bluuebunny/crossref_metadata_2025 huggingface dataset:
Tumor Temporal Proteome Profiling Reveals the Immunological Triple Offensive Induced by Synthetic Anti-Cancer Salmonella
Authors: Yang Shuxin , Zhao Wenjuan , Zhu Muchun , Hu Huijuan , Wang Weijie , Zang Zhongsheng , Jin Meiling , Bi Jiacheng , Huang Jiandong , Liu Chenli , Li Xuefei , Yin Peng , Li Nan
Published: August 2021

The engineered “obligate” anaerobic Salmonella typhimurium strain YB1 shows a prominent ability to repress tumor growth and metastasis, which has great potential as a novel cancer immunotherapy. However, the antitumor mechanism of YB1 remains unelucidated. To resolve the proteome dynamics induced by the engineered bacteria, we applied tumor temporal proteome profiling on murine bladder tumors after intravenous injection of either YB1 or PBS as a negative control. Our data suggests that during the two weeks treatment of YB1 injections, the cured tumors experienced three distinct phases of the immune response. Two days after injection, the innate immune response was activated, particularly the complement and blood coagulation pathways. In the meantime, the phagocytosis was initiated. The professional phagocytes such as macrophages and neutrophils were recruited, especially the infiltration of iNOS+ and CD68+ cells was enhanced. Seven days after injection, substantial amount of T cells was observed at the invasion margin of the tumor. As a result, the tumor shrunk significantly. Overall, the temporal proteome profiling can systematically reveal the YB1 induced immune responses in tumor, showing great promise for elucidating the mechanism of bacteria-mediated cancer immunotherapy.
The Pathophysiology and Treatment of Graft-Versus-Host Disease: Lessons Learnt From Animal Models
Authors: Teshima Takanori , Hill Geoffrey R.
Published: August 2021

Allogeneic hematopoietic cell transplantation (HCT) is a curative treatment for hematologic malignancies, bone marrow failure syndromes, and inherited immunodeficiencies and metabolic diseases. Graft-versus-host disease (GVHD) is the major life-threatening complication after allogeneic HCT. New insights into the pathophysiology of GVHD garnered from our understanding of the immunological pathways within animal models have been pivotal in driving new therapeutic paradigms in the clinic. Successful clinical translations include histocompatibility matching, GVHD prophylaxis using cyclosporine and methotrexate, posttransplant cyclophosphamide, and the use of broad kinase inhibitors that inhibit cytokine signaling (e.g. ruxolitinib). New approaches focus on naïve T cell depletion, targeted cytokine modulation and the inhibition of co-stimulation. This review highlights the use of animal transplantation models to guide new therapeutic principles.
Type 2 Innate Lymphoid Cells: Protectors in Type 2 Diabetes
Authors: Painter Jacob D. , Akbari Omid
Published: August 2021

Type 2 innate lymphoid cells (ILC2) are the innate counterparts of Th2 cells and are critically involved in the maintenance of homeostasis in a variety of tissues. Instead of expressing specific antigen receptors, ILC2s respond to external stimuli such as alarmins released from damage. These cells help control the delicate balance of inflammation in adipose tissue, which is a determinant of metabolic outcome. ILC2s play a key role in the pathogenesis of type 2 diabetes mellitus (T2DM) through their protective effects on tissue homeostasis. A variety of crosstalk takes place between resident adipose cells and ILC2s, with each interaction playing a key role in controlling this balance. ILC2 effector function is associated with increased browning of adipose tissue and an anti-inflammatory immune profile. Trafficking and maintenance of ILC2 populations are critical for tissue homeostasis. The metabolic environment and energy source significantly affect the number and function of ILC2s in addition to affecting their interactions with resident cell types. How ILC2s react to changes in the metabolic environment is a clear determinant of the severity of disease. Treating sources of metabolic instability via critical immune cells provides a clear avenue for modulation of systemic homeostasis and new treatments of T2DM.
Biological Sound Sources Drive Soundscape Characteristics of Two Australian Marine Parks
Authors: McCordic Jessica A. , DeAngelis Annamaria I. , Kline Logan R. , McBride Candace , Rodgers Giverny G. , Rowell Timothy J. , Smith Jeremy , Stanley Jenni A. , Stokoe Allison , Van Parijs Sofie M.
Published: August 2021

Soundscapes represent an intrinsic aspect of a habitat which, particularly in protected areas, should be monitored and managed to mitigate human impacts. Soundscape ecology characterizes acoustic interactions within an environment, integrating biological, anthropogenic, climatological, and geological sound sources. Monitoring soundscapes in marine protected areas is particularly important due to the reliance of many marine species on sound for biological functions, including communication and reproduction. In this study we establish a baseline understanding of underwater soundscapes within two marine National Park Zones (NPZs) along the east coast of Australia: Cod Grounds Marine Park and an NPZ surrounding Pimpernel Rock within Solitary Islands Marine Park. In each of the NPZs, underwater recorders were deployed twice during the austral winter (33–35 days, 2018 and 60–69 days, 2019) and once during the austral summer (35–71 days, 2018–2019). We used the resulting acoustic recordings to determine hourly presence of anthropogenic and biological sounds between 20 Hz and 24 kHz and analyze their contributions to patterns of received sound levels. Sounds from vessels were recorded on most days throughout monitoring but were not found to influence long-term patterns of sound levels over their corresponding frequencies. Biological sources included dolphins, snapping shrimp, fish choruses, humpback whales, and dwarf minke whales. Dolphins, snapping shrimp, and fish choruses were present in all deployments. Median ambient sound levels showed a consistent diel pattern with increased levels resulting from crepuscular fish choruses combined with a higher intensity of snapping shrimp snaps during those times. Singing humpback whales strongly influenced the overall sound levels throughout the winter migration, while dwarf minke whales were consistently detected in the 2019 winter deployment but were only present in 2 h among the earlier deployments. Patterns of acoustic spectra were similar between the two NPZs, and patterns of soundscape measurements were observed to be driven by seasonal differences in biological contributions rather than anthropogenic sound sources, indicating that these NPZs are not yet heavily impacted by anthropogenic noise. These baseline measurements will prove invaluable in long-term monitoring of the biological health of NPZs.
Using Machine Learning Algorithms to Predict Candidaemia in ICU Patients With New-Onset Systemic Inflammatory Response Syndrome
Authors: Yuan Siyi , Sun Yunbo , Xiao Xiongjian , Long Yun , He Huaiwu
Published: August 2021

