bluuebunny/crossref_metadata_2025 huggingface dataset:
Distinctive Evasion Mechanisms to Allow Persistence of Borrelia burgdorferi in Different Human Cell Lines
Authors: Karvonen Kati , Nykky Jonna , Marjomäki Varpu , Gilbert Leona
Published: October 2021

Lyme borreliosis is a multisystemic disease caused by the pleomorphic bacteria of theBorrelia burgdorferi sensu latocomplex. The exact mechanisms for the infection to progress into a prolonged sequelae of the disease are currently unknown, although immune evasion and persistence of the bacteria in the host are thought to be major contributors. The current study investigatedB. burgdorferiinfection processes in two human cell lines, both non-immune and non-phagocytic, to further understand the mechanisms of infection of this bacterium. By utilizing light, confocal, helium ion, and transmission electron microscopy, borrelial infection of chondrosarcoma (SW1353) and dermal fibroblast (BJ) cells were examined from an early 30-min time point to a late 9-days post-infection. Host cell invasion, viability of both the host andB. burgdorferi, as well as, co-localization with lysosomes and the presence of different borrelial pleomorphic forms were analyzed. The results demonstrated differences of infection between the cell lines starting from early entry asB. burgdorferiinvaded BJ cells in coiled forms with less pronounced host cell extensions, whereas in SW1353 cells, micropodial interactions with spirochetes were always seen. Moreover, infection of BJ cells increased in a dose dependent manner throughout the examined 9 days, while the percentage of infection, although dose dependent, decreased in SW1353 cells after reaching a peak at 48 h. Furthermore, blebs, round body and damagedB. burgdorferiforms, were mostly observed from the infected SW1353 cells, while spirochetes dominated in BJ cells. Both infected host cell lines grew and remained viable after 9 day post-infection. Although damaged forms were noticed in both cell lines, co-localization with lysosomes was low in both cell lines, especially in BJ cells. The invasion of non-phagocytic cells and the lack of cytopathic effects onto the host cells byB. burgdorferiindicated one mechanism of immune evasion for the bacteria. The differences in attachment, pleomorphic form expressions, and the lack of lysosomal involvement between the infected host cells likely explain the ability of a bacterium to adapt to different environments, as well as, a strategy for persistence inside a host.
Contribution of Maternal and Paternal Transmission to Bacterial Colonization in Nematostella vectensis
Authors: Baldassarre Laura , Levy Shani , Bar-Shalom Rinat , Steindler Laura , Lotan Tamar , Fraune Sebastian
Published: October 2021

Microbial communities confer multiple beneficial effects to their multicellular hosts. To evaluate the evolutionary and ecological implications of the animal-microbe interactions, it is essential to understand how bacterial colonization is secured and maintained during the transition from one generation to the next. However, the mechanisms of symbiont transmission are poorly studied for many species, especially in marine environments, where the surrounding water constitutes an additional source of microbes. Nematostella vectensis, an estuarine cnidarian, has recently emerged as model organism for studies on host-microbes interactions. Here, we use this model organism to study the transmission of bacterial colonizers, evaluating the contribution of parental and environmental transmission to the establishment of bacterial communities of the offspring. We induced spawning in adult male and female polyps of N. vectensis and used their gametes for five individual fertilization experiments. While embryos developed into primary polyps, we sampled each developmental stage and its corresponding medium samples. By analyzing the microbial community compositions of all samples through 16S rRNA gene amplicon sequencing, we showed that all host tissues harbor microbiota significantly different from the surrounding medium. Interestingly, oocytes and sperms are associated with distinct bacterial communities, indicating the specific vertical transmission of bacterial colonizers by the gametes. These differences were consistent among all the five families analyzed. By overlapping the identified bacterial ASVs associated with gametes, offspring and parents, we identified specific bacterial ASVs that are well supported candidates for vertical transmission via mothers and fathers. This is the first study investigating bacteria transmission in N. vectensis, and among few on marine spawners that do not brood larvae. Our results shed light on the consistent yet distinct maternal and paternal transfer of bacterial symbionts along the different life stages and generations of an aquatic invertebrate.
Metagenomic and Metatranscriptomic Insight Into Oral Biofilms in Periodontitis and Related Systemic Diseases
Authors: Huang Yi , Zhao Xinyuan , Cui Li , Huang Shaohong
Published: October 2021

The oral microbiome is one of the most complex microbial communities in the human body and is closely related to oral and systemic health. Dental plaque biofilms are the primary etiologic factor of periodontitis, which is a common chronic oral infectious disease. The interdependencies that exist among the resident microbiota constituents in dental biofilms and the interaction between pathogenic microorganisms and the host lead to the occurrence and progression of periodontitis. Therefore, accurately and comprehensively detecting periodontal organisms and dissecting their corresponding functional activity characteristics are crucial for revealing periodontitis pathogenesis. With the development of metagenomics and metatranscriptomics, the composition and structure of microbial communities as well as the overall functional characteristics of the flora can be fully profiled and revealed. In this review, we will critically examine the currently available metagenomic and metatranscriptomic evidence to bridge the gap between microbial dysbiosis and periodontitis and related systemic diseases.
The Trp-rich Antimicrobial Amphiphiles With Intramolecular Aromatic Interactions for the Treatment of Bacterial Infection
Authors: Wang Zhihua , Li Qiuke , Li Jinze , Li Jiawei , Shang Lu , Chou Shuli , Lyu Yinfeng , Shan Anshan
Published: October 2021

