bluuebunny/crossref_metadata_2025 huggingface dataset:
Membrane Interactions and Toxicity by Misfolded Protein Oligomers
Authors: Gonzalez-Garcia Mario , Fusco Giuliana , De Simone Alfonso
Published: March 2021

The conversion of otherwise soluble proteins into insoluble amyloid aggregates is associated with a range of neurodegenerative disorders, including Alzheimer’s and Parkinson’s diseases, as well as non-neuropathic conditions such as type II diabetes and systemic amyloidoses. It is increasingly evident that the most pernicious species among those forming during protein aggregation are small prefibrillar oligomers. In this review, we describe the recent progress in the characterization of the cellular and molecular interactions by toxic misfolded protein oligomers. A fundamental interaction by these aggregates involves biological membranes, resulting in two major model mechanisms at the onset of the cellular toxicity. These include the membrane disruption model, resulting in calcium imbalance, mitochondrial dysfunction and intracellular reactive oxygen species, and the direct interaction with membrane proteins, leading to the alteration of their native function. A key challenge remains in the characterization of transient interactions involving heterogeneous protein aggregates. Solving this task is crucial in the quest of identifying suitable therapeutic approaches to suppress the cellular toxicity in protein misfolding diseases.
Placenta-Derived MicroRNAs in the Pathophysiology of Human Pregnancy
Authors: Xu Peng , Ma Yeling , Wu Hongyu , Wang Yan-Ling
Published: March 2021

In placental mammals, reproductive success, and maternal-fetal health substantially depend on a well-being placenta, the interface between the fetus and the mother. Disorders in placental cells are tightly associated with adverse pregnancy outcomes including preeclampsia (PE), fetal growth restriction, etc. MicroRNAs (miRNAs) represent small non-coding RNAs that regulate post-transcriptional gene expression and are integral to a wide range of healthy or diseased cellular proceedings. Numerous miRNAs have been detected in human placenta and increasing evidence is revealing their important roles in regulating placental cell behaviors. Recent studies indicate that placenta-derived miRNAs can be released to the maternal circulation via encapsulating into the exosomes, and they potentially target various maternal cells to provide a hormone-like means of intercellular communication between the mother and the fetus. These placental exosome miRNAs are attracting more and more attention due to their differential expression in pregnant complications, which may provide novel biomarkers for prediction of the diseases. In this review, we briefly summarize the current knowledge and the perspectives of the placenta-derived miRNAs, especially the exosomal transfer of placental miRNAs and their pathophysiological relevance to PE. The possible exosomal-miRNA-targeted strategies for diagnosis, prognosis or therapy of PE are highlighted.
Playing the Whack-A-Mole Game: ERK5 Activation Emerges Among the Resistance Mechanisms to RAF-MEK1/2-ERK1/2- Targeted Therapy
Authors: Tubita Alessandro , Tusa Ignazia , Rovida Elisabetta
Published: March 2021

Molecularly tailored therapies have opened a new era, chronic myeloid leukemia being the ideal example, in the treatment of cancer. However, available therapeutic options are still unsatisfactory in many types of cancer, and often fail due to the occurrence of resistance mechanisms. With regard to small-molecule compounds targeting the components of the Mitogen-Activated Protein Kinase (MAPK) cascade RAF-MEK1/2-ERK1/2, these drugs may result ineffective as a consequence of the activation of compensatory pro-survival/proliferative signals, including receptor tyrosine kinases, PI3K, as well as other components of the MAPK family such as TPL2/COT. The MAPK ERK5 has been identified as a key signaling molecule in the biology of several types of cancer. In this review, we report pieces of evidence regarding the activation of the MEK5-ERK5 pathway as a resistance mechanism to RAF-MEK1/2-ERK1/2 inhibitors. We also highlight the known and possible mechanisms underlying the cross-talks between the ERK1/2 and the ERK5 pathways, the characterization of which is of great importance to maximize, in the future, the impact of RAF-MEK1/2-ERK1/2 targeting. Finally, we emphasize the need of developing additional therapeutically relevant MEK5-ERK5 inhibitors to be used for combined treatments, thus preventing the onset of resistance to cancer therapies relying on RAF-MEK1/2-ERK1/2 inhibitors.
A Genetic Model Reveals Biological Features of Neonatal CD4 Helper Cells Undergone Homeostasis in Mice
Authors: Lei Lei , Zhang Xingzhe , Yang Xiaofeng , Su Yanhong , Liu Haiyan , Yang Hang , Wang Jinli , Zou Yujing , Wang Xin , Jiao Anjun , Zhang Cangang , Zheng Huiqiang , Zhang Jiahui , Zhang Dan , Shi Lin , Zhou Xiaobo , Sun Chenming , Zhang Baojun
Published: March 2021

CD4+ T cells are essential for regulating effective immune response to pathogens and immune balance. Recent studies have demonstrated the unique features of T cells in neonate mice, such as more sensitive to antigen response and preference toward T helper 2 (Th2) response and regulatory T cells (Tregs) differentiation. However, the biological characteristics of neonatal age-derived CD4+ T cells following homeostasis remain unclear. Here we utilized a lineage tracing model of TCRδCreERR26ZsGreen to mark neonatal- and adult-derived CD4+ T cells followed by a combination analysis of activation, proliferation, survival, and differentiation. Our results showed that neonatal CD4+ T cells had higher capacity of activation, proliferation, apoptosis, and differentiation toward Th2 and T helper 17 (Th17) lineages, accompanied by a reduced potential for T helper 1 (Th1), T helper 9 (Th9), and Treg lineages. In contrast, tracked neonatal CD4+ T cells exhibited similar characters of above-mentioned of tracked adult cells in adult mice. Therefore, our data support a natural requirement for CD4+ T cells to acquire fully-equipped functional potentials of adult cells.
Late 3d Metal-Catalyzed (Cross-) Dimerization of Terminal and Internal Alkynes
Authors: Weber Sebastian M. , Hilt Gerhard
Published: March 2021

