2022

With programmed death 1/ligand 1 (PD-1/PD-L1) as the cornerstone, anti-PD antibodies have pioneered revolutionary immunotherapies for malignancies. But most patients struggled to respond to anti-PD owing to primary or acquired resistance or even hyperprogression, pointing to more efforts needed to explore this axis. PD-1 constrains T-cell immunoreactivity via engaging with PD-L1 of tumor/myeloid cells is the canonical PD-1/PD-L1 axis function mode. Studies are increasingly aware of the impact of noncanonical PD-1/PD-L1 expression in various cancers. PD-L1 induced on activated T-cells ligates to PD-1 to mediate self-tolerance or acts on intratumoral myeloid cells and other T-cells, affecting their survival, differentiation and immunophenotyping, leading to tumor immunosuppression. Myeloid PD-1 interferes with their proliferation, differentiation, cytokine secretion and phagocytosis, mediating remarkable pro-tumor effects. Tumor cell intrinsic PD-1 signaling has diverse functions in different tumors, resulting in pro-proliferation or proliferation inhibition. These nonclassical PD-1/PD-L1 functions may be novel anti-PD mechanisms or causes of treatment resistance. This review highlights the nonnegligible role of T-cell-intrinsic PD-L1 and tumor/myeloid PD-1 in the cell interplay network and the complex impact on the efficacy of anti-PD antibodies. Reconsidering and rational utilization of the comprehensive PD-1/PD-L1 axis could cumulate breakthroughs in precision treatment and combination for anti-PD therapies.
Assessing the Potential Impact of River Chemistry on Arctic Coastal Production
Authors: Gibson Georgina A. , Elliot Scott , Clement Kinney Jaclyn , Piliouras Anastasia , Jeffery Nicole
Published: May 2022

The Arctic coastal margin receives a disproportionately large fraction of the global river discharge. The bio-geochemistry of the river water as it empties into the marine environment reflects inputs and processes that occur as the water travels from its headwaters. Climate-induced changes to Arctic vegetation and permafrost melt may impact river chemistry. Understanding the impact of river nutrients on coastal marine production, and how this may change in the future, are important for resource managers and community members who monitor and rely on coastal food resources. Using the Energy Exascale Earth System Model we explore the impact of timing and river nutrient concentrations on primary production in each coastal Arctic region and then assess how this influences secondary production and particle fluxes supporting the benthic food web. Our results indicate that while the concentration of Arctic river nitrogen can have a significant impact on annual average nitrogen and primary production in the coastal Arctic, with production increases of up to 20% in the river influenced interior Seas, the timing of the river nutrient inputs into the marine environment appears less important. Bloom timing and partitioning between small and large phytoplankton were minimally impacted by both river nutrient concentration and timing, suggesting that in general, coastal Arctic ecosystem dynamics will continue to be primarily driven by light availability, rather than nutrients. Under a doubling river nutrient scenario, the percentage increase in the POC flux to the benthos on river influenced Arctic coastal shelves was 2-4 times the percentage increase in primary production, suggesting changes to the river nutrient concentration has the potential to modify the Arctic food web structure and dynamics. Generally, the nutrient-induced changes to primary production were smaller than changes previously simulated in response to ice reduction and temperature increase. However, in the Laptev Sea, the production increase resulting from a doubling of river nutrients exceeded the production increase simulated with an atmospheric warming scenario. Dissolved organic carbon is presently poorly represented in the model so its impact on production is hard to simulate. Applying established relationships between modeled DOC, total DOC, and light absorption we illustrate that DOC could play a very important role in modulating production. Our findings highlight the importance of developing more realistic river nutrient and discharge forcing for Earth System Models such that their impact on the critical Arctic coastal domain can be more adequately resolved.
Intra-Annual Sea Level Fluctuations and Variability of Mesoscale Processes in the Northern Japan/East Sea From Satellite Altimetry Data
Authors: Trusenkova Olga , Kaplunenko Dmitry
Published: May 2022