Antibiotic resistance is emerging as a hot issue with the abuse and overuse of antibiotics, and the shortage of effective antimicrobial agents against multidrug resistant bacteria creates a huge problem to treat the threatening nosocomial skin and soft tissue infection. Antimicrobial peptides (AMPs) exhibite enormous potential as one of the most promising candidates of antibiotic to fight against pathogenic infections because of its unique membrane penetration mechanism to kill pathogens, whereas the clinical application of AMPs still faces the challenges of production cost, stability, safety, and design strategy. Herein, a series of Trp-rich peptides was designed following the principle of paired Trp plated at the ith and ith+4 position on the backbone of peptides, based on the template (VKKX)4, where X represents W, A, or L, to study the effect of intramolecular aromatic interactions on the bioactivity of AMPs. Through comparing the antimicrobial performance, hemolysis, cytotoxicity, and stability, VW5 which is equipped with the characters of direct antimicrobial efficacy (GM=1.68μM) and physical destruction of bacterial membrane (SEM and electron microscopy) stood out from the engineering peptides. VW5 also performed well in mice models, which could significantly decrease the bacterial colony (VW5 vs infection group, 12.72±2.26 vs 5.52±2.01×109CFU/abscess), the area of dermo-necrosis (VW5 vs infection group, 0.74±0.29 vs 1.86±0.98mm2) and the inflammation cytokine levels at the abscess site without causing toxicity to the skin. Overall, this study provides a strategy and template to diminish the randomness in the exploration and design of novel peptides.
Responses of Arbuscular Mycorrhizal Fungi Diversity and Community to 41-Year Rotation Fertilization in Brown Soil Region of Northeast China
Authors: Zhang Shiyu , Luo Peiyu , Yang Jinfeng , Irfan Muhammad , Dai Jian , An Ning , Li Na , Han Xiaori
Published: October 2021

Arbuscular mycorrhizal fungi (AMF) play vital roles in the growth and development of plants, ecosystem sustainability, and stability in agroecosystem, such as transporting nutrients to host plants, improving soil physical structure, and enhancing the stress resistance of host plants. However, the effects of fertilization on AMF diversity and community in brown soil areas are still unclear. The purpose of this study is to explore changes in AMF diversity and community structures and finding out the factors that influenced the changes after 41 years of fertilization in brown soil. Samples were collected from five treatments of the long-term fertilization experiment in June 2019, including CK (no fertilizer), N (mineral nitrogen fertilizer), NP (mineral nitrogen and phosphate fertilizer), M (pig manure), and MNP (pig manure, mineral nitrogen, and phosphate fertilizer). Illumina HiSeq sequencing was used to determine AMF diversity and community structure. The relationship between AMF communities in soil and roots and environmental factors was analyzed by redundancy analysis. The results showed that the soil nutrient content of manure treatments was generally higher than that of chemical fertilizer treatments and no fertilizer treatment. Long-term fertilization increased AMF spore density, which increased with the increase of soil fertility. The moderate content of soil available phosphorus was beneficial to the colonization of AMF. AMF diversity in soil decreased with soil fertility, but AMF diversity in roots was influenced only by soil nitrate–nitrogen and pH. Glomus was the dominant genus in both soil and root samples. AMF community structure in soil and roots had a different response to long-term fertilization. Application of manure had a greater impact on AMF community structure in soil, whereas application of exogenous phosphate fertilizer had a greater impact on that in roots. Soil ammonium nitrogen, nitrate–nitrogen, total nitrogen, organic carbon, total potassium, and available potassium were the most important factors that influenced taxa of AMF in soil, whereas soil ammonium nitrogen, nitrate–nitrogen, total nitrogen, organic carbon, total potassium, available potassium, available phosphorus, and plant phosphorus and potassium content were the most important factors influencing taxa of AMF in maize roots under long-term fertilization in brown soil.
Uncovering the Role of Metabolism in Oomycete–Host Interactions Using Genome-Scale Metabolic Models
Authors: Rodenburg Sander Y. A. , Seidl Michael F. , de Ridder Dick , Govers Francine
Published: October 2021

Metabolism is the set of biochemical reactions of an organism that enables it to assimilate nutrients from its environment and to generate building blocks for growth and proliferation. It forms a complex network that is intertwined with the many molecular and cellular processes that take place within cells. Systems biology aims to capture the complexity of cells, organisms, or communities by reconstructing models based on information gathered by high-throughput analyses (omics data) and prior knowledge. One type of model is a genome-scale metabolic model (GEM) that allows studying the distributions of metabolic fluxes, i.e., the “mass-flow” through the network of biochemical reactions. GEMs are nowadays widely applied and have been reconstructed for various microbial pathogens, either in a free-living state or in interaction with their hosts, with the aim to gain insight into mechanisms of pathogenicity. In this review, we first introduce the principles of systems biology and GEMs. We then describe how metabolic modeling can contribute to unraveling microbial pathogenesis and host–pathogen interactions, with a specific focus on oomycete plant pathogens and in particular Phytophthora infestans. Subsequently, we review achievements obtained so far and identify and discuss potential pitfalls of current models. Finally, we propose a workflow for reconstructing high-quality GEMs and elaborate on the resources needed to advance a system biology approach aimed at untangling the intimate interactions between plants and pathogens.
Discovering the Potentials of Four Phage Endolysins to Combat Gram-Negative Infections
Authors: Vasina Daria V. , Antonova Nataliia P. , Grigoriev Igor V. , Yakimakha Victoria S. , Lendel Anastasiya M. , Nikiforova Maria A. , Pochtovyi Andrei A. , Remizov Timofey A. , Usachev Evgeny V. , Shevlyagina Natalia V. , Zhukhovitsky Vladimir G. , Fursov Mikhail V. , Potapov Vasiliy D. , Vorobev Aleksei M. , Aleshkin Andrey V. , Laishevtsev Aleksei I. , Makarov Valentine V. , Yudin Sergey M. , Tkachuk Artem P. , Gushchin Vladimir A.
Published: October 2021

