bluuebunny/crossref_metadata_2025 huggingface dataset:
Embryo Development and Behavior in Sea Urchin (Tripneustes gratilla) Under Different Light Emitting Diodes Condition
Authors: Li Yi-Yen , Su Feng-Jie , Hsieh Yi-Jui , Huang Tai-Chun , Wang Yung-Song
Published: June 2021

This study aims to evaluate the effect of light-emitting diodes (LEDs) of different wavelengths on the embryonic development, covering behavior, righting behavior, and phototaxis of collector urchins (Tripneustes gratilla). The collector urchins were divided into three groups according to the type of LED illumination they received: full-spectrum (400–750 nm wavelength), red light (630 nm), or blue light (450 nm). The results of the embryonic development experiment indicated that the blue LED group had the highest proportion of embryos reaching the prism stage at the 24th hour and the highest proportion of embryos entering the 4-arm pluteus stage, but it also had the highest death rate at the 48th hour. The full-spectrum and red LED groups exhibited similar speeds of embryonic development. In the experiment on covering behavior performed on adult urchins, our findings indicated that the blue LED group gripped the most acrylic sheets for cover, exhibiting the most covering behavior, followed by the full-spectrum group and then the red LED group. Moreover, behavior varied with coloration, as collector urchins with a lower level of melanin exhibited more covering behavior than those with a higher melanin level. In addition, the righting behavior experiments demonstrated that the blue LED group spent the longest time righting themselves. It is possible that the relatively strong stimulation from the blue LED illumination led to a higher level of stress in the collector urchins and hence slowed their righting. The phototaxis experiment revealed the most significant negative phototactic response in collector urchins when they were under the blue LED light, followed by the full-spectrum light; the red LED light did not induce any positive or negative phototactic response in the collector urchins. This experimental result verified collector urchins’ high sensitivity to and dislike of the blue LED light. The study results confirmed that the blue LED light environment accelerated the embryonic development of collector urchins; however, the relatively strong stimulation from that light also caused them to engage in covering behavior or move away from the light. These results indicate that short-wavelength irradiation significantly affects the embryonic development and behavior pattern of this species.
Urethral Catheter Biofilms Reveal Plasticity in Bacterial Composition and Metabolism and Withstand Host Immune Defenses in Hypoxic Environment
Authors: Yu Yanbao , Singh Harinder , Tsitrin Tamara , Bekele Shiferaw , Lin Yi-Han , Sikorski Patricia , Moncera Kelvin J. , Torralba Manolito G. , Morrow Lisa , Wolcott Randall , Nelson Karen E. , Pieper Rembert
Published: June 2021

Biofilms composed of multiple microorganisms colonize the surfaces of indwelling urethral catheters that are used serially by neurogenic bladder patients and cause chronic infections. Well-adapted pathogens in this niche are Escherichia coli, Proteus, and Enterococcus spp., species that cycle through adhesion and multilayered cell growth, trigger host immune responses, are starved off nutrients, and then disperse. Viable microbial foci retained in the urinary tract recolonize catheter surfaces. The molecular adaptations of bacteria in catheter biofilms (CBs) are not well-understood, promising new insights into this pathology based on host and microbial meta-omics analyses from clinical specimens. We examined catheters from nine neurogenic bladder patients longitudinally over up to 6 months. Taxonomic analyses from 16S rRNA gene sequencing and liquid chromatography–tandem mass spectrometry (LC-MS/MS)–based proteomics revealed that 95% of all catheter and corresponding urinary pellet (UP) samples contained bacteria. CB biomasses were dominated by Enterobacteriaceae spp. and often accompanied by lactic acid and anaerobic bacteria. Systemic antibiotic drug treatments of patients resulted in either transient or lasting microbial community perturbations. Neutrophil effector proteins were abundant not only in UP but also CB samples, indicating their penetration of biofilm surfaces. In the context of one patient who advanced to a kidney infection, Proteus mirabilis proteomic data suggested a combination of factors associated with this disease complication: CB biomasses were high; the bacteria produced urease alkalinizing the pH and triggering urinary salt deposition on luminal catheter surfaces; P. mirabilis utilized energy-producing respiratory systems more than in CBs from other patients. The NADH:quinone oxidoreductase II (Nqr), a Na+ translocating enzyme not operating as a proton pump, and the nitrate reductase A (Nar) equipped the pathogen with electron transport chains promoting growth under hypoxic conditions. Both P. mirabilis and E. coli featured repertoires of transition metal ion acquisition systems in response to human host-mediated iron and zinc sequestration. We discovered a new drug target, the Nqr respiratory system, whose deactivation may compromise P. mirabilis growth in a basic pH milieu. Animal models would not allow such molecular-level insights into polymicrobial biofilm metabolism and interactions because the complexity cannot be replicated.
Structure, Application, and Biochemistry of Microbial Keratinases
Authors: Li Qingxin
Published: June 2021