Intra-annual sea level fluctuations and variability of mesoscale processes based on eddy kinetic energy (EKE) were studied in the northern (northward of 41 N) Japan/East Sea (JES) using data from satellite altimetry for 1993–2020. Decomposition to empirical orthogonal functions (EOF) was performed of the high-pass filtered, with the cut-off period of 250 days, sea level anomalies. The leading mode accounting for the major fraction of the variance yielded sea level fluctuations which were simultaneous in the entire sea and occurred in the range from 70 to 250 days without any preferable timescale. EKE in the northern sea was also expanded to EOF and yielded the leading mode capturing mesoscale variability within the Primorye (Liman) Current and the Tsushima Warm Current. The seasonal signal was found in the simultaneous intra-annual sea level fluctuations, which matches that of EKE, and, as found in the earlier studies, of the mean currents. The sea level rises, the mean currents intensify and EKE increases in summer and fall and the opposite changes occur in winter and spring, with the seasonal extremes in October/November and March/April, respectively. This is in line with the EKE generation by instability of the mean currents. The intra-annual sea level fluctuations and EKE manifest rich variability on quasi-biennial, interannual and decadal timescales. However, in contrast with the seasonal signal, the low-frequency variability does not match, implying different kinds of forcing, probably by local wind in the northern JES and by the transport variations in the Korea – Tsushima Strait (KTS) in the southern JES. Intra-annual simultaneous SLA reveal changing relationship with Pacific Decadal Oscillation (PDO): both were in-phase in 1993–1994 and from late 2007 to 2013 and out-of-phase from 1997 to 2002, while there was no specific relationship in other times. However, the relationship of these SLA with the interannual KTS transport variation seems inconclusive.
Safety Evaluation of Cervical Dorsal Instrumentation in Geriatric Patients: Experience at a Level 1 Center for Spinal Surgery—A Single Center Cohort Study
Authors: Shabo Ehab , Brandecker Simon , Rana Shaleen , Bara Gregor , Scorzin Jasmin E. , Eichhorn Lars , Vatter Hartmut , Banat Mohammed
Published: May 2022

Objective

Dorsal instrumentation of the cervical spine is an established treatment in spine surgery. However, careful planning is required, particularly in elderly patients. This study evaluates early clinical outcomes in geriatric patients undergoing complex spine surgery.

Methods

In this retrospective, single center cohort study, we included all geriatric patients (aged ≥65 years) who underwent dorsal instrumentation between January 2013 and December 2020. We analyzed postoperative complications and the 30-day in-hospital mortality rate. Furthermore, the Charlson comorbidity index (CCI) and Clavien-Dindo grading system (CDG) were used to assess the patients' comorbidity burden.

Results

In total, 153 patients were identified and included. The mean age of patients was 78 years (SD ± 7). Traumatic injury (53.6%) was the most common reason for surgery. 60.8% of the patients underwent dorsal instrumentation with 3 or more levels. The most common comorbidities were arterial hypertension (64%), diabetes mellitus (22.2%), coronary heart disease and atrial fibrillation (19.6%). The most common adverse event (AE) was pneumonia (4%) and the most common surgery-related complication was wound infection (5.2%). Among patients categorized as high risk for AE (CCI > 5), 14.6% suffered a postoperative AE. In our univariate analysis, we found no risk factors for high rates of complications or mortality.

Conclusion

Our data demonstrates that older patients were at no significant risk of postoperative complications. The CCI/CDG scores may identify patients at higher risk for adverse events after dorsal instrumentation, and these assessments should become an essential component of stratification in this older patient population.
Exploring the Evolutionary History and Phylodynamics of Human Immunodeficiency Virus Type 1 Outbreak From Unnao, India Using Phylogenetic Approach
Authors: Patil Ajit , Patil Sandip , Rao Amrita , Gadhe Sharda , Kurle Swarali , Panda Samiran
Published: May 2022