Endolysin-based therapeutics are promising antibacterial agents and can successfully supplement the existing antibacterial drugs array. It is specifically important in the case of Gram-negative pathogens, e.g., ESKAPE group bacteria, which includes Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species, and are highly inclined to gain multiple antibiotic resistance. Despite numerous works devoted to the screening of new lytic enzymes and investigations of their biochemical properties, there are significant breaches in some aspects of their operating characteristics, including safety issues of endolysin use. Here, we provide a comprehensive study of the antimicrobial efficacy aspects of four Gram-negative bacteria-targeting endolysins LysAm24, LysAp22, LysECD7, and LysSi3, their in vitro and in vivo activity, and their biological safety. These endolysins possess a wide spectrum of action, are active against planktonic bacteria and bacterial biofilms, and are effective in wound and burn skin infection animal models. In terms of safety, these enzymes do not contribute to the development of short-term resistance, are not cytotoxic, and do not significantly affect the normal intestinal microflora in vivo. Our results provide a confident base for the development of effective and safe candidate dosage forms for the treatment of local and systemic infections caused by Gram-negative bacterial species.
Players in Mitochondrial Dynamics and Female Reproduction
Authors: Zou Weiwei , Ji Dongmei , Zhang Zhiguo , Yang Li , Cao Yunxia
Published: October 2021

Mitochondrial dynamics (fission and fusion) are essential physiological processes for mitochondrial metabolic function, mitochondrial redistribution, and mitochondrial quality control. Various proteins are involved in regulating mitochondrial dynamics. Aberrant expression of these proteins interferes with mitochondrial dynamics and induces a range of diseases. Multiple therapeutic approaches have been developed to treat the related diseases in recent years, but their curative effects are limited. Meanwhile, the role of mitochondrial dynamics in female reproductive function has attracted progressively more attention, including oocyte development and maturation, fertilization, and embryonic development. Here, we reviewed the significance of mitochondrial dynamics, proteins involved in mitochondrial dynamics, and disorders resulting from primary mitochondrial dynamic dysfunction. We summarized the latest therapeutic approaches of hereditary mitochondrial fusion–fission abnormalities and reviewed the recent advances in female reproductive mitochondrial dynamics.
Emerging Contributions of Solid-State NMR Spectroscopy to Chromatin Structural Biology
Authors: Ackermann Bryce E. , Debelouchina Galia T.
Published: October 2021

The eukaryotic genome is packaged into chromatin, a polymer of DNA and histone proteins that regulates gene expression and the spatial organization of nuclear content. The repetitive character of chromatin is diversified into rich layers of complexity that encompass DNA sequence, histone variants and post-translational modifications. Subtle molecular changes in these variables can often lead to global chromatin rearrangements that dictate entire gene programs with far reaching implications for development and disease. Decades of structural biology advances have revealed the complex relationship between chromatin structure, dynamics, interactions, and gene expression. Here, we focus on the emerging contributions of magic-angle spinning solid-state nuclear magnetic resonance spectroscopy (MAS NMR), a relative newcomer on the chromatin structural biology stage. Unique among structural biology techniques, MAS NMR is ideally suited to provide atomic level information regarding both the rigid and dynamic components of this complex and heterogenous biological polymer. In this review, we highlight the advantages MAS NMR can offer to chromatin structural biologists, discuss sample preparation strategies for structural analysis, summarize recent MAS NMR studies of chromatin structure and dynamics, and close by discussing how MAS NMR can be combined with state-of-the-art chemical biology tools to reconstitute and dissect complex chromatin environments.
A Myeloid Signature-Based Nomogram Predicts the Postoperative Recurrence of Intrahepatic Cholangiocarcinoma
Authors: Liang Jing , Zhou Hui , Huang Xiang-Qi , Liu Yan-Fei , Zhang Lei , He Dan , Cui Yongmei , Guo Jinrui , Hu Kunpeng , Wu Chong
Published: October 2021

