bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterizing all-cause excess mortality patterns during COVID-19 pandemic in Mexico
Authors: Dahal Sushma , Banda Juan M. , Bento Ana I. , Mizumoto Kenji , Chowell Gerardo
Published: March 2021

Background

Low testing rates and delays in reporting hinder the estimation of the mortality burden associated with the COVID-19 pandemic. During a public health emergency, estimating all cause excess deaths above an expected level of death can provide a more reliable picture of the mortality burden. Here, we aim to estimate the absolute and relative mortality impact of COVID-19 pandemic in Mexico.

Methods

We obtained weekly mortality time series due to all causes for Mexico, and by gender, and geographic region from 2015 to 2020. We also compiled surveillance data on COVID-19 cases and deaths to assess the timing and intensity of the pandemic and assembled weekly series of the proportion of tweets about ‘death’ from Mexico to assess the correlation between people’s media interaction about ‘death’ and the rise in pandemic deaths. We estimated all-cause excess mortality rates and mortality rate ratio increase over baseline by fitting Serfling regression models and forecasted the total excess deaths for Mexico for the first four weeks of 2021 using the generalized logistic growth model.

Results

We estimated the all-cause excess mortality rate associated with the COVID-19 pandemic in Mexico in 2020 at 26.10 per 10,000 population, which corresponds to 333,538 excess deaths. Males had about 2-fold higher excess mortality rate (33.99) compared to females (18.53). Mexico City reported the highest excess death rate (63.54) and RR (2.09) compared to rest of the country (excess rate=23.25, RR=1.62). While COVID-19 deaths accounted for only 38.64% of total excess deaths in Mexico, our forecast estimate that Mexico has accumulated a total of ∼61610 [95% PI: 60003, 63216] excess deaths in the first four weeks of 2021. Proportion of tweets was significantly correlated with the excess mortality (ρ=0.508 [95% CI: 0.245, 0.701], p-value=0.0004).

Conclusion

The COVID-19 pandemic has heavily affected Mexico. The lab-confirmed COVID-19 deaths accounted for only 38.64% of total all cause excess deaths (333,538) in Mexico in 2020. This reflects either the effect of low testing rates in Mexico, or the surge in number of deaths due to other causes during the pandemic. A model-based forecast indicates that an average of 61,610 excess deaths have occurred in January 2021.
Age-dependent immune response to the Biontech/Pfizer BNT162b2 COVID-19 vaccination
Authors: Müller Lisa , Andrée Marcel , Moskorz Wiebke , Drexler Ingo , Walotka Lara , Grothmann Ramona , Ptok Johannes , Hillebrandt Jonas , Ritchie Anastasia , Rabl Denise , Ostermann Philipp Niklas , Robitzsch Rebekka , Hauka Sandra , Walker Andreas , Menne Christopher , Grutza Ralf , Timm Jörg , Adams Ortwin , Schaal Heiner
Published: March 2021

Background

The SARS-CoV-2 pandemic has led to the development of various vaccines. Real-life data on immune responses elicited in the most vulnerable group of vaccinees over 80 years old is still underrepresented despite the prioritization of the elderly in vaccination campaigns.

Methods

We conducted a cohort study with two age groups, young vaccinees below the age of 60 and elderly vaccinees over the age of 80, to compare their antibody responses to the first and second dose of the BNT162b2 COVID-19 vaccination.

Results

While the majority of participants in both groups produced specific IgG antibody titers against SARS-CoV-2 spike protein, titers were significantly lower in elderly participants. Although the increment of antibody levels after the second immunization was higher in elderly participants, the absolute mean titer of this group remained lower than the <60 group. After the second vaccination, 31.3 % of the elderly had no detectable neutralizing antibodies in contrast to the younger group, in which only 2.2% had no detectable neutralizing antibodies.

Conclusion

Our data suggests that lower frequencies of neutralizing antibodies after BNT162b2 vaccination in the elderly population may require earlier revaccination to ensure strong immunity and protection against infection.
Manipulating vector transmission reveals local processes in bacterial communities of bats
Authors: McKee Clifton D. , Webb Colleen T. , Kosoy Michael Y. , Bai Ying , Osikowicz Lynn M. , Suu-Ire Richard , Ntiamoa-Baidu Yaa , Cunningham Andrew A. , Wood James L. N. , Hayman David T. S.
Published: March 2021

Infectious diseases result from multiple interactions among microbes and hosts, but community ecology approaches are rarely applied. Manipulation of vector populations provides a unique opportunity to test the importance of vectors in infection cycles while also observing changes in pathogen community diversity and species interactions. Yet for many vector-borne infections in wildlife, a biological vector has not been experimentally verified and few manipulative studies have been performed. Using a captive colony of fruit bats in Ghana, we observed changes in the community ofBartonellabacteria over time after the decline and subsequent reintroduction of bat flies. With reduced transmission, community changes were attributed to ecological drift and potential selection through interspecies competition mediated by host immunity. This work demonstrated that forces maintaining diversity in communities of free-living macroorganisms act in similar ways in communities of symbiotic microorganisms, both within and among hosts. Additionally, this study is the first to experimentally test the role of bat flies as vectors ofBartonellaspecies.
Insights into the susceptibility of rice to a floral disease
Authors: Li Guo-Bang , Fan Jing , Liu Jie , Wu Jin-Long , Hu Xiao-Hong , He Jia-Xue , Shen Shuai , Wang He , Zhu Yong , He Feng , Gao Han , Gishkori Zeeshan Ghulam Nabi , Zhao Jing-Hao , Li Yan , Huang Fu , Huang Yan-Yan , Zhao Zhi-Xue , Zhang Ji-Wei , Zhou Shi-Xin , Pu Mei , Chen Xuewei , Wang Jing , Li Weitao , Wu Xian-Jun , Ning Yuese , Sun Wenxian , Wang Wen-Ming
Published: March 2021