Certain rural and semiurban settings in the Unnao district, Uttar Pradesh, India observed an unprecedented increase in the detection of HIV cases during July 2017. Subsequent investigations through health camps and a follow-up case-control study attributed the outbreak to the unsafe injection exposures during treatment. In this study, we have undertaken a secondary analysis to understand the phylogenetic aspects of the outbreak-associated HIV-1 sequences along with the origin and phylodynamics of these sequences. The initial phylogenetic analysis indicated separate monophyletic grouping and there was no mixing of outbreak-associated sequences with sequences from other parts of India. Transmission network analysis using distance-based and non-distance-based methods revealed the existence of transmission clusters within the monophyletic Unnao clade. The median time to the most recent common ancestor (tMRCA) for sequences from Unnao using the pol gene region was observed to be 2011.87 [95% highest posterior density (HPD): 2010.09–2013.53], while the estimates using envelope (env) gene region sequences traced the tMRCA to 2010.33 (95% HPD: 2007.76–2012.99). Phylodynamics estimates demonstrated that the pace of this local epidemic has slowed down in recent times before the time of sampling, but was certainly on an upward track since its inception till 2014.
Metabolomic Analysis of Lactobacillus acidophilus, L. gasseri, L. crispatus, and Lacticaseibacillus rhamnosus Strains in the Presence of Pomegranate Extract
Authors: Chamberlain MaryClaire , O'Flaherty Sarah , Cobián Natalia , Barrangou Rodolphe
Published: May 2022

Lactobacillus species are prominent inhabitants of the human gastrointestinal tract that contribute to maintaining a balanced microbial environment that positively influences host health. These bacterial populations can be altered through use of probiotic supplements or via dietary changes which in turn affect the host health. Utilizing polyphenolic compounds to selectively stimulate the growth of commensal bacteria can have a positive effect on the host through the production of numerous metabolites that are biologically active. Four Lactobacillus strains were grown in the presence of pomegranate (POM) extract. Two strains, namely, L. acidophilus NCFM and L. rhamnosus GG, are commonly used probiotics, while the other two strains, namely, L. crispatus NCK1351 and L. gasseri NCK1342, exhibit probiotic potential. To compare and contrast the impact of POM on the strains' metabolic capacity, we investigated the growth of the strains with and without the presence of POM and identified their carbohydrate utilization and enzyme activity profiles. To further investigate the differences between strains, an untargeted metabolomic approach was utilized to quantitatively and qualitatively define the metabolite profiles of these strains. Several metabolites were produced significantly and/or exclusively in some of the strains, including mevalonate, glutamine, 5-aminoimidazole-4-carboxamide, phenyllactate, and fumarate. The production of numerous discrete compounds illustrates the unique characteristics of and diversity between strains. Unraveling these differences is essential to understand the probiotic function and help inform strain selection for commercial product formulation.
Recombination in Positive-Strand RNA Viruses
Authors: Wang Haiwei , Cui Xingyang , Cai Xuehui , An Tongqing
Published: May 2022

RNA recombination is a major driver of genetic shifts tightly linked to the evolution of RNA viruses. Genomic recombination contributes substantially to the emergence of new viral lineages, expansion in host tropism, adaptations to new environments, and virulence and pathogenesis. Here, we review some of the recent progress that has advanced our understanding of recombination in positive-strand RNA viruses, including recombination triggers and the mechanisms behind them. The study of RNA recombination aids in predicting the probability and outcome of viral recombination events, and in the design of viruses with reduced recombination frequency as candidates for the development of live attenuated vaccines. Surveillance of viral recombination should remain a priority in the detection of emergent viral strains, a goal that can only be accomplished by expanding our understanding of how these events are triggered and regulated.
Reconstruction of the Evolutionary Origin, Phylodynamics, and Phylogeography of the Porcine Circovirus Type 3
Authors: Cui Yongqiu , Hou Lei , Pan Yang , Feng Xufei , Zhou jianwei , Wang Dedong , Guo Jinshuo , Liu Changzhe , Shi Yongyan , Sun Tong , Yang Xiaoyu , Zhu Ning , Tong Xinxin , Wang Yongxia , Liu Jue
Published: May 2022