Intrahepatic cholangiocarcinoma (iCCA) is the second most common cancer in liver, with a high recurrence rate after surgery. Recently, we identified a CD11b-CD169-based myeloid response score (MRS), which showed remarkable prognostic potential in hepatocellular carcinoma (HCC). Here, we aimed to verify the prognostic value of the MRS in iCCA and establish an MRS-based nomogram to predict the postoperative prognosis of iCCA patients. From April 2005 to March 2017, a total of 84 patients from the Third Affiliated Hospital of Sun Yat-sen University were enrolled. Preoperative clinical information and surgical specimens of enrolled patients were collected. Among these, tissues from 75 patients passed the clinical data quality control and the staining quality control. The protein expression of CD11b and CD169 in iCCA samples were detected by immunohistochemistry (IHC). Kaplan-Meier analysis and receiver operating characteristic (ROC) curves revealed that the MRS had a high discriminatory ability for predicting the time to recurrence (TTR) of iCCA patients after surgery. Three independent risk factors selected by a Cox proportional hazards regression analysis, namely, the MRS, the tumor size and the status of vascular invasion, were included to construct a nomogram to predict the recurrence of iCCA after resection surgery. ROC curves, calibration analysis and decision curve analysis (DCA) suggested that this nomogram had notable discriminatory power, stability and clinical usefulness in predicting the postoperative recurrence. Together, we explored the prognostic value of the MRS in iCCA, and constructed an MRS-based nomogram which may help to predict postoperative recurrence and aid clinical decisions for iCCA patients.
Mapping Function from Dynamics: Future Challenges for Network-Based Models of Protein Structures
Authors: Pacini Lorenza , Dorantes-Gilardi Rodrigo , Vuillon Laurent , Lesieur Claire
Published: October 2021

Proteins fulfill complex and diverse biological functions through the controlled atomic motions of their structures (functional dynamics). The protein composition is given by its amino-acid sequence, which was assumed to encode the function. However, the discovery of functional sequence variants proved that the functional encoding does not come down to the sequence, otherwise a change in the sequence would mean a change of function. Likewise, the discovery that function is fulfilled by a set of structures and not by a unique structure showed that the functional encoding does not come down to the structure either. That leaves us with the possibility that a set of atomic motions, achievable by different sequences and different structures, encodes a specific function. Thanks to the exponential growth in annual depositions in the Protein Data Bank of protein tridimensional structures at atomic resolutions, network models using the Cartesian coordinates of atoms of a protein structure as input have been used over 20 years to investigate protein features. Combining networks with experimental measures or with Molecular Dynamics (MD) simulations and using typical or ad-hoc network measures is well suited to decipher the link between protein dynamics and function. One perspective is to consider static structures alone as alternatives to address the question and find network measures relevant to dynamics that can be subsequently used for mining and classification of dynamic sequence changes functionally robust, adaptable or faulty. This way the set of dynamics that fulfill a function over a diversity of sequences and structures will be determined.
Optimizing Cognitive Training for the Treatment of Cognitive Dysfunction in Parkinson’s Disease: Current Limitations and Future Directions
Authors: Guglietti Bianca , Hobbs David , Collins-Praino Lyndsey E.
Published: October 2021

Cognitive dysfunction, primarily involving impairments in executive function, visuospatial function and memory, is one of the most common non-motor symptoms of Parkinson’s disease (PD). Currently, the only pharmacological treatments available for the treatment of cognitive dysfunction in PD provide variable benefit, making the search for potential non-pharmacological therapies to improve cognitive function of significant interest. One such therapeutic strategy may be cognitive training (CT), which involves the repetition of standardized tasks with the aim of improving specific aspects of cognition. Several studies have examined the effects of CT in individuals with PD and have shown benefits in a variety of cognitive domains, but the widespread use of CT in these individuals may be limited by motor impairments and other concerns in study design. Here, we discuss the current state of the literature on the use of CT for PD and propose recommendations for future implementation. We also explore the potential use of more recent integrative, adaptive and assistive technologies, such as virtual reality, which may optimize the delivery of CT in PD.
Acute Effects of Different Exercise Intensities on Executive Function and Oculomotor Performance in Middle-Aged and Older Adults: Moderate-Intensity Continuous Exercise vs. High-Intensity Interval Exercise
Authors: Tsai Chia-Liang , Chang Yu-Chuan , Pan Chien-Yu , Wang Tsai-Chiao , Ukropec Jozef , Ukropcová Barbara
Published: October 2021

A wealth of evidence has shown that a single bout of aerobic exercise can facilitate executive function. However, none of current studies on this topic have addressed whether the magnitude of the acute-exercise benefit on executive function and oculomotor performance is influenced by different aerobic exercise modes. The present study was thus aimed toward an investigation of the acute effects of high-intensity interval exercise (HIIE) vs. moderate-intensity continuous exercise (MICE) on executive-related oculomotor performance in healthy late middle-aged and older adults. Using a within-subject design, twenty-two participants completed a single bout of 30 min of HIIE, MICE, or a non-exercise-intervention (REST) session in a counterbalanced order. The behavioral [e.g., reaction times (RTs), coefficient of variation (CV) of the RT], and oculomotor (e.g., saccade amplitude, saccade latency, and saccadic peak velocity) indices were measured when participants performed antisaccade and prosaccade tasks prior to and after an intervention mode. The results showed that a 30-min single-bout of HIIE and MICE interventions shortened the RTs in the antisaccade task, with the null effect on the CV of the RT in the late middle-aged and older adults. In terms of oculomotor metrics, although the two exercise modes could not modify the performance in terms of saccade amplitudes and saccade latencies, the participants’ saccadic peak velocities while performing the oculomotor paradigm were significantly altered only following an acute HIIE intervention. The present findings suggested that a 30-min single-bout of HIIE and MICE interventions modulated post-exercise antisaccade control on behavioral performance (e.g., RTs). Nevertheless, the HIIE relative MICE mode appears to be a more effective aerobic exercise in terms of oculomotor control (e.g., saccadic peak velocities) in late middle-aged and older adults.
Multi-Domain Touchscreen-Based Cognitive Assessment of C57BL/6J Female Mice Shows Whole-Body Exposure to 56Fe Particle Space Radiation in Maturity Improves Discrimination Learning Yet Impairs Stimulus-Response Rule-Based Habit Learning
Authors: Soler Ivan , Yun Sanghee , Reynolds Ryan P. , Whoolery Cody W. , Tran Fionya H. , Kumar Priya L. , Rong Yuying , DeSalle Matthew J. , Gibson Adam D. , Stowe Ann M. , Kiffer Frederico C. , Eisch Amelia J.
Published: October 2021

