bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of Agenesis of the Dorsal Pancreas With HNF1B Heterozygote Mutation: A Case Report
Authors: Guo Mei , Xu Qinqin , Yu Xuefeng , Yang Qin , Shao Shiying
Published: October 2021

Background

Agenesis of the dorsal pancreas (ADP) is a rare disease, the pathogenic mechanism of which is partially related to variants of hepatocyte nuclear factor 1B (HNF1B) gene.

Case Presentation

We report a case of ADP, which presented with acute ketoacidosis, hyperuricemia, and liver dysfunction. In this case, the HNF1B score was estimated as 16 and a heterozygous variant of HNF1B in exon 2 (c.513G>A-p.W171X) was identified through gene sequencing.

Conclusions

A good understanding of the clinical comorbidities of ADP is essential for avoiding missed diagnosis to a great extent. Moreover, estimation of HNF1B score is recommended before genetic testing.
Unraveling the Olfactory Biases of Male Euglossine Bees: Species-Specific Antennal Responses and Their Evolutionary Significance for Perfume Flowers
Authors: Brandt Katharina , Dötterl Stefan , Ramírez Santiago R. , Etl Florian , Machado Isabel Cristina , Navarro Daniela Maria do Amaral Ferraz , Dobler Daniel , Reiser Oliver , Ayasse Manfred , Milet-Pinheiro Paulo
Published: October 2021

Male euglossine bees exhibit unique adaptations for the acquisition and accumulation of chemical compounds from “perfume flowers” and other sources. During courtship display, male bees expose perfume mixtures, presumably to convey species-specific recognition and/or mate choice signals to females. Because olfaction regulates both signal production (in males) and signal detection (in females) in this communication system, strong selective pressures are expected to act on the olfactory system, which could lead to sensory specialization in favor of an increased sensitivity to specific chemical compounds. The floral scents of euglossine-pollinated plants are hypothesized to have evolved in response to the preexisting sensory biases of their male euglossine bee pollinators. However, this has never been investigated at the peripheral olfactory circuitry of distinct pollinating genera. Here, we present a comparative analysis using electroantennography (EAG) of males across the phylogeny of 29 euglossine bee species, among them Euglossa and Eulaema species. First, we tested whether antennal responses differ among different euglossine genera, subgenera and species. Secondly, we conducted a comparative phylogenetic analysis to investigate the macroevolutionary patterns of antennal responses across the euglossine bee phylogeny. We found that antennal response profiles are very unique on the species level and differ on the subgenus and the genus level. The differences can be explained by chemical compounds typically found in the floral scent bouquets of perfume flowers and specific compounds of species either pollinated by Euglossa (e.g., ipsdienol) or Eulaema bees (e.g., (−)-(E)-carvone epoxide). Also, we detected a phylogenetic signal in mean antennal responses and found that especially at the species level of our simulation the overall antennal responses exhibit greater disparity relative to a null model of pure Brownian-motion across the phylogeny. Altogether, our results suggest that (1) euglossine bee species exhibit species-specific antennal responses that differ among euglossine genera and subgenera, (2) antennal responses diverge early after speciation events, and (3) scent composition of perfume flowers evolved in response to pollinator-mediated selection imposed by preexisting sensory biases in euglossine bees.
Silver Linings at the Dawn of a “Golden Age”
Authors: Britton Kate , Crowley Brooke E. , Bataille Clément P. , Miller Joshua H. , Wooller Matthew J.
Published: October 2021

Nearly four decades after the first applications of strontium isotope analyses in archaeology and paleoecology research, it could be said that we are entering a “Golden Age”. Here, we reflect on major past developments and current strengths in strontium isotope research, as well as speculate on future directions. We review (1) the currently limited number of (but much needed) controlled feeding experiments, (2) recent advances in isoscape mapping and spatial assignment, and (3) the strength of multi-proxy approaches (including both the integration of strontium isotopes with other isotope systems and complementary techniques such as ancient DNA analyses). We also explore the integration of strontium isotope research with other types of paleoecological or archaeology data, as well as with evidence and interpretative frameworks from other fields (such as conservation ecology, conservation paleobiology or history). This blending is critical as we seek to advance the field beyond simply distinguishing local or relatively sedentary individuals from those that were non-local or highly mobile. We finish with a call for future research centered on balancing methodological developments and novel applications with critical self-reflection, deeper theoretical considerations and cross-disciplinarity.
PADI4 Polymorphisms Confer Risk of Anti-CCP-Positive Rheumatoid Arthritis in Synergy With HLA-DRB1*04 and Smoking
Authors: Massarenti Laura , Enevold Christian , Damgaard Dres , Ødum Niels , Garred Peter , Frisch Morten , Shelef Miriam A. , Jacobsen Søren , Nielsen Claus Henrik
Published: October 2021