Crop floral diseases are economically important as they reduce grain yield and quality and even introduce food toxins. Rice false smut has emerged as a serious floral disease producing mycotoxins. However, very little is known on the interaction mechanisms between rice flower and the causal fungusUstilaginoidea virens. Here we show that a conserved anti-fungal immunity in rice flower is disarmed byU. virensvia a secreted protein UvChi1. UvChi1 functioned as an essential virulence factor and directly interacted with the chitin receptor CEBiP and co-receptor CERK1 in rice to disrupt their oligomerizations and subsequent immune responses. Moreover, intraspecific-conserved UvChi1 could target OsCEBiP/OsCERK1 receptor complex in at least 98.5% of 5232 surveyed rice accessions. These results demonstrate thatU. virensutilizes a crucial virulence factor to subvert chitin-triggered flower immunity in most rice varieties, providing new insights into the susceptibility of rice to false smut disease.

One Sentence Summary

The fungal pathogenUstilaginoidea virensdisarms chitin-triggered immunity in rice flower via a secreted chitinase.
Novel Paju Apodemus Paramyxovirus 1 and 2, Harbored byApodemus agrariusin The Republic of Korea
Authors: Lee Seung-Ho , No Jin Sun , Kim Kijin , Budhathoki Shailesh , Park Kyungmin , Lee Geum Young , Cho Seungchan , Choi Hyeok Sun , Kim Bong-Hyun , Cho Seunghee , Kim Jong Woo , Lee Jin Gyeong , Cho Seung Hye , Kim Heung-Chul , Klein Terry A. , Uhm Chang-Sub , Kim Won-Keun , Song Jin-Won
Published: March 2021

Paramyxoviruses, negative-sense single-stranded RNA viruses, pose a potential threat to public health. Currently, 78 species and 17 genera of paramyxoviruses are classified and harbored by multiple natural reservoirs, including rodents, bats, birds, reptiles, and fish.Jeilongvirushas been proposed as a novel paramyxovirus genus containing J-, Beilong, and Tailam viruses, found in wild rodents. Using RT-PCR, 824Apodemus agrariusindividuals were examined for the prevalence of paramyxovirus infections. Paramyxovirus RNA was detected in 108 (13.1%) rodents captured at 14 trapping sites in Korea. We first present two genetically distinct novel paramyxoviruses (genusJeilongvirus), Paju Apodemus paramyxoviruses 1 (PAPV-1) and 2 (PAPV-2), fromA. agrarius. Six PAPV strains were completely sequenced using next-generation and Sanger sequencing. PAPV-1 genome comprised 19,716 nucleotides, with eight genes (3′-N-P/V/C-M-F-SH-TM-G-L-5′), whereas PAPV-2 genome contained 17,475 nucleotides, with seven genes (3′-N-P/V/C-M-F-TM-G-L-5′). The disparity between PAPV-1 and -2 revealed the presence of theSHgene and length of theGgene in the genome organization. The phylogenies of PAPV-1 and -2 belong to distinct genetic lineages ofJeilongvirusdespite being from the same natural host. PAPV-1 clustered with Beilong and Tailam viruses, while PAPV-2 formed a genetic lineage with Mount Mabu Lophuromys virus-1. PAPV-1 infected human epithelial and endothelial cells, facilitating the induction of type I/III interferons, interferon-stimulated genes, and proinflammatory cytokines. Therefore, this study provides profound insights into the molecular epidemiology, virus-host interactions, and zoonotic potential of novel rodent-borne paramyxoviruses.

Importance

Paramyxoviruses are a critical public health and socio-economic burden to humans. Rodents play a crucial role in transmitting pathogens to humans. In the last decade, novel paramyxoviruses have been discovered in different rodents. Here, we found thatApodemus agrariusharbored two distinct genotypes of the novel paramyxoviruses, Paju Apodemus paramyxovirues 1 (PAPV-1) and 2 (PAPV-2), possessing unique genome structures that are responsible for encoding TM and G proteins of different sizes. In addition, PAPV-1 infected human epithelial and endothelial cells, facilitating the induction of type I/III IFNs, ISGs, and proinflammatory cytokines. Thus, this study provides significant insights into molecular prevalence, virus-host interactions of paramyxoviruses. These observations raise the awareness of physicians and scientists about the emergence of new rodent-borne paramyxoviruses.
Suppression of PIK3CA-driven epileptiform activity by acute pathway control
Authors: Roy Achira , Han Victor Z. , Bard Angela M. , Wehle Devin T. , Smith Stephen E. P. , Ramirez Jan-Marino , Kalume Franck , Millen Kathleen J.
Published: March 2021

Patients harboring mutations in the PI3K-AKT-MTOR signaling pathway often develop a spectrum of neurodevelopmental disorders including epilepsy. A significant proportion of them remain unresponsive to conventional anti-seizure medications. Understanding mutation-specific pathophysiology is thus critical for molecularly targeted therapies. We previously determined that mouse models expressing patient-related activating mutation inPIK3CAare epileptic and acutely treatable with PI3K inhibition, irrespective of dysmorphology (Roy et al. 2015). Using the same mutant model, we have now identified physiological mechanisms underlying the dysregulated neuronal excitability and its acute attenuation. We show that Pik3ca-driven hyperexcitability in hippocampal pyramidal neurons is mediated by changes in multiple non-synaptic, cell-intrinsic properties. These are distinct from mechanisms driving epilepsy in TSC/RHEB models. Further, we report that acute inhibition of PI3K or AKT, but not MTOR, suppresses the intrinsic epileptiform nature of the mutant neurons. These data represent an important step towards precision therapeutics against intractable epilepsy, using pathway drugs originally developed as anti-cancer agents.
Lipid production fromZygosaccharomyces siamensisAP1 using glycerol as a carbon source
Authors: Ilmi M , Siswantoro M
Published: March 2021