Astronauts during interplanetary missions will be exposed to galactic cosmic radiation, including charged particles like56Fe. Most preclinical studies with mature, “astronaut-aged” rodents suggest space radiation diminishes performance in classical hippocampal- and prefrontal cortex-dependent tasks. However, a rodent cognitive touchscreen battery unexpectedly revealed56Fe radiation improves the performance of C57BL/6J male mice in a hippocampal-dependent task (discrimination learning) without changing performance in a striatal-dependent task (rule-based learning). As there are conflicting results on whether the female rodent brain is preferentially injured by or resistant to charged particle exposure, and as the proportion of female vs. male astronauts is increasing, further study on how charged particles influence the touchscreen cognitive performance of female mice is warranted. We hypothesized that, similar to mature male mice, mature female C57BL/6J mice exposed to fractionated whole-body56Fe irradiation (3 × 6.7cGy56Fe over 5 days, 600 MeV/n) would improve performance vs. Sham conditions in touchscreen tasks relevant to hippocampal and prefrontal cortical function [e.g., location discrimination reversal (LDR) and extinction, respectively]. In LDR,56Fe female mice more accurately discriminated two discrete conditioned stimuli relative to Sham mice, suggesting improved hippocampal function. However,56Fe and Sham female mice acquired a new simple stimulus-response behavior and extinguished this acquired behavior at similar rates, suggesting similar prefrontal cortical function. Based on prior work on multiple memory systems, we next tested whether improved hippocampal-dependent function (discrimination learning) came at the expense of striatal stimulus-response rule-based habit learning (visuomotor conditional learning). Interestingly,56Fe female mice took more days to reach criteria in this striatal-dependent rule-based test relative to Sham mice. Together, our data support the idea of competition between memory systems, as an56Fe-induced decrease in striatal-based learning is associated with enhanced hippocampal-based learning. These data emphasize the power of using a touchscreen-based battery to advance our understanding of the effects of space radiation on mission critical cognitive function in females, and underscore the importance of preclinical space radiation risk studies measuring multiple cognitive processes, thereby preventing NASA’s risk assessments from being based on a single cognitive domain.
Predictors and Correlates of Perceived Cognitive Decline in Retired Professional Rugby League Players
Authors: Van Patten Ryan , Iverson Grant L. , Terry Douglas P. , Levi Christopher R. , Gardner Andrew J.
Published: October 2021

Objective: Rugby league is an international full-contact sport, with frequent concussive injuries. Participation in other full-contact sports such as American football has been considered to be a risk factor for neuropsychiatric sequelae later-in-life, but little research has addressed the mental and cognitive health of retired professional rugby league players. We examined predictors and correlates of perceived (self-reported) cognitive decline in retired National Rugby League (NRL) players.

Methods: Participants were 133 retired male elite level rugby league players in Australia. Participants completed clinical interviews, neuropsychological testing, and self-report measures. The Informant Questionnaire on Cognitive Decline in the Elderly, self-report (IQCODE-Self), measured perceived cognitive decline.

Results: The median age of the sample was 55.0 (M = 53.1, SD = 13.9, range = 30–89) and the median years of education completed was 12.0 (M = 11.9, SD = 2.6, range = 7–18). The retired players reported a median of 15.0 total lifetime concussions (M = 28.0, SD = 36.6, range = 0–200). The mean IQCODE-Self score was 3.2 (SD = 0.5; Range = 1.3–5.0); 10/133 (7.5%) and 38/133 (28.6%) scored above conservative and liberal cutoffs for cognitive decline on the IQCODE-Self, respectively. Perceived cognitive decline was positively correlated with current depressive symptoms, negatively correlated with years of professional sport exposure and resilience, and unrelated to objective cognition and number of self-reported concussions. A multiple regression model with perceived cognitive decline regressed on age, concussion history, professional rugby league exposure, depression, resilience, objective cognitive functioning, daytime sleepiness, and pain severity showed depression as the only significant predictor.