Background: Distinguishing ICU patients with candidaemia can help with the precise prescription of antifungal drugs to create personalized guidelines. Previous prediction models of candidaemia have primarily used traditional logistic models and had some limitations. In this study, we developed a machine learning algorithm trained to predict candidaemia in patients with new-onset systemic inflammatory response syndrome (SIRS).

Methods: This retrospective, observational study used clinical information collected between January 2013 and December 2017 from three hospitals. The ICU patient data were used to train 4 machine learning algorithms–XGBoost, Support Vector Machine (SVM), Random Forest (RF), ExtraTrees (ET)–and a logistic regression (LR) model to predict patients with candidaemia.

Results: Of the 8,002 cases of new-onset SIRS (in 7,932 patients) included in the analysis, 137 new-onset SIRS cases (in 137 patients) were blood culture positive for candidaemia. Risk factors, such as fungal colonization, diabetes, acute kidney injury, the total number of parenteral nutrition days and renal replacement therapy, were important predictors of candidaemia. The XGBoost machine learning model outperformed the other models in distinguishing patients with candidaemia [XGBoost vs. SVM vs. RF vs. ET vs. LR; area under the curve (AUC): 0.92 vs. 0.86 vs. 0.91 vs. 0.90 vs. 0.52, respectively]. The XGBoost model had a sensitivity of 84%, specificity of 89% and negative predictive value of 99.6% at the best cut-off value.

Conclusions: Machine learning algorithms can potentially predict candidaemia in the ICU and have better efficiency than previous models. These prediction models can be used to guide antifungal treatment for ICU patients when SIRS occurs.
Preexposure and Postexposure Prophylaxis of Rabies With Adeno-Associated Virus Expressing Virus-Neutralizing Antibody in Rodent Models
Authors: Huang Fei , Ren Meishen , Pei Jie , Mei Hong , Sui Baokun , Wu Qiong , Chai Benjie , Yang Ruicheng , Zhou Ming , Fu Zhen F. , Zhou Huiping , Zhao Ling
Published: August 2021

Rabies, a fatal disease in humans and other mammals, is caused by the rabies virus (RABV), and it poses a public health threat in many parts of the world. Once symptoms of rabies appear, the mortality is near 100%. There is currently no effective treatment for rabies. In our study, two human-derived RABV-neutralizing antibodies (RVNA), CR57 and CR4098, were cloned into adeno-associated virus (AAV) vectors, and recombinant AAVs expressing RVNA were evaluated for postexposure prophylaxis after intrathecal injection into RABV-infected rats. At 4days post-infection with a lethal dose of RABV, 60% of the rats that received an intrathecal injection of AAV-CR57 survived, while 100% of the rats inoculated with AAV-enhanced green fluorescent protein (EGFP) succumbed to rabies. Overall, these results demonstrate that AAV-encoding RVNA can be utilized as a potential human rabies postexposure prophylaxis.
Effects of Heavy Metals/Metalloids and Soil Properties on Microbial Communities in Farmland in the Vicinity of a Metals Smelter
Authors: Hu Xuewu , Wang Jianlei , Lv Ying , Liu Xingyu , Zhong Juan , Cui Xinglan , Zhang Mingjiang , Ma Daozhi , Yan Xiao , Zhu Xuezhe
Published: August 2021

Microorganisms play a fundamental role in biogeochemical cycling and are highly sensitive to environmental factors, including the physiochemical properties of the soils and the concentrations of heavy metals/metalloids. In this study, high-throughput sequencing of the 16S rRNA gene was used to study the microbial communities of farmland soils in farmland in the vicinity of a lead–zinc smelter. Proteobacteria, Acidobacteria, Actinobacteria, Bacteroidetes, and Gemmatimonadetes were the predominant phyla in the sites of interest. Sphingomonas, Gemmatimonas, Lysobacter, Flavisolibacter, and Chitinophaga were heavy metal-/metalloid-tolerant microbial groups with potential for bioremediation of the heavy metal/metalloid contaminated soils. However, the bacterial diversity was different for the different sites. The contents of heavy metal/metalloid species and the soil properties were studied to evaluate the effect on the soil bacterial communities. The Mantel test revealed that soil pH, total cadmium (T-Cd), and available arsenic played a vital role in determining the structure of the microbial communities. Further, we analyzed statistically the heavy metals/metalloids and the soil properties, and the results revealed that the microbial richness and diversity were regulated mainly by the soil properties, which correlated positively with organic matter and available nitrogen, while available phosphorus and available potassium were negatively correlated. The functional annotation of the prokaryotic taxa (FAPROTAX) method was used to predict the function of the microbial communities. Chemoheterotrophy and airborne chemoheterotrophy of the main microbial community functions were inhibited by soil pH and the heavy metals/metalloids, except in the case of available lead. Mantel tests revealed that T-Cd and available zinc were the dominant factors affecting the functions of the microbial communities. Overall, the research indicated that in contaminated soils, the presence of multiple heavy metals/metalloids, and the soil properties synergistically shaped the structure and function of the microbial communities.
Spatially Resolved Immunometabolism to Understand Infectious Disease Progression
Authors: Tans Roel , Dey Shoumit , Dey Nidhi Sharma , Calder Grant , O’Toole Peter , Kaye Paul M. , Heeren Ron M. A.
Published: August 2021