Yeasts are considered as potential lipid producer because they are easy to cultivate, able to grow in high cell densities and can produce high concentrations of lipids. Previously we had isolated a promising lipid producing yeast,Zygosaccharomyces siamensisAP1, from wild honey of Central Sulawesi, Indonesia. The strain was able to produce around 19% (w/w biomass) of lipid on glucose. However, its ability to produce lipid on other types of carbon source is still not studied. In this study, we compared the strain ability to produce lipid on glycerol and glucose using different C/N ratio. We also investigated optimum temperature, pH, and growth time for lipid production on glycerol. We found that growing the strain on glycerol with C/N ratio 120 gave the highest lipid content (29.7%). We also found that optimum growth temperature and pH are 30°C and 5, respectively. Maximum lipid biomass, 0.28 g/L, was produced when the strain was grown in the optimum conditions for 72 hours. In conclusion, our results suggest that glycerol is a potential cheap carbon source for lipid production fromZ. siamensisAP1. We suggest further study to increase lipid yield either by fermentation or strain improvement.
Stabilization of Brain Network Dynamics during Childhood and Adolescence is Associated with Gene Expressions
Authors: Lei Tianyuan , Liao Xuhong , Chen Xiaodan , Zhao Tengda , Xu Yuehua , Xia Mingrui , Zhang Jiaying , Sun Xiaochen , Wei Yongbin , Men Weiwei , Wang Yanpei , Hu Mingming , Zhao Gai , Du Bin , Wu Qian , Tan Shuping , Gao Jiahong , Qin Shaozheng , Tao Sha , Dong Qi , He Yong
Published: March 2021

Functional brain networks require dynamic reconfiguration to support flexible cognitive function. However, the developmental principles shaping brain network dynamics remain poorly understood. Here, we report the longitudinal development of large-scale brain network dynamics during childhood and adolescence, and its connection with gene expression profiles. Using a multilayer network model, we show the temporally varying modular architecture of child brain networks, with higher network switching primarily in the association cortex and lower switching in the primary regions. This topographical profile exhibits progressive maturation, which manifests as reduced modular dynamics, particularly in the transmodal (e.g., default-mode and frontoparietal) and sensorimotor regions. These developmental refinements mediate age-related enhancements of global network segregation and are linked with the expression profiles of genes associated with the enrichment of ion transport and nucleobase-containing compound transport. These results highlight a progressive stabilization of brain dynamics, which expand our understanding of the neural mechanisms that underlie cognitive development.
The methylation ofSDC2andTFPI2defined three methylator phenotypes of colorectal cancer
Authors: Lei Ruixue , Zhao Yanteng , Huang Kai , Wan Kangkang , Li Tingting , Yang Haijun , Lv Xianping
Published: March 2021

Methylation-based noninvasive molecular diagnostics are easy and feasible tools for the early detection of colorectal cancer (CRC). However, many of them have the limitation of low sensitivity with some CRCs detection failed in clinical practice. In this study, the clinical and pathological characteristics, as well as molecular features of three methylator-groups, defined by the promoter methylation status ofSDC2andTFPI2, were investigated in order to improve the performance of CRC detection. The Illumina Infinium 450k Human DNA methylation data and clinical information of CRCs were collected from The Cancer Genome Atlas (TCGA) project and Gene Expression Omnibus (GEO) database. CRC samples were divided into three groups, HH (dual-positive), HL (single positive) and LL (dual-negative) according to the methylation status ofSDC2andTFPI2promoters. Differences in age, tumor location, microsatellite instable status and differentially expressed genes (DEGs) were evaluated among the three groups and these findings were then confirmed in our inner CRC dataset. The combination of methylatedSDC2andTFPI2showed a superior performance of distinguishing CRCs from normal controls than each alone. Samples of HL group were more often originated from left-side CRCs whereas very few of them were from right-side (P< 0.05). HH grouped CRCs showed a higher level of microsatellite instability and mutation load than other two groups (mean nonsynonymous mutations for HH/HL/LL: 10.55/3.91/7.02,P= 0.0055). All mutations ofBRAF, one of the five typical CpG island methylator phenotype (CIMP) related genes, were found in HH group (HH/HL/LL: 51/0/0,P= 0.018). Also there was a significantly older patient age at the diagnosis in HH group. Gene expression analysis identified 37, 84 and 22 group-specific DEGs for HH, HL and LL, respectively. Functional enrichment analysis suggested that HH specific DEGs were mainly related to the regulation of transcription and other processes, while LL specific DEGs were enriched in the biological processes of extracellular matrix interaction and cell migration. The three defined mathylator groups showed great difference in tumor location, patient age, MSI and ECM biological process, which could facilitate the development of more effective biomarkers for CRC detection.
Integrative multi-omics approach for stratification of tumor recurrence risk groups of Hepatocellular Carcinoma patients
Authors: Kaur Harpreet , Lathwal Anjali , Raghava Gajendra P.S.
Published: March 2021