Keratinases belong to a class of proteases that are able to degrade keratins into amino acids. Microbial keratinases play important roles in turning keratin-containing wastes into value-added products by participating in the degradation of keratin. Keratin is found in human and animal hard tissues, and its complicated structures make it resistant to degradation by common proteases. Although breaking disulfide bonds are involved in keratin degradation, keratinase is responsible for the cleavage of peptides, making it attractive in pharmaceutical and feather industries. Keratinase can serve as an important tool to convert keratin-rich wastes such as feathers from poultry industry into diverse products applicable to many fields. Despite of some progress made in isolating keratinase-producing microorganisms, structural studies of keratinases, and biochemical characterization of these enzymes, effort is still required to expand the biotechnological application of keratinase in diverse fields by identifying more keratinases, understanding the mechanism of action and constructing more active enzymes through molecular biology and protein engineering. Herein, this review covers structures, applications, biochemistry of microbial keratinases, and strategies to improve its efficiency in keratin degradation.
Expanded Diversity and Phylogeny of mer Genes Broadens Mercury Resistance Paradigms and Reveals an Origin for MerA Among Thermophilic Archaea
Authors: Christakis Christos A. , Barkay Tamar , Boyd Eric S.
Published: June 2021

Mercury (Hg) is a highly toxic element due to its high affinity for protein sulfhydryl groups, which upon binding, can destabilize protein structure and decrease enzyme activity. Prokaryotes have evolved enzymatic mechanisms to detoxify inorganic Hg and organic Hg (e.g., MeHg) through the activities of mercuric reductase (MerA) and organomercury lyase (MerB), respectively. Here, the taxonomic distribution and evolution of MerAB was examined in 84,032 archaeal and bacterial genomes, metagenome assembled genomes, and single-cell genomes. Homologs of MerA and MerB were identified in 7.8 and 2.1% percent of genomes, respectively. MerA was identified in the genomes of 10 archaeal and 28 bacterial phyla previously unknown to code for this functionality. Likewise, MerB was identified in 2 archaeal and 11 bacterial phyla previously unknown to encode this functionality. Surprisingly, homologs of MerB were identified in a number of genomes (∼50% of all MerB-encoding genomes) that did not encode MerA, suggesting alternative mechanisms to detoxify Hg(II) once it is generated in the cytoplasm. Phylogenetic reconstruction of MerA place its origin in thermophilic Thermoprotei (Crenarchaeota), consistent with high levels of Hg(II) in geothermal environments, the natural habitat of this archaeal class. MerB appears to have been recruited to the mer operon relatively recently and likely among a mesophilic ancestor of Euryarchaeota and Thaumarchaeota. This is consistent with the functional dependence of MerB on MerA and the widespread distribution of mesophilic microorganisms that methylate Hg(II) at lower temperature. Collectively, these results expand the taxonomic and ecological distribution of mer-encoded functionalities, and suggest that selection for Hg(II) and MeHg detoxification is dependent not only on the availability and type of mercury compounds in the environment but also the physiological potential of the microbes who inhabit these environments. The expanded diversity and environmental distribution of MerAB identify new targets to prioritize for future research.
Oral Microbiome Dysbiosis Is Associated With Symptoms Severity and Local Immune/Inflammatory Response in COVID-19 Patients: A Cross-Sectional Study
Authors: Soffritti Irene , D’Accolti Maria , Fabbri Chiara , Passaro Angela , Manfredini Roberto , Zuliani Giovanni , Libanore Marco , Franchi Maurizio , Contini Carlo , Caselli Elisabetta
Published: June 2021

The human oral microbiome (HOM) is the second largest microbial community after the gut and can impact the onset and progression of several localized and systemic diseases, including those of viral origin, especially for viruses entering the body via the oropharynx. However, this important aspect has not been clarified for the new pandemic human coronavirus SARS-CoV-2, causing COVID-19 disease, despite it being one of the many respiratory viruses having the oropharynx as the primary site of replication. In particular, no data are available about the non-bacterial components of the HOM (fungi, viruses), which instead has been shown to be crucial for other diseases. Consistent with this, this study aimed to define the HOM in COVID-19 patients, to evidence any association between its profile and the clinical disease. Seventy-five oral rinse samples were analyzed by Whole Genome Sequencing (WGS) to simultaneously identify oral bacteria, fungi, and viruses. To correlate the HOM profile with local virus replication, the SARS-CoV-2 amount in the oral cavity was quantified by digital droplet PCR. Moreover, local inflammation and secretory immune response were also assessed, respectively by measuring the local release of pro-inflammatory cytokines (L-6, IL-17, TNFα, and GM-CSF) and the production of secretory immunoglobulins A (sIgA). The results showed the presence of oral dysbiosis in COVID-19 patients compared to matched controls, with significantly decreased alpha-diversity value and lower species richness in COVID-19 subjects. Notably, oral dysbiosis correlated with symptom severity (p = 0.006), and increased local inflammation (p < 0.01). In parallel, a decreased mucosal sIgA response was observed in more severely symptomatic patients (p = 0.02), suggesting that local immune response is important in the early control of virus infection and that its correct development is influenced by the HOM profile. In conclusion, the data presented here suggest that the HOM profile may be important in defining the individual susceptibility to SARS-CoV-2 infection, facilitating inflammation and virus replication, or rather, inducing a protective IgA response. Although it is not possible to determine whether the alteration in the microbial community is the cause or effect of the SARS-CoV-2 replication, these parameters may be considered as markers for personalized therapy and vaccine development.
A Simple in situ Assay to Assess Plant-Associative Bacterial Nitrogenase Activity
Authors: Haskett Timothy L. , Knights Hayley E. , Jorrin Beatriz , Mendes Marta D. , Poole Philip S.
Published: June 2021