Peptidylarginine deiminases (PADs) catalyze citrullination, a post-translational modification playing a pathogenic role in anti-citrullinated protein antibody (ACPA)-positive rheumatoid arthritis (RA). The interplay between single nucleotide polymorphisms (SNPs) in thePADIgenes and known risk factors for ACPA-positive RA, including smoking, HLA-DR4 and -1, and the PTPN22 R620W polymorphism, was investigated. We typed fourPADI2SNPs, fourPADI4SNPs, and the PTPN22 R620W SNP in 445 Danish RA patients and 533 age-matched healthy controls, as well as in 200 North American RA patients and 100 age- and sex-matched controls. TheHLA-DRB1locus was typed in the Danish cohort. Logistic regression analyses, adjusted for age, sex, smoking status, and PTPN22 R620W, revealed increased risk of anti-CCP-positive RA in carriers of rs11203367(T) (OR: 1.22, p=0.03) and reduced risk in carriers of rs2240335(A) inPADI4(OR: 0.82, p=0.04). rs74058715(T) inPADI4conferred reduced risk of anti-CCP-negative RA (OR: 0.38, p=0.003). InHLA-DRB1*04-positive individuals, specifically, the risk of anti-CCP-positive RA was increased by carriage ofPADI4rs1748033(T) (OR: 1.54, p=0.007) and decreased by carriage ofPADI4rs74058715(T) (OR: 0.44, p=0.01), and we observed an interaction between these SNPs andHLA-DRB1*04(p=0.004 and p=0.008, respectively) Thus,PADI4polymorphisms associate with ACPA-positive RA, particularly inHLA-DRB1*04-positive individuals, and with ACPA-negative RA independently ofHLA-DRB1*04.
DNA Vaccines Targeting Novel Cancer-Associated Antigens Frequently Expressed in Head and Neck Cancer Enhance the Efficacy of Checkpoint Inhibitor
Authors: Wang Chuan , Zainal Nur Syafinaz , Chai San Jiun , Dickie James , Gan Chai Phei , Zulaziz Natasha , Lye Bryan Kit Weng , Sutavani Ruhcha V. , Ottensmeier Christian H. , King Emma V. , Abraham Mannil Thomas , Ismail Siti Mazlipah binti , Lau Shin Hin , Kallarakkal Thomas George , Mun Kein Seong , Zain Rosnah binti , Abdul Rahman Zainal Ariff , Thomas Gareth J. , Cheong Sok Ching , Savelyeva Natalia , Lim Kue Peng
Published: October 2021

HPV-independent head and neck squamous cell carcinoma (HNSCC) is a common cancer globally. The overall response rate to anti-PD1 checkpoint inhibitors (CPIs) in HNSCC is ~16%. One major factor influencing the effectiveness of CPI is the level of tumor infiltrating T cells (TILs). Converting TILlow tumors to TILhigh tumors is thus critical to improve clinical outcome. Here we describe a novel DNA vaccines to facilitate the T-cell infiltration and control tumor growth. We evaluated the expression of target antigens and their respective immunogenicity in HNSCC patients. The efficacy of DNA vaccines targeting two novel antigens were evaluated with or without CPI using a syngeneic model. Most HNSCC patients (43/44) co-expressed MAGED4B and FJX1 and their respective tetramer-specific T cells were in the range of 0.06-0.12%. In a preclinical model, antigen-specific T cells were induced by DNA vaccines and increased T cell infiltration into the tumor, but not MDSC or regulatory T cells. The vaccines inhibited tumor growth and improved the outcome alone and upon combination with anti-PD1 and resulted in tumor clearance in approximately 75% of mice. Pre-existence of MAGED4B and FJX1-reactive T cells in HNSCC patients suggests that these widely expressed antigens are highly immunogenic and could be further expanded by vaccination. The DNA vaccines targeting these antigens induced robust T cell responses and with the anti-PD1 antibody conferring excellent tumor control. This opens up an opportunity for combination immunotherapy that might benefit a wider population of HNSCC patients in an antigen-specific manner.
Association Between Serum Osmolality and Acute Kidney Injury in Critically Ill Patients: A Retrospective Cohort Study
Authors: Yang Jie , Cheng Yisong , Wang Ruoran , Wang Bo
Published: October 2021

Purposes: Acute kidney injury (AKI) is a common complication in critically ill patients and is usually associated with poor outcomes. Serum osmolality has been validated in predicting critically ill patient mortality. However, data about the association between serum osmolality and AKI is still lacking in ICU. Therefore, the purpose of the present study was to investigate the association between early serum osmolality and the development of AKI in critically ill patients.

Methods: The present study was a retrospective cohort analysis based on the medical information mart for intensive care III (MIMIC-III) database. 20,160 patients were involved in this study and divided into six subgroups according to causes for ICU admission. The primary outcome was the incidence of AKI after ICU admission. The association between early serum osmolality and AKI was explored using univariate and multivariate logistic regression analyses.

Results: The normal range of serum osmolality was 285–300 mmol/L. High serum osmolality was defined as serum osmolality >300 mmol/L and low serum osmolality was defined as serum osmolality <285 mmol/L. Multivariate logistic regression indicated that high serum osmolality was independently associated with increased development of AKI with OR = 1.198 (95% CL = 1.199–1.479, P < 0.001) and low serum osmolality was also independently associated with increased development of AKI with OR = 1.332 (95% CL = 1.199–1.479, P < 0.001), compared with normal serum osmolality, respectively.

Conclusions: In critically ill patients, early high serum osmolality and low serum osmolality were both independently associated with an increased risk of development of AKI.
Gene Therapy in Inherited Retinal Diseases: An Update on Current State of the Art
Authors: Amato Alessia , Arrigo Alessandro , Aragona Emanuela , Manitto Maria Pia , Saladino Andrea , Bandello Francesco , Battaglia Parodi Maurizio
Published: October 2021

Background: Gene therapy cannot be yet considered a far perspective, but a tangible therapeutic option in the field of retinal diseases. Although still confined in experimental settings, the preliminary results are promising and provide an overall scenario suggesting that we are not so far from the application of gene therapy in clinical settings. The main aim of this review is to provide a complete and updated overview of the current state of the art and of the future perspectives of gene therapy applied on retinal diseases.