Conclusion: This is the first large study examining subjectively experienced cognitive decline in retired professional rugby league players. Similar to studies from the general population and specialty clinics, no relationship was found between objective cognitive test performance and perceived cognitive decline. Depressive symptoms emerged as the strongest predictor of perceived cognitive decline, suggesting that subjective reports of worsening cognition in retired elite rugby league players might reflect psychological distress rather than current cognitive impairment.
Effects of Robot-Aided Rehabilitation on the Ankle Joint Properties and Balance Function in Stroke Survivors: A Randomized Controlled Trial
Authors: Zhai Xiaoxue , Wu Qiong , Li Xin , Xu Quan , Zhang Yanlin , Fan Senchao , Zhang Li-Qun , Pan Yu
Published: October 2021

Background:Stroke survivors with impaired control of the ankle due to stiff plantarflexors often experience abnormal posture control, which affects balance and locomotion. Forceful stretching may decrease ankle stiffness and improve balance. Recently, a robot-aided stretching device was developed to decrease ankle stiffness of patient post-stroke, however, their benefits compared to manual stretching exercises have not been done in a randomized controlled trial, and the correlations between the ankle joint biomechanical properties and balance are unclear.

Objective:To compare the effects of robot-aided to manual ankle stretching training in stroke survivors with the spastic ankle on the ankle joint properties and balance function post-stroke, and further explore the correlations between the ankle stiffness and balance.

Methods:Twenty inpatients post-stroke with ankle spasticity received 20 minutes of stretching training daily over two weeks. The experimental group used a robot-aided stretching device, and the control group received manual stretching. Outcome measures were evaluated before and after training. The primary outcome measure was ankle stiffness. The secondary outcome measures were passive dorsiflexion ranges of motion, dorsiflexor muscle strength, Modified Ashworth Scale (MAS), Fugl-Meyer Motor Assessment of Lower Extremity (FMA-LE), Berg Balance Scale (BBS), Modified Barthel Index (MBI), and the Pro-Kin balance test.

Results:After training, two groups showed significantly within-group improvements in dorsiflexor muscle strength, FMA-LE, BBS, MBI (P< 0.05). The between-group comparison showed no significant differences in all outcome measures (P> 0.0025). The experimental group significantly improved in the stiffness and passive range of motion of dorsiflexion, MAS. In the Pro-Kin test, the experimental group improved significantly with eyes closed and open (P< 0.05), but significant improvements were found in the control group only with eyes open (P< 0.05). Dorsiflexion stiffness was positively correlated with the Pro-Kin test results with eyes open and the MAS (P< 0.05).

Conclusions:The robot-aided and manual ankle stretching training provided similar significant improvements in the ankle properties and balance post-stroke. However, only the robot-aided stretching training improved spasticity and stiffness of dorsiflexion significantly. Ankle dorsiflexion stiffness was correlated with balance function.

Clinical Trial Registration:www.chictr.org.cnChiCTR2000030108.
Recombinant Adeno-Associated Virus Serotype 9 Gene Therapy in Spinal Muscular Atrophy
Authors: Kotulska Katarzyna , Fattal-Valevski Aviva , Haberlova Jana
Published: October 2021

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease caused by deletion or mutation of the SMN1 gene. It is characterized by a progressive loss of motor neurons resulting in muscle weakness. The disease affects 1 in 11,000 live births and before the era of treatment SMA was a leading genetic cause of mortality in infants. Recently, disease modifying therapies have been introduced in clinical practice. They include intrathecal and oral antisense oligonucleotides binding to pre-mRNA of SMN2 gene and increasing the translation of fully functional SMN protein as well as SMN1 gene replacement therapy. Onasemnogene abeparvovec uses the adeno-associated virus 9 (AAV9) vector to deliver the SMN1 gene. Phase 1 and phase 3 clinical trials showed that a single administration of onasemnogene abeparvovec resulted in improvement of motor functions in the majority of infants with SMA. Currently, phase 3 trials in SMA1 and SMA2 patients, as well as presymptomatic infants diagnosed with SMA, are ongoing. The drug was approved for medical use in the US in 2019, and in Japan and the European Union in 2020. Thus, first real-world data on efficacy and safety of onasemnogene abeparvovec in SMA patients are available.
Revisiting Nonlinear Functional Brain Co-activations: Directed, Dynamic, and Delayed
Authors: Cifre Ignacio , Miller Flores Maria T. , Penalba Lucia , Ochab Jeremi K. , Chialvo Dante R.
Published: October 2021

The center stage of neuro-imaging is currently occupied by studies of functional correlations between brain regions. These correlations define the brain functional networks, which are the most frequently used framework to represent and interpret a variety of experimental findings. In the previous study, we first demonstrated that the relatively stronger blood oxygenated level dependent (BOLD) activations contain most of the information relevant to understand functional connectivity, and subsequent work confirmed that a large compression of the original signals can be obtained without significant loss of information. In this study, we revisit the correlation properties of these epochs to define a measure of nonlinear dynamic directed functional connectivity (nldFC) across regions of interest. We show that the proposed metric provides at once, without extensive numerical complications, directed information of the functional correlations, as well as a measure of temporal lags across regions, overall offering a different and complementary perspective in the analysis of brain co-activation patterns. In this study, we provide further details for the computations of these measures and for a proof of concept based on replicating existing results from an Autistic Syndrome database, and discuss the main features and advantages of the proposed strategy for the study of brain functional correlations.
Single-Trial EEG Classification via Orthogonal Wavelet Decomposition-Based Feature Extraction
Authors: Qi Feifei , Wang Wenlong , Xie Xiaofeng , Gu Zhenghui , Yu Zhu Liang , Wang Fei , Li Yuanqing , Wu Wei
Published: October 2021