Infectious diseases, including those of viral, bacterial, fungal, and parasitic origin are often characterized by focal inflammation occurring in one or more distinct tissues. Tissue-specific outcomes of infection are also evident in many infectious diseases, suggesting that the local microenvironment may instruct complex and diverse innate and adaptive cellular responses resulting in locally distinct molecular signatures. In turn, these molecular signatures may both drive and be responsive to local metabolic changes in immune as well as non-immune cells, ultimately shaping the outcome of infection. Given the spatial complexity of immune and inflammatory responses during infection, it is evident that understanding the spatial organization of transcripts, proteins, lipids, and metabolites is pivotal to delineating the underlying regulation of local immunity. Molecular imaging techniques like mass spectrometry imaging and spatially resolved, highly multiplexed immunohistochemistry and transcriptomics can define detailed metabolic signatures at the microenvironmental level. Moreover, a successful complementation of these two imaging techniques would allow multi-omics analyses of inflammatory microenvironments to facilitate understanding of disease pathogenesis and identify novel targets for therapeutic intervention. Here, we describe strategies for downstream data analysis of spatially resolved multi-omics data and, using leishmaniasis as an exemplar, describe how such analysis can be applied in a disease-specific context.
Proviral Turnover During Untreated HIV Infection Is Dynamic and Variable Between Hosts, Impacting Reservoir Composition on ART
Authors: Brooks Kelsie , Omondi F. Harrison , Liang Richard H. , Sudderuddin Hanwei , Jones Bradley R. , Joy Jeffrey B. , Brumme Chanson J. , Hunter Eric , Brumme Zabrina L.
Published: August 2021

Human immunodeficiency virus (HIV) can persist as an integrated provirus, in a transcriptionally repressed state, within infected cells. This small yet enduring pool of cellular reservoirs that harbor replication-competent HIV is the main barrier to cure. Entry of viral sequences into cellular reservoirs begins shortly after infection, and cells containing integrated proviral DNA are extremely stable once suppressive antiretroviral therapy (ART) is initiated. During untreated HIV infection however, reservoir turnover is likely to be more dynamic. Understanding these dynamics is important because the longevity of the persisting proviral pool during untreated infection dictates reservoir composition at ART initiation. If the persisting proviral pool turns over slowly pre-ART, then HIV sequences seeded into it during early infection would have a high likelihood of persisting for long periods. However, if pre-ART turnover was rapid, the persisting proviral pool would rapidly shift toward recently circulating HIV sequences. One-way to estimate this turnover rate is from the age distributions of proviruses sampled shortly after therapy initiation: this is because, at the time of sampling, the majority of proviral turnover would have already occurred prior to ART. Recently, methods to estimate a provirus’ age from its sequence have made this possible. Using data from 12 individuals with HIV subtype C for whom proviral ages had been determined phylogenetically, we estimated that the average proviral half-life during untreated infection was 0.78 (range 0.45–2.38) years, which is >15 times faster than that of proviral DNA during suppressive ART. We further show that proviral turnover during untreated infection correlates with both viral setpoint and rate of CD4+ T-cell decline during this period. Overall, our results support dynamic proviral turnover pre-ART in most individuals, which helps explain why many individuals’ reservoirs are skewed toward younger HIV sequences. Broadly, our findings are consistent with the notion that active viral replication creates an environment less favorable to proviral persistence, while viral suppression creates conditions more favorable to persistence, where ART stabilizes the proviral pool by dramatically slowing its rate of decay. Strategies to inhibit this stabilizing effect and/or to enhance reservoir turnover during ART could represent additional strategies to reduce the HIV reservoir.
Extremophilic Exopolysaccharides: Biotechnologies and Wastewater Remediation
Authors: Banerjee Aparna , Sarkar Shrabana , Govil Tanvi , González-Faune Patricio , Cabrera-Barjas Gustavo , Bandopadhyay Rajib , Salem David R. , Sani Rajesh K.
Published: August 2021

Various microorganisms thrive under extreme environments, like hot springs, hydrothermal vents, deep marine ecosystems, hyperacid lakes, acid mine drainage, high UV exposure, and more. To survive against the deleterious effect of these extreme circumstances, they form a network of biofilm where exopolysaccharides (EPSs) comprise a substantial part. The EPSs are often polyanionic due to different functional groups in their structural backbone, including uronic acids, sulfated units, and phosphate groups. Altogether, these chemical groups provide EPSs with a negative charge allowing them to (a) act as ligands toward dissolved cations as well as trace, and toxic metals; (b) be tolerant to the presence of salts, surfactants, and alpha-hydroxyl acids; and (c) interface the solubilization of hydrocarbons. Owing to their unique structural and functional characteristics, EPSs are anticipated to be utilized industrially to remediation of metals, crude oil, and hydrocarbons from contaminated wastewaters, mines, and oil spills. The biotechnological advantages of extremophilic EPSs are more diverse than traditional biopolymers. The present review aims at discussing the mechanisms and strategies for using EPSs from extremophiles in industries and environment bioremediation. Additionally, the potential of EPSs as fascinating biomaterials to mediate biogenic nanoparticles synthesis and treat multicomponent water contaminants is discussed.
In vitro Activity of Contezolid Against Methicillin-Resistant Staphylococcus aureus, Vancomycin-Resistant Enterococcus, and Strains With Linezolid Resistance Genes From China
Authors: Wang Siheng , Cai Chang , Shen Yingbo , Sun Chengtao , Shi Qingxin , Wu Ningjun , Zheng Shufang , Qian Jiao , Zhang Rong , Zhou Hongwei
Published: August 2021

