bluuebunny/crossref_metadata_2025 huggingface dataset:
Coralline Algae at the Paleocene/Eocene Thermal Maximum in the Southern Pyrenees (N Spain)
Authors: Aguirre Julio , Baceta Juan I. , Braga Juan C.
Published: July 2022

During the Paleocene/Eocene Thermal Maximum, ~55.6 Ma, the Earth experienced the warmest event of the last 66 Ma due to a massive release of CO2. This event lasted for ~100 thousands of years with the consequent ocean acidification (estimated pH = 7.8-7.6). In this paper, we analyze the effects of this global environmental shift on coralline algal assemblages in the Campo and Serraduy sections, in the south-central Pyrenees (Huesca, N Spain), where the PETM is recorded within coastal-to-shallow marine carbonate and siliciclastic deposits. In both sections, coralline algae occur mostly as fragments, although rhodoliths and crusts coating other organisms are also frequent. Rhodoliths occur either dispersed or locally forming dense concentrations (rhodolith beds). Distichoplax biserialis and geniculate forms (mostly Jania nummulitica) of the order Corallinales dominated the algal assemblages followed by Sporolithales and Hapalidiales. Other representatives of Corallinales, namely Spongites, Lithoporella as well as Neogoniolithon, Karpathia, and Hydrolithon, are less abundant. Species composition does not change throughout the Paleocene/Eocene boundary but the relative abundance of coralline algae as components of the carbonate sediments underwent a reduction. They were abundant during the late Thanetian but became rare during the early Ypresian. This abundance decrease is due to a drastic change in the local paleoenvironmental conditions immediately after the boundary. A hardground at the top of the Thanetian carbonates was followed by continental sedimentation. After that, marine sedimentation resumed in shallow, very restricted lagoon and peritidal settings, where muddy carbonates rich in benthic foraminifera, e.g., milioliids (with abundant Alveolina) and soritids, and eventually stromatolites were deposited. These initial restricted conditions were unfavorable for coralline algae. Adverse conditions continued to the end of the study sections although coralline algae reappeared and were locally frequent in some beds, where they occurred associated with corals. In Serraduy, the marine reflooding was also accompanied by significant terrigenous supply, precluding algal development. Therefore, the observed changes in coralline algal assemblages during the PETM in the Pyrenees were most likely related to local paleoenvironmental shifts rather than to global oceanic or atmospheric alterations.
Assessment of Rhodolith Diversity in the Northwestern Gulf of Mexico Including the Description of Sporolithon gracile sp. nov. (Sporolithales, Rhodophyta), and Three New Species of Roseolithon (Hapalidiales, Rhodophyta)
Authors: Richards Joseph , Kittle Ronald P. , Schmidt William E. , Sauvage Thomas , Gurgel Carlos F. D. , Gabriel Daniela , Fredericq Suzanne
Published: July 2022

In the past, non-geniculate coralline algae in the northwestern Gulf of Mexico have been identified based primarily on comparative morpho-anatomy. Recent studies employing DNA sequencing techniques combined with morpho-anatomical studies using SEM have revealed a wealth of previously undocumented diversity of rhodolith-forming non-geniculate coralline algae in the Corallinales, Hapalidiales and Sporolithales from mesophotic hard bank communities at 45-90 meters depth. Although many advances in the last decade have been made in clarifying species names and describing new species of corallines from offshore Louisiana and Texas, total diversity estimates are still incomplete and many species remain to be described. Collections from offshore Louisiana at Parker Bank in the newly expanded Flower Garden Banks National Marine Sanctuary yielded thin, finely branched rhodoliths. DNA sequence analyses of plastid-encoded psbA and rbcL loci, and nuclear-encoded LSU rDNA of these rhodolith-forming specimens revealed that some belong to an unnamed species of Sporolithon (Sporolithales) that we herein newly describe. Additionally, comparative DNA sequence analyses of rhodolith collections from Ewing Bank and other hard banks offshore Louisiana were conducted to assess rhodolith diversity in these mesophotic communities. The results revealed new reports of taxa for the region, including new rhodolith-forming species of Roseolithon (Hapalidiales) to be described herein as well. Our new biodiversity findings will be compared with historical studies from the NW Gulf of Mexico.
Predictive Risk Factors at Admission and a “Burning Point” During Hospitalization Serve as Sequential Alerts for Critical Illness in Patients With COVID-19
Authors: Yin Zhengrong , Zhou Mei , Xu Juanjuan , Wang Kai , Hao Xingjie , Tan Xueyun , Li Hui , Wang Fen , Dai Chengguqiu , Ma Guanzhou , Wang Zhihui , Duan Limin , Jin Yang
Published: July 2022

Background

We intended to establish a novel critical illness prediction system combining baseline risk factors with dynamic laboratory tests for patients with coronavirus disease 2019 (COVID-19).

Methods

We evaluated patients with COVID-19 admitted to Wuhan West Union Hospital between 12 January and 25 February 2020. The data of patients were collected, and the illness severity was assessed.