Achieving high classification performance is challenging due to non-stationarity and low signal-to-noise ratio (low SNR) characteristics of EEG signals. Spatial filtering is commonly used to improve the SNR yet the individual differences in the underlying temporal or frequency information is often ignored. This paper investigates motor imagery signals via orthogonal wavelet decomposition, by which the raw signals are decomposed into multiple unrelated sub-band components. Furthermore, channel-wise spectral filtering via weighting the sub-band components are implemented jointly with spatial filtering to improve the discriminability of EEG signals, with an l2-norm regularization term embedded in the objective function to address the underlying over-fitting issue. Finally, sparse Bayesian learning with Gaussian prior is applied to the extracted power features, yielding an RVM classifier. The classification performance of SEOWADE is significantly better than those of several competing algorithms (CSP, FBCSP, CSSP, CSSSP, and shallow ConvNet). Moreover, scalp weight maps of the spatial filters optimized by SEOWADE are more neurophysiologically meaningful. In summary, these results demonstrate the effectiveness of SEOWADE in extracting relevant spatio-temporal information for single-trial EEG classification.
Spatial Resolution of Suprachoroidal–Transretinal Stimulation Estimated by Recording Single-Unit Activity From the Cat Lateral Geniculate Nucleus
Authors: Miyoshi Tomomitsu , Morimoto Takeshi , Sawai Hajime , Fujikado Takashi
Published: October 2021

Retinal prostheses are devices used to restore visual sensation in patients suffering from photoreceptor degeneration, such as retinitis pigmentosa. Suprachoroidal–transretinal stimulation (STS) is a prosthesis with retinal electrodes located in the sclera. STS has the advantage that it is safer than epiretinal or subretinal prostheses, as the implant is not directly attached to the retinal tissue. We have previously reported feasibility of STS with animal experiments and clinical trials. However, functional evaluation with neurophysiological experiments is still largely missing. To estimate the spatial resolution of STS, single-unit activities in response to STS were recorded from relay cells in the dorsal lateral geniculate nucleus of cats, and the response probability of the units was analyzed in relation to the distance between the stimulus location and the receptive field of each recorded unit. A platinum electrode was attached to the sclera after lamellar resection, and the return electrode was placed in the vitreous. The stimulating current, which ranged from 50 to 500 μA, was applied between these electrodes, and the probability of spike responses occurring just after retinal stimulation was measured. The distance at half-maximum of response was determined from the collected response probabilities as a function of stimulus intensity for all units characterized by their distances from the receptive field center to the stimulation point. As the stimulation became weaker, this distance decreased to 1.8° at 150 and 100 μA. As another estimation, the radius of 25% response probability was 1.4° at 100 μA. The diameter of the stimulated cat retinal area, 3.6° or 2.8°, corresponds to human visual acuity of 0.005 or 0.007, or finger counting. Considering the lower hazard to the retina of STS and its potentially large visual field coverage, STS is an attractive method for retinal prosthetic device development.
Oxidative Stress and Cognitive Decline: The Neuroprotective Role of Natural Antioxidants
Authors: Franzoni Ferdinando , Scarfò Giorgia , Guidotti Sara , Fusi Jonathan , Asomov Muzaffar , Pruneti Carlo
Published: October 2021

Free- radicals (Oxygen and Nitrogen species) are formed in mitochondria during the oxidative phosphorylation. Their high reactivity, due to not-engaged electrons, leads to an increase of the oxidative stress. This condition affects above all the brain, that usually needs a large oxygen amount and in which there is the major possibility to accumulate “Reacting Species.” Antioxidant molecules are fundamental in limiting free-radical damage, in particular in the central nervous system: the oxidative stress, in fact, seems to worsen the course of neurodegenerative diseases. The aim of this review is to sum up natural antioxidant molecules with the greatest neuroprotective properties against free radical genesis, understanding their relationship with the Central Nervous System.
A Novel Histological Technique to Assess Severity of Traumatic Brain Injury in Rodents: Comparisons to Neuroimaging and Neurological Outcomes
Authors: Frank Dmitry , Gruenbaum Benjamin F. , Shelef Ilan , Zvenigorodsky Vladislav , Benjamin Yair , Shapoval Olha , Gal Ron , Zlotnik Alexander , Melamed Israel , Boyko Matthew
Published: October 2021

Here we evaluate an alternative protocol to histologically examine blood-brain barrier (BBB) breakdown, brain edema, and lesion volume following traumatic brain injury (TBI) in the same set of rodent brain samples. We further compare this novel histological technique to measurements determined by magnetic resonance imaging (MRI) and a neurological severity score (NSS). Sixty-six rats were randomly assigned to a sham-operated, mild TBI, moderate TBI, or severe TBI group. 48 h after TBI, NSS, MRI and histological techniques were performed to measure TBI severity outcome. Both the histological and MRI techniques were able to detect measurements of severity outcome, but histologically determined outcomes were more sensitive. The two most sensitive techniques for determining the degree of injury following TBI were NSS and histologically determined BBB breakdown. Our results demonstrate that BBB breakdown, brain edema, and lesion volume following TBI can be accurately measured by histological evaluation of the same set of brain samples.
Impact of Type of Postoperative Complications on Long-Term Survival of Gastric Cancer Patients: Results From a High-Volume Institution in China
Authors: Pang Hua-Yang , Zhao Lin-Yong , Wang Hui , Chen Xiao-Long , Liu Kai , Zhang Wei-Han , Yang Kun , Chen Xin-Zu , Hu Jian-Kun
Published: October 2021

Background

This study aimed to evaluate the impact of postoperative complication and its etiology on long-term survival for gastric cancer (GC) patients with curative resection.