Contezolid is a novel oxazolidinone, which exhibits potent activity against gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE), and penicillin-resistant Streptococcus pneumoniae (PRSP). In this study, the in vitro activity of contezolid was compared with linezolid (LZD), tigecycline (TGC), teicoplanin (TEC), vancomycin (VA), daptomycin (DAP), and florfenicol (FFC) against MRSA and VRE strains isolated from China. Contezolid revealed considerable activity against MRSA and VRE isolates with MIC90 values of 0.5 and 1.0 μg/mL, respectively. For VRE strains with different resistance genotypes, including vanA- and vanM-type strains, contezolid did not exhibit significantly differential antibacterial activity. Furthermore, the antimicrobial activity of contezolid is similar to or slightly better than that of linezolid against MRSA and VRE strains. Subsequently, the activity of contezolid was tested against strains carrying linezolid resistance genes, including Staphylococcus capitis carrying cfr gene and Enterococcus faecalis carrying optrA gene. The results showed that contezolid exhibited similar antimicrobial efficacy to linezolid against strains with linezolid resistance genes. In general, contezolid may have potential benefits to treat the infections caused by MRSA and VRE pathogens.
Vestibular and Auditory Hair Cell Regeneration Following Targeted Ablation of Hair Cells With Diphtheria Toxin in Zebrafish
Authors: Jimenez Erin , Slevin Claire C. , Colón-Cruz Luis , Burgess Shawn M.
Published: August 2021

Millions of Americans experience hearing or balance disorders due to loss of hair cells in the inner ear. The hair cells are mechanosensory receptors used in the auditory and vestibular organs of all vertebrates as well as the lateral line systems of aquatic vertebrates. In zebrafish and other non-mammalian vertebrates, hair cells turnover during homeostasis and regenerate completely after being destroyed or damaged by acoustic or chemical exposure. However, in mammals, destroying or damaging hair cells results in permanent impairments to hearing or balance. We sought an improved method for studying hair cell damage and regeneration in adult aquatic vertebrates by generating a transgenic zebrafish with the capacity for targeted and inducible hair cell ablation in vivo. This model expresses the human diphtheria toxin receptor (hDTR) gene under the control of the myo6b promoter, resulting in hDTR expressed only in hair cells. Cell ablation is achieved by an intraperitoneal injection of diphtheria toxin (DT) in adult zebrafish or DT dissolved in the water for larvae. In the lateral line of 5 days post fertilization (dpf) zebrafish, ablation of hair cells by DT treatment occurred within 2 days in a dose-dependent manner. Similarly, in adult utricles and saccules, a single intraperitoneal injection of 0.05 ng DT caused complete loss of hair cells in the utricle and saccule by 5 days post-injection. Full hair cell regeneration was observed for the lateral line and the inner ear tissues. This study introduces a new method for efficient conditional hair cell ablation in adult zebrafish inner ear sensory epithelia (utricles and saccules) and demonstrates that zebrafish hair cells will regenerate in vivo after this treatment.
Evolutionary Constraints on Connectivity Patterns in the Mammalian Suprachiasmatic Nucleus
Authors: Spencer Connor , Tripp Elizabeth , Fu Feng , Pauls Scott
Published: August 2021

The mammalian suprachiasmatic nucleus (SCN) comprises about 20,000 interconnected oscillatory neurons that create and maintain a robust circadian signal which matches to external light cues. Here, we use an evolutionary game theoretic framework to explore how evolutionary constraints can influence the synchronization of the system under various assumptions on the connection topology, contributing to the understanding of the structure of interneuron connectivity. Our basic model represents the SCN as a network of agents each with two properties—a phase and a flag that determines if it communicates with its neighbors or not. Communication comes at a cost to the agent, but synchronization of phases with its neighbors bears a benefit. Earlier work shows that when we have “all-to-all” connectivity, where every agent potentially communicates with every other agent, there is often a simple trade-off that leads to complete communication and synchronization of the system: the benefit must be greater than twice the cost. This trade-off for all-to-all connectivity gives us a baseline to compare to when looking at other topologies. Using simulations, we compare three plausible topologies to the all-to-all case, finding that convergence to synchronous dynamics occurs in all considered topologies under similar benefit and cost trade-offs. Consequently, sparser, less biologically costly topologies are reasonable evolutionary outcomes for organisms that develop a synchronizable oscillatory network. Our simulations also shed light on constraints imposed by the time scale on which we observe the SCN to arise in mammals. We find two conditions that allow for a synchronizable system to arise in relatively few generations. First, the benefits of connectivity must outweigh the cost of facilitating the connectivity in the network. Second, the game at the core of the model needs to be more cooperative than antagonistic games such as the Prisoner’s Dilemma. These results again imply that evolutionary pressure may have driven the system towards sparser topologies, as they are less costly to create and maintain. Last, our simulations indicate that models based on the mutualism game fare the best in uptake of communication and synchronization compared to more antagonistic games such as the Prisoner’s Dilemma.
Comparison of Drug Availability in the Inner Ear After Oral, Transtympanic, and Combined Administration
Authors: Li Yang , Kanzaki Sho , Shibata Shinsuke , Nakamura Masaya , Ozaki Masahiro , Okano Hideyuki , Ogawa Kaoru
Published: August 2021