Methods: We carefully revised the entire literature to report all the relevant findings related to the experimental procedures and the future scenarios of gene therapy applied in retinal diseases. A clinical background and a detailed description of the genetic features of each retinal disease included are also reported.

Results: The current literature strongly support the hope of gene therapy options developed for retinal diseases. Although being considered in advanced stages of investigation for some retinal diseases, such as choroideremia (CHM), retinitis pigmentosa (RP), and Leber's congenital amaurosis (LCA), gene therapy is still quite far from a tangible application in clinical practice for other retinal diseases.

Conclusions: Gene therapy is an extremely promising therapeutic tool for retinal diseases. The experimental data reported in this review offer a strong hope that gene therapy will be effectively available in clinical practice in the next years.
ARHGAP11A Is a Prognostic Biomarker and Correlated With Immune Infiltrates in Gastric Cancer
Authors: Fan Biao , Ji Ke , Bu Zhaode , Zhang Ji , Yang Heli , Li Jialin , Wu Xiaojiang
Published: October 2021

Background: ARHGAP11A, belongs to RhoGAPs family, is vital for cell motility. However, the role of ARHGAP11A in gastric cancer is obscure.

Methods: The expression level of ARHGAP11A was analyzed by Oncomine database. The correlation of ARHGAP11A expression with immune infiltrates and associated gene markers was clarified by Tumor IMmune Estimation Resource and Gene Expression Profiling Interactive Analysis database. The correlation between ARHGAP11A expression and the patient prognosis was identified by Kaplan-Meier plotter and PrognoScan. Genetic changes of ARHGAP11A were analyzed by cBioPortal. The protein-protein interaction network and gene functional enrichment analysis were constructed and performed by GeneMANIA and Metascape.

Results: We found that the expression levels of ARHGAP11A were elevated in various cancers including gastric cancer when compared with normal tissues. High expression of ARHGAP11A was significantly correlated with a better prognosis in gastric cancer. We revealed that the expression of ARHGAP11A was negatively associated with infiltration levels of CD8+ T cells, CD4+ T cells, macrophages and dendritic cells. In addition, ARHGAP11A expression was significantly correlated with gene markers of these immune cells. Lastly, gene functional enrichment analysis indicated that ARHGAP11A involved in regulating lymphocyte activation, cell division, cell killing, myeloid leukocyte differentiation and leukocyte apoptosis.

Conclusion: Our findings demonstrated that ARHGAP11A was a valuable prognostic biomarker in gastric cancer. Further work is needed to validate its role and underlying mechanisms in regulating immune infiltrates.
A Wedge-Shaped Au Thin Film: Integrating Multiple Surface Plasmon Resonance Sensors in a Single Chip and Enhancing the Figure of Merit
Authors: Shimizu Hiromasa , Ogura Takahiro , Maeda Takumi , Suzuki Shogo
Published: October 2021

We show here the design, fabrication, and characterization of a wedge-shaped Au thin film with an enhanced figure of merit (FOM). This is achieved by using a reflectivity change in an attenuated total reflection (ATR) setup by slightly modulating the wavenumber of the surface plasmon polariton by means of the varying thickness of the Au thin film. The wedge-shaped Au thin film is equivalent to multiple surface plasmon resonance (SPR) transducers integrated in a single chip and was fabricated by an electron-beam evaporation process with the position of the shutter controlled during the deposition. The FOM, defined as the difference between the maximum and minimum values of the normalized reflectivity change (ΔR/R) divided by the corresponding difference of the incident angles, was 8.0-times larger than that based on the reflectivity R. Also, we demonstrated that the wedge-shaped Au thin film was able to detect ethanol gas at a concentration of 0.2%, corresponding to a refractive index change of 2 × 10−5, without any surface functionalization. Since the sensing signal can be obtained with a single image from the wedge-shaped Au thin film without precise thickness control of the metal thickness, no other materials or modulation equipment is necessary, and the sensing chip can be employed in simple and highly sensitive systems.
Peripheral Inflammation Results in Increased Excitability of Capsaicin-Insensitive Nociceptive DRG Neurons Mediated by Upregulation of ASICs and Voltage-Gated Ion Channels
Authors: Duzhyy Dmytro E. , Voitenko Nana V. , Belan Pavel V.
Published: October 2021

Previously, we have characterized the capsaicin-insensitive low pH-sensitive (caps−lpH+) subtype of small-sized nociceptive dorsal root ganglion (DRG) neurons that express acid-sensing ion channels, T-type Ca2+ channels, and have isolectin B4-negative phenotype. These neurons demonstrated increased excitability in a model of long-term diabetes, contributing to chronic pain sensation. Here we studied changes in the excitability of the caps−lpH+ neurons and underlying changes in the functional expression and gating properties of ion channels under complete Freund's adjuvant (CFA)-induced peripheral inflammation. We have found that, under these pathological conditions, the functional expression of the acid-sensing ion channels (ASICs) and voltage-gated Na+ channels, was increased. In addition, T-type Ca2+ current was significantly increased in the neurons at the membrane potentials close to its resting value. Altogether, the observed changes in the channel functioning shifted a pH level evoking an action potential (AP) toward its physiological value and led to an increase of evoked and spontaneous excitability of the caps−lpH+ neurons that may contribute to hyperalgesia and chronic inflammatory pain.
A Comparison of Clinical, Electro-Diagnostic, Laboratory, and Treatment Outcome Differences in a Cohort of HIV-Infected and HIV-Uninfected Patients With Myasthenia Gravis
Authors: Moodley Kaminie , Bill Pierre L. A. , Patel Vinod B.
Published: October 2021