Assessment of plant-associative bacterial nitrogen (N) fixation is crucial for selection and development of elite diazotrophic inoculants that could be used to supply cereal crops with nitrogen in a sustainable manner. Although diazotrophic bacteria possess diverse oxygen tolerance mechanisms, most require a sub 21% oxygen environment to achieve optimal stability and function of the N-fixing catalyst nitrogenase. Consequently, assessment of N fixation is routinely carried out on “free-living” bacteria grown in the absence of a host plant and such experiments may not accurately divulge activity in the rhizosphere where the availability and forms of nutrients such as carbon and N, which are key regulators of N fixation, may vary widely. Here, we present a modified in situ acetylene reduction assay (ARA), utilizing the model cereal barley as a host to comparatively assess nitrogenase activity in diazotrophic bacteria. The assay is rapid, highly reproducible, applicable to a broad range of diazotrophs, and can be performed with simple equipment commonly found in most laboratories that investigate plant-microbe interactions. Thus, the assay could serve as a first point of order for high-throughput identification of elite plant-associative diazotrophs.
Long COVID or Post-acute Sequelae of COVID-19 (PASC): An Overview of Biological Factors That May Contribute to Persistent Symptoms
Authors: Proal Amy D. , VanElzakker Michael B.
Published: June 2021

The novel virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a pandemic of coronavirus disease 2019 (COVID-19). Across the globe, a subset of patients who sustain an acute SARS-CoV-2 infection are developing a wide range of persistent symptoms that do not resolve over the course of many months. These patients are being given the diagnosis Long COVID or Post-acute sequelae of COVID-19 (PASC). It is likely that individual patients with a PASC diagnosis have different underlying biological factors driving their symptoms, none of which are mutually exclusive. This paper details mechanisms by which RNA viruses beyond just SARS-CoV-2 have be connected to long-term health consequences. It also reviews literature on acute COVID-19 and other virus-initiated chronic syndromes such as post-Ebola syndrome or myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) to discuss different scenarios for PASC symptom development. Potential contributors to PASC symptoms include consequences from acute SARS-CoV-2 injury to one or multiple organs, persistent reservoirs of SARS-CoV-2 in certain tissues, re-activation of neurotrophic pathogens such as herpesviruses under conditions of COVID-19 immune dysregulation, SARS-CoV-2 interactions with host microbiome/virome communities, clotting/coagulation issues, dysfunctional brainstem/vagus nerve signaling, ongoing activity of primed immune cells, and autoimmunity due to molecular mimicry between pathogen and host proteins. The individualized nature of PASC symptoms suggests that different therapeutic approaches may be required to best manage care for specific patients with the diagnosis.
Sclerostin-Mediated Impaired Osteogenesis by Fibroblast-Like Synoviocytes in the Particle-Induced Osteolysis Model
Authors: Jagga Supriya , Sharma Ashish Ranjan , Lee Yeon Hee , Nam Ju-Suk , Lee Sang-Soo
Published: June 2021

Engineered biomaterials are envisioned to replace, augment, or interact with living tissues for improving the functional deformities associated with end-stage joint pathologies. Unfortunately, wear debris from implant interfaces is the major factor leading to periprosthetic osteolysis. Fibroblast-like synoviocytes (FLSs) populate the intimal lining of the synovium and are in direct contact with wear debris. This study aimed to elucidate the effect of Ti particles as wear debris on human FLSs and the mechanism by which they might participate in the bone remodeling process during periprosthetic osteolysis. FLSs were isolated from synovial tissue from patients, and the condition medium (CM) was collected after treating FLSs with sterilized Ti particles. The effect of CM was analyzed for the induction of osteoclastogenesis or any effect on osteogenesis and signaling pathways. The results demonstrated that Ti particles could induce activation of the NFκB signaling pathway and induction of COX-2 and inflammatory cytokines in FLSs. The amount of Rankl in the conditioned medium collected from Ti particle–stimulated FLSs (Ti CM) showed the ability to stimulate osteoclast formation. The Ti CM also suppressed the osteogenic initial and terminal differentiation markers for osteoprogenitors, such as alkaline phosphate activity, matrix mineralization, collagen synthesis, and expression levels of Osterix, Runx2, collagen 1α, and bone sialoprotein. Inhibition of the WNT and BMP signaling pathways was observed in osteoprogenitors after the treatment with the Ti CM. In the presence of the Ti CM, exogenous stimulation by WNT and BMP signaling pathways failed to stimulate osteogenic activity in osteoprogenitors. Induced expression of sclerostin (SOST: an antagonist of WNT and BMP signaling) in Ti particle–treated FLSs and secretion of SOST in the Ti CM were detected. Neutralization of SOST in the Ti CM partially restored the suppressed WNT and BMP signaling activity as well as the osteogenic activity in osteoprogenitors. Our results reveal that wear debris–stimulated FLSs might affect bone loss by not only stimulating osteoclastogenesis but also suppressing the bone-forming ability of osteoprogenitors. In the clinical setting, targeting FLSs for the secretion of antagonists like SOST might be a novel therapeutic approach for preventing bone loss during inflammatory osteolysis.
The Cerebellum Is Related to Cognitive Dysfunction in White Matter Hyperintensities
Authors: Cao Shanshan , Nie Jiajia , Zhang Jun , Chen Chen , Wang Xiaojing , Liu Yuanyuan , Mo Yuting , Du Baogen , Hu Yajuan , Tian Yanghua , Wei Qiang , Wang Kai
Published: June 2021

Objective

White matter hyperintensities (WMHs) on magnetic resonance imaging (MRI) is frequently presumed to be secondary to cerebral small vessel disease (CSVD) and associated with cognitive decline. The cerebellum plays a key role in cognition and has dense connections with other brain regions. Thus, the aim of this study was to investigate if cerebellar abnormalities could occur in CSVD patients with WMHs and the possible association with cognitive performances.