Although combination of oral and transtympanic drug therapy (CT) has been proved more effective and safer for idiopathic sudden sensorineural hearing loss (ISSNHL) by some clinical trials, there are few laboratory researches on the pharmacokinetics in the inner ear following CT on account of structural limitations of the inner ear. The aim of the present study was to investigate the pharmacokinetic behaviors of CT in the inner ear of mice. Eighteen transgenic GFAP-Luc mice which express luciferase in cochlear spiral ganglion cells were divided into oral administration (OR) group, transtympanic injection route (TT) group and CT group, and luciferin was delivered into the inner ear of these mice through oral, transtympanic or combined routes, respectively. A new in vivo imaging system was used to observe luciferin/luciferase signals and the compare the pharmacokinetics of different administration routes in the inner ear of mice. Bioluminescence signals were observed in the inner ear 3.3 ± 2.6 min after CT, significantly earlier than that of OR group (15.8 ± 7.4 min). CT owned the longest reaching-peak time and largest area under the curve (AUC) among three groups. Compared to TT, CT had longer biological half-life and higher AUC value, but did not displayed stronger peak value. There were significant differences in the peak values between OR group and TT group and between OR group and CT group. This study suggests that the OR route is less effective than the TT or CT route, and combination of OR and TT can deliver more drugs into the inner ear and confer a longer therapeutic window, but cannot increase drug intensity.
Short-Wave Sensitive (“Blue”) Cone Activation Is an Aggravating Factor for Visual Snow Symptoms
Authors: Hepschke Jenny L. , Martin Paul R. , Fraser Clare L.
Published: August 2021

Background and Purpose: Visual Snow (VS) is a disorder characterised by the subjective perception of black-and-white visual static. The aetiology of this condition is not known. In our previous work we suggested that there is a link between short-wave (S or “blue” cone) signals and severity of visual snow symptoms. Therefore we aimed to further characterise this potential link.

Methods: Patients (n = 22) with classic VS based on the diagnostic criteria and healthy controls (n = 12), underwent Intuitive Colorimetry (IC) testing (Cerium Visual Technologies). Twelve hue directions (expressed as angle in CIE 1976 LUV space relative to D65) were rated on a five-point scale from preferred (relieving, positive score) to non-preferred (exacerbating, negative score), and overall preferred and non-preferred angles were chosen.

Results: A non-preferred violet region near the tritanopic confusion line / S-cone axis (267 deg.) was strongly associated with exacerbation of VS symptoms (range 250–310 deg, mean 276 ± 16, n = 20, Rayleigh p < 0.001). Two subjects with non-preferred region > 90 deg from mean were considered as outliers. Median rank at hue angle 270 deg was significantly lower than at angle 90 (−1.5 vs. 0.0, p < 0.001, Wilcoxon non-parametric rank-sum test). Patients showed preference for one of two spectral regions which relieved VS symptoms: orange-yellow (range 50–110 deg., mean 79 ± 24, n = 14) and turquoise-blue (range (210–250 deg., mean 234 ± 27, n = 8).

Conclusion: Our results show that visual snow symptoms are exacerbated by colour modulation that selectively increased levels of S-cone excitation. Because S-cone signals travel on primordial brain pathways that regulate cortical rhythms (koniocellular pathways) we hypothesis that these pathways contribute to the pathogenesis of this disorder.
Blockade of TRPC Channels Limits Cholinergic-Driven Hyperexcitability and Seizure Susceptibility After Traumatic Brain Injury
Authors: Carver Chase M. , DeWitt Haley R. , Stoja Aiola P. , Shapiro Mark S.
Published: August 2021

We investigated the contribution of excitatory transient receptor potential canonical (TRPC) cation channels to posttraumatic hyperexcitability in the brain 7 days following controlled cortical impact model of traumatic brain injury (TBI) to the parietal cortex in male adult mice. We investigated if TRPC1/TRPC4/TRPC5 channel expression is upregulated in excitatory neurons after TBI in contribution to epileptogenic hyperexcitability in key hippocampal and cortical circuits that have substantial cholinergic innervation. This was tested by measuring TRPC1/TRPC4/TRPC5 protein and messenger RNA (mRNA) expression, assays of cholinergic function, neuronal Ca2+imaging in brain slices, and seizure susceptibility after TBI. We found region-specific increases in expression of TRPC1, TRPC4, and TRPC5 subunits in the hippocampus and cortex following TBI. The dentate gyrus, CA3 region, and cortex all exhibited robust upregulation of TRPC4 mRNA and protein. TBI increased cFos activity in dentate gyrus granule cells (DGGCs) and layer 5 pyramidal neurons both at the time of TBI and 7 days post-TBI. DGGCs displayed greater magnitude and duration of acetylcholine-induced rises in intracellular Ca2+in brain slices from mice subjected to TBI. The TBI mice also exhibited greater seizure susceptibility in response to pentylenetetrazol-induced kindling. Blockade of TRPC4/TRPC5 channels with M084 reduced neuronal hyperexcitation and impeded epileptogenic progression of kindling. We observed that the time-dependent upregulation of TRPC4/TRPC5-containing channels alters cholinergic responses and activity of principal neurons acting to increase proexcitatory sensitivity. The underlying mechanism includes acutely decreased acetylcholinesterase function, resulting in greater Gq/11-coupled muscarinic receptor activation of TRPC channels. Overall, our evidence suggests that TBI-induced plasticity of TRPC channels strongly contributes to overt hyperexcitability and primes the hippocampus and cortex for seizures.
Cortical Re-organization After Traumatic Brain Injury Elicited Using Functional Electrical Stimulation Therapy: A Case Report
Authors: Milosevic Matija , Nakanishi Tomoya , Sasaki Atsushi , Yamaguchi Akiko , Nomura Taishin , Popovic Milos R. , Nakazawa Kimitaka
Published: August 2021