Results

Among 1,150 enrolled patients, 296 (25.7%) patients developed into critical illness. A baseline nomogram model consists of seven variables including age [odds ratio (OR), 1.028; 95% confidence interval (CI), 1.004–1.052], sequential organ failure assessment (SOFA) score (OR, 4.367; 95% CI, 3.230–5.903), neutrophil-to-lymphocyte ratio (NLR; OR, 1.094; 95% CI, 1.024–1.168), D-dimer (OR, 1.476; 95% CI, 1.107–1.968), lactate dehydrogenase (LDH; OR, 1.004; 95% CI, 1.001–1.006), international normalised ratio (INR; OR, 1.027; 95% CI, 0.999–1.055), and pneumonia area interpreted from computed tomography (CT) images (medium vs. small [OR, 4.358; 95% CI, 2.188–8.678], and large vs. small [OR, 9.567; 95% CI, 3.982–22.986]) were established to predict the risk for critical illness at admission. The differentiating power of this nomogram scoring system was perfect with an area under the curve (AUC) of 0.960 (95% CI, 0.941–0.972) in the training set and an AUC of 0.958 (95% CI, 0.936–0.980) in the testing set. In addition, a linear mixed model (LMM) based on dynamic change of seven variables consisting of SOFA score (value, 2; increase per day [I/d], +0.49), NLR (value, 10.61; I/d, +2.07), C-reactive protein (CRP; value, 46.9 mg/L; I/d, +4.95), glucose (value, 7.83 mmol/L; I/d, +0.2), D-dimer (value, 6.08 μg/L; I/d, +0.28), LDH (value, 461 U/L; I/d, +13.95), and blood urea nitrogen (BUN value, 6.51 mmol/L; I/d, +0.55) were established to assist in predicting occurrence time of critical illness onset during hospitalization.

Conclusion

The two-checkpoint system could assist in accurately and dynamically predicting critical illness and timely adjusting the treatment regimen for patients with COVID-19.
Varying Clinical Phenotypes of Mitochondrial DNA T12811C Mutation: A Case Series Report
Authors: Xu Qingdan , Sun Ping , Feng Chaoyi , Chen Qian , Sun Xinghuai , Chen Yuhong , Tian Guohong
Published: July 2022

The T12811C mitochondrial DNA (mtDNA) mutation has been reported in Leber hereditary optic neuropathy (LHON) previously, with vision loss as the main manifestation. The involvement of other organ systems, including the central and peripheral nervous system, heart, and extraocular muscles, has not been well described. This case series report investigated four patients with T12811C mtDNA mutation, verified through a next generation sequencing. Two male patients presented with bilateral subacute visual decrease combined with involvement of multiple organ systems: leukoencephalopathy, hypertrophic cardiomyopathy, neurosensory deafness, spinal cord lesion and peripheral neuropathies. Two female patients presented with progressive ptosis and ophthalmoplegia, one of whom also manifested optic atrophy. This study found out that patients harboring T12811C mtDNA mutation manifested not only as vision loss, but also as a multi-system disorder affecting the nervous system, heart, and extraocular muscles.
Correlation Analysis of the Bacterial Community and Wood Properties of Populus × euramericana cv. “74/76” Wet Heartwood
Authors: Fan Jianmin , Wang Shijie , Ding Changjun , Ma Changming , Chen Xinghao , Wang Jinmao , Yang Minsheng , Su Xiaohua
Published: July 2022

Wetwood disease of poplar limits the processing and manufacturing of poplar, and the pathogenic bacteria of wet heartwood are poorly known. We used high-throughput sequencing methods to analyze the bacterial community of the heartwood, sapwood, root tissue, and rhizosphere soil of Populus × euramericana cv. “74/76” (poplar 107) in wetwood trees and healthy trees to explore the cause of poplar wetwood disease. Bacterial diversity and community structure were analyzed, and the correlation between wood properties and bacterial relative abundance was analyzed to explore their relationship. Two alpha-diversity indices of endophytic bacteria in the heartwood of wetwood trees were significantly (p < 0.05) lower than that in the heartwood of healthy trees, and the community structure between the two types of trees was significantly different. No significant differences in the alpha-diversity indices nor community structure were observed in the sapwood, root tissue, or rhizosphere bacterial community of diseased and healthy trees. The distribution of dominant bacteria genus in the heartwood of diseased and healthy trees differed. Proteiniphilum, Actinotalea, and Methanobacterium were the dominant genera in diseased trees’ heartwood. Proteiniphilum, Dysgonomonas, and Bacteroides were the dominant genera in healthy trees’ heartwood. The relative abundance of Proteiniphilum, Actinotalea, and Methanobacterium was significantly higher in the heartwood of wetwood trees than those of healthy trees. A db-RDA analysis found that these three bacterial genera were positively correlated with the rate of wet heartwood. These three bacterial genera may be the main pathogens causing poplar wetwood disease.
Tryptophan Supplementation Enhances Intestinal Health by Improving Gut Barrier Function, Alleviating Inflammation, and Modulating Intestinal Microbiome in Lipopolysaccharide-Challenged Piglets
Authors: Liu Guangmang , Lu Jiajia , Sun Weixiao , Jia Gang , Zhao Hua , Chen Xiaoling , Kim In Ho , Zhang Ruinan , Wang Jing
Published: July 2022