Porcine circovirus type 3 (PCV3) is a newly identified virus associated with porcine dermatitis and nephropathy syndrome (PDNS) and multisystemic inflammatory responses in pigs. Recent studies suggests that PCV3 originated from bat circoviruses; however, the origin time, mode of spread, and geographic distribution of PCV3 remain unclear. In this study, the evolutionary origin, phylodynamics, and phylogeography of PCV3 were reconstructed based on the available complete genome sequences. PCV3 showed a closer relationship with bird circovirus than with bat circovirus, but their common ancestor was bat circovirus, indicating that birds may be intermediate hosts for the spread of circoviruses in pigs. Using the BEAST and phylogenetic analyses, three different clades of PCV3 (PCV3a, PCV3b, and PCV3c) were identified, with PCV3a being the most prevalent PCV3 clade. Further studies indicated that the earliest origin of PCV3 can be traced back to 1907.53–1923.44, with a substitution rate of 3.104 × 10–4 to 6.8524 × 10–4 substitution/site/year. A phylogeographic analysis highlighted Malaysia as the earliest location of the original PCV3, which migrated to Asia, America, and Europe. Overall, this study provides novel insights into the evolutionary origin, spread mode, and geographic distribution of PCV3, which will facilitate the prevention and control of PCV3 epidemics in the future.
Functional Connectome Dynamics After Mild Traumatic Brain Injury According to Age and Sex
Authors: Amgalan Anar , Maher Alexander S. , Imms Phoebe , Ha Michelle Y. , Fanelle Timothy A. , Irimia Andrei
Published: May 2022

Neural and cognitive deficits after mild traumatic brain injury (mTBI) are paralleled by changes in resting state functional correlation (FC) networks that mirror post-traumatic pathophysiology effects on functional outcomes. Using functional magnetic resonance images acquired both acutely and chronically after injury (∼1 week and ∼6 months post-injury, respectively), we map post-traumatic FC changes across 136 participants aged 19–79 (52 females), both within and between the brain’s seven canonical FC networks: default mode, dorsal attention, frontoparietal, limbic, somatomotor, ventral attention, and visual. Significant sex-dependent FC changes are identified between (A) visual and limbic, and between (B) default mode and somatomotor networks. These changes are significantly associated with specific functional recovery patterns across all cognitive domains (p < 0.05, corrected). Changes in FC between default mode, somatomotor, and ventral attention networks, on the one hand, and both temporal and occipital regions, on the other hand, differ significantly by age group (p < 0.05, corrected), and are paralleled by significant sex differences in cognitive recovery independently of age at injury (p < 0.05, corrected). Whereas females’ networks typically feature both significant (p < 0.036, corrected) and insignificant FC changes, males more often exhibit significant FC decreases between networks (e.g., between dorsal attention and limbic, visual and limbic, default-mode and somatomotor networks, p < 0.0001, corrected), all such changes being accompanied by significantly weaker recovery of cognitive function in males, particularly older ones (p < 0.05, corrected). No significant FC changes were found across 35 healthy controls aged 66–92 (20 females). Thus, male sex and older age at injury are risk factors for significant FC alterations whose patterns underlie post-traumatic cognitive deficits. This is the first study to map, systematically, how mTBI impacts FC between major human functional networks.
Single-Stage Endovascular Treatment of Severe Cranial Artery Stenosis Coexisted With Ipsilateral Distal Tandem Intracranial Aneurysm
Authors: Ni Hongyang , Zhong Zhihong , Zhu Jun , Jiang Hong , Hu Jinqing , Lin Dong , Bian Liuguan
Published: May 2022

Objective

The coexistence of severe cranial artery stenosis and ipsilateral distal tandem intracranial aneurysm is an unusual phenomenon. Currently, there is no consensus to provide treatment guidelines for concomitant lesions. This study aims to evaluate the safety and effectiveness of single-stage endovascular treatment in patients under this special condition.

Methods

We illustrated a case series of 10 patients with the coexistence of severe cranial artery stenosis and ipsilateral distal tandem intracranial aneurysm in our hospital. And a systematic PubMed search of English-language literature published between 1990 and 2021 was carried out using the keywords: “(carotid OR vertebral OR subclavian artery stenosis) AND (aneurysm) AND (coincident OR coexist OR concomitant OR simultaneous OR ipsilateral).” Clinical information, including age, gender of the patients, as well as symptoms (artery stenosis or aneurysm), localization of artery stenosis and aneurysm, treatment, and outcome, were collected and analyzed.