Functional electrical stimulation therapy (FEST) can improve motor function after neurological injuries. However, little is known about cortical changes after FEST and weather it can improve motor function after traumatic brain injury (TBI). Our study examined cortical changes and motor improvements in one male participant with chronic TBI suffering from mild motor impairment affecting the right upper-limb during 3-months of FEST and during 3-months follow-up. In total, 36 sessions of FEST were applied to enable upper-limb grasping and reaching movements. Short-term assessments carried out using transcranial magnetic stimulation (TMS) showed reduced cortical silent period (CSP), indicating cortical and/or subcortical inhibition after each intervention. At the same time, no changes in motor evoked potentials (MEPs) were observed. Long-term assessments showed increased MEP corticospinal excitability after 12-weeks of FEST, which seemed to remain during both follow-ups, while no changes in CSP were observed. Similarly, long-term assessments using TMS mapping showed larger hand MEP area in the primary motor cortex (M1) after 12-weeks of FEST as well as during both follow-ups. Corroborating TMS results, functional magnetic resonance imaging (fMRI) data showed M1 activations increased during hand grip and finger pinch tasks after 12-weeks of FEST, while gradual reduction of activity compared to after the intervention was seen during follow-ups. Widespread changes were seen not only in the M1, but also sensory, parietal rostroventral, supplementary motor, and premotor areas in both contralateral and ipsilateral hemispheres, especially during the finger pinch task. Drawing test performance showed improvements after the intervention and during follow-ups. Our findings suggest that task-specific and repetitive FEST can effectively increase cortical activations by integrating voluntary motor commands and sensorimotor network through functional electrical stimulation (FES). Overall, our results demonstrated cortical re-organization in an individual with chronic TBI after FEST.
Vagus Nerve Stimulation as a Potential Adjuvant to Rehabilitation for Post-stroke Motor Speech Disorders
Authors: Morrison Robert A. , Hays Seth A. , Kilgard Michael P.
Published: August 2021

Stroke often leaves lasting impairments affecting orofacial function. While speech therapy is able to enhance function after stroke, many patients see only modest improvements after treatment. This partial restoration of function after rehabilitation suggests that there is a need for further intervention. Rehabilitative strategies that augment the effects of traditional speech therapy hold promise to yield greater efficacy and reduce disability associated with motor speech disorders. Recent studies demonstrate that brief bursts of vagus nerve stimulation (VNS) can facilitate the benefits of rehabilitative interventions. VNS paired with upper limb rehabilitation enhances recovery of upper limb function in patients with chronic stroke. Animal studies reveal that these improvements are driven by VNS-dependent synaptic plasticity in motor networks. Moreover, preclinical evidence demonstrates that a similar strategy of pairing VNS can promote synaptic reorganization in orofacial networks. Building on these findings, we postulate that VNS-directed orofacial plasticity could target post-stroke motor speech disorders. Here, we outline the rationale for pairing VNS with traditional speech therapy to enhance recovery in the context of stroke of speech motor function. We also explore similar treatments that aim to enhance synaptic plasticity during speech therapy, and how VNS differs from these existing therapeutic strategies. Based on this evidence, we posit that VNS-paired speech therapy shows promise as a means of enhancing recovery after post-stroke motor speech disorders. Continued development is necessary to comprehensively establish and optimize this approach, which has the potential to increase quality of life for the many individuals suffering with these common impairments.
Cabp2-Gene Therapy Restores Inner Hair Cell Calcium Currents and Improves Hearing in a DFNB93 Mouse Model
Authors: Oestreicher David , Picher Maria Magdalena , Rankovic Vladan , Moser Tobias , Pangrsic Tina
Published: August 2021

Clinical management of auditory synaptopathies like other genetic hearing disorders is currently limited to the use of hearing aids or cochlear implants. However, future gene therapy promises restoration of hearing in selected forms of monogenic hearing impairment, in which cochlear morphology is preserved over a time window that enables intervention. This includes non-syndromic autosomal recessive hearing impairment DFNB93, caused by defects in the CABP2 gene. Calcium-binding protein 2 (CaBP2) is a potent modulator of inner hair cell (IHC) voltage-gated calcium channels CaV1.3. Based on disease modeling in Cabp2–/– mice, DFNB93 hearing impairment has been ascribed to enhanced steady-state inactivation of IHC CaV1.3 channels, effectively limiting their availability to trigger synaptic transmission. This, however, does not seem to interfere with cochlear development and does not cause early degeneration of hair cells or their synapses. Here, we studied the potential of a gene therapeutic approach for the treatment of DFNB93. We used AAV2/1 and AAV-PHP.eB viral vectors to deliver the Cabp2 coding sequence into IHCs of early postnatal Cabp2–/– mice and assessed the level of restoration of hair cell function and hearing. Combining in vitro and in vivo approaches, we observed high transduction efficiency, and restoration of IHC CaV1.3 function resulting in improved hearing of Cabp2–/– mice. These preclinical results prove the feasibility of DFNB93 gene therapy.
Protein and Energy Intake Assessment and Their Association With In-Hospital Mortality in Critically Ill COVID-19 Patients: A Prospective Cohort Study
Authors: Hajimohammadebrahim-Ketabforoush Melika , Vahdat Shariatpanahi Zahra , Vahdat Shariatpanahi Maryam , Shahbazi Erfan , Shahbazi Shaahin
Published: August 2021

Background and Aim: It is partially known that nutritional intake could alleviate proteolysis and course of disease severity in patients with COVID-19; however, not enough data are available in this regard. The present study aimed to assess protein and energy intake and their association with in-hospital mortality in critically ill COVID-19 patients.