This review will outline the recent advances in chemo-, regio-, and stereoselective (cross-) dimerization of terminal alkynes to generate 1,3-enynes using different types of iron and cobalt catalysts with altering oxidation states of the active species. In general, the used ligands have a crucial effect on the stereoselectivity of the reaction; e.g., bidentate phosphine ligands in cobalt catalysts can generate theE-configuredhead-to-headdimerization product, while tridentate phosphine ligands can generate either theZ-configuredhead-to-headdimerization product or the branchedhead-to-tailisomer. Furthermore, the hydroalkynylation of silyl-substituted acetylenes as donors to internal alkynes as acceptors will be discussed using cobalt and nickel catalysts.
Visceral Leishmaniasis-HIV Coinfection as a Predictor of Increased Leishmania Transmission at the Village Level in Bihar, India
Authors: Cloots Kristien , Marino Pia , Burza Sakib , Gill Naresh , Boelaert Marleen , Hasker Epco
Published: March 2021

Background

Visceral leishmaniasis (VL) is on the verge of being eliminated as a public health problem in the Indian subcontinent. Although Post-kala-azar dermal leishmaniasis (PKDL) is recognized as an important reservoir of transmission, we hypothesized that VL patients co-infected with Human Immunodeficiency Virus (HIV) may also be important reservoirs of sustained leishmania transmission. We therefore investigated to what extent cases of PKDL or VL-HIV are associated with VL incidence at the village level in Bihar, India.

Methods

VL, VL-HIV, and PKDL case data from six districts within the highly VL-endemic state of Bihar, India were collected through the Kala-Azar Management Information System for the years 2014–2019. Multivariate analysis was done using negative binomial regression controlling for year as a fixed effect and block (subdistrict) as a random effect.

Findings

Presence of VL-HIV+ and PKDL cases were both associated with a more than twofold increase in VL incidence at village level, with Incidence Rate Ratios (IRR) of 2.16 (95% CI 1.81–2.58) and 2.37 (95% CI 2.01–2.81) for VL-HIV+ and PKDL cases respectively. A sensitivity analysis showed the strength of the association to be similar in each of the six included subdistricts.

Conclusions

These findings indicate the importance of VL-HIV+ patients as infectious reservoirs for Leishmania, and suggest that they represent a threat equivalent to PKDL patients towards the VL elimination initiative on the Indian subcontinent, therefore warranting a similar focus.
Next-Generation Sequencing Reveals the Progression of COVID-19
Authors: Chen Xiaomin , Kang Yutong , Luo Jing , Pang Kun , Xu Xin , Wu Jinyu , Li Xiaokun , Jin Shengwei
Published: March 2021

The novel coronavirus SARS-CoV-2 (causing the disease COVID-19) has caused a highly transmissible and ongoing pandemic worldwide. Due to its rapid development, next-generation sequencing plays vital roles in many aspects. Here, we summarize the current knowledge on the origin and human transmission of SARS-CoV-2 based on NGS analysis. The ACE2 expression levels in various human tissues and relevant cells were compared to provide insights into the mechanism of SAS-CoV-2 infection. Gut microbiota dysbiosis observed by metagenome sequencing and the immunogenetics of COVID-19 patients according to single-cell sequencing analysis were also highlighted. Overall, the application of these sequencing techniques could be meaningful for finding novel intermediate SARS-CoV-2 hosts to block interspecies transmission. This information will further benefit SARS-CoV-2 diagnostic development and new therapeutic target discovery. The extensive application of NGS will provide powerful support for our fight against future public health emergencies.
Monitoring Mosquito-Borne Arbovirus in Various Insect Regions in China in 2018
Authors: Fang Yuan , Zhang Wei , Xue Jing-Bo , Zhang Yi
Published: March 2021

Background

Increases in global travel and trade are changing arbovirus distributions worldwide. Arboviruses can be introduced by travelers, migratory birds, or vectors transportedviainternational trade. Arbovirus surveillance in field-collected mosquitoes may provide early evidence for mosquito-borne disease transmission.

Methods

During the seasons of high mosquito activity of 2018, 29,285 mosquitoes were sampled from seven sentinel sites in various insect regions. The mosquitoes were analyzed by RT-PCR for alphaviruses, flaviviruses, and orthobunyaviruses.