Postoperative tumor recurrence is one of the major concerns associated with the poor prognosis of HCC patients. There is yet to elucidate a standard surveillance system for HCC recurrence risk owing to complexity of this malignancy. Generation of multi-omics data from patients facilitate the identification of robust signatures for various diseases. Thus, the current study is an attempt to develop the prognostic models employing multi-omics data to significantly (p-value <0.05) stratify the recurrence high-risk (median Recurrence Free Survival time (RFS) =<12 months) and low-risk groups (median RFS >12 months). First, we identified key 90RNA, 50miRNA and 50 methylation features and developed prognostic models; attained reasonable performance (C-Index >0.70, HR >2.5), on training and validation datasets. Subsequently, we developed a prognostic (PI) model by integrating the four multi-omics features (SUZ12, hsa-mir-3936, cg18465072, and cg22852503), that are biologically inter-linked with each other. This model achieved reasonable performance on training and validation dataset, i.e. C-Index 0.72, HR of 2.37 (1.61 - 3.50), p-value of 6.72E-06, Brier score 0.19 on training dataset, and C-Index 0.72 (95% CI: 0.63 - 0.80), HR of 2.37 (95% CI: 1.61 - 3.50), p-value of 0.015, Brier score 0.19 on validation dataset. Eventually, Drugbank data was investigated to elucidate therapeutic potential of these signatures. We have identified nine potential drugs against three genes (CA9, IL1A, KCNJ15) that are positively correlated with the tumor recurrence. We anticipate these results from our study will help researchers and clinicians to improve the HCC recurrence surveillance, eventually outcome of patients.
Preparation of functional IgY that potently neutralizes HIV-1 in TZM-bl Cell line
Authors: Wei Jinchen , Zhang Yanqun , Zeng Yonglian , Yang Yang , Liang Ronggan , Liang Chengqin , Dai Zhigang , He Songqing , Wu Shuwen , Xu Qing
Published: March 2021

AIDS caused by HIV is one of the most serious public health challenges in the world. As we all know, Antiretroviral therapy (ART) is the most effective way to treat AIDS so far, however, forthe reasons of drug resistance, side effects, compliance, economy, limited its using widely. On the other hand, AIDS cannot be completely cured by ART. While the characterization of bnAbs (broadly neutralizing antibodies) in potent HIV neutralization provides considerable insight into HIV curing, it also can be used for passive immunotherapy or combination with ART for HIV-1 treatment. Here we report a novel technology to produce an neutralized activity bnAbs named HIV-1-IgY, which was extracted from the immunized Chicken egg by pNL4-3 virus antigens, and further purified using Water dilution and Salting out method. The specificity, titer and neutralizing activity of HIV-1-IgY was analyzed by Western blotting, ELISA and TZM-bl cell line evaluation system respectively. The results showed that theHIV-1-IgY has high neutralized activity to HIV in vitro; nearly 90% of HIV-1 were neutralized at 1.89μM in TZM-blsystem, which indicated that IgY may be a source of antibodies for AIDS prevention and treatment. Despite its needs to further consider and evaluate neutralized activity in-vivo and the potential mechanisms, Our data showed that we obtained an HIV-1-IgY which could effectively neutralize HIV-l IIIB virus in vitro.
Inhibition of CDK4/6 Overcomes Primary Resistance to PD-1 Blockade in Malignant Mesothelioma
Authors: Jang Hee-Jin , Truong Cynthia Y. , Lo Eric M. , Holmes Hudson M. , Ramos Daniela , Ramineni Maheshwari , Lee Ju-Seog , Wang Daniel Y. , Pietropaolo Massimo , Ripley R Taylor , Burt Bryan M. , Lee Hyun-Sung
Published: March 2021

Background

Despite the profound number of malignant pleural mesothelioma (MPM) patients now treated with PD-1 blockade, insight into the underpinnings of rational therapeutic strategies to treat resistance to checkpoint immunotherapy remain unrealized. Our objective was to develop a novel therapeutic approach to overcome primary resistance to PD-1 blockade in MPM.

Methods

We generated a transcriptome signature of resistance to PD-1 blockade in MPM patients treated with nivolumab (4 responders and 4 non-responders). We used the TCGA MPM cohort (N=73) to determine what genomic alterations were associated with the resistance signature. We tested whether regulation of identified molecules could overcome resistance to PD-1 blockade in an immunocompetent mouse malignant mesothelioma model.

Results

Immunogenomic analysis by applying our anti-PD-1 resistance signature to the TCGA cohort revealed that deletion ofCDKN2Awas highly associated with primary resistance to PD-1 blockade. Under the hypothesis that resistance to PD-1 blockade can be overcome byCDK4/6inhibition, we tested whetherCDK4/6inhibitors could overcome resistance to PD-1 blockade in subcutaneous tumors derived fromCdkn2a(−/−)AB1 malignant mesothelioma cells, which were resistant to PD-1 blockade. The combination of daily oral administration ofCDK4/6inhibitors (abemaciclib or palbociclib) and intraperitoneal anti-PD-1 treatment markedly suppressed tumor growth, compared with anti-PD-1 orCDK4/6inhibitor alone.

Conclusions

We identified a novel therapeutic target,CDK4/6, to overcome primary resistance to PD-1 blockade through comprehensive immunogenomic approaches. These data provide a rationale for undertaking clinical trials ofCDK4/6inhibitors in the more than 40% of patients with MPM who demonstrate loss ofCDKN2A.
Inhibiting SARS-CoV-2 infectionin vitroby suppressing its receptor, angiotensin-converting enzyme 2, via aryl-hydrocarbon receptor signal
Authors: Tanimoto Keiji , Hirota Kiichi , Fukazawa Takahiro , Matsuo Yoshiyuki , Nomura Toshihito , Tanuza Nazmul , Hirohashi Nobuyuki , Bono Hidemasa , Sakaguchi Takemasa
Published: March 2021