Methods: A total of 126 patients with COVID-19, who were critically ill, ≥5 days and a subset of 111 patients in ICU ≥10 days completed the present prospective observational cohort study.

Results: Protein and energy intakes on Day 5 of ICU admission in survivors were 46 and 58% of target values, respectively. These values in non-survivors were 42 and 50% of target values, respectively (p < 0.05). In the sample ≥10 days, protein and energy intakes in survivors reached 64 and 87% of target values, respectively, without statistically significant differences with non-survivors. In the sample ≥5 days, Cox proportional hazard regression was adjusted for GLIM, APACHE II, comorbidity, and age; the results indicated that the patients with protein and energy intake lower than 0.59 g/kg/day and 14 kcal/kg/day, had ~2-fold mortality hazard (protein: HR, 2.38; 95% CI, 1.40–4.03; P = 0.001 and energy: HR, 2.23; 95% CI, 1.27–3.92; P = 0.005).

Conclusion: Actual protein and energy intakes in critically ill patients with COVID-19 are in suboptimal levels compared with goal recommendations in these patients. Moreover, higher amounts of protein and energy intakes in the early acute phase were significantly associated with better survival and lower risk of in-hospital mortality.
Identification of Target PTEN-Based miR-425 and miR-576 as Potential Diagnostic and Immunotherapeutic Biomarkers of Colorectal Cancer With Liver Metastasis
Authors: Hu Xiaoyun , Chen Qiuchen , Guo Hao , Li Kuo , Fu Boshi , Chen Yu , Zhao Haishan , Wei Minjie , Li Yalun , Wu Huizhe
Published: August 2021

A major complication of colorectal cancer (CRC), one of the most common and fatal types of cancers, is secondary liver metastasis. For patients with this fate, there are very few biomarkers available in clinical application, and the disease remains incurable. Recently, increasing studies demonstrated that tumorigenesis and development are closely related to immune escape, indicating that the roles of immune-related indicators might have been neglected in the past in colorectal cancer liver metastases (CRLM). Here, we unveil that elevated miR-425 and miR-576 promote CRLM through inhibiting PTEN-mediated cellular immune function. Specifically, miR-425 and miR-576 were identified for their significant upregulation in CRLM compared with the primary CRC tissues based on GSE81581 (n = 8) and GSE44121 (n = 18) datasets. Besides, we determined that the two microRNAs (miRNAs) coparticipated in restraining P53 and transforming growth factor beta (TGF-β) signaling pathways associated with tumor metastasis, and both shortened the overall survival of the patients with metastatic susceptibility. Notably, in situ hybridization on relatively large samples of paired CRC tissues (n = 157) not only substantiated that the expression of miR-425 and miR-576 was dramatically upregulated in CRLM but also revealed that they were closely related to tumor deterioration, especially liver metastases. Moreover, we further confirmed that the combination of miR-425 and miR-576 was an effective predictive model for liver metastases and poor clinical outcomes. Mechanically, downregulated PTEN (GSE81558, n = 6) was verified to be a shared target of miR-425 and miR-576 acting as metastasis-related oncogenes, on account of the presence of binding sites (+2928–+2934 and +4371–+4378, respectively) and the collaborative suppression of P53/TGF-β signaling in CRLM, which was further confirmed in CRC cells (HCT116 and SW480) based on systematic molecular biology experiments. Importantly, the target PTEN was strongly associated with microsatellite instability, tumor microenvironment, and immune cell infiltration. Thus, we speculate that miR-425 and miR-576 are novel biomarkers for CRLM prevention and immunotherapy and upstream inhibitors of the PTEN-P53/TGF-β function axis.
GZ17-6.02 and Pemetrexed Interact to Kill Osimertinib-Resistant NSCLC Cells That Express Mutant ERBB1 Proteins
Authors: Booth Laurence , West Cameron , Moore Robert P. , Von Hoff Daniel , Dent Paul
Published: August 2021

We determined the molecular mechanisms by which the novel therapeutic GZ17-6.02 killed non-small cell lung cancer (NSCLC) cells. Erlotinib, afatinib, and osimertinib interacted with GZ17-6.02 to kill NSCLC cells expressing mutant EGFR proteins. GZ17-6.02 did not interact with any EGFR inhibitor to kill osimertinib-resistant cells. GZ17-6.02 interacted with the thymidylate synthase inhibitor pemetrexed to kill NSCLC cells expressing mutant ERBB1 proteins or mutant RAS proteins or cells that were resistant to EGFR inhibitors. The drugs interacted to activate ATM, the AMPK, and ULK1 and inactivate mTORC1, mTORC2, ERK1/2, AKT, eIF2α; and c-SRC. Knockdown of ATM or AMPKα1 prevented ULK1 activation. The drugs interacted to cause autophagosome formation followed by flux, which was significantly reduced by knockdown of ATM, AMPKα1, and eIF2α, or by expression of an activated mTOR protein. Knockdown of Beclin1, ATG5, or [BAX + BAK] partially though significantly reduced drug combination lethality as did expression of activated mTOR/AKT/MEK1 or over-expression of BCL-XL. Expression of dominant negative caspase 9 weakly reduced killing. The drug combination reduced the expression of HDAC2 and HDAC3, which correlated with lower PD-L1, IDO1, and ODC levels and increased MHCA expression. Collectively, our data support consideration of combining GZ17-6.02 and pemetrexed in osimertinib-resistant NSCLC.
Integrative Analysis of Minichromosome Maintenance Proteins and Their Prognostic Significance in Melanoma
Authors: Han Wei , Wu Yi-Zhu , Zhao Xiao-Yu , Gong Zhen-Hua , Shen Guo-Liang
Published: August 2021

Background

Minichromosome maintenance (MCM) is known for participating in cell cycle progression, as well as DNA replication. While the diverse expression patterns and prognostic values ofMCMs in melanoma still remained unclear.