Tryptophan (Trp) can modify the gut microbiota. However, there is no information about the effect of Trp on intestinal microbiota after lipopolysaccharide (LPS) challenge. This study aimed to investigate the effect of Trp on intestinal barrier function, inflammation, antioxidant status, and microbiota in LPS-challenged piglets. A total of 18 weaned castrated piglets were randomly divided into three treatments with 6 replicate per treatment, namely, (i) non-challenged control (CON); (ii) LPS-challenged control (LPS-CON); and (iii) LPS + 0.2% Trp (LPS-Trp). After feeding with control or 0.2% tryptophan-supplemented diets for 35 days, pigs were intraperitoneally injected with LPS (100 μg/kg body weight) or saline. At 4 h post-challenge, all pigs were slaughtered, and colonic samples were collected. The samples were analyzed for gut microbiota, fatty acids, antioxidant parameters, and the expression of mRNA and protein. The community bar chart showed that Trp supplementation to LPS-challenged pigs increased the relative abundance of Anaerostipes (P < 0.05) and tended to increase the relative abundance of V9D2013_group (P = 0.09), while decreased the relative abundance of Corynebacterium (P < 0.05) and unclassified_c__Bacteroidia (P < 0.01). Gas chromatography showed that Trp increased the concentrations of acetate, propionate, butyrate, and isovalerate in the colonic digesta (P < 0.05). Trp reduced the mRNA level of pro-inflammatory cytokines (P < 0.01), and increased mRNA level of aryl hydrocarbon receptor, cytochrome P450 (CYP) 1A1 and CYP1B1 (P < 0.05). Correlation analysis results showed that acetate, propionate, and butyrate concentrations were positively correlated with mRNA level of occludin and CYP1B1 (P < 0.05), and were negatively correlated with pro-inflammatory cytokines gene expression (P < 0.05). Isovalerate concentration was positively correlated with catalase activity (P < 0.05), and was negatively correlated with pro-inflammatory cytokines gene expression (P < 0.05). Furthermore, Trp enhanced the antioxidant activities (P < 0.01), and increased mRNA and protein expressions of claudin-1, occludin, and zonula occludens-1 (P < 0.01) after LPS challenge. These results suggest that Trp enhanced intestinal health by a modulated intestinal microbiota composition, improved the short chain fatty acids synthesis, reduced inflammation, increased antioxidant capacity, and improved intestinal barrier function.
Targeting DNA-Protein Crosslinks via Post-Translational Modifications
Authors: Leng Xueyuan , Duxin Julien P.
Published: July 2022

Covalent binding of proteins to DNA forms DNA-protein crosslinks (DPCs), which represent cytotoxic DNA lesions that interfere with essential processes such as DNA replication and transcription. Cells possess different enzymatic activities to counteract DPCs. These include enzymes that degrade the adducted proteins, resolve the crosslinks, or incise the DNA to remove the crosslinked proteins. An important question is how DPCs are sensed and targeted for removal via the most suited pathway. Recent advances have shown the inherent role of DNA replication in triggering DPC removal by proteolysis. However, DPCs are also efficiently sensed and removed in the absence of DNA replication. In either scenario, post-translational modifications (PTMs) on DPCs play essential and versatile roles in orchestrating the repair routes. In this review, we summarize the current knowledge of the mechanisms that trigger DPC removal via PTMs, focusing on ubiquitylation, small ubiquitin-related modifier (SUMO) conjugation (SUMOylation), and poly (ADP-ribosyl)ation (PARylation). We also briefly discuss the current knowledge gaps and emerging hypotheses in the field.
Ellagic Acid: A Dietary-Derived Phenolic Compound for Drug Discovery in Mild Cognitive Impairment
Authors: Wang Wenjun , Wang Shaohui , Liu Yue , Wang Xiaobo , Nie Jia , Meng Xianli , Zhang Yi
Published: July 2022

Ellagic acid (EA), a naturally occurring polyphenolic compound, is detected in free form or linked to polyols or sugars, constituting hydrolyzable tannins or ellagitannins in distinct fruits, nuts, and herbs. Today, a considerable number of botanicals and enriched foods containing EA are commercially available as nutraceuticals and used to prevent mild cognitive impairment (MCI) due to the excellent neuroprotective capacity of EA. Here, this study aims to provide an overview of the physicochemical properties, source, and pharmacokinetics of EA and to emphasize the importance and mechanisms of EA in the prevention and management of MCI. To date, preclinical studies of EA and its derivatives in various cell lines and animal models have advanced the idea of dietary EA as a feasible agent capable of specifically targeting and improving MCI. The molecular mechanisms of EA and its derivatives to prevent or reduce MCI are mainly through reducing neuroinflammation, oxidative stress, neuronal apoptosis, synaptic dysfunction and loss, and defective mitochondrial functions. Nevertheless, well-designed and correctly large randomized controlled trials in the human population need to be performed to reinforce the scientific facticity of the beneficial effects of EA against MCI. Synchronously, the mechanism of EA against MCI is least provided cynosure and expects more attention from the emerging research community.
Trait Anxiety Does Not Predict the Anxiogenic Response to Sleep Deprivation
Authors: Sundelin Tina , Holding Benjamin C.
Published: July 2022

Sleep deprivation has in several studies been found to increase anxiety. However, the extent to which this anxiogenic effect depends on one’s underlying trait anxiety has not previously been determined. Using two separate sleep-loss experiments, the current research investigated whether trait anxiety (STAI-T) moderates the increase in state anxiety (STAI-S) following one night of total sleep loss (study 1, N = 182, age 25.3 ± 6.5, 103 women) and two nights of partial sleep restriction (study 2, N = 67, age 26.5 ± 7.4, 38 women). Both studies showed the expected anxiogenic effect of sleep loss, and a clear relationship between trait anxiety and state anxiety. However, the anxiogenic effect of sleep loss was not moderated by trait anxiety, as there was an equal impact regardless of trait anxiety level. These findings indicate that, although sleep loss is related to general anxiety as well as anxiety disorders, for a non-clinical sample the anxiogenic effect of short-term sleep loss is not affected by baseline levels of anxiety.
Delta-Catenin as a Modulator of Rho GTPases in Neurons
Authors: Donta Maxsam S. , Srivastava Yogesh , McCrea Pierre D.
Published: July 2022