Since understanding molecular mechanisms of SARS-CoV-2 infection is extremely important for developing effective therapies against COVID-19, we focused on the internalization mechanism of SARS-CoV-2 via ACE2. Although cigarette smoke is generally believed to be harmful to the pathogenesis of COVID-19, cigarette smoke extract (CSE) treatments were surprisingly found to suppress the expression of ACE2 in HepG2 cells. We thus tried to clarify the mechanism of CSE effects on expression of ACE2 in mammalian cells. Because RNA-seq analysis suggested that suppressive effects onACE2might be inversely correlated with induction of the genes regulated by aryl hydrocarbon receptor (AHR), the AHR agonists 6-formylindolo(3,2-b)carbazole (FICZ) and omeprazole (OMP) were tested to assess whether those treatments affected ACE2 expression. Both FICZ and OMP clearly suppressedACE2expression in a dose-dependent manner along with inducingCYP1A1. Knock-down experiments indicated a reduction ofACE2by FICZ treatment in an AHR-dependent manner. Finally, treatments of AHR agonists inhibited SARS-CoV-2 infection into Vero E6 cells as determined with immunoblotting analyses detecting SARS-CoV-2 specific nucleocapsid protein. We here demonstrate that treatment with AHR agonists, including CSE, FICZ, and OMP, decreases expression of ACE2 via AHR activation, resulting in suppression of SARS-CoV-2 infection in mammalian cells.
Focal Laser Stimulation of Fly Nociceptors Activates Distinct Axonal and Dendritic Ca2+Signals
Authors: Basak Rajshekhar , Sutradhar Sabyasachi , Howard Jonathon
Published: March 2021

DrosophilaClass IV neurons are polymodal nociceptors that detect noxious mechanical, thermal, optical and chemical stimuli. Escape behaviors in response to attacks by parasitoid wasps are dependent on Class IV cells, whose highly branched dendritic arbors form a fine meshwork that is thought to enable detection of the wasp’s needle-like ovipositor barb. To understand how mechanical stimuli trigger cellular responses, we used a focused 405-nm laser to create highly local lesions to probe the precise position needed in evoke responses. By imaging calcium signals in dendrites, axons, and soma in response to stimuli of varying positions, intensities and spatial profiles, we discovered that there are two distinct nociceptive pathways. Direct stimulation to dendrites (the contact pathway) produces calcium responses in axons, dendrites and the cell body whereas stimulation adjacent to the dendrite (the non-contact pathway) produces calcium responses in the axons only. We interpret the non-contact pathway as damage to adjacent cells releasing diffusible molecules that act on the dendrites. Axonal responses have higher sensitivities and shorter latencies. In contrast, dendritic responses have lower sensitivities and longer latencies. Stimulation of finer, distal dendrites leads to smaller responses than stimulation of coarser, proximal dendrites, as expected if the contact response depends on the geometric overlap of the laser profile and the dendrite diameter. Because the axon signals to the CNS to trigger escape behaviors, we propose that the density of the dendritic meshwork is high not only to enable direct contact with the ovipositor, but also to enable neuronal activation via diffusing signals from damaged surrounding cells. Dendritic contact evokes responses throughout the dendritic arbor, even to regions distant and distal from the stimulus. These dendrite-wide calcium signals may facilitate hyperalgesia or cellular morphological changes following dendritic damage.

Statement of Significance

Animals encounter a wide range of noxious stimuli in the natural world. Nociceptive neurons are specialized cells that sense harmful stimuli and trigger avoidance responses. Class IV cells, located under the cuticle inDrosophilalarvae, are polymodal nociceptors that respond to noxious mechanical, thermal, optical, and chemical stimuli. To investigate the spatial requirements of mechanoreception in Class IV neurons, we measured calcium signals evoked by a focused laser beam that creates highly localized tissue damage. We discovered that different cellular compartments – axons and dendrites – responded differentially depending on whether the stimulus makes direct contact with the neuron or not. This provides evidence that mechanical nociception in Class IV cells occurs via two distinct pathways.
Locus specific epigenetic modalities of random allelic expression imbalance
Authors: Marion-Poll Lucile , Forêt Benjamin , Zielinski Dina , Massip Florian , Attia Mikael , Carter Ava C , Syx Laurène , Chang Howard Y , Gendrel Anne-Valerie , Heard Edith
Published: March 2021

Most autosomal genes are thought to be expressed from both alleles, with some notable exceptions, including imprinted genes and genes showing random monoallelic expression (RME). The extent and nature of RME has been the subject of debate. Here we investigate the expression of several candidate RME genes in F1 hybrid mouse cells before and after differentiation, to define how they become persistently, monoallelically expressed. Clonal monoallelic expression was not observed in ESCs, but when we assessed expression status in more than 200 clones of neuronal progenitor cells, we observed high frequencies of monoallelism. We uncovered unforeseen modes of allelic expression that appear to be gene-specific and epigenetically regulated. This non-canonical allelic regulation has important implications for development and disease, including autosomal dominant disorders and opens up novel therapeutic perspectives.
Universal gene co-expression network reveals receptor-like protein genes conferring broad-spectrum resistance in pepper (Capsicum annuumL.)
Authors: Kang Won-Hee , Lee Junesung , Koo Namjin , Kwon Ji-Su , Park Boseul , Kim Yong-Min , Yeom Seon-In
Published: March 2021

