The contribution and mechanism of hypoxia/USP19/Beclin-1 feed-forward loop in cervical cancer.

Cervical cancer ranks fourth in female mortality. Since the mechanisms for pathogenesis of cervical cancer are still poorly understood, the effective treatment options are lacking. Beclin-1 exhibits an inhibitory role in cervical cancer via suppressing the proliferation, invasion, and migration of cervical cancer cells. It is reported that USP19 removes the K11-linked ubiquitination of Beclin-1 to protect Beclin-1 from proteasomal degradation. Interestingly, we found that hypoxia induced a significant decrease of both Beclin-1 and USP19, suggesting that hypoxia could dually inhibit the protein level of Beclin-1 through a type 2 coherent feed-forward loop (C2-FFL, hypoxia ⊸ Beclin-1 integrating with hypoxia ⊸ USP19 → Beclin-1) to promote the occurrence and development of cervical cancer. Furthermore, mathematical modeling revealed that under the hypoxic environment of solid tumor, the hypoxia/USP19/Beclin-1 coherent feed-forward loop could significantly reduce the protein level of Beclin-1, greatly enhance the sensitivity of Beclin-1 to hypoxia, strikingly restrict the heterogeneity of Beclin-1, and contribute to the low positive rate of Beclin-1 in cervical cancer. It is expected to have significance for elucidating the underlying mechanisms of the occurrence and development of cervical cancer and to provide novel targets and strategies for prevention and treatment of cervical cancer.

Angiogenesis-related immune response may be the prelude to the syndesmophyte formation in Ankylosing spondylitis.

BACKGROUND: Ankylosing spondylitis (AS) is a chronic autoimmune arthritis that mainly affects spine joints. To date, the pathogenesis of AS remains unclear, although immune cells and innate immune response cytokines have been suggested to be crucial players. METHODS: By adopting a single-cell RNA sequencing approach in the AS cynomolgus model, we profiled and characterized PBMC proportions along disease progression. RESULTS: Here, our primary focus was on the activation of an immune cascade-initiating lymphocyte subtype known as CD4+CXCR5+ T follicular helper (Tfh) cells. These Tfhs demonstrated a localized residence in AS bone lesion as an ectopic lymphoid structure. Moreover, Tfhs would serve as an upstream initiator for a pro-angiogenic cascade. Then, an expansion in CD14+ monocytes and DC cells subsets resulted in enhanced expression of angiogenesis genes in these AS cynomolgus monkeys. With a confirmed higher abundance of TNF-α accompanying H-type vascular invasion in the osteophytic region, pronounced expansion of Tfhs at such lesion site signaling for monocytes and DCs intrusion is considered as the prelude to the characteristic angiogenic bony outgrowth in AS known as syndesmophytes. CONCLUSIONS: We explored the intimate relationship between local inflammation and bone formation in AS from the perspective of nascent vascularisation. Hence, our study lays the foundation for elucidating a unified AS pathogenesis through the immune-angiogenesis-osteogenesis axis.

Relation between iodine nutrition and thyroid diseases in Qinghai, China.