Methods

A total of 104 right-handed patients with WMHs were divided into the mild WMHs group (n = 39), moderate WMHs group (n = 37), and severe WMHs group (n = 28) according to the Fazekas scale, and 36 healthy controls were matched for sex ratio, age, education years, and acquired resting-state functional MRI. Analysis of voxel-based morphometry of gray matter volume (GMV) and seed-to-whole-brain functional connectivity (FC) was performed from the perspective of the cerebellum, and their correlations with neuropsychological variables were explored.

Results

The analysis revealed a lower GMV in the bilateral cerebellum lobule VI and decreased FC between the left- and right-sided cerebellar lobule VI with the left anterior cingulate gyri in CSVD patients with WMHs. Both changes in structure and function were correlated with cognitive impairment in patients with WMHs.

Conclusion

Our study revealed damaged GMV and FC in the cerebellum associated with cognitive impairment. This indicates that the cerebellum may play a key role in the modulation of cognitive function in CSVD patients with WMHs.
The Role of Protein Persulfidation in Brain Aging and Neurodegeneration
Authors: Petrovic Dunja , Kouroussis Emilia , Vignane Thibaut , Filipovic Milos R.
Published: June 2021

Hydrogen sulfide (H2S), originally considered a toxic gas, is now a recognized gasotransmitter. Numerous studies have revealed the role of H2S as a redox signaling molecule that controls important physiological/pathophysiological functions. The underlying mechanism postulated to serve as an explanation of these effects is protein persulfidation (P-SSH, also known as S-sulfhydration), an oxidative posttranslational modification of cysteine thiols. Protein persulfidation has remained understudied due to its instability and chemical reactivity similar to other cysteine modifications, making it very difficult to selectively label. Recent developments of persulfide labeling techniques have started unraveling the role of this modification in (patho)physiology. PSSH levels are important for the cellular defense against oxidative injury, albeit they decrease with aging, leaving proteins vulnerable to oxidative damage. Aging is one of the main risk factors for many neurodegenerative diseases. Persulfidation has been shown to be dysregulated in Parkinson's, Alzheimer's, Huntington's disease, and Spinocerebellar ataxia 3. This article reviews the latest discoveries that link protein persulfidation, aging and neurodegeneration, and provides future directions for this research field that could result in development of targeted drug design.
Long-Term Use of a Sensory Prosthesis Improves Function in a Patient With Peripheral Neuropathy: A Case Report
Authors: Wrisley Diane M. , McLean Gillian , Hill Jennifer Baity , Oddsson Lars I. E.
Published: June 2021

Background: Peripheral neuropathy (PN) can result in either partial or complete loss of distal sensation resulting in an increased fall risk. Walkasins® uses a shoe insert to detect the magnitude and direction of sway and sends signals to a leg unit that provides sensory balance cues. The objective of this case report is to describe the long-term influence of the Walkasins® lower limb sensory neuroprosthesis on balance and gait for an individual with diabetic PN.

Case Description: A 51-year-old male with a 3-year history of PN and a 10-year history of type II diabetes mellitus was fitted bilaterally with Walkasins® and utilized them 8–10 hours/day for more than 2 years. Although, vibration and tactile sensation thresholds were severely impaired at his 1st metatarsophalangeal joint and the lateral malleolus bilaterally he could perceive tactile stimuli from the Walkasins® above the ankles.

Outcomes: Following Walkasins® use, his Activities-specific Balance Confidence Scale (ABC) scores improved from 33 to 80%. His mean Vestibular Activities of Daily Living (VADL) scores decreased from 3.54 to 1. His Functional Gait Assessment (FGA) scores increased from 13/30 to 28/30 and his miniBESTest scores improved from 15/28 to 26/28. Gait speed increased from 0.23 to 1.5 m/s. The patient described a decrease in pain and cramping throughout his lower extremities and an increase in function.

Discussion: Gait and balance improved with the use of the Walkasins® and participation in a wellness program. This improvement suggests that the use of sensory substitution devices, such as the Walkasins®, may replace sensory deficits related to gait and balance dysfunction experienced by patients with PN. Further research is needed to determine if other patients will have a similar response and what the necessary threshold of sensory function is to benefit from use of the Walkasins®.
Mendelian Randomization of Dyslipidemia on Cognitive Impairment Among Older Americans
Authors: Fu Mingzhou , Bakulski Kelly M. , Higgins Cesar , Ware Erin B.
Published: June 2021

Background: Altered lipid metabolism may be a risk factor for dementia, and blood cholesterol level has a strong genetic component. We tested the hypothesis that dyslipidemia (either low levels of high-density lipoprotein cholesterol (HDL-C) or high total cholesterol) is associated with cognitive status and domains, and assessed causality using genetic predisposition to dyslipidemia as an instrumental variable.