Small Rho GTPases are molecular switches that are involved in multiple processes including regulation of the actin cytoskeleton. These GTPases are activated (turned on) and inactivated (turned off) through various upstream effector molecules to carry out many cellular functions. One such upstream modulator of small Rho GTPase activity is delta-catenin, which is a protein in the p120-catenin subfamily that is enriched in the central nervous system. Delta-catenin affects small GTPase activity to assist in the developmental formation of dendrites and dendritic spines and to maintain them once they mature. As the dendritic arbor and spine density are crucial for synapse formation and plasticity, delta-catenin’s ability to modulate small Rho GTPases is necessary for proper learning and memory. Accordingly, the misregulation of delta-catenin and small Rho GTPases has been implicated in several neurological and non-neurological pathologies. While links between delta-catenin and small Rho GTPases have yet to be studied in many contexts, known associations include some cancers, Alzheimer’s disease (AD), Cri-du-chat syndrome, and autism spectrum disorder (ASD). Drawing from established studies and recent discoveries, this review explores how delta-catenin modulates small Rho GTPase activity. Future studies will likely elucidate how PDZ proteins that bind delta-catenin further influence small Rho GTPases, how delta-catenin may affect small GTPase activity at adherens junctions when bound to N-cadherin, mechanisms behind delta-catenin’s ability to modulate Rac1 and Cdc42, and delta-catenin’s ability to modulate small Rho GTPases in the context of diseases, such as cancer and AD.
Nutritional and Metabolic Factors, Ethanol and Cholesterol, Interact With Calcium-Dependent N-Methyl-D-Aspartate Receptor Inhibition by Tricyclic Antidepressants
Authors: Boikov Sergei I. , Sibarov Dmitry A. , Antonov Sergei M.
Published: July 2022

It is known that overexpression of N-methyl-D-aspartate receptors (NMDARs) contributes to central sensitization and development of neuropathic pain. Tricyclic antidepressants (TCAs), amitriptyline (ATL), and desipramine (DES) exhibit analgetic anti-NMDAR activity and are commonly utilized for pain therapy. This property is determined by their ability to enhance the calcium-dependent desensitization (CDD) of NMDARs. Coincidently ethanol and cholesterol, the ubiquitous food supplements, also modulate NMDAR CDD. The convergence of the effects of these compounds on a similar calcium-dependent process allows to assume their interaction on NMDARs. Since there is no information on whether ethanol supplementation and cholesterol deficit interfere with TCA inhibition of NMDARs at a cellular level, here we investigated this issue. Whole-cell NMDA-activated currents were recorded in rat cortical neurons of primary cultures to study how the IC50 values for TCA inhibition of NMDARs are influenced by ethanol and cholesterol extraction from the plasma membrane with methyl-β-cyclodextrin. Ethanol at 0.03% did not reliably affect the steady-state NMDA-activated currents. At this threshold concentration ethanol, however, increased IC50s for ATL and DES abolishing their calcium-dependent inhibition of NMDARs but did not change IC50 for clomipramine (CLO), which is calcium-independent. Whereas the ethanol effects on ATL-induced NMDAR inhibition reached a maximum at 2 mM external [Ca2+], for DES the maximum was achieved already at 1 mM external [Ca2+], that correlates with the manifestation of the calcium-dependent inhibition of NMDARs by these agents. Cholesterol depletion also increased IC50s for both ATL and DES abolishing the calcium-dependent inhibition of NMDARs. The restitution of cholesterol in the plasma membrane reversed the ATL IC50 back to the low values, by a restoration of calcium-dependence of ATL. These observations are consistent with the explanation that either 0.03% ethanol or cholesterol extraction may interrupt some intermediate step of CDD transduction or augment NMDAR CDD to the maximal level so that ATL and DES could not further enhance CDD. It is likely that anti-NMDAR action of ATL and DES against neuropathic pain could demonstrate peculiarities in therapeutic profiles during cholesterol decline in aging or medical treatments and ethanol supplementations even in quantities that are insufficient to cause the symptoms of intoxication.
Circulating Pro-inflammatory Cytokines Do Not Explain Interindividual Variability in Visceral Sensitivity in Healthy Individuals
Authors: Pawlik Robert J. , Petrakova Liubov , Brotte Lisa , Engler Harald , Benson Sven , Elsenbruch Sigrid
Published: July 2022

A role of the immune system in the pathophysiology of pain and hyperalgesia has received growing attention, especially in the context of visceral pain and the gut-brain axis. While acute experimental inflammation can induce visceral hyperalgesia as part of sickness behavior in healthy individuals, it remains unclear if normal plasma levels of circulating pro-inflammatory cytokines contribute to interindividual variability in visceral sensitivity. We herein compiled data from a tightly screened and well-characterized sample of healthy volunteers (N = 98) allowing us to assess associations between visceral sensitivity and gastrointestinal symptoms, and plasma concentrations of three selected pro-inflammatory cytokines (i.e., TNF-α, IL-6, and IL-8), along with cortisol and stress-related psychological variables. For analyses, we compared subgroups created to have distinct pro-inflammatory cytokine profiles, modelling healthy individuals at putative risk or resilience, respectively, for symptoms of the gut-brain axis, and compared them with respect to rectal sensory and pain thresholds and subclinical GI symptoms. Secondly, we computed multiple regression analyses to test if circulating pro-inflammatory markers predict visceral sensitivity in the whole sample. Despite pronounced subgroup differences in pro-inflammatory cytokine and cortisol concentrations, we observed no differences in measures of visceroception. In regression analyses, cytokines did not emerge as predictors. The pain threshold was predicted by emotional state and trait variables, especially state anxiety, together explaining 10.9% of the variance. These negative results do not support the hypothesis that systemic cytokine levels contribute to normal interindividual variability in visceroception in healthy individuals. Trajectories to visceral hyperalgesia as key marker in disorders of gut-brain interactions likely involve complex interactions of biological and psychological factors in keeping with a psychosocial model. Normal variations in systemic cytokines do not appear to constitute a vulnerability factor in otherwise healthy individuals, calling for prospective studies in at risk populations.
A Convolutional Neural Network Model for Detecting Sellar Floor Destruction of Pituitary Adenoma on Magnetic Resonance Imaging Scans
Authors: Feng Tianshun , Fang Yi , Pei Zhijie , Li Ziqi , Chen Hongjie , Hou Pengwei , Wei Liangfeng , Wang Renzhi , Wang Shousen
Published: July 2022

Objective

Convolutional neural network (CNN) is designed for image classification and recognition with a multi-layer neural network. This study aimed to accurately assess sellar floor invasion (SFI) of pituitary adenoma (PA) using CNN.