Objective: To investigate the adult iodine nutrition and the prevalence of thyroid diseases in Qinghai Province, and analyze the correlation between iodine and thyroid diseases, so as to provide a basis for adjusting the salt iodization plan in Qinghai Province. Methods: Using cluster and stratified sampling method to select 2628 permanent residents over 18 years old in Qinghai Province for questionnaire survey, physical examination, thyroid color ultrasound, and laboratory index detection. Results: 1. The coverage of iodized salt in adults is 99.71%. 2. The detection rates of thyroid disorders in adults were as follows: Clinical hyperthyroidism was 1.20%, subclinical hyperthyroidism was 0.20%, clinical hypothyroidism was 1.00%, subclinical hypothyroidism was 29.20%, and the goiter was 2.10%. The percentages positivity of TPO Ab, TG Ab, goiter was 9.80%, 9.20%, 2.10%, respectively. Among them single thyroid nodule was 6.40%, multi-nodule thyroid gland was 1.80%. 3. The percentages of mild iodine deficiency, moderate iodine deficiency, Severe iodine deficiency, adequate iodine intake (AI), more than adequate iodine intake (MAI)and excessive iodine intake (EI)were 8.41%, 2.17%, 0.26%, 33.22%, 28.35%, and 27.59%, respectively. The percentages of mild, moderate and severe iodine deficiency in urban populations (7.13%, 0.87%, 0.0%) were significantly lower than those in rural populations (9.81%, 3.59%, 0.56%) (P < 0.05), and the rates of adequate, more than adequate iodine intake in urban populations (36.03%, 30.93%) were significantly higher than that in rural populations (30.14%, 25.52%). The rate of excess iodine intake was higher in rural areas (30.38%) than in urban areas (25.04%). 4. The positive rates of subclinical hypothyroidism, goiter, TPO Ab and TG Ab in female adults (35.28%, 3.39%, 13.54%, 13.94%) were higher than those in male adults (23.58%, 0.96%, 6.266%, 4.79%). The detection rate of single thyroid nodules was higher in urban (8.01%) than rural populations (4.70%), while the detection rate of hypothyroidism, subclinical hypothyroidism, and goiter (0.58%, 25.84%, 1.38%) was lower than that in rural populations (1.52%, 32.96%, 2.96%) (P<0.05). 5. There was no statistical significance in the detection rates of clinical hyperthyroidism, subclinical hypothyroidism, subclinical hypothyroidism, goiter, thyroid nodules, TPO Ab and TG Ab positive rates in different iodine nutritional status (P>0.05). The positive rate of hypothyroidism in the iodine deficiency group is higher than in other iodine nutrition groups. Conclusion: The nutritional status of iodine in Qinghai Province is iodine excess. Subclinical hypothyroidism was detected at a high rate. Subclinical hypothyroidism, goiter, TPO Ab, and TG Ab were more common in female than in male. The proportion of mild, moderate, and severe iodine deficiency was higher in urban areas than in rural areas. The detection rate of thyroid nodules was higher in urban than in rural areas, and that of hypothyroidism, subclinical hypothyroidism, and goiter was lower than that in rural populations. The detection rate of clinical hypothyroidism was statistically significant in different iodine nutritional states (P< 0.05).

The RING finger protein family in health and disease.

Ubiquitination is a highly conserved and fundamental posttranslational modification (PTM) in all eukaryotes regulating thousands of proteins. The RING (really interesting new gene) finger (RNF) protein, containing the RING domain, exerts E3 ubiquitin ligase that mediates the covalent attachment of ubiquitin (Ub) to target proteins. Multiple reviews have summarized the critical roles of the tripartite-motif (TRIM) protein family, a subgroup of RNF proteins, in various diseases, including cancer, inflammatory, infectious, and neuropsychiatric disorders. Except for TRIMs, since numerous studies over the past decades have delineated that other RNF proteins also exert widespread involvement in several diseases, their importance should not be underestimated. This review summarizes the potential contribution of dysregulated RNF proteins, except for TRIMs, to the pathogenesis of some diseases, including cancer, autoimmune diseases, and neurodegenerative disorder. Since viral infection is broadly involved in the induction and development of those diseases, this manuscript also highlights the regulatory roles of RNF proteins, excluding TRIMs, in the antiviral immune responses. In addition, we further discuss the potential intervention strategies targeting other RNF proteins for the prevention and therapeutics of those human diseases.

Genome-wide identification and characterization of mungbean CIRCADIAN CLOCK ASSOCIATED 1 like genes reveals an important role of VrCCA1L26 in flowering time regulation.