Methods: Using data from European and African genetic ancestry participants in the Health and Retirement Study, we selected observations at the first non-missing biomarker assessment (waves 2006–2012). Cognition domains were assessed using episodic memory, mental status, and vocabulary tests. Overall cognitive status was categorized in three levels (normal, cognitive impairment non-dementia, dementia). Based on 2018 clinical guidelines, we compared low HDL-C or high total cholesterol to normal levels. Polygenic scores for dyslipidemia were used as instrumental variables in a Mendelian randomization framework. Multivariable logistic regressions and Wald-type ratio estimators were used to examine associations.

Results: Among European ancestry participants (n = 8,781), at risk HDL-C levels were associated with higher odds of cognitive impairment (OR = 1.20, 95% CI: 1.03, 1.40) and worse episodic memory, specifically. Using cumulative genetic risk for HDL-C levels as a valid instrumental variable, a significant causal estimate was observed between at risk low HDL-C levels and higher odds of dementia (OR = 2.15, 95% CI: 1.16, 3.99). No significant associations were observed between total cholesterol levels and cognitive status. No significant associations were observed in the African ancestry sample (n = 2,101).

Conclusion: Our study demonstrates low blood HDL-C is a potential causal risk factor for impaired cognition during aging in non-Hispanic whites of European ancestry. Dyslipidemia can be modified by changing diets, health behaviors, and therapeutic strategies, which can improve cognitive aging. Studies on low density lipoprotein cholesterol, the timing of cholesterol effects on cognition, and larger studies in non-European ancestries are needed.
Deep Learning-Based Approaches for Decoding Motor Intent From Peripheral Nerve Signals
Authors: Luu Diu K. , Nguyen Anh T. , Jiang Ming , Xu Jian , Drealan Markus W. , Cheng Jonathan , Keefer Edward W. , Zhao Qi , Yang Zhi
Published: June 2021

Previous literature shows that deep learning is an effective tool to decode the motor intent from neural signals obtained from different parts of the nervous system. However, deep neural networks are often computationally complex and not feasible to work in real-time. Here we investigate different approaches' advantages and disadvantages to enhance the deep learning-based motor decoding paradigm's efficiency and inform its future implementation in real-time. Our data are recorded from the amputee's residual peripheral nerves. While the primary analysis is offline, the nerve data is cut using a sliding window to create a “pseudo-online” dataset that resembles the conditions in a real-time paradigm. First, a comprehensive collection of feature extraction techniques is applied to reduce the input data dimensionality, which later helps substantially lower the motor decoder's complexity, making it feasible for translation to a real-time paradigm. Next, we investigate two different strategies for deploying deep learning models: a one-step (1S) approach when big input data are available and a two-step (2S) when input data are limited. This research predicts five individual finger movements and four combinations of the fingers. The 1S approach using a recurrent neural network (RNN) to concurrently predict all fingers' trajectories generally gives better prediction results than all the machine learning algorithms that do the same task. This result reaffirms that deep learning is more advantageous than classic machine learning methods for handling a large dataset. However, when training on a smaller input data set in the 2S approach, which includes a classification stage to identify active fingers before predicting their trajectories, machine learning techniques offer a simpler implementation while ensuring comparably good decoding outcomes to the deep learning ones. In the classification step, either machine learning or deep learning models achieve the accuracy and F1 score of 0.99. Thanks to the classification step, in the regression step, both types of models result in a comparable mean squared error (MSE) and variance accounted for (VAF) scores as those of the 1S approach. Our study outlines the trade-offs to inform the future implementation of real-time, low-latency, and high accuracy deep learning-based motor decoder for clinical applications.
Cognitive Profiles of Amyotrophic Lateral Sclerosis Differ in Resting-State Functional Connectivity: An fMRI Study
Authors: Temp Anna G. M. , Dyrba Martin , Büttner Charlotte , Kasper Elisabeth , Machts Judith , Kaufmann Jörn , Vielhaber Stefan , Teipel Stefan , Prudlo Johannes
Published: June 2021

Background

Half of all amyotrophic lateral sclerosis-frontotemporal spectrum disorder (ALS-FTSD) patients are classified as cognitively impaired, of which 10% have frontotemporal dementia (FTD), and an additional 40% suffer from a frontotemporal syndrome not severe enough to be described as dementia (cognitively impaired/ALSci). As changes in cerebral function measured by resting-state magnet resonance imaging (rs-fMRI) are known in ALS, we investigated whether group differences in resting-state functional connectivity (RSFC) networks could be observed between ALS patients with different cognitive profiles against healthy controls (HC). Furthermore, we correlated cognition and motor functioning with network connectivity.

Methods

Healthy controls, 69, and 97 ALS patients underwent functional MRI scanning and cognitive assessment. The ALS patients were categorized as non-impaired (ALSni; n = 68), cognitively impaired (ALSci; n = 21), and ALS-FTD (n = 8). Group differences in connectivity of the default mode network (DMN), motor network (MN), and ventral attention network (VAN) were investigated using a full-factorial model; correlations between global cognitive performance, shifting, and motor symptom severity were established using Pearson’s correlation.

Results

At a liberal alpha level of uncorrected p < 0.005 and a cluster size exceeding 20 voxels, we found widespread decreases in functional connectivity in all three networks when comparing ALS patients to HC. Similar patterns of hypoconnectivity in the bilateral motor cortices and frontotemporal emerged when comparing the ALSci and ALS-FTD patients to those not cognitively impaired. Hyperconnectivity in the DMN temporal gyrus correlated with worse global cognition; moreover, hyperconnectivity in the VAN thalamus, insula, and putamen correlated with worse shifting ability. Better-preserved motor function correlated with higher MN connectivity. Only the motor-related effects prevailed at a more conservative significance level of pFDR< 0.001.