Methods

From January 2009 to December 2014, a total of 1,667 GC patients who had undergone curative gastrectomy were analyzed. Patients with severe complications (SCs) (Clavien–Dindo grade III or higher complications or those causing a hospital stay of 15 days or longer) were separated into a “complication group.” Univariate and multivariate analyses were performed to reveal the relationship between postoperative complications and long-term survival. A 2:1 propensity score matching (PSM) was used to balance baseline parameters between the two groups.

Results

SCs were diagnosed in 168 (10.08%) patients, including different etiology: infectious complications (ICs) in 111 (6.66%) and non-infectious complications (NICs) in 71 (4.26%) patients. Multivariate analysis showed that presence of SCs (P=0.001) was an independent prognostic factor for overall survival, and further analysis by complication type demonstrated that the deteriorated overall survival was mainly caused by ICs (P=0.004) rather than NICs (P=0.068). After PSM, patients with SCs (p=0.002) still had a significantly decreased overall survival, and the presence of ICs (P=0.002) rather than NICs (P=0.067) showed a negative impact on long-term survival.

Conclusion

Serious complications, particularly of an infectious type, may have a negative impact on overall survival of GC patients. However, additional multicenter prospective studies with larger sample size are required to verify this issue.
Prognostic Nomogram for Liver Metastatic Colon Cancer Based on Histological Type, Tumor Differentiation, and Tumor Deposit: A TRIPOD Compliant Large-Scale Survival Study
Authors: Kuai Le , Zhang Ying , Luo Ying , Li Wei , Li Xiao-dong , Zhang Hui-ping , Liu Tai-yi , Yin Shuang-yi , Li Bin
Published: October 2021

Objective

A proportional hazard model was applied to develop a large-scale prognostic model and nomogram incorporating clinicopathological characteristics, histological type, tumor differentiation grade, and tumor deposit count to provide clinicians and patients diagnosed with colon cancer liver metastases (CLM) a more comprehensive and practical outcome measure.

Methods

Using the Transparent Reporting of multivariable prediction models for individual Prognosis or Diagnosis (TRIPOD) guidelines, this study identified 14,697 patients diagnosed with CLM from 1975 to 2017 in the Surveillance, Epidemiology, and End Results (SEER) 21 registry database. Patients were divided into a modeling group (n=9800), an internal validation group (n=4897) using computerized randomization. An independent external validation cohort (n=60) was obtained. Univariable and multivariate Cox analyses were performed to identify prognostic predictors for overall survival (OS). Subsequently, the nomogram was constructed, and the verification was undertaken by receiver operating curves (AUC) and calibration curves.

Results

Histological type, tumor differentiation grade, and tumor deposit count were independent prognostic predictors for CLM. The nomogram consisted of age, sex, primary site, T category, N category, metastasis of bone, brain or lung, surgery, and chemotherapy. The model achieved excellent prediction power on both internal (mean AUC=0.811) and external validation (mean AUC=0.727), respectively, which were significantly higher than the American Joint Committee on Cancer (AJCC) TNM system.

Conclusion

This study proposes a prognostic nomogram for predicting 1- and 2-year survival based on histopathological and population-based data of CLM patients developed using TRIPOD guidelines. Compared with the TNM stage, our nomogram has better consistency and calibration for predicting the OS of CLM patients.
MiRNA-146a/AKT/β-Catenin Activation Regulates Cancer Stem Cell Phenotype in Oral Squamous Cell Carcinoma by Targeting CD24
Authors: Ghuwalewala Sangeeta , Ghatak Dishari , Das Sumit , Roy Stuti , Das Pijush , Butti Ramesh , Gorain Mahadeo , Nath Somsubhra , Kundu Gopal C. , Roychoudhury Susanta
Published: October 2021

CD44highCD24low population has been previously reported as cancer stem cells (CSCs) in Oral Squamous Cell Carcinoma (OSCC). Increasing evidence suggests potential involvement of microRNA (miRNA) network in modulation of CSC properties. MiRNAs have thus emerged as crucial players in tumor development and maintenance. However, their role in maintenance of OSCC stem cells remains unclear. Here we report an elevated expression of miR-146a in the CD44highCD24low population within OSCC cells and primary HNSCC tumors. Moreover, over-expression of miR-146a results in enhanced stemness phenotype by augmenting the CD44highCD24low population. We demonstrate that miR-146a stabilizes β-catenin with concomitant loss of E-cadherin and CD24. Interestingly, CD24 is identified as a novel functional target of miR-146a and ectopic expression of CD24 abrogates miR-146a driven potential CSC phenotype. Mechanistic analysis reveals that higher CD24 levels inhibit AKT phosphorylation leading to β-catenin degradation. Using stably expressing miR-146a/CD24 OSCC cell lines, we also validate that the miR-146a/CD24/AKT loop significantly alters tumorigenic ability in vivo. Furthermore, we confirmed that β-catenin trans-activates miR-146a, thereby forming a positive feedback loop contributing to stem cell maintenance. Collectively, our study demonstrates that miR-146a regulates CSCs in OSCC through CD24-AKT-β-catenin axis.