Results

We detected three strains of Japanese encephalitis virus (JEV), five strains of Getah virus (GETV), and 45 strains of insect-specific flaviviruses including Aedes flavivirus (AeFV, 1), Chaoyang virus (CHAOV, 1), Culex flavivirus (CxFV, 17), Hanko virus (HANKV, 2), QuangBinh virus (QBV, 22), and Yunnan Culex flavivirus (YNCxFV, 2). Whole genomes of one strain each of GETV, CxFV, CHAOV, and AeFV were successfully amplified. Phylogenetic analysis revealed that the new JEV strains detected in the Shanghai and Hubei Provinces belong to the GI-b strain and are phylogenetically close to the NX1889 strain (MT134112) isolated from a patient during a JE outbreak in Ningxia in 2018. GETVs were found in Inner Mongolia, Hubei, and Hainan and belonged to Group III. They were closely related to strains isolated from swine. HANKV was recorded for the first time in China and other ISFVs were newly detected at several sentinel sites. The bias-corrected maximum likelihood estimation value for JEV in Jinshan, Shanghai was 4.52/1,000 (range 0.80–14.64). Hence, there is a potential risk of a JEV epidemic in that region.

Conclusion

GI-b is the dominant circulating JEV genotype in nature and poses a health risk to animals and humans. The potential threat of widespread GETV distribution as a zoonosis is gradually increasing. The present study also disclosed the dispersion and host range of ISFVs. These findings highlight the importance of tracing the movements of the vectors and hosts of mosquito-borne pathogens in order to prevent and control arbovirus outbreaks in China.
Ibrexafungerp, a Novel Oral Triterpenoid Antifungal in Development: Overview of Antifungal Activity Against Candida glabrata
Authors: Gamal Ahmed , Chu Sherman , McCormick Thomas S. , Borroto-Esoda Katyna , Angulo David , Ghannoum Mahmoud A.
Published: March 2021

Systemic infections caused by Candida species are an important cause of morbidity and mortality among immunocompromised and non-immunocompromised patients. In particular, Candida glabrata is an emerging species within the Candida family that causes infections ranging from superficial to life-threatening systemic disease. Echinocandins and azoles are typically the first-line therapies used to treat infections caused by C. glabrata, however, there is an increasing prevalence of resistance to these antifungal agents in patients. Thus, a need exists for novel therapies that demonstrate high efficacy against C. glabrata. Ibrexafungerp is a first-in-class glucan synthase inhibitor with oral availability developed to address this increasing antifungal resistance. Ibrexafungerp demonstrates broad in vitro activity against wild-type, azole-resistant, and echinocandin-resistant C. glabrata species. Furthermore, ibrexafungerp has shown efficacy in low pH environments, which suggests its potential effectiveness in treating vulvovaginal candidiasis. Additional preclinical and clinical studies are needed to further examine the mechanism(s) of ibrexafungerp, including acting as a promising new agent for treating C. glabrata infections.
Role of NFAT in the Progression of Diabetic Atherosclerosis
Authors: Cai Yaoyao , Yao Haipeng , Sun Zhen , Wang Ying , Zhao Yunyun , Wang Zhongqun , Li Lihua
Published: March 2021

Nuclear factor of activated T cells (NFAT) is a transcription factor with a multidirectional regulatory function, that is widely expressed in immune cells, including cells in the cardiovascular system, and non-immune cells. A large number of studies have confirmed that calcineurin/NFAT signal transduction is very important in the development of vascular system and cardiovascular system during embryonic development, and plays some role in the occurrence of vascular diseases such as atherosclerosis, vascular calcification, and hypertension. Recent in vitro and in vivo studies have shown that NFAT proteins and their activation in the nucleus and binding to DNA-related sites can easily ɨnduce the expression of downstream target genes that participate in the proliferation, migration, angiogenesis, and vascular inflammation of vascular wall related cells in various pathophysiological states. NFAT expression is regulated by various signaling pathways, including CD137-CD137L, and OX40-OX40L pathways. As a functionally diverse transcription factor, NFAT interacts with a large number of signaling molecules to modulate intracellular and extracellular signaling pathways. These NFAT-centered signaling pathways play important regulatory roles in the progression of atherosclerosis, such as in vascular smooth muscle cell phenotypic transition and migration, endothelial cell injury, macrophage-derived foam cell formation, and plaque calcification. NFAT and related signaling pathways provide new therapeutic targets for vascular diseases such as atherosclerosis. Hence, further studies of the mechanism of NFAT in the occurrence and evolution of atherosclerosis remain crucial.
Environmental Risk Factors and Congenital Heart Disease: An Umbrella Review of 165 Systematic Reviews and Meta-Analyses With More Than 120 Million Participants
Authors: Zhang Tie-Ning , Wu Qi-Jun , Liu Ya-Shu , Lv Jia-Le , Sun Hui , Chang Qing , Liu Chun-Feng , Zhao Yu-Hong
Published: March 2021

Background: The etiology of congenital heart disease (CHD) has been extensively studied in the past decades. Therefore, it is critical to clarify clear hierarchies of evidence between types of environmental factors and CHD.

Methods: Electronic searches in PubMed, Embase, Web of Science, Cochrane database were conducted from inception to April 20, 2020 for meta-analyses investigating the aforementioned topic.

Results: Overall, 41 studies including a total of 165 meta-analyses of different environmental factors and CHD were examined, covering a wide range of risk factors. The summary random effects estimates were significant at P < 0.05 in 63 meta-analyses (38%), and 15 associations (9%) were significant at P < 10−6. Of these meta-analyses, eventually one risk factor (severe obesity; relative risk: 1.38, 95% confidence interval: 1.30–1.47) had significant summary associations at P < 10−6, included more than 1,000 cases, had 95% prediction intervals excluding the null value, and were not suggestive of large heterogeneity (I2 < 50%), small-study effects (P-value for Egger's test > 0.10), or excess significance (P > 0.10). Eight associations (5%) (including maternal lithium exposure, maternal obesity, maternal alcohol consumption, and maternal fever) had results that were significant at P < 10−6, included more than 1,000 cases, and had 95% prediction intervals excluding the null value (highly suggestive).