Conclusion

Resting-state functional connectivity differs between cognitive profiles of ALS and is directly associated with clinical presentation, specifically with motor function, and cognitive shifting.
Non-ketotic Hyperglycemia Chorea-Ballismus and Intracerebral Hemorrhage: A Case Report and Literature Review
Authors: Dong Mingming , E Jian-Yu , Zhang Liyang , Teng Weiyu , Tian Li
Published: June 2021

Non-ketotic hyperglycemia chorea-ballismus (NKH-CB) is a rare metabolical syndrome secondary to the hyperglycemic condition, which is characterized by a triad of acute or subacute hemichorea-hemiballismus, hyperglycemic state, and unique abnormalities limited to the striatum on neuroimaging. Several related case studies on this disorder have been reported previously, but NKH-CB had never been associated with intracerebral hemorrhage (ICH). Herein, we report an uncommon case of NKH-CB and ICH that occurred simultaneously in one patient, which provides a challenge for clinicians in making a correct diagnosis. An 88-year-old woman with a long-term history of poor-controlled type 2 diabetes mellitus and hypertension, who presented with a sudden-onset headache, restlessness, severe bilateral choreiform and ballistic movements, elevated levels of glucose and osmolality in the serum, an increased white blood cell count, and two-type hyperdense signs on CT imaging, was finally diagnosed with NKH-CB and ICH. Despite administrated active treatments, the patient's clinical status did not improve and ultimately passed away. This case is reported to remind clinicians to consider the possibility of NKH-CB when patients present sudden-onset choreiform and ballistic movements. It is also the first entity with two-type hyperdense signs on CT imaging simultaneously, which helps us distinguish NKH-CB from ICH more intuitively.
Fetal Neuroprotective Strategies: Therapeutic Agents and Their Underlying Synaptic Pathways
Authors: Elsayed Nada A. , Boyer Theresa M. , Burd Irina
Published: June 2021

Synaptic signaling is integral for proper brain function. During fetal development, exposure to inflammation or mild hypoxic-ischemic insult may lead to synaptic changes and neurological damage that impairs future brain function. Preterm neonates are most susceptible to these deleterious outcomes. Evaluating clinically used and novel fetal neuroprotective measures is essential for expanding treatment options to mitigate the short and long-term consequences of fetal brain injury. Magnesium sulfate is a clinical fetal neuroprotective agent utilized in cases of imminent preterm birth. By blocking N-methyl-D-aspartate receptors, magnesium sulfate reduces glutamatergic signaling, which alters calcium influx, leading to a decrease in excitotoxicity. Emerging evidence suggests that melatonin and N-acetyl-L-cysteine (NAC) may also serve as novel putative fetal neuroprotective candidates. Melatonin has important anti-inflammatory and antioxidant properties and is a known mediator of synaptic plasticity and neuronal generation. While NAC acts as an antioxidant and a precursor to glutathione, it also modulates the glutamate system. Glutamate excitotoxicity and dysregulation can induce perinatal preterm brain injury through damage to maturing oligodendrocytes and neurons. The improved drug efficacy and delivery of the dendrimer-bound NAC conjugate provides an opportunity for enhanced pharmacological intervention. Here, we review recent literature on the synaptic pathways underlying these therapeutic strategies, discuss the current gaps in knowledge, and propose future directions for the field of fetal neuroprotective agents.
Red-Fleshed Apple Anthocyanin Extracts Attenuate Male Reproductive System Dysfunction Caused by Busulfan in Mice
Authors: Xu Jihua , Zhang Xiang , Sun Xiaohong , Lv Qiang , Zhang Yugang
Published: June 2021

In this research, we analyzed the effect of an intragastrical oral administration of red-fleshed apple anthocyanin extract (RAAE) on busulfan-treated mice. First, we showed that the most abundant component in RAAE was cyanidin 3-O-galactoside. To determine the effect of the RAAE, the mice were divided into control and four other different concentrations of RAAE feeding treatment groups (BA0, no RAAE; BA.1, 0.1 mg/kg; BA1, 1 mg/kg; and BA5, 5 mg/kg) following busulfan injection. We observed that RAAE treatments displayed ameliorative effects on male reproductive system dysfunction caused by busulfan, such as recovering the irregular arrangements of seminiferous tubules, increasing the number of spermatogonia and spermatocytes, improving sperm concentration by 3-fold in BA.1, and improving sperm motility by 2-fold in BA1. The liquid chromatography with tandem mass spectrometry (LC-MS/MS) analysis showed significant up- or downregulation of certain metabolites, such as lysophosphatidylcholine (LysoPC), L-arginine, glycine, anandamide, and L-carnitine, which could contribute to the positive effects of RAAE, especially in PBA1 (plasma of BA1) and PBA5 (plasma of BA5). Taken together, the results indicate that 1 mg/kg of RAAE is a suitable concentration for rescuing spermatogenesis in mice. The research suggests that RAAE could be a potential nutraceutical for protecting spermatogenesis after busulfan therapy in cancer.
Longitudinal Genomic Evolution of Conventional Papillary Thyroid Cancer With Brain Metastasis
Authors: Luo Han , Liao Xue , Qin Yun , Hou Qianqian , Xue Zhinan , Liu Yang , Shen Feiyang , Wang Yuelan , Jiang Yong , Song Linlin , Chen Haining , Zhang Lingyun , Wei Tao , Dai Lunzhi , Yang Li , Zhang Wei , Li Zhihui , Xu Heng , Zhu Jingqiang , Shu Yang
Published: June 2021

Background

Brain metastasis is extremely rare but predicts dismal prognosis in papillary thyroid cancer (PTC). Dynamic evaluation of stepwise metastatic lesions was barely conducted to identify the longitudinal genomic evolution of brain metastasis in PTC.