There is limited literature comparing the clinical parameters and treatment outcomes in HIV-infected and HIV-uninfected myasthenia gravis (MG) patients. The aim of the study was to investigate the clinical differences and treatment outcomes in the two categories of patients, particularly the safe use of immunosuppressive therapy in immunocompromised patients. The study was a retrospective analysis of medical records of MG patients from the neuromuscular unit at Inkosi Albert Luthuli Central Hospital in Kwa-Zulu Natal between 2003 and 2019. One hundred and seventy-eight (178) patients fulfilled the clinical criteria for MG. Twenty-four (13.4%) were HIV-infected and 154 (86.5%) were HIV-uninfected. There were 116 (65%) females, median 45 years, (IQR 40–62), 90 (50.5%) black African, 66 (37%) Indian, 20 (11.2%) white, and 2 (1.1%) of mixed ancestry. In the HIV-infected cohort, 20 (87%) had generalized MG, 12 (50%) bulbar, and 14 (60.9%) respiratory onset MG, 12 (50%) presented with MG Foundation of America (MGFA) class five diseases at diagnosis, six (25%) presented with MG crisis during the 5-year follow-up. Thirteen (54%) of the HIV-infected group required rescue therapy using (plasma exchange or IV immunoglobulin) combined with pulse cyclophosphamide compared with 17 (11%) in the HIV-uninfected cohort, respectively. At 5 years, 8 (33%) of the HIV-infected group remained refractory to treatment compared with 10 (6.5%) HIV-uninfected cohort, respectively. No adverse events were documented in HIV-infected patients receiving combination rescue therapy (PLEX or IVIG combined with IV cyclophosphamide). In conclusion HIV-infected MG patients are more likely to require combination rescue therapy with PE/IVIG and IV cyclophosphamide compared with those who were HIV-uninfected. No side effects were documented in the HIV-infected group receiving the above therapy.
Serum Albumin Levels as a Potential Marker for the Predictive and Prognostic Factor in Sudden Sensorineural Hearing Loss: A Prospective Cohort Study
Authors: Zheng Zhong , Liu Chengqi , Shen Ying , Xia Liang , Xiao Lili , Sun Yuanyuan , Wang Hui , Chen Zhengnong , Wu Yaqin , Shi Haibo , Feng Yanmei , Yin Shankai
Published: October 2021

Objectives: As a common otology emergency, sudden sensorineural hearing loss (SSNHL) has a great impact on quality of life. The diagnosis and treatment of SSNHL remain challenging. This study aims to identify and investigate the association of liver functions with SSNHL.

Methods: A total of 135 SSNHL patients and 135 sex- and age-matched controls were prospectively enrolled. The baseline and clinical characteristics, along with liver function levels of participators, were collected. Linear correlation, logistic regression, and receiving operator characteristic curve analysis tests were applied to examine the association between liver function levels and SSNHL.

Results: There were no differences in baseline characteristics between SSNHL and control groups. The albumin (ALB) level of the SSNHL group was significantly lower than that in the control group (p < 0.001). The logistic regression showed that the low ALB level may be a predictive factor of SSNHL with an adjusted OR of 0.809 (95% CI, 0.742–0.882, p < 0.001). By comparing the indicators of different prognosis groups, we found that the effective group had a significantly lower hearing impair onset and higher ALB (p = 0.001) and AGR (p = 0.003) levels than the ineffective group. Logistic regression revealed that the hearing level onset (OR, 0.976; 95% CI, 0.956–0.997; p = 0.026) and ALB level (OR, 1.181; 95% CI, 1.071–1.301; p = 0.001) showed strong associations with treatment outcome.

Conclusions: Lower ALB levels, within the normal ranges, were associated with the occurrence and unfavorable outcome of SSNHL. However, further research on the underlying mechanisms needs to be conducted.
Effect of Epidemic Intermittent Fasting on Cardiometabolic Risk Factors: A Systematic Review and Meta-Analysis of Randomized Controlled Trials
Authors: Yang Fan , Liu Can , Liu Xu , Pan Xiandu , Li Xinye , Tian Li , Sun Jiahao , Yang Shengjie , Zhao Ran , An Na , Yang Xinyu , Gao Yonghong , Xing Yanwei
Published: October 2021

Intermittent fasting (IF) has gained attention as a promising diet for weight loss and dysmetabolic diseases management. This systematic review aimed to investigate the effects of IF on cardiometabolic risk factors (CMRFs). A systematic literature search was carried out using three electronic databases, namely PubMed, Embase, and the Cochrane Library, until October 2020. Randomized controlled trials that compared the IF intervention with a control group diet were included. Fourteen effect sizes were expressed as weighted mean difference (WMD) using a fixed-effects model and 95% confidence intervals (CI). Compared to the ones within control groups, participants exposed to the IF intervention reduced their body weight (WMD, −1.78 kg; 95% CI, −2.21 to −1.35; p <0.05), waist circumference (WMD, −1.19 cm; 95% CI, −1.8 to −0.57; p <0.05), fat mass (WMD, −1.26 kg; 95% CI, −1.57 to −0.95; p <0.05), body mass index (WMD, −0.58 kg/m2; 95% CI, −0.8 to −0.37; p <0.05), systolic blood pressure (WMD, −2.14 mmHg; 95% CI: −3.54 to −0.73; p <0.05), diastolic blood pressure (WMD: −1.38 mmHg, 95% CI, −2.35 to −0.41, p <0.05), fasting blood glucose (WMD: −0.053 mmol/L; 95% CI: −0.105 to 0.001; p <0.05), fasting insulin (WMD, −0.8 mIU/L; 95% CI, −1.15 to −0.44; p <0.05), insulin resistance (WMD, −0.21; 95% CI, −0.36 to −0.05; p <0.05), total cholesterol (WMD, −0.10 mmol/L; 95% CI, −0.17 to −0.02; p <0.05), and triglycerides (WMD, −0.09 mmol/L; 95% CI, −0.13 to −0.04; p <0.05). No effects were observed for low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, or glycosylated hemoglobin. This meta-analysis supports the role of IF in improving the component composition of CMRFs, including weight, waist circumference, fat mass, BMI, blood pressure, total cholesterol, triglycerides, fasting insulin, and insulin resistance, compared to a control group diet. Further research on IF interventions should take into account long-term and well-designed administration to draw definitive conclusions.
Bioluminescence Tomography Based on One-Dimensional Convolutional Neural Networks
Authors: Yu Jingjing , Dai Chenyang , He Xuelei , Guo Hongbo , Sun Siyu , Liu Ying
Published: October 2021