Methods

In the present study, the transcriptional and clinical profiles ofMCMs were explored in patients with melanoma from multiple databases, including GEO, TCGA, ONCOMINE, GEPIA, UALCAN, cBioPortal, and TIMER databases.

Results

We found that the elevated expressions ofMCM2–6andMCM10were significantly expressed in melanoma compared to normal skin. High mRNA levels ofMCM4,MCM5, andMCM10were closely related to worse prognosis in patients with melanoma. GSEA showed hallmark pathways were most involved in mTORC1 signaling, G2M checkpoint, E2F targets, and mitotic spindle. Furthermore, we found potential correlations between theMCMexpression and the immune cell infiltration, including B cells, CD4+ T cells, CD8+ T cells, neutrophils, macrophages, and dendritic cells.

Conclusion

UpregulatedMCMgene expression in melanoma probably played a crucial part in the development and progression of melanoma. The upregulatedMCM4/5/10expressions could be used as potential prognostic markers to improve the poor outcome and prognostic accuracy in patients with melanoma. Our study might shed light on the selection of prognostic biomarkers as well as the underlying molecular pathogenesis of melanoma.
Molecular Phenotyping of AR Signaling for Predicting Targeted Therapy in Castration Resistant Prostate Cancer
Authors: Hamid Agus Rizal A. H. , Luna-Velez Maria V. , Dudek Aleksandra M. , Jansen Cornelius F. J. , Smit Frank , Aalders Tilly W. , Verhaegh Gerald W. , Schaafsma Ewout , Sedelaar John P. M. , Schalken Jack A.
Published: August 2021

Castration-resistant prostate cancer (CRPC) is defined by resistance of the tumor to androgen deprivation therapy (ADT). Several molecular changes, particularly in the AR signaling cascade, have been described that may explain ADT resistance. The variety of changes may also explain why the response to novel therapies varies between patients. Testing the specific molecular changes may be a major step towards personalized treatment of CRPC patients. The aim of our study was to evaluate the molecular changes in the AR signaling cascade in CRPC patients. We have developed and validated several methods which are easy to use, and require little tissue material, for exploring AR signaling pathway changes simultaneously. We found that the AR signaling pathway is still active in the majority of our CRPC patients, due to molecular changes in AR signaling components. There was heterogeneity in the molecular changes observed, but we could classify the patients into 4 major subgroups which are: AR mutation, AR amplification, active intratumoral steroidogenesis, and combination of AR amplification and active intratumoral steroidogenesis. We suggest characterizing the AR signaling pathway in CRPC patients before beginning any new treatment, and a recent fresh tissue sample from the prostate or a metastatic site should be obtained for the purpose of this characterization.
A Single-Institution Experience in the Use of Chest Radiographs for Hospitalized Children Labeled as Asthma Exacerbation
Authors: Beyyumi Ela , Tawil Mohamed I. , AlDhanhani Huda , Jameel Sara , Mouhssine Manal , AlNuaimi Hasa M. , Hamdoun Osama , Alabdouli Amnah , Alsamri Mohammed T. , Ghatasheh Ghassan A. , Zoubeidi Taoufik , Souid Abdul-Kader
Published: August 2021

Background: Risks of diagnostic radiation have become more notable lately, particularly in young children with chronic medical conditions. This study reports on the cumulative radiation from chest radiographs in children with asthma. Its main purpose was to review our current practice and suggest minimizing the use of chest radiographs.

Methods: The study was retrospective and conducted at a pediatric tertiary center. Eligibility criteria included children 2–15 y, admitted between January 2017 and December 2018 for asthma management.

Results: Of the 643 children admitted as “asthma exacerbation,” 243 [40% females; age (mean ± SD) 5.4±3.3 y] met the study criteria for inclusion. Ninety-two (38%) children had a temperature of 38.8±0.7°C on the day of admission. Antibiotics were prescribed for 148 (61%) children, mainly for presumed pneumonia. Chest radiographs were requested for 214 (88%) children, mainly on the day of admission. Only 38 (18%) chest radiographs showed focal/multifocal pneumonia justifying antibiotic use. Significant predictors for requesting chest radiographs were antibiotic use for presumed pneumonia, lower oxygen saturation at presentation, and a requested blood culture. The rate of chest radiographs per year was negatively related to the child's age; the younger the child the higher the rate (model coefficient −0.259, P < 0.001). For children < 5 y, the rate of chest radiographs was 1.39 ± 1.21/y and radiation dose 0.028 ± 0.025 mSv/y. The corresponding rates for children ≥5 y were 0.78 ± 0.72/y and 0.008 ± 0.007 mSv/y, respectively (P < 0.001).

Conclusion: Chest radiographs were commonly requested for children with asthma, especially younger children. Prospective studies are necessary to measure the impact of this practice on the children's health.