Method

Chronologically resected specimen was analyzed by whole exome sequencing, including four metastatic lymph nodes (lyn 1–4) and brain metastasis lesion (BM). Phylogenetic tree was reconstructed to infer the metastatic pattern and the potential functional mutations.

Results

Contrasting with lyn1, ipsilateral metastatic lesions (lyn2–4 and BM) with shared biallelic mutations of TSC2 indicated different genetic originations from multifocal tumors. Lyn 3/4, particularly lyn4 exhibited high genetic similarity with BM. Besides the similar mutational compositions and signatures, shared functional mutations (CDK4R24C, TP53R342*) were observed in lyn3/4 and BM. Frequencies of these mutations gradually increase along with the metastasis progression. Consistently, TP53 knockout and CDK4R24C introduction in PTC cells significantly decreased radioiodine uptake and increased metastatic ability.

Conclusion

Genomic mutations in CDK4 and TP53 during the tumor evolution may contribute to the lymph node and brain metastasis of PTC.
First-Line Treatment Options for PD-L1–Negative Non-Small Cell Lung Cancer: A Bayesian Network Meta-Analysis
Authors: Peng Ling , Liang Wen-Hua , Mu De-Guang , Xu Song , Hong Shao-Dong , Stebbing Justin , Liang Fei , Xia Yang
Published: June 2021

Background

First-line treatment strategies for programmed death-ligand 1 (PD-L1) negative non-small cell lung cancer (NSCLC) patients include chemotherapy and combination with anti-angiogenesis drugs and/or immune checkpoint inhibitor. We conducted a Bayesian network meta-analysis to evaluate the efficacy of these therapeutic options.

Methods

We included phase III randomized controlled trials comparing two or more treatments in the first-line setting for NSCLC, including data in PD-L1–negative patients. First-line strategies were compared and ranked based on the effectiveness in terms of overall survival (OS) and progression-free survival (PFS). A rank was assigned to each treatment after Markov Chain Monte Carlo analyses.

Results

Fourteen trials involving 14 regimens matched our eligibility criteria. For OS, none of the treatment were significantly more effective than chemotherapy. Nivolumab plus ipilimumab plus chemotherapy was probably the best option based on analysis of the treatment ranking (probability = 30.1%). For PFS, nivolumab plus chemotherapy plus bevacizumab, atezolizumab plus chemotherapy plus bevacizumab, and atezolizumab plus chemotherapy were statistically superior to chemotherapy in pairwise comparison. Nivolumab plus chemotherapy plus bevacizumab was likely to be the preferred option based on the analysis of the treatment ranking (probability = 72.9%).

Conclusions

Nivolumab plus chemotherapy, in combination with angiogenesis inhibition or anti-cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4), had maximal benefits for NSCLC patient of PD-L1–negative expression. These findings may facilitate individualized treatment strategies. Safety at an individual patient level should be considered in decision making. Further validation is warranted.
TIPE2 Suppresses Malignancy of Pancreatic Cancer Through Inhibiting TGFβ1 Mediated Signaling Pathway
Authors: Feng Fang , Liu Chunliang , Bian Huahui , Cai Wei , Zhou Ying , Zhou Li , Zhuang Zhixiang
Published: June 2021

Pancreatic cancer is one of the major reasons of cancer-associated deaths due to poor diagnosis, high metastasis and drug resistance. Therefore, it is important to understand the cellular and molecular mechanisms of pancreatic cancer to identify new targets for the treatment. TIPE2 is an essential regulator of tumor apoptosis, inflammation and immune homeostasis. However, the role of TIPE2 is still not fully understood in pancreatic cancer. In this study, we found the expression of TIPE2 was decreased in pancreatic cancer tissues compare to paracancerous tissues, which was negatively correlated with tumor size in patients. Overexpression of TIPE2 significantly decreased cell proliferation, metastasis and increased apoptotic events in pancreatic cancer cell lines. Moreover, the results obtained from real time PCR and western blot revealed that TIPE2 was also involved in inhibiting MMPs and N-Cadherin expression while increasing Bax expression in pancreatic cancer cells. Similarly, TIPE2 could inhibit tumor growth in vivo, decrease the expression of Ki-67 and N-Cadherin, and increase the expression of Bax by IHC analysis in tumor tissues isolated from tumor-bearing mice. Mechanistic studies exhibited that TIPE2 might suppress pancreatic cancer development through inhibiting PI3K/AKT and Raf/MEK/ERK signaling pathways triggered by TGFβ1. Moreover, the tumor-infiltrating lymphocytes from tumor-bearing mice were analyzed by flow cytometry, and showed that TIPE2 could promote T cell activation to exert an anti-tumor effect possibly through activation of DCs in a TGFβ1 dependent manner. In general, we described the multiple regulatory mechanisms of TIPE2 in pancreatic tumorigenesis and tumor microenvironment, which suggested TIPE2 may act as a potential therapeutic target in pancreatic cancer.
Molecular and Phenotypic Profiling for Precision Medicine in Pancreatic Cancer: Current Advances and Future Perspectives
Authors: Miyabayashi Koji , Nakagawa Hayato , Koike Kazuhiko
Published: June 2021