Bioluminescent tomography (BLT) has increasingly important applications in preclinical studies. However, the simplified photon propagation model and the inherent ill-posedness of the inverse problem limit the quality of BLT reconstruction. In order to improve the reconstruction accuracy of positioning and reconstruction efficiency, this paper presents a deep-learning optical reconstruction method based on one-dimensional convolutional neural networks (1DCNN). The nonlinear mapping relationship between the surface photon flux density and the distribution of the internal bioluminescence sources is directly established, which fundamentally avoids solving the ill-posed inverse problem iteratively. Compared with the previous reconstruction method based on multilayer perceptron, the training parameters in the 1DCNN are greatly reduced and the learning efficiency of the model is improved. Simulations verify the superiority and stability of the 1DCNN method, and the in vivo experimental results further show the potential of the proposed method in practical applications.
Myricetin Induces Autophagy and Cell Cycle Arrest of HCC by Inhibiting MARCH1-Regulated Stat3 and p38 MAPK Signaling Pathways
Authors: Yang Wei , Su Jiaqi , Li Mingjing , Li Tiantian , Wang Xu , Zhao Mingdong , Hu Xuemei
Published: October 2021

Myricetin is a type of natural flavonol known for its anticancer activity. However, the molecular mechanism of myricetin in anti-hepatocellular carcinoma (HCC) is not well defined. Previous studies indicated that downregulation of membrane-associated RING-CH finger protein 1 (MARCH1) contributed to the treatment of a variety of cancers. Whether the anticancer property of myricetin is associated with MARCH1 expression remains to be investigated. This research explored the anti-HCC mechanism of myricetin. Our results indicate that myricetin induces autophagy and arrests cell cycle at the G2/M phase to suppress the proliferation of HCC cells by downregulating MARCH1. Myricetin reduces MARCH1 protein in Hep3B and HepG2 cells. Interestingly, myricetin upregulates the MARCH1 mRNA level in Hep3B cells but downregulates it in HepG2 cells. The knockdown of MARCH1 by siRNAs (small interfering RNAs) decreases the phosphorylated p38 MAPK (p-p38 MAPK) and Stat3 (p-Stat3), and inhibits HCC cell viability. Moreover, myricetin inhibits p38 MAPK and Stat3 signaling pathways by downregulating MARCH1 to repress HCC growth both in vitro and in vivo. Bafilomycin A1 (BafA1), an autophagy inhibitor, has synergetic effect with myricetin to inhibit HCC growth. Taken together, our results reveal that myricetin inhibits the proliferation of HCC cells by inhibiting MARCH1-regulated p38 MAPK and Stat3 signaling pathways. This research provides a new molecular mechanism for myricetin in anti-HCC and suggests that targeting MARCH1 could be a novel treatment strategy in developing anticancer therapeutics.
Acoustic Frequency-Based Approach for Identification of Photoacoustic Surgical Biomarkers
Authors: Gonzalez Eduardo A. , Graham Camryn A. , Lediju Bell Muyinatu A.
Published: October 2021

Spectral unmixing techniques for photoacoustic images are often used to isolate signal origins (e.g., blood, contrast agents, lipids). However, these techniques often require many (e.g., 12–59) wavelength transmissions for optimal performance to exploit the optical properties of different biological chromophores. Analysis of the acoustic frequency response of photoacoustic signals has the potential to provide additional discrimination of photoacoustic signals from different materials, with the added benefit of potentially requiring only a few optical wavelength emissions. This study presents our initial results testing this hypothesis in a phantom experiment, given the task of differentiating photoacoustic signals from deoxygenated hemoglobin (Hb) and methylene blue (MB). Coherence-based beamforming, principal component analysis, and nearest neighbor classification were employed to determine ground-truth labels, perform feature extraction, and classify image contents, respectively. The mean ± one standard deviation of classification accuracy was increased from 0.65 ± 0.16 to 0.88 ± 0.17 when increasing the number of wavelength emissions from one to two, respectively. When using an optimal laser wavelength pair of 710–870 nm, the sensitivity and specificity of detecting MB over Hb were 1.00 and 1.00, respectively. Results are highly promising for the differentiation of photoacoustic-sensitive materials with comparable performance to that achieved with more conventional multispectral laser wavelength approaches.
Lactate Is a Metabolic Mediator That Shapes Immune Cell Fate and Function
Authors: Caslin Heather L. , Abebayehu Daniel , Pinette Julia A. , Ryan John J.
Published: October 2021