Results

In the majority of the patients, symptoms were attributed to severe artery stenosis, and the coexisted lesions were located in the anterior circulation system. Most patients achieved an excellent clinical outcome, and no death was observed. No differences were found in a prognosis between single-stage or multiple-stage endovascular treatment.

Conclusions

A single-stage endovascular procedure is technically feasible and effective to treat the coexistence of severe cranial artery stenosis and ipsilateral distal tandem intracranial aneurysm in the anterior circulation as well as in the posterior circulation.
Predicting Outcome for Early Attention Training After Acquired Brain Injury
Authors: Bartfai Aniko , Elg Mattias , Schult Marie-Louise , Markovic Gabriela
Published: May 2022

Background

The training of impaired attention after acquired brain injury is central for successful reintegration in daily living, social, and working life. Using statistical process control, we found different improvement trajectories following attention training in a group of relatively homogeneous patients early after acquired brain injury (ABI).

Objective

To examine the contribution of pre-injury factors and clinical characteristics to differences in outcome after early attention training.

Materials and Methods

Data collected in a clinical trial comparing systematic attention training (APT) with activity-based attention training (ABAT) early after brain injury were reanalyzed.

Results

Stroke patients (p = 0.004) with unifocal (p = 0.002) and right hemisphere lesions (p = 0.045), and those with higher mental flexibility (TMT 4) (p = 0.048) benefitted most from APT training. Cognitive reserve (p = 0.030) was associated with CHANGE and APT as the sole pre-injury factor. For TBI patients, there was no statistical difference between the two treatments.

Conclusion

Our study identifies indiscernible factors predicting improvement after early attention training. APT is beneficial for patients with right-hemispheric stroke in an early recovery phase. Knowledge of prognostic factors, including the level of attention deficit, diagnosis, and injury characteristics, is vital to maximizing the efficiency of resource allocation and the effectiveness of rehabilitative interventions to enhance outcomes following stroke and TBI.
Electroconvulsive Therapy-Induced Changes in Functional Brain Network of Major Depressive Disorder Patients: A Longitudinal Resting-State Electroencephalography Study
Authors: Sun Shuting , Yang Peng , Chen Huayu , Shao Xuexiao , Ji Shanling , Li Xiaowei , Li Gongying , Hu Bin
Published: May 2022

Objectives

Several studies have shown abnormal network topology in patients with major depressive disorder (MDD). However, changes in functional brain networks associated with electroconvulsive therapy (ECT) remission based on electroencephalography (EEG) signals have yet to be investigated.

Methods

Nineteen-channel resting-state eyes-closed EEG signals were collected from 24 MDD patients pre- and post-ECT treatment. Functional brain networks were constructed by using various coupling methods and binarization techniques. Changes in functional connectivity and network metrics after ECT treatment and relationships between network metrics and clinical symptoms were explored.

Results

ECT significantly increased global efficiency, edge betweenness centrality, local efficiency, and mean degree of alpha band after ECT treatment, and an increase in these network metrics had significant correlations with decreased depressive symptoms in repeated measures correlation. In addition, ECT regulated the distribution of hubs in frontal and occipital lobes.

Conclusion

ECT modulated the brain’s global and local information-processing patterns. In addition, an ECT-induced increase in network metrics was associated with clinical remission.