Conclusion: This umbrella review shows that many environmental factors have substantial evidence in relation to the risk of developing CHD. More and better-designed studies are needed to establish robust evidence between environmental factors and CHD.

Systematic Review Registration: [PROSPERO], identifier [CRD42020193381].
Landslide Susceptibility Modeling Using a Hybrid Bivariate Statistical and Expert Consultation Approach in Canada Hill, Sarawak, Malaysia
Authors: Daniel Marelyn Telun , Ng Tham Fatt , Abdul Kadir Mohd. Farid , Pereira Joy Jacqueline
Published: March 2021

Landslide susceptibility assessment was conducted in Canada Hill, Sarawak, Malaysia through a combined bivariate statistics and expert consultation approach using geographical information system, which captures landslide-conditioning parameters specific to the study area; to ensure its usefulness in practice. Over the past four decades, many landslide parameters and increasingly sophisticated statistical methods have been used in landslide research. However, the findings have had very limited use in practice as the actual ground conditions are not well represented. The weakness is due to poor quality of data in landslide inventories and inadequate understanding of landslide-conditioning parameters. In this study, bivariate statistical method was used in conjunction with an iterative process of expert consultation. Thirteen original landslide-conditioning parameters were narrowed down to six, with the addition of a unique parameter, planar failure potential, which was selected based on expert input. The parameter captures planar failure landslides, which has the highest impact in the study area, causing loss of lives and property destruction. The inaugural landslide susceptibility map for the study area has five classes; very low, low, moderate, high and very high susceptibility. All major planar failures and most smaller circular failures fall within the very high susceptibility class, with a success rate of 75.8%. The approach used in this study has improved the quality of the landslide inventory and delineated key conditioning parameters. The resultant map captures local conditions, which is useful for landslide management.
Beyond the Early Adopters: Escape Rooms in Science Education
Authors: Veldkamp Alice , Knippels Marie-Christine P. J. , van Joolingen Wouter R.
Published: March 2021

Case studies report enthusiastically on the implementation of escape rooms in science education. This mixed-method study explores beyond the early adopting teacher, as the perceptions of 50 teachers and 270 students were investigated. Escape rooms are time restricted games where participants work together and accomplish a specific goal. The escape rooms’ usability for education in terms of goals, experiences during gameplay, outcomes, and boundary conditions are studied, using multiple data sources: online questionnaires, interviews, classroom observations and movie clips made by students about their experiences. The use of mixed methods and large samples on this topic is a novelty. Results show that teachers of different ages, gender and teaching experience were appealed in particular to the diversity of activities offered that call for multiple skills and teamwork. Students experienced the need to think hard using multiple thinking skills and enjoyed the feeling of autonomy and mastery during gameplay. This is interesting, as an escape room setup is very strict, with few degrees of freedom. According to teachers and students, escape rooms are suitable for processing, rehearsing and formative assessment of science knowledge and skills. However, the time restriction during gameplay appears to be an ambiguous factor in student learning.
A Predictive Nomogram for Red Blood Cell Transfusion in Pheochromocytoma Surgery: A Study on Improving the Preoperative Management of Pheochromocytoma
Authors: Guo Ying , You Lili , Hu Huijun , Tong Anli , Zhang Xiaoyun , Yan Li , Zhang Shaoling
Published: March 2021

Purpose

Surgery is the major treatment option for pheochromocytoma but carries potential risks, including hemorrhage and hemodynamic instability. Even with laparoscopic adrenalectomy, intraoperative blood transfusion happens from time to time, but few studies have investigated risk factors. For the first time we develop and validate a nomogram for prediction of red blood cell transfusion in pheochromocytoma surgery.

Methods

There were 246 patients in our center and 56 patients in Peking Union Medical College Hospital, who underwent pheochromocytoma surgery, enrolled in the study. We incorporated clinical and radiological risk factors, and presented this with a nomogram. Lasso regression model was used for feature selection. Logistic regression analysis was performed to identify the odd ratios. The performance of the nomogram was assessed with respect to its discrimination, calibration and clinical usefulness.

Results

Thirty-two features were reduced to five, which were phenoxybenzamine use, phenoxybenzamine treatment duration, preinduction heart rate, tumor diameter and surgical procedure. The model showed good discrimination (C-index, 0.857; 95% CI, 0.781–0.836) and application in the validation sets also gave good discrimination (internal validation: C-index, 0.831; 95% CI, 0.750–0.822; external validation: C-index, 0.924; 95% CI, 0.766–1.000). Calibration tested with the Hosmer-Lemeshow test yielded a good agreement between prediction and observation (training P=0.358; internal validation P=0.205; external validation P=0.395). Odd ratios of phenoxybenzamine use, phenoxybenzamine treatment duration, preinduction HR, tumor diameter and open surgery were 13.32 (95% CI, 1.48–197.38; P = 0.034), 1.04 (95% CI, 0.99–1.08; P = 0.092), 1.04 (95% CI, 1.01–1.08; P=0.006), 1.03 (95% CI, 1.02–1.06; P<0.001), 17.13 (95% CI, 5.18–78.79; P<0.001), respectively. Decision curve analysis demonstrated the clinical usefulness of the nomogram.