Receptor-like proteins (RLPs) on the plant cell surface have been implicated in immune responses and developmental processes. Although hundreds ofRLPgenes have been identified in plants, only a few RLPs have been functionally characterized in a limited number of plant species. Here, we identifiedRLPsin the pepper (Capsicum annuum) genome, and performed comparative transcriptomics coupled with the analysis of conserved gene co-expression networks (GCNs) to reveal the role of core RLP regulators in pepper–pathogen interactions. A total of 102 RNA-seq datasets of pepper plants infected with four pathogens were used to construct CaRLP-targeted GCNs (CaRLP-GCN). All resistance-responsive CaRLP-GCNs were merged to construct a universal GCN. Fourteen hubCaRLPs, tightly connected with defense related gene clusters, were identified in eight modules. Based on the CaRLP-GCNs, we experimentally tested whether hubCaRLPsin the universal GCN are involved in biotic stress response. Of the nine hubCaRLPstested by virus-induced gene silencing (VIGS), three genes (CaRLP264,CaRLP277, andCaRLP351) showed defense suppression with less hypersensitive response (HR)-like cell death in race-specific and non-host resistance response to viruses and bacteria, respectively, and consistently enhanced susceptibility toRalstonia solanacearumand/orPhytophthora capsici. These data suggest that keyCaRLPsexhibit conserved functions in response to multiple biotic stresses and can be used for engineering of a plant with broad-spectrum resistance. Altogether, we show that generation of a universal GCN using comprehensive transcriptome datasets could provide important clues for uncovering genes involved in various biological processes.
The NADPH oxidase NOX2 is a marker of adverse prognosis involved in chemoresistance of Acute Myeloid Leukemias
Authors: Rosa Paolillo , Mathias Boulanger , Pierre Gâtel , Ludovic Gabellier , Denis Tempé , Rawan Hallal , Marion De Toledo , Jérome Moreaux , Hayeon Baik , Gueret Elise , Christian Récher , Jean-Emmanuel Sarry , Guillaume Cartron , Marc Piechaczyk , Guillaume Bossis
Published: March 2021

Resistance to chemotherapeutic drugs is a major cause of treatment failure in Acute Myeloid Leukemias (AML). To better characterize the mechanisms of chemoresistance, we first identified genes whose expression is dysregulated in AML cells resistant to daunorubicin (DNR) or cytarabine (Ara-C), the main drugs used for the induction therapy. The genes found activated are mostly linked to immune signaling and inflammation. Among them, we identified a strong up-regulation of the NOX2 NAPDH oxidase subunit genes (CYBB,CYBA,NCF1,NCF2,NCF4andRAC2). The ensuing increase in NADPH oxidase activity, which is particularly strong in DNR-resistant cells, participates in the acquisition and/or maintenance of resistance to DNR. In addition, analyzing gp91phox(CYBB-encoded Nox2 catalytic sub-unit) expression at the surface of leukemic blasts from 74 patients at diagnosis showed that NOX2 is generally more expressed and active in leukemic cells from the FAB M4/M5 subtypes compared to FAB M0-M2 ones. Using a gene expression-based score we demonstrate that high NOX2 subunit genes expression is a marker of adverse prognosis, independent of the cytogenetic-based risk classification, in AML patients.
The genetics of gene expression in aC. elegansmulti parental recombinant inbred line population
Authors: Snoek Basten L. , Sterken Mark G. , Nijveen Harm , Volkers Rita J.M. , Riksen Joost , Rosenstiel Philip C. , Schulenburg Hinrich , Kammenga Jan E.
Published: March 2021

Studying genetic variation of gene expression provides a powerful way to unravel the molecular components underlying complex traits. Expression QTL studies have been performed in several different model species, yet most of these linkage studies have been based on genetic segregation of two parental alleles. Recently we developed a multi-parental segregating population of 200 recombinant inbred lines (mpRILs) derived from four wild isolates (JU1511, JU1926, JU1931 and JU1941) in the nematodeCaenorhabditis elegans. We used RNA-seq to investigate how multiple alleles affect gene expression in these mpRILs. We found 1,789 genes differentially expressed between the parental lines. Transgression, expression beyond any of the parental lines in the mpRILs, was found for 7,896 genes. For expression QTL mapping almost 9,000 SNPs were available. By combining these SNPs and the RNA-seq profiles of the mpRILs, we detected almost 6,800 eQTLs. Mosttrans-eQTLs (63%) co-locate in six newly identifiedtrans-bands. Thetrans-eQTLs found in previous 2-parental allele eQTL experiments and this study showed some overlap (17.5%- 46.8%), highlighting on the one hand that a large group of genes is affected by polymorphic regulators across populations and conditions, on the other hand it shows that the mpRIL population allows identification of novel gene expression regulatory loci. Taken together, the analysis of our mpRIL population provides a more refined insight intoC. eleganscomplex trait genetics and eQTLs in general, as well as a starting point to further test and develop advanced statistical models for detection of multi-allelic eQTLs and systems genetics studying the genotype-phenotype relationship.
Genotyping-by-sequencing-based identification ofArabidopsispattern recognition receptor RLP32 recognizing proteobacterial translation initiation factor IF1
Authors: Fan Li , Fröhlich Katja , Melzer Eric , Albert Isabell , Pruitt Rory N. , Zhang Lisha , Albert Markus , Kim Sang-Tae , Chae Eunyoung , Weigel Detlef , Gust Andrea A. , Nürnberger Thorsten
Published: March 2021