Lactate and the associated H+ ions are still introduced in many biochemistry and general biology textbooks and courses as a metabolic by-product within fast or oxygen-independent glycolysis. However, the role of lactate as a fuel source has been well-appreciated in the field of physiology, and the role of lactate as a metabolic feedback regulator and distinct signaling molecule is beginning to gain traction in the field of immunology. We now know that while lactate and the associated H+ ions are generally immunosuppressive negative regulators, there are cell, receptor, mediator, and microenvironment-specific effects that augment T helper (Th)17, macrophage (M)2, tumor-associated macrophage, and neutrophil functions. Moreover, we are beginning to uncover how lactate and H+ utilize different transporters and signaling cascades in various immune cell types. These immunomodulatory effects may have a substantial impact in cancer, sepsis, autoimmunity, wound healing, and other immunomodulatory conditions with elevated lactate levels. In this article, we summarize the known effects of lactate and H+ on immune cells to hypothesize potential explanations for the divergent inflammatory vs. anti-inflammatory effects.
Hormonome Dynamics During Microgametogenesis in Different Nicotiana Species
Authors: Záveská Drábková Lenka , Pokorná Eva , Dobrev Petre I. , Kůrková Jana , Steinbachová Lenka , Honys David , Motyka Václav
Published: October 2021

Plant microgametogenesis involves stages leading to the progressive development of unicellular microspores into mature pollen. Despite the active and continuing interest in the study of male reproductive development, little is still known about the hormonomics at each ontogenetic stage. In this work, we characterized the profiles and dynamics of phytohormones during the process of microgametogenesis in four Nicotiana species (Nicotiana tabacum, Nicotiana alata, Nicotiana langsdorffii, and Nicotiana mutabilis). Taking advantage of advanced HPLC-ESI-MS/MS, twenty to thirty endogenous hormone derivatives were identified throughout pollen ontogenesis, including cytokinins, auxins, ABA and its derivatives, jasmonates, and phenolic compounds. The spectra of endogenous phytohormones changed dynamically during tobacco pollen ontogeny, indicating their important role in pollen growth and development. The different dynamics in the accumulation of endogenous phytohormones during pollen ontogenesis between N. tabacum (section Nicotiana) and the other three species (section Alatae) reflects their different phylogenetic positions and origin within the genus Nicotiana. We demonstrated the involvement of certain phytohormone forms, such as cis-zeatin- and methylthiol-type CKs, some derivatives of abscisic acid, phenylacetic and benzoic acids, in pollen development for the first time here. Our results suggest that unequal levels of endogenous hormones and the presence of specific derivatives may be characteristic for pollen development in different phylogenetic plant groups. These results represent the currently most comprehensive study of plant hormones during the process of pollen development.
Physiological and Comparative Transcriptomic Analysis Provide Insight Into Cotton (Gossypium hirsutum L.) Root Senescence in Response
Authors: Zhu Lingxiao , Liu Liantao , Sun Hongchun , Zhang Yongjiang , Zhu Jijie , Zhang Ke , Li Anchang , Bai Zhiying , Wang Guiyan , Li Cundong
Published: October 2021

Nitrogen (N) deficiency is one of the pivotal environmental factors that induce leaf senescence. However, little is known regarding the impact of low N on root senescence in cotton. Thus, the objective of this study was to investigate the effect of low nitrogen on root senescence. In this study, the molecular mechanism of cotton root senescence in response to nitrogen deficiency was investigated by combing physiological and transcriptomic analysis when no nitrogen and normal nitrogen (138mg N·kg−1 soil). The results showed that: (1) nitrogen starvation induced the premature senescence of leaf, while delaying root senescence. (2) The increase in catalase (CAT) activity at 60, 80, and 100days after emergence (DAE), combined with decrease of malonaldehyde content at 60, 80, and 100 DAE, and the content of abscisic acid (ABA), all of these contributed to the delay of root senescence by low nitrogen treatment. (3) To study the molecular mechanisms underlying root senescence, the gene expression profiling between low nitrogen and normal nitrogen treatments were compared pairwise at 20, 40, 60, 80, and 100 DAE. A total of 14,607 genes were identified to be differentially expressed at these five points. (5) Most genes involved in glutathione (GSH) and ascorbate peroxidase (APX) synthesis were upregulated, while ABA, apoptosis, caspase, and cell cycle-related differentially expressed genes (DEGs) were downregulated. Coupled with the physiology data, these results provide new insights into the effect of nitrogen starvation on root senescence.
Cultivation of Intrapreneurship: A Framework and Challenges
Authors: Huang Lan-Ying , Yang Lin Shu-Min , Hsieh Ying-Jiun
Published: October 2021

Intrapreneurship has drawn research attention over the past decades considering its crucial role in innovation, organizational performance, and employee career planning. Intrapreneurial research based on various concepts also emerges. In spite of the increasing concern in the field, contributions in the field are fragmented. Particularly, intrapreneurship research is still lacking an integrated framework based on which, enablers and important facilitating mechanisms can be identified to enhance intrapreneurship. To close the above research gap, the study develops a holistic intrapreneurial framework. Specifically, the study first examines intrapreneurship in relation to other prominent concepts (i.e., innovation, entrepreneurship, and sustainability). This study then identifies enablers of intrapreneurship at both individual and organizational level. Notably, extant research largely examines intrapreneurship either at the organizational or individual level, and concentrates in corporate entrepreneurship or individual intrapreneurial employees. Research providing a holistic perspective on enablers for intrapreneurship is rare. The study further integrates these intrapreneurial enablers with facilitating mechanisms and proposes a framework of intrapreneurship. The framework makes it possible to clearly identify pivotal antecedents to intrapreneurship based on various theoretical lenses and analytical levels applied. Finally, the study addresses a list of managerial and technological challenges arising from the above framework and suggests future research agenda.
English Speakers’ Implicit Gender Concepts Influence Their Processing of French Grammatical Gender: Evidence for Semantically Mediated Cross-Linguistic Influence
Authors: Nicoladis Elena , Westbury Chris , Foursha-Stevenson Cassandra
Published: October 2021