Conclusions

This study presents a nomogram that may be used to facilitate the prediction of red blood cell transfusion in pheochromocytoma surgery and help to do the preoperative management more efficiently.
A Markov Regime Switching Model for Ultra-Short-Term Wind Power Prediction Based on Toeplitz Inverse Covariance Clustering
Authors: Fan Hang , Zhang Xuemin , Mei Shengwei , Zhang Junzi
Published: March 2021

The rapid development of wind energy has brought a lot of uncertainty to the power system. The accurate ultra-short-term wind power prediction is the key issue to ensure the stable and economical operation of the power system. It is also the foundation of the intraday and real-time electricity market. However, most researches use one prediction model for all the scenarios which cannot take the time-variant and non-stationary property of wind power time series into consideration. In this paper, a Markov regime switching method is proposed to predict the ultra-short-term wind power of multiple wind farms. In the regime switching model, the time series is divided into several regimes that represent different hidden patterns and one specific prediction model can be designed for each regime. The Toeplitz inverse covariance clustering (TICC) is utilized to divide the wind power time series into several hidden regimes and each regime describes one special spatiotemporal relationship among wind farms. To represent the operation state of the wind farms, a graph autoencoder neural network is designed to transform the high-dimensional measurement variable into a low-dimensional space which is more appropriate for the TICC method. The spatiotemporal pattern evolution of wind power time series can be described in the regime switching process. Markov chain Monte Carlo (MCMC) is used to generate the time series of several possible regime numbers. The Kullback-Leibler (KL) divergence criterion is used to determine the optimal number. Then, the spatiotemporal graph convolutional network is adopted to predict the wind power for each regime. Finally, our Markov regime switching method based on TICC is compared with the classical one-state prediction model and other Markov regime switching models. Tests on wind farms located in Northeast China verified the effectiveness of the proposed method.
Mismatch Between Risk and Response May Amplify Lethal and Non-lethal Effects of Humans on Wild Animal Populations
Authors: Smith Justine A. , Gaynor Kaitlyn M. , Suraci Justin P.
Published: March 2021

Human activity has rapidly transformed the planet, leading to declines of animal populations around the world through a range of direct and indirect pathways. Humans have strong numerical effects on wild animal populations, as highly efficient hunters and through unintentional impacts of human activity and development. Human disturbance also induces costly non-lethal effects by changing the behavior of risk-averse animals. Here, we suggest that the unique strength of these lethal and non-lethal effects is amplified by mismatches between the nature of risk associated with anthropogenic stimuli and the corresponding response by wild animals. We discuss the unique characteristics of cues associated with anthropogenic stimuli in the context of animal ecology and evolutionary history to explore why and when animals fail to appropriately (a) detect, (b) assess, and (c) respond to both benign and lethal stimuli. We then explore the costs of over-response to a benign stimulus (Type I error) and under-response to a lethal stimulus (Type II error), which can scale up to affect individual fitness and ultimately drive population dynamics and shape ecological interactions. Finally, we highlight avenues for future research and discuss conservation measures that can better align animal perception and response with risk to mitigate unintended consequences of human disturbance.
Complete Metamorphosis in Manduca sexta Involves Specific Changes in DNA Methylation Patterns
Authors: Gegner Jasmin , Vogel Heiko , Billion André , Förster Frank , Vilcinskas Andreas
Published: March 2021

The transition between morphologically distinct phenotypes during complete metamorphosis in holometabolous insects is accompanied by fundamental transcriptional reprogramming. Using the tobacco hornworm (Manduca sexta), a powerful model for the analysis of insect evolution and development, we conducted a genome-wide comparative analysis of gene expression and DNA methylation in caterpillars and adults to determine whether complete metamorphosis has an epigenetic basis in this species. Bisulfite sequencing indicated a generally low level of DNA methylation with a unimodal CpGO/E distribution. Expression analysis revealed that 24 % of all known M. sexta genes (3.729) were upregulated in last-instar larvae relative to the adult moth, whereas 26 % (4.077) were downregulated. We also identified 4.946 loci and 4.960 regions showing stage-specific differential methylation. Interestingly, genes encoding histone acetyltransferases and histone deacetylases were differentially methylated in the larvae and adults, indicating there is crosstalk between different epigenetic mechanisms. The distinct sets of methylated genes in M. sexta larvae and adults suggest that complete metamorphosis involves epigenetic modifications associated with profound transcriptional reprogramming, involving approximately half of all the genes in this species.
Dynamics of Natural Regeneration: Implications for Landscape Restoration in the Atlantic Forest, Brazil
Authors: Siminski Alexandre , Zambiazi Daisy Christiane , dos Santos Karine Louise , Fantini Alfredo Celso
Published: March 2021