Pattern-triggered immunity (PTI) is a central component of plant immunity. Activation of PTI relies on the recognition of microbe-derived structures, termed patterns, through plant encoded surface-resident pattern recognition receptors (PRRs). We have identified proteobacterial translation initiation factor 1 (IF1) as an immunogenic pattern that triggers PTI inArabidopsis thalianaand some related Brassicaceae species. Unlike most other immunogenic patterns identified, IF1 elicitor activity cannot be assigned to a small peptide epitope, suggesting that tertiary fold features are required for IF1 receptor activation. We have deployed natural variation in IF1 sensitivity to identify leucine-rich repeat (LRR) receptor-like protein 32 (RLP32) as the correspondingArabidopsisreceptor using a restriction site-associated DNA sequencing (RAD-seq) approach. Transgenic expression of RLP32 confers IF1 sensitivity torlp32mutants, IF1-insensitiveArabidopsisaccessions and IF1-insensitiveNicotiana benthamiana. RLP32 binds IF1 specifically and forms complexes with LRR receptor kinases SOBIR1 and BAK1 to mediate signaling. Similar to previously identified PRRs RLP32 confers resistance toPseudomonas syringaeinfection, highlighting an unexpectedly complex array of bacterial pattern sensors within a single plant species.
SARS-CoV-2 variant with higher affinity to ACE2 shows reduced sera neutralization susceptibility
Authors: Vogel Monique , Chang Xinyue , Sousa Augusto Gilles , Mohsen Mona O. , Speiser Daniel E. , Bachmann Martin F.
Published: March 2021

Background

Several new variants of SARS-CoV-2 have emerged since fall 2020 which have multiple mutations in the receptor binding domain (RBD) of the spike protein.

Objective

We aimed to assess how mutations in the SARS-CoV-2 RBD affect receptor affinity to angiotensin-converting enzyme 2 (ACE2) and neutralization by anti-RBD serum antibodies.

Methods

We produced a SARS-CoV-2 RBD mutant (RBDmut) with key mutations (E484K, K417N, N501Y) from the newly emerged Brazilian variant. Using Biolayer Interferometry, we analyzed the binding of this mutant to ACE2, and the susceptibility to neutralization by sera from vaccinated mice and COVID-19 convalescent patients.

Results

Kinetic profiles showed increased RBDmut - ACE2 affinity compared to RBDwt, and binding of vaccine-elicited or convalescent sera was significantly reduced. Likewise, both sera types showed significantly reduced ability to block RBDmut - ACE2 binding indicating that antibodies induced by RBDwt have reduced capability to neutralize mutant virus.

Conclusion

Our physiochemical data show enhanced infectivity and reduced neutralization by polyclonal antibodies of the Brazilian variant of SARS-CoV-2.

Capsule summary

SARS-CoV-2 variant with Brazilian RBD mutations shows increased ACE2 affinity and reduced susceptibility to blockage by vaccine-elicited and convalescent sera.
Self-organization of Tissue Growth by Interfacial Mechanical Interactions in Multi-layered Systems
Authors: Chen Tailin , Zhao Yan , Zhao Xinbin , Li Shukai , Cao Jialing , Du Jing , Cao Yanping , Fan Yubo
Published: March 2021

Morphogenesis is a spatially and temporally regulated process involved in various physiological and pathological transformations. In addition to the associated biochemical factors, the physical regulation of morphogenesis has attracted increasing attention. However, the driving force of morphogenesis initiation remains elusive. Here, we show that during the growth of multi-layered tissues, morphogenetic process can be self-organized by the progression of compression gradient stemmed from the interfacial mechanical interactions between layers. In tissues with low fluidity, the compression gradient is progressively strengthened during growth and induces stratification by triggering symmetric-to-asymmetric cell division reorientation at the critical tissue size. In tissues with high fluidity, compression gradient is dynamic and induces cell junction remodelling regulated cell rearrangement leading to 2D in-plane morphogenesis instead of 3D deformation. Morphogenesis can be tuned by manipulating tissue fluidity, cell adhesion forces and mechanical properties to influence the progression of compression gradient during the development of cultured cell sheets and chicken embryos. Together, the dynamics of compression gradient arised from interfacial mechanical interaction provides a conserved mechanism underlying morphogenesis initiation and size control during tissue growth.
GDAP1 loss of function inhibits the mitochondrial pyruvate dehydrogenase complex by altering the actin cytoskeleton
Authors: Wolf Christina , Pouya Alireza , Bitar Sara , Pfeiffer Annika , Bueno Diones , Arndt Sabine , Tenzer Stefan , Dal Bello Federica , Vianello Caterina , Ritz Sandra , Schwirz Jonas , Dobrindt Kristina , Peitz Michael , Hanschmann Eva-Maria , Boussaad Ibrahim , Brüstle Oliver , Giacomello Marta , Krüger Rejko , Methner Axel
Published: March 2021

Charcot-Marie-Tooth (CMT) disease 4A is an autosomal-recessive polyneuropathy caused by mutations of ganglioside-induced differentiation-associated protein 1 (GDAP1), a putative glutathione transferase, which affects mitochondrial shape and alters cellular Ca2+homeostasis. Here, we identify the underlying mechanism. We found that patient-derived motoneurons andGDAP1knockdown SH-SY5Y cells display two phenotypes: more tubular mitochondria and a metabolism characterized by glutamine dependence and fewer cytosolic lipid droplets. GDAP1 interacts with the actin-depolymerizing protein Cofilin-1 in a redoxdependent manner, suggesting a role for actin signaling. Consistently, GDAP1 loss causes less F-actin close to mitochondria, which restricts mitochondrial localization of the fission factor dynamin-related protein 1, instigating tubularity. Changes in the actin cytoskeleton also disrupt mitochondria-ER contact sites. This results in lower mitochondrial Ca2+levels and inhibition of the pyruvate dehydrogenase complex, explaining the metabolic changes upon GDAP1 loss of function. Together, these findings reconcile GDAP1-associated phenotypes and implicate disrupted actin signaling in CMT4A pathophysiology.
Combination ofin vivophage therapy data within silicomodel highlights key parameters for treatment efficacy
Authors: Delattre Raphaëlle , Seurat Jérémy , Haddad Feyrouz , Nguyen Thu-Thuy , Gaborieau Baptiste , Kane Rokhaya , Dufour Nicolas , Ricard Jean-Damien , Guedj Jérémie , Debarbieux et Laurent
Published: March 2021