Significance

These findings might present the evidence for us to understand how ECT regulated the topology organization in functional brain networks of clinically remitted depressive patients.
Amelioratory Effect of Resistant Starch on Non-alcoholic Fatty Liver Disease via the Gut-Liver Axis
Authors: Zhu Weifeng , Zhou Ying , Tsao Rong , Dong Huanhuan , Zhang Hua
Published: May 2022

Non-alcoholic fatty liver disease (NAFLD) is a hepatic manifestation of metabolic syndrome with a global prevalence. Impaired gut barrier function caused by an unhealthy diet plays a key role in disrupting the immune-metabolic homeostasis of the gut-liver axis (GLA), leading to NAFLD. Therefore, dietary interventions have been studied as feasible alternative therapeutic approaches to ameliorate NAFLD. Resistant starches (RSs) are prebiotics that reduce systemic inflammation in patients with metabolic syndrome. The present review aimed to elucidate the mechanisms of the GLA in alleviating NAFLD and provide insights into how dietary RSs counteract diet-induced inflammation in the GLA. Emerging evidence suggests that RS intake alters gut microbiota structure, enhances mucosal immune tolerance, and promotes the production of microbial metabolites such as short-chain fatty acids (SCFAs) and secondary bile acids. These metabolites directly stimulate the growth of intestinal epithelial cells and elicit GPR41/GPR43, FXR, and TGR5 signaling cascades to sustain immune-metabolic homeostasis in the GLA. The literature also revealed the dietary-immune-metabolic interplay by which RSs exert their regulatory effect on the immune-metabolic crosstalk of the GLA and the related molecular basis, suggesting that dietary intervention with RSs may be a promising alternative therapeutic strategy against diet-induced dysfunction of the GLA and, ultimately, the risk of developing NAFLD.
The Probiotic Lactobacillus paracasei Ameliorates Diarrhea Cause by Escherichia coli O8via Gut Microbiota Modulation1
Authors: Ren Shunan , Wang Chunjie , Chen Aorigele , Lv Wenting , Gao Ruijuan
Published: May 2022

Introduction

Koumiss is a fermented horse milk food containing abundant probiotics. Lactobacillus paracasei is a bacterial strain isolated from koumiss that helps regulate the intestinal microbiota. One of the major cause of diarrhea is an imbalance of the intestinal flora. The aim of this study was to investigate whether Lactobacillus paracasei can ameliorate E. coli-induced diarrhea and modulate the gut microbiota.

Methods

Mouse models of diarrhea were established via intragastric E. coli O8 administration. We then attempted to prevent or treat diarrhea in the mice via intragastric administration of a 3 × 108 CFU/mL L. paracasei cell suspension. The severity of diarrhea was evaluated based on the body weight, diarrhea rate, and index, fecal diameter, ileum injury, hematoxylin-eosin (H&E) staining, and diamine oxidase (DAO) and zonulin expression. Expression of the tight junction (TJ) proteins claudin-1, occludin, and zona occludens (ZO-)1 were detected by immunohistochemistry (IHC). Gastrointestinal mRNA expression levels of interleukin (IL)-6, IL-1β, and tumor necrosis factor (TNF)-α were detected by real-time polymerase chain reaction (RT-PCR). The microbial composition was analyzed by 16s rRNA sequencing.

Results

The L. paracasei demonstrated excellent therapeutic efficacy against diarrhea. It elevated the TJ protein levels and downregulated proinflammatory cytokines IL-6, IL-1β, TNF-α, and p65, myosin light chain 2 (MLC2), myosin light chain kinase (MLCK). Moreover L. paracasei increased those bacteria, which can product short-chain fatty acid (SCFA) such Alistipes, Odoribacter, Roseburia, and Oscillibacter.

Conclusion

L. paracasei ameliorated diarrhea by inhibiting activation of the nuclear factor kappa B (NF-κB)-MLCK pathway and increasing the abundance of gut microbiota that produce SCFA.
Identification of Synergistic Drug Combinations to Target KRAS-Driven Chemoradioresistant Cancers Utilizing Tumoroid Models of Colorectal Adenocarcinoma and Recurrent Glioblastoma
Authors: Gupta Kshama , Jones Jeremy C. , Farias Virginea De Araujo , Mackeyev Yuri , Singh Pankaj K. , Quiñones-Hinojosa Alfredo , Krishnan Sunil
Published: May 2022