Second language (L2) learners often show influence from their first language (L1) in all domains of language. This cross-linguistic influence could, in some cases, be mediated by semantics. The purpose of the present study was to test whether implicit English gender connotations affect L1 English speakers’ judgments of the L2 French gender of objects. We hypothesized that gender estimates derived from word embedding models that measure similarity of word contexts in English would affect accuracy and response time on grammatical gender (GG) decision in L2 French. L2 French learners were asked to identify the GG of French words estimated to be either congruent or incongruent with the implicit gender in English. The results showed that they were more accurate with words that were congruent with English gender connotations than words that were incongruent, suggesting that English gender connotations can influence grammatical judgments in French. Response times showed the same pattern. The results are consistent with semantics-mediated cross-linguistic influence.
What Can Neural Activity Tell Us About Cognitive Resources in Aging?
Authors: Tagliabue Chiara F. , Mazza Veronica
Published: October 2021

A reduction in cognitive resources has been originally proposed to account for age-related decrements in several cognitive domains. According to this view, aging limits the pool of available cognitive supplies: Compared to younger adults, elderly exhaust the resources more rapidly as task difficulty increases, hence a dramatic performance drop. Neurophysiological indexes (e.g., BOLD response and EEG activity) may be instrumental to quantify the amount of such cognitive resources in the brain and to pinpoint the stage of stimulus processing where the decrement in age-related resources is evident. However, as we discuss in this mini-review, the most recent studies on the neurophysiological markers of age-related changes lack a consistent coupling between neural and behavioral effects, which casts doubt on the advantage of measuring neural indexes to study resource deployment in aging. For instance, in the working memory (WM) domain, recent cross-sectional studies found varying patterns of concurrent age-related brain activity, ranging from equivalent to reduced and increased activations of old with respect to younger adults. In an attempt to reconcile these seemingly inconsistent findings of brain-behavior coupling, we focus on the contribution of confounding sources of variability and propose ways to control for them. Finally, we suggest an alternative perspective to explain age-related effects that implies a qualitative (instead of or along with a quantitative) difference in the deployment of cognitive resources in aging.
Phenotypic Trade-Offs: Deciphering the Impact of Neurodiversity on Drug Development in Fragile X Syndrome
Authors: Bui Truong An , Shatto Julie , Cuppens Tania , Droit Arnaud , Bolduc François V.
Published: October 2021

Fragile X syndrome (FXS) is the most common single-gene cause of intellectual disability and autism spectrum disorder. Individuals with FXS present with a wide range of severity in multiple phenotypes including cognitive delay, behavioral challenges, sleep issues, epilepsy, and anxiety. These symptoms are also shared by many individuals with other neurodevelopmental disorders (NDDs). Since the discovery of the FXS gene, FMR1, FXS has been the focus of intense preclinical investigation and is placed at the forefront of clinical trials in the field of NDDs. So far, most studies have aimed to translate the rescue of specific phenotypes in animal models, for example, learning, or improving general cognitive or behavioral functioning in individuals with FXS. Trial design, selection of outcome measures, and interpretation of results of recent trials have shown limitations in this type of approach. We propose a new paradigm in which all phenotypes involved in individuals with FXS would be considered and, more importantly, the possible interactions between these phenotypes. This approach would be implemented both at the baseline, meaning when entering a trial or when studying a patient population, and also after the intervention when the study subjects have been exposed to the investigational product. This approach would allow us to further understand potential trade-offs underlying the varying effects of the treatment on different individuals in clinical trials, and to connect the results to individual genetic differences. To better understand the interplay between different phenotypes, we emphasize the need for preclinical studies to investigate various interrelated biological and behavioral outcomes when assessing a specific treatment. In this paper, we present how such a conceptual shift in preclinical design could shed new light on clinical trial results. Future clinical studies should take into account the rich neurodiversity of individuals with FXS specifically and NDDs in general, and incorporate the idea of trade-offs in their designs.
Association of Gene Polymorphisms in APOE and BIN1 With Dementia of Alzheimer's Type Susceptibility in Chinese Han Population
Authors: Li Xiaoyue , Zhang Yelei , Chen Xinyu , Yuan Hongwei , Wang Zhiqiang , Wang Guoqiang , Zhang Kai , Liu Huanzhong
Published: October 2021

Objectives: Dementia of the Alzheimer's type (DAT) is the most common chronic neurodegenerative disease. At present, the pathogenesis of DAT is not completely clear, and there are no drugs that can cure the disease. Once an individual is diagnosed with DAT, the survival time is only 3 to 9 years. Therefore, there is an urgent need to determine the etiology of DAT and the associated influencing factors to find a breakthrough in the treatment of DAT.

Methods: We studied the relationship between polymorphisms in several genes (including BIN1 and APOE) and DAT susceptibility and the effects of sex differences on DAT. Our study included 137 patients with DAT and 509 healthy controls (HCs).

Results: The APOE rs429358 polymorphism CC and CT genotypes were associated with an increased risk of DAT in women. We found a significant association between APOE ε4 and DAT. The frequency of the ε4 allele in the DAT group (15.5%) was higher than that in the HC group (8.7%). The BIN1 rs7561528 polymorphism was associated with a decreased risk of DAT in men.