This study aimed to understand post-agricultural natural forest regeneration in the Southern Brazilian Atlantic Forest and its possible role as a cost-effective, passive approach to forest restoration. The study characterized vegetation structure, floristic composition, and the dynamics of secondary forest chronosequences. Data were collected from 159 plots (10 × 10 m each) across forest remnants in Santa Catarina State, covering forest ages that ranged from 2 to 60 years of regeneration after swidden agriculture. Only areas with no signs of degradation were sampled in order to provide a description of vegetation characteristics that could be used to identify and monitor natural regeneration. A total of 11,455 woody plants were identified and classified into 334 species representing 71 families. As the succession process unfolds, the continuous turnover of species makes forests more diverse and structurally complex. Floristic similarity among forest types is observed during the early stages of succession, but decreases over time. Pioneer species dominate young secondary forests, representing about 40% of the basal area up to 10 years of regeneration. Shade-tolerant species start colonizing the sites at early ages; however, they become more important structural elements only after 30 years of succession. The observed patterns of forest structure and species diversity largely conform to the post-agricultural succession seen in many tropical forests. The high species diversity found in this study highlights the importance of natural regeneration as a strategy to restore ecosystems. Floristic data can be used as a reference for choosing suitable species for active restoration, as well as contributing to the design of integrated restoration strategies. We herein reinforce the potential of natural regeneration as part of large-scale restoration programs, which would be particularly attractive to family farmers by the low cost of supplies and labor.
Interstitial Lung Disease in Common Variable Immunodeficiency
Authors: Lopes Joao Pedro , Ho Hsi-en , Cunningham-Rundles Charlotte
Published: March 2021

Interstitial lung disease (ILD) is a common complication in patients with common variable immunodeficiency (CVID) and often associated with other features, such as bronchiectasis and autoimmunity. As the ILD term encompasses different acute and chronic pulmonary conditions, the diagnosis is commonly made based on imaging features; histopathology is less frequently available. From a cohort of 637 patients with CVID followed at our center over 4 decades, we reviewed the data for 46 subjects (30 females, 16 males) who had lung biopsies with proven ILD. They had a median age at CVID diagnosis of 26 years old, with a median IgG level at diagnosis of 285.0 mg/dL with average isotype switched memory B cells of 0.5%. Lung biopsy pathology revealed granulomas in 25 patients (54.4%), lymphoid interstitial pneumonia in 13 patients (28.3%), lymphoid hyperplasia not otherwise specified in 7 patients (15.2%), cryptogenic organizing pneumonia in 7 patients (15.2%), follicular bronchitis in 4 patients (8.7%), and predominance of pulmonary fibrosis in 4 patients (8.7%). Autoimmune manifestations were common and were present in 28 (60.9%) patients. Nine patients (19.6%) died, with a median age at death of 49-years-old. Lung transplant was done in 3 of these patients (6.5%) who are no longer alive. These analyses reveal the high burden of this complication, with almost one-fifth of the group deceased in this period. Further understanding of the causes of the development and progression of ILD in CVID patients is required to define the best management for this patient population.
TCRMatch: Predicting T-Cell Receptor Specificity Based on Sequence Similarity to Previously Characterized Receptors
Authors: Chronister William D. , Crinklaw Austin , Mahajan Swapnil , Vita Randi , Koşaloğlu-Yalçın Zeynep , Yan Zhen , Greenbaum Jason A. , Jessen Leon E. , Nielsen Morten , Christley Scott , Cowell Lindsay G. , Sette Alessandro , Peters Bjoern
Published: March 2021

The adaptive immune system in vertebrates has evolved to recognize non-self antigens, such as proteins expressed by infectious agents and mutated cancer cells. T cells play an important role in antigen recognition by expressing a diverse repertoire of antigen-specific receptors, which bind epitopes to mount targeted immune responses. Recent advances in high-throughput sequencing have enabled the routine generation of T-cell receptor (TCR) repertoire data. Identifying the specific epitopes targeted by different TCRs in these data would be valuable. To accomplish that, we took advantage of the ever-increasing number of TCRs with known epitope specificity curated in the Immune Epitope Database (IEDB) since 2004. We compared seven metrics of sequence similarity to determine their power to predict if two TCRs have the same epitope specificity. We found that a comprehensive k-mer matching approach produced the best results, which we have implemented into TCRMatch, an openly accessible tool (http://tools.iedb.org/tcrmatch/) that takes TCR β-chain CDR3 sequences as an input, identifies TCRs with a match in the IEDB, and reports the specificity of each match. We anticipate that this tool will provide new insights into T cell responses captured in receptor repertoire and single cell sequencing experiments and will facilitate the development of new strategies for monitoring and treatment of infectious, allergic, and autoimmune diseases, as well as cancer.
Low Densities of the Ghost Crab Ocypode quadrata Related to Large Scale Human Modification of Sandy Shores
Authors: Barboza Carlos A. M. , Mattos Gustavo , Soares-Gomes Abílio , Zalmon Ilana Rosental , Costa Leonardo Lopes
Published: March 2021

Sandy beaches are the most common ecosystems of coastal regions and provide direct and indirect essential services for millions of people, such as coastal protection, fishing, tourism, and recreational activities. However, the natural habitats of sandy shores are being modified at rates never experienced before, making beaches key monitoring sites of marine ecosystems worldwide. The ghost crab species Ocypode quadrata is the most conspicuous crustacean of sandy beaches along the Western Atlantic coast and has been successfully used as an indicator of anthropogenic disturbance and environmental variability. To investigate the potential role of a “triple whammy” [(1) urbanization; (2) use of resources; (3) decreasing resilience] on the most common bioindicator of sandy shores, we compiled a dataset including 214 records of burrows density from 94 microtidal sandy beach sectors covering a range of over 65° of latitude. The response of burrows density to synergetic effects of human modification of natural systems and environmental changes was investigated using linear models. We used the cumulative Human Modification (HMc) index, a standardized geographic projection of changes of natural systems, as a predictor of urbanization, industrialization and use of resources. The predictor wave energy, tidal range and temperature (sea surface and air) were included as potential effects of climate changes. Literature review showed records mainly concentrated at sub-tropical and temperate regions. HMc values were clearly negatively related to burrows density, thereby supporting an effect of modification of natural habitat at large spatial scale. Sea surface temperature and air temperature were positive related with density and the lack of a general pattern of the relationship between burrows density, interactions between wave energy and tide range, supported unclear patterns reported at regional scales. Finally, we argue that ghost crabs are valuable targets for protection actions on sandy beaches that can benefit coexisting species and provide natural habitat conservation.
Elevated Calf Mortality and Long-Term Responses of Wild Bottlenose Dolphins to Extreme Climate Events: Impacts of Foraging Specialization and Provisioning
Authors: Mann Janet , Foroughirad Vivienne , McEntee Molly H. F. , Miketa Madison L. , Evans Taylor C. , Karniski Caitlin , Krzyszczyk Ewa , Patterson Eric M. , Strohman John C. , Wallen Megan M.
Published: March 2021