Treatment resistance is observed in all advanced cancers. Colorectal cancer (CRC) presenting as colorectal adenocarcinoma (COAD) is the second leading cause of cancer deaths worldwide. Multimodality treatment includes surgery, chemotherapy, and targeted therapies with selective utilization of immunotherapy and radiation therapy. Despite the early success of anti-epidermal growth factor receptor (anti-EGFR) therapy, treatment resistance is common and often driven by mutations in APC, KRAS, RAF, and PI3K/mTOR and positive feedback between activated KRAS and WNT effectors. Challenges in the direct targeting of WNT regulators and KRAS have caused alternative actionable targets to gain recent attention. Utilizing an unbiased drug screen, we identified combinatorial targeting of DDR1/BCR-ABL signaling axis with small-molecule inhibitors of EGFR-ERBB2 to be potentially cytotoxic against multicellular spheroids obtained from WNT-activated and KRAS-mutant COAD lines (HCT116, DLD1, and SW480) independent of their KRAS mutation type. Based on the data-driven approach using available patient datasets (The Cancer Genome Atlas (TCGA)), we constructed transcriptomic correlations between gene DDR1, with an expression of genes for EGFR, ERBB2-4, mitogen-activated protein kinase (MAPK) pathway intermediates, BCR, and ABL and genes for cancer stem cell reactivation, cell polarity, and adhesion; we identified a positive association of DDR1 with EGFR, ERBB2, BRAF, SOX9, and VANGL2 in Pan-Cancer. The evaluation of the pathway network using the STRING database and Pathway Commons database revealed DDR1 protein to relay its signalingviaadaptor proteins (SHC1, GRB2, and SOS1) and BCR axis to contribute to the KRAS-PI3K-AKT signaling cascade, which was confirmed by Western blotting. We further confirmed the cytotoxic potential of our lead combination involving EGFR/ERBB2 inhibitor (lapatinib) with DDR1/BCR-ABL inhibitor (nilotinib) in radioresistant spheroids of HCT116 (COAD) and, in an additional devastating primary cancer model, glioblastoma (GBM). GBMs overexpress DDR1 and share some common genomic features with COAD like EGFR amplification and WNT activation. Moreover, genetic alterations in genes like NF1 make GBMs have an intrinsically high KRAS activity. We show the combination of nilotinib plus lapatinib to exhibit more potent cytotoxic efficacy than either of the drugs administered alone in tumoroids of patient-derived recurrent GBMs. Collectively, our findings suggest that combinatorial targeting of DDR1/BCR-ABL with EGFR-ERBB2 signaling may offer a therapeutic strategy against stem-like KRAS-driven chemoradioresistant tumors of COAD and GBM, widening the window for its applications in mainstream cancer therapeutics.
One-Step Nucleic Acid Amplification System in Comparison to the Intraoperative Frozen Section and Definitive Histological Examination Among Breast Cancer Patients: A Retrospective Survival Study
Authors: Bertozzi Serena , Londero Ambrogio P. , Bulfoni Michela , Seriau Luca , Agakiza Diane , Pasqualucci Alberto , Andretta Michela , Orsaria Maria , Mariuzzi Laura , Cedolini Carla
Published: May 2022

Simple Summary

Implementing intraoperative assessment of sentinel lymph nodes by one-step nucleic acid amplification in early breast cancer can reduce the surgical burden to the patient and the costs to the health system. However, only limited data are available in terms of long-term disease-free survival and overall survival. Therefore, this study aims to compare disease-free survival and overall survival between one-step nucleic acid amplification, frozen section, and definitive histology. These results could impact the healthcare community, adding further proof to the body of evidence supporting the broader adoption of this innovative technology that enables a safe reduction in patient surgical burden and healthcare costs.

Background

The one-step nucleic acid amplification (OSNA) system is a novel molecular technique, which consents to quick intraoperative detection of sentinel lymph node metastases by the amplification of cytokeratin 19 mRNA. Our study aims to evaluate the OSNA method in comparison with frozen section (FS) and definitive histological examination of the sentinel lymph node biopsy among early breast cancer patients considering disease-free survival (DFS) and overall survival (OS).