The clinical (re)development of phage therapy to treat antibiotic resistant infections requires grasping specific biological properties of bacteriophages (phages) as antibacterial. However, identification of optimal dosing regimens is hampered by the poor understanding of phage-bacteria interactionsin vivo.Here we developed a general strategy couplingin vitroandin vivoexperiments with a mathematical model to characterize the interplay between phage and bacterial dynamics during pneumonia induced by a pathogenic strain ofEscherichia coli.The model estimates some key parameters for phage therapeutic efficacy, in particular the impact of dose and route of administration on phage dynamics and the synergism of phage and the innate immune response on the bacterial clearance rate. Simulations predict a low impact of the intrinsic phage characteristics in agreement with the current semi-empirical choices of phages for compassionate treatments. Model-based approaches will foster the deployment of future phage therapy clinical trials.
Taxonomic bias in AMP prediction of invertebrate peptides
Authors: Rádai Zoltán , Kiss Johanna , Nagy Nikoletta A.
Published: March 2021

Invertebrate antimicrobial peptides (AMPs) are at the forefront in the search for agents of therapeutic utility against multi-resistant microbial pathogens, and in recent years substantial advances took place in thein silicoprediction of antimicrobial function of amino acid sequences. A yet neglected aspect is taxonomic bias in the performance of these tools. Owing to differences in the prediction algorithms and used training data sets between tools, and phylogenetic differences in sequence diversity, physicochemical properties and evolved biological functions of AMPs between taxa, notable discrepancies may exist in performance between the currently available prediction tools. Here we tested if there is taxonomic bias in the prediction power in 10 tools with a total of 20 prediction algorithms in 19 invertebrate taxa, using a data set containing 1525 AMP and 3050 non-AMP sequences. We found that most of the tools exhibited considerable variation in performance between tested invertebrate groups. Based on the per-taxa performances and on the variation in performances across taxa we provide guidance in choosing the best-performing prediction tool for all assessed taxa, by listing the highest scoring tool for each of them.
Published Anti-SARS-CoV-2 In Vitro Hits Share Common Mechanisms of Action that Synergize with Antivirals
Authors: Xing Jing , Paithankar Shreya , Liu Ke , Uhl Katie , Li Xiaopeng , Ko Meehyun , Kim Seungtaek , Haskins Jeremy , Chen Bin
Published: March 2021

The global efforts in the past few months have led to the discovery of around 200 drug repurposing candidates for COVID-19. Although most of them only exhibited moderate anti- SARS-CoV-2 activity, gaining more insights into their mechanisms of action could facilitate a better understanding of infection and the development of therapeutics. Leveraging large-scale drug-induced gene expression profiles, we found 36% of the active compounds regulate genes related to cholesterol homeostasis and microtubule cytoskeleton organization. The expression change upon drug treatment was further experimentally confirmed in human lung primary small airway. Following bioinformatics analysis on COVID-19 patient data revealed that these genes are associated with COVID-19 patient severity. The expression level of these genes also has predicted power on anti-SARS-CoV-2 efficacy in vitro, which led to the discovery of monensin as an inhibitor of SARS-CoV-2 replication in Vero-E6 cells. The final survey of recent drug- combination data indicated that drugs co-targeting cholesterol homeostasis and microtubule cytoskeleton organization processes more likely present a synergistic effect with antivirals. Therefore, potential therapeutics should be centered around combinations of targeting these processes and viral proteins.
Spinal Cord Injury Reduces Serum Levels of Fibroblast Growth Factor-21 and Impairs its Signaling Pathways in Liver and Adipose Tissue in Mice
Authors: Liu Xin-Hua , Graham Zachary A. , Harlow Lauren , Pan Jiangping , Azulai Daniella , Bauman William A. , Yarrow Joshua , Cardozo Christopher P.
Published: March 2021

Spinal cord injury (SCI) results in dysregulation of carbohydrate and lipid metabolism; the underlying cellular and physiological mechanisms remain unclear. Fibroblast growth factor 21 (FGF21) is a circulating protein primarily secreted by the liver that lowers blood glucose levels, corrects abnormal lipid profiles, and mitigates non-alcoholic fatty liver disease. FGF21 acts via activating FGF receptor 1 and ß-klotho in adipose tissue and stimulating release of adiponectin from adipose tissue which in turn signals in the liver and skeletal muscle. We examined FGF21/adiponectin signaling after spinal cord transection in mice fed a high fat diet (HFD) or a standard mouse chow. Tissues were collected at 84 days after spinal cord transection or a sham SCI surgery. SCI reduced serum FGF21 levels and hepatic FGF21 expression, as well as β-klotho and FGF receptor-1 (FGFR1) mRNA expression in adipose tissue. SCI also reduced serum levels and adipose tissue mRNA expression of adiponectin and leptin, two major adipokines. In addition, SCI suppressed hepatic type 2 adiponectin receptor (AdipoR2) mRNA expression and PPARα activation in the liver. Post-SCI mice fed a HFD had further suppression of serum FGF21 levels and hepatic FGF21 expression. Elevated serum free fatty acid (FFA) levels after HFD feeding were observed in post-SCI mice but not in shammice, suggesting defective FFA uptake after SCI. Moreover, after SCI several genes that are implicated in insulin’s action had reduced expression in tissues of interest. These findings suggest that downregulated FGF21/adiponectin signaling and impaired responsiveness of adipose tissues to FGF21 may, at least in part, contribute to the overall picture of metabolic dysfunction after SCI.