As demands for wildlife tourism increase, provisioning has become a popular means of providing up-close viewing to the public. At Monkey Mia, Shark Bay, Australia, up to five adult female Indo-Pacific bottlenose dolphins (Tursiops aduncus) visit a 100 m stretch of beach daily to receive fish handouts. In 2011, a severe marine heatwave (MHW) devastated seagrass and fish populations in Shark Bay. Offspring survival declined precipitously among seagrass specialists (dolphins that forage disproportionately in seagrass habitat). As all provisioned dolphins at the site are seagrass specialists, we examined how provisioned and non-provisioned seagrass specialists responded to the MHW. Using 27 years of data we compare habitat use, home range size, calf mortality, and predation risk between provisioned and non-provisioned females and their offspring before and after the MHW. Our results show that provisioned females have extremely small home ranges compared to non-provisioned females, a pattern attributable to their efforts to remain near the site of fish handouts. However, weaned offspring (juveniles) born to provisioned females who are not provisioned themselves also had much smaller home ranges, suggesting a persistent maternal effect on their behavior. After the MHW, adult females increased their use of seagrass habitats, but not their home range size. Provisioned females had significantlylowercalf mortality than non-provisioned females, a pattern most evident pre-MHW, and, in the first 5 years after the MHW (peri-MHW, 2011–2015), calf mortality did not significantly increase for either group. However, the ecosystem did not recover, and post-MHW (2016–2020), calf mortality was substantially higher, regardless of provisioning status. With few survivors, the impact of the MHW on juvenile mortality post-weaning is not known. However, over three decades, juvenile mortality among offspring of provisioned vs. non-provisioned females did not statistically differ. Thus, the survival benefits accrued to calves in the provisioned group likely cease after weaning. Finally, although shark attack rates on seagrass specialists did not change over time, elevated predation on calves cannot be ruled out as a cause of death post-MHW. We discuss our results as they relate to anthropogenic influences on dolphin behavioral plasticity and responses to extreme climate events.
PLK:Δgra9 Live Attenuated Strain Induces Protective Immunity Against Acute and Chronic Toxoplasmosis
Authors: Li Jixu , Galon Eloiza May , Guo Huanping , Liu Mingming , Li Yongchang , Ji Shengwei , Zafar Iqra , Gao Yang , Zheng Weiqing , Adjou Moumouni Paul Franck , Rizk Mohamed Abdo , Tumwebaze Maria Agnes , Benedicto Byamukama , Ringo Aaron Edmond , Masatani Tatsunori , Xuan Xuenan
Published: March 2021

Toxoplasmosis is a zoonotic parasitic disease caused by the obligate intracellular protozoa Toxoplasma gondii, which threatens a range of warm-blooded mammals including humans. To date, it remains a challenge to find safe and effective drug treatment or vaccine against toxoplasmosis. In this study, our results found that the development of a mutant strain based on gene disruption of dense granule protein 9 (gra9) in type II PLK strain decreased parasite replication in vivo, severely attenuated virulence in mice, and significantly reduced the formation of cysts in animals. Hence, we developed an immunization scheme to evaluate the protective immunity of the attenuated strain of Δgra9 in type II PLK parasite as a live attenuated vaccine against toxoplasmosis in the mouse model. Δgra9 vaccination-induced full immune responses characterized by significantly high levels of pro-inflammatory cytokine interferon gamma (IFN-γ) and interleukin-12 (IL-12), maintained the high T. gondii-specific immunoglobulin G (IgG) level, and mixed high IgG1/IgG2a levels. Their levels provided the complete protective immunity which is a combination of cellular and humoral immunity in mouse models against further infections of lethal doses of type I RH, type II PLK wild-type tachyzoites, or type II PLK cysts. Results showed that Δgra9 vaccination proved its immunogenicity and potency conferring 100% protection against acute and chronic T. gondii challenges. Together, Δgra9 vaccination provided safe and efficient immune protection against challenging parasites, suggesting that PLK:Δgra9 is a potentially promising live attenuated vaccine candidate.
Identification of a DNA Repair Gene Signature and Establishment of a Prognostic Nomogram Predicting Biochemical-Recurrence-Free Survival of Prostate Cancer
Authors: Long Gongwei , Ouyang Wei , Zhang Yucong , Sun Guoliang , Gan Jiahua , Hu Zhiquan , Li Heng
Published: March 2021

Background: The incidence of prostate cancer (PCa) is high and increasing worldwide. The prognosis of PCa is relatively good, but it is important to identify the patients with a high risk of biochemical recurrence (BCR) so that additional treatment could be applied.