Methods

In this study, we included all women who underwent sentinel lymph node biopsy (SLNB) for breast cancers classified as TNM stage I and II in our center between January 2005 and January 2017, and the follow-up was collected up to January 2019. We divided patients among three groups based on SLNB evaluation: definitive histological examination, intra-operative FS, or OSNA.

Results

We included 2412 SLNBs: 727 by definitive histological examination, 697 by FS, and 988 by OSNA. Isolated tumor cells were found in 2.32% of cases, micrometastasis in 9.12%, and macrometastases in 13.64%. Surgical procedure duration was significantly shorter in OSNA than in FS (42.1 minutes ±5.1 vs. 70.1 minutes ±10.5, p <0.05). No significant differences have been observed among the three groups regarding OS, DSF, cumulative local, or distant metastases. In particular 5-year DFS was 96.38% in definitive histology (95% C.I. 95.02-97.75%), 96.37% in FS (95% C.I. 94.98-97.78%), and 96.51% in OSNA group (95% C.I. 95.32-97.72%).

Conclusions

No difference in OS and DFS was found comparing OSNA, FS, and definitive histology. Furthermore, reduced operative time was found in the OSNA group.
A Lung Cancer Patient Harboring a Rare Oncogenic EGFR Exon 20 V786M Mutation Responded to a Third-Generation Tyrosine Kinase Inhibitor: Case Report and Review of the Literature
Authors: Zhu Qi , Jiang Mingyun , Li Wenfei , Sun Shuangli , Li Jisheng , Stebbing Justin , Liang Xiaodong , Peng Ling
Published: May 2022

Background

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are effective treatments for non-small cell lung cancer (NSCLC) patients with activating EGFR mutations. There are many uncommon and rare mutations in the EGFR gene. The efficacy of the EGFR-TKIs is largely unknown for cancers harboring uncommon or rare EGFR mutations.

Case Presentation

A 69-year-old woman was diagnosed with adenocarcinoma cT4N2M1c, stage IVB. Next-generation sequencing (NGS) confirmed a rare EGFR V786M mutation. During chemotherapy, immune checkpoint inhibitor (ICI), and anti-angiogenic treatment, no radiological response was observed. Subsequent third-generation EGFR TKI showed a remarkable therapeutic effect. Structural prediction revealed that the V786M mutation induces conformational change at the dimer interface, without altering the ATP binding to the EGFR tyrosine kinase domain (TKD). Consistently, docking simulations indicated that the affinity of ATP to the V786M mutant was not disturbed, which explained the TKI sensitivity.

Conclusions

Our data confirmed the activating role on EGFR V786M mutation. Together with structural predictions and clinical evidence for activity of TKIs against EGFR V786M mutations, these findings warrant further investigation.
Two Distinct Neural Mechanisms Underlying Acupuncture Analgesia
Authors: Kato Yasutaka , Yachi Kazuhiro , Hoshi Hideyuki , Okada Toyoji , Shigihara Yoshihito
Published: May 2022

Acupuncture analgesia is a traditional treatment with a long history, although it lacks scientific evidence. It is reportedly associated with the central nervous system, including various brain regions, from the cortices to the brain stem. However, it remains unclear whether the distributed regions behave as a single unit or consist of multiple sub-units playing different roles. Magnetoencephalography is a neuroimaging technique that can measure the oscillatory frequency of neural signals and brain regions. The frequency band of neural signals allows further understanding of the characteristics of the acupuncture-related neural systems. This study measured resting-state brain activity using magnetoencephalography in 21 individuals with chronic pain before and after acupuncture treatment. The subjective level of pain was assessed using a visual analog scale, and brain activity was compared to identify the brain regions and the frequencies associated with acupuncture analgesia. Here, we categorized the changes in resting-state brain activity into two groups: low-frequency oscillatory activity (<3 Hz) in the left middle occipital and right superior partial lobule and high-frequency oscillatory activity (81–120 Hz) on both sides of the prefrontal, primary sensory, and right fusiform gyri. These findings suggest that acupuncture analgesia influences two or more sub-units of the neural systems, which helps us understand the neural mechanisms underlying acupuncture analgesia.