Methods

A total of 1413 coronal and sagittal magnetic resonance images were collected from 695 patients with PAs. The enrolled images were divided into the invasive group (n = 530) and the non-invasive group (n = 883) according to the surgical observation of SFI. Before model training, 100 images were randomly selected for the external testing set. The remaining 1313 cases were randomly divided into the training and validation sets at a ratio of 80:20 for model training. Finally, the testing set was imported to evaluate the model performance.

Results

A CNN model with a 10-layer structure (6-layer convolution and 4-layer fully connected neural network) was constructed. After 1000 epoch of training, the model achieved high accuracy in identifying SFI (97.0 and 94.6% in the training and testing sets, respectively). The testing set presented excellent performance, with a model prediction accuracy of 96%, a sensitivity of 0.964, a specificity of 0.958, and an area under the receptor operator curve (AUC-ROC) value of 0.98. Four images in the testing set were misdiagnosed. Three images were misread with SFI (one with conchal type sphenoid sinus), and one image with a relatively intact sellar floor was not identified with SFI.

Conclusion

This study highlights the potential of the CNN model for the efficient assessment of PA invasion.
Brain Amyloid Index as a Probable Marker Bridging Between Subjective Memory Complaint and Objective Cognitive Performance
Authors: Choe Young Min , Suh Guk-Hee , Lee Boung Chul , Choi Ihn-Geun , Lee Jun Ho , Kim Hyun Soo , Hwang Jaeuk , Kim Jee Wook
Published: July 2022

Background

The association between types of subjective memory complaint (SMC), poor objective cognitive performance, and brain Aβ deposition have been poorly understood. We investigated the association between types of SMC and objective global cognitive performance, then assessed whether this association is mediated by the brain amyloid prediction index (API).

Methods

In total, 173 non-demented older adults [63 cognitively normal (CN) and 110 mild cognitive impairment (MCI)] underwent comprehensive clinical assessments. Objective global cognitive performance and brain amyloid index were measured using the total score (TS) of the Consortium to Establish a Registry for Alzheimer’s Disease neuropsychological battery and API, respectively. In total, four items of SMC from the subjective memory complaints questionnaire (SMCQ) (SMCQ1: a feeling of memory problem; SMCQ2: the feeling of worse memory than 10 years ago; SMCQ3: the feeling of worse memory than others of similar age; or SMCQ4: the feeling of difficulty in everyday life) in global memory function were assessed.

Results

In non-demented and participants with MCI, SMCQ3-positive and SMCQ4-positive groups were associated with decreased TS. In participants with MCI, the SMCQ3-positive group was associated with increased API, and API was associated with decreased TS, but the SMCQ4-positive group did not. In addition, the association between the SMCQ3-positive group and poor TS disappeared when API was controlled as a covariate, indicating that API has a mediation effect.

Conclusion

The present findings suggest that SMC, a feeling of worse memory performance than others in a similar age group, in the older adults without dementia is associated with poor objective cognitive performanceviaincreased brain amyloid index.
Research on the Mechanism of Cognitive Decline in Patients With Acoustic Neuroma
Authors: Deng Xueyun , Liu Lizhen , Luo Jun , Liu Lihua , Hui Xuhui , Feng Hua
Published: July 2022

Little is known about neuropsychological research on patients with acoustic neuroma (AN), especially cognitive neuropsychology. We aim to compare the cognitive function of patients with AN and healthy controls (HCs) and explore possible underlying mechanisms. Various neuropsychological assessments were performed on all participants. Tract-based spatial statistics (TBSS) was used to compare DTI metrics such as fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD), and mean diffusivity (MD). Correlation analysis was analyzed between DTI metrics and cognitive scales. Compared with the HC group, the AN group performed worse in the neuropsychological evaluations, and TBSS analysis showed widespread alteration of the FA, AD, RD, and MD, which correlated with the cognitive function. These white matter tracts include minor forceps, major forceps, anterior thalamic radiation, superior longitudinal fasciculus, corticospinal tract, and right inferior fronto-occipital fasciculus. Meanwhile, we found for the first time that cognitive decline was related to the decrease of FA in minor forceps, which can be used as a neurobiological marker of cognitive impairment in patients with AN. The occurrence of cognition impairment is common in patients with AN. Including neuropsychological evaluation in the routine clinical assessment and appropriate treatment may strengthen clinical management and improve the quality of life of patients.
Highly Parallelized, Multicolor Optogenetic Recordings of Cellular Activity for Therapeutic Discovery Applications in Ion Channels and Disease-Associated Excitable Cells
Authors: Borja Gabriel B. , Zhang Hongkang , Harwood Benjamin N. , Jacques Jane , Grooms Jennifer , Chantre Romina O. , Zhang Dawei , Barnett Adam , Werley Christopher A. , Lu Yang , Nagle Steven F. , McManus Owen B. , Dempsey Graham T.
Published: July 2022