Pancreatic cancer is the most common lethal malignancy, with little improvement in patient outcomes over the decades. The development of early detection methods and effective therapeutic strategies are needed to improve the prognosis of patients with this disease. Recent advances in cancer genomics have revealed the genetic landscape of pancreatic cancer, and clinical trials are currently being conducted to match the treatment to underlying mutations. Liquid biopsy-based diagnosis is a promising method to start personalized treatment. In addition to genome-based medicine, personalized models have been studied as a tool to test candidate drugs to select the most efficacious treatment. The innovative three-dimensional organoid culture platform, as well as patient-derived xenografts can be used to conduct genomic and functional studies to enable personalized treatment approaches. Combining genome-based medicine with drug screening based on personalized models may fulfill the promise of precision medicine for pancreatic cancer.
Linker Design Impacts Antibody-Drug Conjugate Pharmacokinetics and Efficacy via Modulating the Stability and Payload Release Efficiency
Authors: Su Dian , Zhang Donglu
Published: June 2021

The development of antibody-drug conjugates (ADCs) has significantly been advanced in the past decade given the improvement of payloads, linkers and conjugation methods. In particular, linker design plays a critical role in modulating ADC stability in the systemic circulation and payload release efficiency in the tumors, which thus affects ADC pharmacokinetic (PK), efficacy and toxicity profiles. Previously, we have investigated key linker parameters such as conjugation chemistry (e.g., maleimide vs. disulfide), linker length and linker steric hindrance and their impacts on PK and efficacy profiles. Herein, we discuss our perspectives on development of integrated strategies for linker design to achieve a balance between ADC stability and payload release efficiency for desired efficacy in antigen-expressing xenograft models. The strategies have been successfully applied to the design of site-specific THIOMABTM antibody-drug conjugates (TDCs) with different payloads. We also propose to conduct dose fractionation studies to gain guidance for optimal dosing regimens of ADCs in pre-clinical models.
Systemic Administration of Tempol Attenuates the Cardiorespiratory Depressant Effects of Fentanyl
Authors: Baby Santhosh , Gruber Ryan , Discala Joseph , Puskovic Veljko , Jose Nijo , Cheng Feixiong , Jenkins Michael , Seckler James , Lewis Stephen
Published: June 2021

Fentanyl is a high-potency opioid receptor agonist that elicits profound analgesia and suppression of breathing in humans and animals. To date, there is limited evidence as to whether changes in oxidant stress are important factors in any of the actions of acutely administered fentanyl. This study determined whether the clinically approved superoxide dismutase mimetic, Tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl), or a potent antioxidant, N-acetyl-L-cysteine methyl ester (L-NACme), modify the cardiorespiratory and analgesic actions of fentanyl. We examined whether the prior systemic injection of Tempol or L-NACme affects the cardiorespiratory and/or analgesic responses elicited by the subsequent injection of fentanyl in isoflurane-anesthetized and/or freely moving male Sprague-Dawley rats. Bolus injections of Tempol (25, 50 or 100 mg/kg, IV) elicited minor increases in frequency of breathing, tidal volume and minute ventilation. The ventilatory-depressant effects of fentanyl (5 μg/kg, IV) given 15 min later were dose-dependently inhibited by prior injections of Tempol. Tempol elicited dose-dependent and transient hypotension that had (except for the highest dose) resolved when fentanyl was injected. The hypotensive responses elicited by fentanyl were markedly blunted after Tempol pretreatment. The analgesic actions of fentanyl (25 μg/kg, IV) were not affected by Tempol (100 mg/kg, IV). L-NACme did not modify any of the effects of fentanyl. We conclude that prior administration of Tempol attenuates the cardiorespiratory actions of fentanyl without affecting the analgesic effects of this potent opioid. As such, Tempol may not directly affect opioid-receptors that elicit the effects of fentanyl. Whether, the effects of Tempol are solely due to alterations in oxidative stress is in doubt since the powerful antioxidant, L-NACme, did not affect fentanyl-induced suppression of breathing.
Distant Relative Genetic Algorithm–Based Structural Reliability Optimization
Authors: Cheng Hu , Yan Xin-Chi , Fu Li
Published: June 2021

In this study, safety margin explicit equation has been established using random variables (i.e., the engineering conditions, structure parameters, structural strength, and external load), and the genetic algorithm (GA)–based structural reliability optimization design has been addressed subsequently. Though the conventional adaptive GA can change automatically with fitness, it is still not unsatisfactory in sufficiently improving the algorithm convergence speed, especially for complex structures. This article presents an improved adaptive technology termed as the distant relative genetic algorithm (DRGA), in which the distant relative pointer and immunity operators can effectively improve the search performance of the GA. In early evolution, by means of cross controlling and avoiding pairing between individuals with the same genes, the methodology prevents the isogenic individuals expanding locally. Besides, the revised algorithm is able to jump out of the local optimal solution, thus ensuring the realization of a fast global convergence. An example based on wing box structure optimization has been demonstrated using the improved method, and the calculation results show that this strategy makes the GA more effective in dealing with the constraint optimization issues.