Conclusions: APOE gene rs429358 and BIN1 gene 7561528 genes may affect the susceptibility to DAT in a Chinese Han population.
Genomic Profiling of Blood-Derived Circulating Tumor DNA from Patients with Advanced Biliary Tract Cancer
Authors: Chen Chen , Wang Tao , Yang Mengmei , Song Jia , Huang Mengli , Bai Yuezong , Su Hao
Published: October 2021

Background: Biliary tract cancer is a highly lethal malignancy with poor clinical outcome. Accumulating evidence indicates targeted therapeutics may provide new hope for improving treatment response in BTC, hence better understanding the genomic profile is particularly important. Since tumor tissue may not be available for some patients, a complementary method is urgently needed. Circulating tumor DNA (ctDNA) provides a noninvasive means for detecting genomic alterations, and has been regarded as a promising tool to guide clinical therapies.

Methods: Next-generation sequencing of 150 cancer-related genes was used to detect gene alterations in blood-derived ctDNA from 154 Chinese patients with BTC. Genomic alterations were analyzed and compared with an internal tissue genomic database and TCGA database.

Results: 94.8% patients had at least one change detected in their ctDNA. The median maximum somatic allele frequency was 6.47% (ranging 0.1–34.8%). TP53 and KRAS were the most often mutated genes. The frequencies of single nucleotide variation in commonly mutated genes in ctDNA were similar to those detected in tissue samples, TP53 (35.1 vs. 40.4%) and KRAS (20.1 vs. 22.6%). Pathway analysis revealed that mutated genes were mapped to several key pathways including PI3K-Akt, p53, ErbB and Ras signaling pathway. In addition, patients harboring LRP1B, TP53, and ErbB family mutations presented significantly higher tumor mutation burden.

Conclusions: These findings demonstrated that ctDNA testing by NGS was feasible in revealing genomic changes and could be a viable alternative to tissue biopsy in patients with metastatic BTC.
High-Resolution 3D Crop Reconstruction and Automatic Analysis of Phenotyping Index Using Machine Learning
Authors: Yang Myongkyoon , Cho Seong-In
Published: October 2021

Beyond the use of 2D images, the analysis of 3D images is also necessary for analyzing the phenomics of crop plants. In this study, we configured a system and implemented an algorithm for the 3D image reconstruction of red pepper plant (Capsicum annuum L.), as well as its automatic analysis. A Kinect v2 with a depth sensor and a high-resolution RGB camera were used to obtain more accurate reconstructed 3D images. The reconstructed 3D images were compared with conventional reconstructed images, and the data of the reconstructed images were analyzed with respect to their directly measured features and accuracy, such as leaf number, width, and plant height. Several algorithms for image extraction and segmentation were applied for automatic analysis. The results showed that the proposed method showed an error of about 5 mm or less when reconstructing and analyzing 3D images, and was suitable for phenotypic analysis. The images and analysis algorithms obtained by the 3D reconstruction method are expected to be applied to various image processing studies.
Long-Term Fertilization and Lime-Induced Soil pH Changes Affect Nitrogen Use Efficiency and Grain Yields in Acidic Soil under Wheat-Maize Rotation
Authors: Daba Nano Alemu , Li Dongchu , Huang Jing , Han Tianfu , Zhang Lu , Ali Sehrish , Khan Muhammad Numan , Du Jiangxue , Liu Shujun , Legesse Tsegaye Gemechu , Liu Lisheng , Xu Yongmei , Zhang Huimin , Wang Boren
Published: October 2021

Liming (L) is a common practice to mitigate soil acidification and enhance soil quality and crop productivity. However, in acidic soil, it is not clear how long-term application of lime and nitrogen (N)-based fertilizer affects soil chemical properties, the wheat and maize grain yields (GY), and N-use efficiency (NUE). Thus, to investigate the effects of N-based fertilizations without L (−L) and with L (+L) on wheat and maize GY and NUE through their effects on soil chemical properties, we analyzed a 28-year field experiment in acidic soil under a wheat-maize system in South China. The analysis was carried out between 1991 and 2010 (before L) and between 2011 and 2018 (after L). We categorized the treatments into (1) no fertilizer (C); nitrogen (N); N and phosphorus (NP); N and potassium (NK); N, P and K (NPK); and NPKCR, NPK and crops residue (CR) applications (NPKCR), before L; and (2) C; N−L; N+L; NP−L; NP+L; NK−L; NK+L; NPK−L; NPK+L; NPKCR−L and NPKCR+L, after L. The effects of long-term fertilization resulted in lower soil pH by 15%, soil available K (AK) by 19%, POlsen by 6%, NO3−-N by 15%, soil organic matter (SOM) by 16%, total N by 16%, and C:N ratio by 13% in −L soil than in +L soil. However, the accumulation of NH4+-N was higher by 40% in −L soil than in +L soil. Wheat and maize GY, N recovery efficiency (REN), and N partial factor productivity (PEPN) were more adversely affected by 8-year fertilizations in −L compared with fertilizations before L and in +L primarily because of the significantly decreased soil pH. Conversely, improvements in wheat and maize yields, REN, and PFPN by 8-year fertilizations in +L were related to increasing soil pH, exchangeable base cations such as Ca2+, Mg2+, and the alleviated toxicity of Al3+. Overall, improvement of GY and NUE from the acidified soil in South China requires the long-term integrated use of fertilizer (NPK), retention of CR, and the +L (i.e., NPKCR+L).