Optogenetic assays provide a flexible, scalable, and information rich approach to probe compound effects for ion channel drug targets in both heterologous expression systems and associated disease relevant cell types. Despite the potential utility and growing adoption of optogenetics, there remains a critical need for compatible platform technologies with the speed, sensitivity, and throughput to enable their application to broader drug screening applications. To address this challenge, we developed the SwarmTM, a custom designed optical instrument for highly parallelized, multicolor measurements in excitable cells, simultaneously recording changes in voltage and calcium activities at high temporal resolution under optical stimulation. The compact design featuring high power LEDs, large numerical aperture optics, and fast photodiode detection enables all-optical individual well readout of 24-wells simultaneously from multi-well plates while maintaining sufficient temporal resolution to probe millisecond response dynamics. The Swarm delivers variable intensity blue-light optogenetic stimulation to enable membrane depolarization and red or lime-light excitation to enable fluorescence detection of the resulting changes in membrane potential or calcium levels, respectively. The Swarm can screen ~10,000 wells/day in 384-well format, probing complex pharmacological interactions via a wide array of stimulation protocols. To evaluate the Swarm screening system, we optimized a series of heterologous optogenetic spiking HEK293 cell assays for several voltage-gated sodium channel subtypes including Nav1.2, Nav1.5, and Nav1.7. The Swarm was able to record pseudo-action potentials stably across all 24 objectives and provided pharmacological characterization of diverse sodium channel blockers. We performed a Nav1.7 screen of 200,000 small molecules in a 384-well plate format with all 560 plates reaching a Z′ > 0.5. As a demonstration of the versatility of the Swarm, we also developed an assay measuring cardiac action potential and calcium waveform properties simultaneously under paced conditions using human induced pluripotent stem (iPS) cell-derived cardiomyocytes as an additional counter screen for cardiac toxicity. In summary, the Swarm is a novel high-throughput all-optical system capable of collecting information-dense data from optogenetic assays in both heterologous and iPS cell-derived models, which can be leveraged to drive diverse therapeutic discovery programs for nervous system disorders and other disease areas involving excitable cells.
The Antidepressant Effect of Deoiled Sunflower Seeds on Chronic Unpredictable Mild Stress in Mice Through Regulation of Microbiota–Gut–Brain Axis
Authors: Lu Xiaomeng , Qi Ce , Zheng Jie , Sun Mei , Jin Long , Sun Jin
Published: July 2022

Objectives

Sunflower seeds provide tryptophan-rich proteins with the potential to protect against depression. Tryptophan is a precursor of serotonin and a substrate for the production of indole derivatives by gut microbiota. This study aimed to investigate the association between the depression-alleviating effects of deoiled and dechlorogenic sunflower seeds (DSFS) and regulation of gut microbiota.

Materials and Methods

Male C57BL/6J mice were fed a diet comprising a source of soy protein (normal and model control), DSFS or whey protein concentrate (positive control) for 7 weeks, and chronic stress-induced depression was induced.

Results

Feeding the DSFS diet prevented depression-like behaviors, intestinal barrier damage, elevated plasma corticosterone, and reduced hippocampal serotonin levels in mice. Meanwhile, Feeding the DSFS diet significantly altered the gut microbiota structure, characterized by elevated relative abundances ofIleibacterium valens,Ruminococcus flavefaciens,Clostridium scindens, andOlsenella massiliensis, which were inversely associated with depressive behaviors and markers of mucosal barrier damage. DSFS also altered the gut metabolite profile, prevented depression-induced gutL-tryptophan depletion, and upregulated its metabolite indoleacetaldehyde.

Conclusion

Feeding the DSFS diet prevented depression in mice by remodeling the gut microbiota and bacterial tryptophan metabolism.
Real-World Effectiveness of Palbociclib Plus Letrozole vs Letrozole Alone for Metastatic Breast Cancer With Lung or Liver Metastases: Flatiron Database Analysis
Authors: Brufsky Adam , Liu Xianchen , Li Benjamin , McRoy Lynn , Layman Rachel M.
Published: July 2022

Background

Cyclin-dependent kinase 4/6 inhibitors are a standard treatment for patients with hormone receptor−positive (HR+)/human epidermal growth factor receptor 2−negative (HER2−) metastatic breast cancer (MBC). However, real-world data on effectiveness in patients with liver or lung metastatic disease is limited. This study compared outcomes of palbociclib plus letrozole versus letrozole alone in patients with HR+/HER2− MBC with lung or liver metastasis treated in routine clinical practice in the United States.

Methods

This retrospective analysis used Flatiron Health’s database of electronic health records. Women with HR+/HER2− MBC and liver or lung metastasis received first-line palbociclib plus letrozole or letrozole alone between February 2015 and February 2019. Real-world progression-free survival (rwPFS) was defined as time from start of treatment to death or disease progression. Stabilized inverse probability treatment weighting (sIPTW) was used to balance baseline demographic and clinical characteristics between palbociclib plus letrozole versus letrozole cohorts. Cox proportional-hazards models were used to estimate the effectiveness of palbociclib plus letrozole versus letrozole alone in rwPFS and overall survival (OS).

Results

The study included 353 patients with lung metastasis, 123 with liver metastasis, and 75 with both. After sIPTW, palbociclib plus letrozole versus letrozole alone was significantlly associated with prolonged rwPFS (hazard ratio (HR), 0.56) and OS (HR, 0.58) (both p<0.001) in all patients. Palbociclib plus letrozole compared with letrozole alone demonstrated a median rwPFS of 16.5 versus 10.5 months, respectively (adjusted HR, 0.52; P<0.001), a median OS of not reached versus 40.3 months (adjusted HR, 0.60; P<0.01) in patients with lung metastasis, and median OS of 30.1 versus 16.8 months (adjusted HR, 0.56; P<0.03 in patients with liver metastasis. In patients with liver metastasis, palbociclib plus letrozole had a median rwPFS of 10.7 months versus 8.0 months in the letrozole alone cohort (adjusted HR, 0.70; P=0.12).