Method: Level 3 mRNA expression and clinicopathological data were obtained from The Cancer Genome Atlas (TCGA) to serve as training data. The GSE84042 dataset was used as a validation set. Univariate Cox, lasso Cox, and stepwise multivariate Cox regression were applied to identify a DNA repair gene (DRG) signature. The performance of the DRG signature was assessed based on Kaplan–Meier curve, receiver operating characteristic (ROC), and Harrell’s concordance index (C-index). Furtherly, a prognostic nomogram was established and evaluated likewise.

Results: A novel four DRG signature was established to predict BCR of PCa, which included POLM, NUDT15, AEN, and HELQ. The ROC and C index presented good performance in both training dataset and validation dataset. The patients were stratified by the signature into high- and low-risk groups with distinct BCR survival. Multivariate Cox analysis revealed that the DRG signature is an independent prognostic factor for PCa. Also, the DRG signature high-risk was related to a higher homologous recombination deficiency (HRD) score. The nomogram, incorporating the DRG signature and clinicopathological parameters, was able to predict the BCR with high efficiency and showed superior performance compared to models that consisted of only clinicopathological parameters.

Conclusion: Our study identified a DRG signature and established a prognostic nomogram, which were reliable in predicting the BCR of PCa. This model could help with individualized treatment and medical decision making.
Transcriptional Inhibition of lncRNA gadd7 by CRISPR/dCas9-KRAB Protects Spermatocyte Viability
Authors: Zhao Jun , Ma Wenmin , Zhong Yucheng , Deng Hao , Zhou Bingyu , Wu Yaqin , Yang Meiqiong , Li Huan
Published: March 2021

Our previous study found that lncRNA gadd7 was up-regulated in the semen of varicocele patients, and could promote the apoptosis of mouse spermatocytes and inhibit their proliferation. Therefore, we further explored whether down-regulation of Gadd seven expression could protect the viability of spermatocytes. Here we designed specific sgRNAs targeting the ORF region of gadd7, and constructed a CRISPR-dCas9-KRAB system that effectively inhibits gadd7 at the transcriptional level. The CRISPRi system can effectively prevent the apoptosis of spermatocytes and enhance their proliferation, which is expected to provide a potentially effective molecular intervention method for the treatment of male infertility caused by varicocele.
Identification of Sox2 and NeuN Double-Positive Cells in the Mouse Hypothalamic Arcuate Nucleus and Their Reduction in Number With Aging
Authors: Sugiura Ayumu , Shimizu Tatsuhiro , Kameyama Takeshi , Maruo Tomohiko , Kedashiro Shin , Miyata Muneaki , Mizutani Kiyohito , Takai Yoshimi
Published: March 2021

The hypothalamus plays a central role in homeostasis and aging. The hypothalamic arcuate nucleus (ARC) controls homeostasis of food intake and energy expenditure and retains adult neural stem cells (NSCs)/progenitor cells. Aging induces the loss of NSCs and the enhancement of inflammation, including the activation of glial cells in the ARC, but aging-associated alterations of the hypothalamic cells remain obscure. Here, we identified Sox2 and NeuN double-positive cells in a subpopulation of cells in the mouse ARC. These cells were reduced in number with aging, although NeuN-positive neuronal cells were unaltered in the total number. Diet-induced obesity mice fed with high-fat diet presented a similar hypothalamic alteration to aged mice. This study provides a new insight into aging-induced changes in the hypothalamus.
Potentiation of Brain-Derived Neurotrophic Factor-Induced Protection of Spiral Ganglion Neurons by C3 Exoenzyme/Rho Inhibitor
Authors: Harre Jennifer , Heinkele Laura , Steffens Melanie , Warnecke Athanasia , Lenarz Thomas , Just Ingo , Rohrbeck Astrid
Published: March 2021

Preservation of the excitability of spiral ganglion neurons (SGN) may contribute to an improved speech perception after cochlear implantation. Thus, the application of exogenous neurotrophic factors such as the neurotrophin brain-derived neurotrophic factor (BDNF) to increase SGN survival in vitro and in vivo is a promising pharmacological approach in cochlear implant (CI) research. Due to the difficult pharmacokinetic profile of proteins such as BDNF, there is a quest for small molecules to mediate the survival of SGN or to increase the efficacy of BDNF. The C3 exoenzyme from Clostridium botulinum could be a potential new candidate for the protection and regeneration of SGN. Inhibition of the RhoA GTPase pathway which can be mediated by C3 is described as a promising strategy to enhance axonal regeneration and to exert pro-survival signals in neurons. Nanomolar concentrations of C3, its enzymatically inactive form C3E174Q, and a 26mer C-terminal peptide fragment covering amino acid 156–181 (C3156-181) potentiated the neuroprotective effect on SGN mediated by BDNF in vitro. The neuroprotective effect of C3/BDNF was reduced to the neuroprotective effect of BDNF alone after the treatment with wortmannin, an inhibitor of the phosphatidylinositol-3-kinase (PI3K).The exoenzyme C3 (wild-type and enzyme-deficient) and the C3 peptide fragment C3154–181 present novel biologically active compounds for the protection of the SGN. The exact underlying intracellular mechanisms that mediate the neuroprotective effect are not clarified yet, but the combination of BDNF (TrkB stimulation) and C3 exoenzyme (RhoA inhibition) can be used to protect SGN in vitro.