Conclusions

In this real-world population, palbociclib in combination with letrozole is associated with improved outcomes compared with letrozole alone for patients with HR+/HER2− MBC and liver or lung metastasis in the first-line setting. The findings support first-line palbociclib in combination with an aromatase inhibitor as standard of care for HR+/HER2− MBC regardless of visceral disease.

Clinical Trial Registration

NCT04176354.
Association Between Cardiac Radiation Exposure and the Risk of Arrhythmia in Breast Cancer Patients Treated With Radiotherapy: A Case–Control Study
Authors: Errahmani Mohamed Yassir , Locquet Médéa , Spoor Daan , Jimenez Gaelle , Camilleri Jérémy , Bernier Marie-Odile , Broggio David , Monceau Virginie , Ferrières Jean , Thariat Juliette , Boveda Serge , Kirova Youlia , Loap Pierre , Langendijk Johannes A. , Crijns Anne , Jacob Sophie
Published: July 2022

Background

Previous studies suggested that radiation therapy (RT) for breast cancer (BC) can induce cardiac arrhythmias and conduction disorders. However, the association with mean heart dose and specific cardiac substructures doses was less studied.

Materials and Methods

We conducted a nested case–control study based on French BC patients, enrolled in the European MEDIRAD-BRACE study (https://clinicaltrials.gov, Identifier: NCT03211442), who underwent three-dimensional conformal radiation therapy (3D-CRT) between 2009 and 2013 and were retrospectively followed until 2019. Cases were incident cases of cardiac arrhythmia. Controls without arrhythmia were selected with propensity-scored matching by age, duration of follow-up, chemotherapy, hypertension, and diabetes (ratio 1:4 or 5). Doses to the whole heart (WH), left and right atria (LA and RA), and left and right ventricles (LV and RV) were obtained after delineation with multi-atlas-based automatic segmentation.

Results

The study included 116 patients (21 cases and 95 controls). Mean age at RT was 64 ± 10 years, mean follow-up was 7.0 ± 1.3 years, and mean interval from RT to arrhythmia was 4.3 ± 2.1 years. None of the results on association between arrhythmia and cardiac doses reached statistical significance. However, the proportion of right-sided BC was higher among patients with arrhythmia than among controls (57% vs. 51%, OR = 1.18, p = 0.73). Neither mean WH dose, nor LV, RV, and LA doses were associated with an increased risk of arrhythmia (OR = 1.00, p > 0.90). In contrast, the RA dose was slightly higher for cases compared to controls [interquartile range (0.61–1.46 Gy) vs. (0.49–1.31 Gy), p = 0.44], and a non-significant trend toward a potentially higher risk of arrhythmia with increasing RA dose was observed (OR = 1.19, p = 0.60). Subanalysis according to BC laterality showed that the association with RA dose was reinforced specifically for left-sided BC (OR = 1.76, p = 0.75), while for right-sided BC, the ratio of mean RA/WH doses may better predict arrhythmia (OR = 2.39, p = 0.35).

Conclusion

Despite non-significant results, our exploratory investigation on BC patients treated with RT is the first study to suggest that right-sided BC patients and the right atrium irradiation may require special attention regarding the risk of cardiac arrhythmia and conduction disorders. Further studies are needed to expand on this topic.
Elevated Small Nuclear Ribonucleoprotein Polypeptide an Expression Correlated With Poor Prognosis and Immune Infiltrates in Patients With Hepatocellular Carcinoma
Authors: Zhang Youfu , Wang Xuyang , Wang Huaxiang , Jiang Yi , Xu Zhidan , Luo Laibang
Published: July 2022

Background

Elevated Small Nuclear Ribonucleoprotein Polypeptide A (SNRPA) can enhance tumor cell growth and proliferation in various cancers. However, rarely studies focus on the comprehensive analysis of SNRPA in hepatocellular carcinoma (HCC).

Methods

TCGA and GEO databases were used to analyze the mRNA expression of SNRPA in HCC. Protein expression of SNAPA was validated using immunohistochemistry. Stably transfected HCC cells were used to investigate the role of SNRPA in the progression of HCC. The functional enrichment analysis was utilized for the biological function prediction. The CIBERSORT and ssGSEA algorithms were used to evaluate the composition of the tumor microenvironment and immunocyte infiltration ratio.

Results

The SNRPA expression was upregulated in HCC and positively correlated with tumor stage and grade. SNRPA overexpression were independent risk factors for poor overall survival (OS) and recurrence-free survival (RFS). In patients with early-stage disease, low alpha-fetoprotein expression, and better differentiation, SNRPA still exhibited the excellent prognostic value. Knockdown of SNRPA inhibited the proliferation and migration while promoting the apoptosis of HCC cells. Higher methylation of the CpG site cg16596691 correlated with longer OS in HCC patients. Genes co-expressed with SNRPA were overexpressed in HCC and correlated with shorter OS. The GO and KEGG enrichment analysis showed that SNRPA expression was related to mRNA splicing, spliceosome signaling. GSEA demonstrated that the main enrichment pathway of SNRPA-related differential genes was spliceosome signaling, cell cycle signaling, P53 signaling pathway, T cell receptor signaling pathway, natural killer cell-mediated signaling. CIBERSORT and ssGSEA algorithm revealed that SNRPA was mainly associated with the higher proportion of CD8+T cells, T cells follicular helper, T cells regulatory, Macrophages M0, and the lower proportion of T cells CD4 memory resting, NK cells resting, Monocytes, and Mast cells resting.

Conclusion

Elevated SNRPA enhances tumor cell proliferation and correlated with poor prognosis and immune infiltrates in patients with HCC.
CD49b Targeting Inhibits Tumor Growth and Boosts Anti-tumor Immunity
Authors: Contreras-Kallens Pamina , Gálvez-Jirón Felipe , De Solminihac Javiera , Elhusseiny Ahmed , González-Arriagada Wilfredo A. , Alcayaga-Miranda Francisca , Noelle Randolph J. , Pino-Lagos Karina
Published: July 2022

The suppressive function of T-regulatory cells (Tregs) can have a detrimental effect on immune responses against tumor cells. Within the Treg cells subset, a new non-classical population has been reported, which expresses high levels of CD49b molecule and, depending on their activation status, can also express the canonical Tregs transcription factor Foxp3. In this report, we sought to characterize Tregs subsets in a murine melanoma model and disrupt the CD49b/CD29 axis by administering an anti-CD29 antibody in tumor-bearing mice. Our data shows that whereas in the draining lymph nodes, the Tr1 cells subset composes <5% of CD4+ T cells, in the tumor, they reach ∼30% of CD4+ T cells. Furthermore, Tr1 cells share the expression of suppressive molecules, such as Nrp-1, PD-1, and CD73, which are highly expressed on Tr1 cells found in tumor-infiltrating leukocytes (TILs). Regardless of the phenotypic similarities with cTreg cells, Tr1 cells display a low proliferative activity, as shown in the kinetics and the incorporation of 5-bromodeoxyuridine (BrdU) experiments. With the intent to impact on Tr1 cells, we administered anti-CD29 antibody into tumor mice, observing that the treatment effectively inhibits tumor growth. This effect is at least mediated by the enrichment of pro-inflammatory T cells, including IFN-γ+ cTreg and IFN-γ+ Tr1 cells (with reduced expression of IL-10), plus Th1 and Tc cells. In this study, we present Tr1 cell characterization in tumor-bearing animals and introduce CD29 as a target for tumor therapy, supported by a meta-analysis indicating that CD29 is present in human biopsies.
Virofree, an Herbal Medicine-Based Formula, Interrupts the Viral Infection of Delta and Omicron Variants of SARS-CoV-2
Authors: Doan Ly Hien , Chu Li-Wei , Huang Zi-Yi , Nguyen Anh Thuc , Lee Chia-Yin , Huang Chien-Ling , Chang Yu-Fen , Hsieh Wen-Yu , Nguyen Trang Thi Huyen , Lin Chao-Hsiung , Su Chun-Li , Chuang Tsung-Hsien , Lai Jin-Mei , Wang Feng-Sheng , Yang Chia-Jui , Liu Hui-Kang , Ping Yueh-Hsin , Huang Chi-Ying F.
Published: July 2022

Coronavirus disease 2019 (COVID-19) remains a threat with the emergence of new variants, especially Delta and Omicron, without specific effective therapeutic drugs. The infection causes dysregulation of the immune system with a cytokine storm that eventually leads to fatal acute respiratory distress syndrome (ARDS) and further irreversible pulmonary fibrosis. Therefore, the promising way to inhibit infection is to disrupt the binding and fusion between the viral spike and the host ACE2 receptor. A transcriptome-based drug screening platform has been developed for COVID-19 to explore the possibility and potential of the long-established drugs or herbal medicines to reverse the unique genetic signature of COVID-19. In silico analysis showed that Virofree, an herbal medicine, reversed the genetic signature of COVID-19 and ARDS. Biochemical validations showed that Virofree could disrupt the binding of wild-type and Delta-variant spike proteins to ACE2 and its syncytial formation via cell-based pseudo-typed viral assays, as well as suppress binding between several variant recombinant spikes to ACE2, especially Delta and Omicron. Additionally, Virofree elevated miR-148b-5p levels, inhibited the main protease of SARS-CoV-2 (Mpro), and reduced LPS-induced TNF-α release. Virofree also prevented cellular iron accumulation leading to ferroptosis which occurs in SARS-CoV-2 patients. Furthermore, Virofree was able to reduce pulmonary fibrosis-related protein expression levels in vitro. In conclusion, Virofree was repurposed as a potential herbal medicine to combat COVID-19. This study highlights the inhibitory effect of Virofree on the entry of Delta and Omicron variants of SARS-CoV-2, which have not had any effective treatments during the emergence of the new variants spreading.
Multi-Objective Drug Design Based on Graph-Fragment Molecular Representation and Deep Evolutionary Learning
Authors: Mukaidaisi Muhetaer , Vu Andrew , Grantham Karl , Tchagang Alain , Li Yifeng
Published: July 2022

Drug discovery is a challenging process with a huge molecular space to be explored and numerous pharmacological properties to be appropriately considered. Among various drug design protocols, fragment-based drug design is an effective way of constraining the search space and better utilizing biologically active compounds. Motivated by fragment-based drug search for a given protein target and the emergence of artificial intelligence (AI) approaches in this field, this work advances the field of in silico drug design by (1) integrating a graph fragmentation-based deep generative model with a deep evolutionary learning process for large-scale multi-objective molecular optimization, and (2) applying protein-ligand binding affinity scores together with other desired physicochemical properties as objectives. Our experiments show that the proposed method can generate novel molecules with improved property values and binding affinities.