BACKGROUND: CIRCADIAN CLOCK ASSOCIATED 1 like (CCA1L) proteins are important components that participate in plant growth and development, and now have been characterized in multiple plant species. However, information on mungbean CCA1L genes is limited. RESULTS: In this study, we identified 27 VrCCA1L genes from the mungbean genome. VrCCA1L genes were unevenly distributed on 10 of the 11 chromosomes and showed one tandem and two interchromosomal duplication events. Two distinct kinds of conserved MYB domains, MYB 1 and MYB 2, were found, and the conserved SHAQK(Y/F) F sequence was found at the C terminus of each MYB 2 domain. The VrCCA1Ls displayed a variety of exon-intron organizations, and 24 distinct motifs were found among these genes. Based on phylogenetic analysis, VrCCA1L proteins were classified into five groups; group I contained the most members, with 11 VrCCA1Ls. VrCCA1L promoters contained different types and numbers of cis-acting elements, and VrCCA1Ls showed different expression levels in different tissues. The VrCCA1Ls also displayed distinct expression patterns under different photoperiod conditions throughout the day in leaves. VrCCA1L26 shared greatest homology to Arabidopsis CCA1 and LATE ELONGATED HYPOCOTYL (LHY). It delayed the flowering time in Arabidopsis by affecting the expression levels of CONSTANS (CO), FLOWERING LOCUS T (FT), and SUPPRESSOR OF OVEREXPRESSION OF CONSTANS 1 (SOC1). CONCLUSION: We identified and characterized 27 VrCCA1L genes from mungbean genome, and investigated their spatio-temporal expression patterns. Further analysis revealed that VrCCA1L26 delayed flowering time in transgenic Arabidopsis plants. Our results provide useful information for further functional characterization of the VrCCA1L genes.

Comparative genomic analysis of high-altitude adaptation for Mongolia Mastiff, Tibetan Mastiff, and Canis Lupus.

Tibetan Mastiff has adapted to the extreme environment of the Qinghai-Tibetan Plateau. Yet, the underlying mechanisms of its high-altitude-adaptation and origin remains elusive. Here, we generated the draft genomes of Mongolia Mastiff, Tibetan Mastiff, and Canis Lupus. The phylogenetic tree uncovered that Tibetan Mastiff and Mongolia Mastiff were derived from Canis Lupus species. The comparative genomic analyses identified that the expansion of gene families related to DNA repair and damage response, and contraction related to ATPase activity revealed the genetic adaptations of Tibetan Mastiff and Canis Lupus to high altitude. In addition, the Tibetan Mastiff and Canis Lupus had signals of positive selection for genes involved in fatty-acid α/ß- oxidation for highland adaptation. Notably, the positively selected TERT of Tibetan Mastiff should be an adaptive trait for correcting DNA damage. These findings suggested that the Tibetan Mastiff and Canis Lupus evolves basic strategies for adaptation to high altitude.

When RING finger family proteins meet SARS-CoV-2.

The pandemic coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is currently the most formidable challenge to humankind. Understanding the complicated virus-host interplay is crucial for fighting against viral infection. A growing number of studies point to the critical roles of RING (really interesting new gene) finger (RNF) proteins during SARS-CoV-2 infection. RNF proteins exert direct antiviral activity by targeting genome and envelope glycoproteins of SARS-CoV-2. Additionally, some RNF members serve as potent regulators for antiviral innate immunity and antibody-dependent neutralization of SARS-CoV-2. Notably, SARS-CoV-2 also hijacks the RNF proteins-mediated ubiquitination process to evade host antiviral innate immunity and enhance viral replication. In this mini-review, we discuss the diverse antiviral mechanisms of RNF proteins and viral immune evasion in an RNF proteins-dependent manner. Understanding the crosstalk between RNF proteins and SARS-CoV-2 infection would help design potential novel targets for COVID-19 treatment.

A new and spontaneous animal model for ankylosing spondylitis is found in cynomolgus monkeys.

BACKGROUND: Ankylosing spondylitis is a progressive, disabling joint disease that affects millions worldwide. Given its unclear etiology, studies of ankylosing spondylitis relied heavily on drug-induced or transgenic rodent models which retain only partial clinical features. There is obviously a lack of a useful disease model to conduct comprehensive mechanistic studies. METHODS: We followed a group of cynomolgus monkeys having joint lesions reported of spinal stiffness for 2 years by conducting hematological testing, radiographic examination, family aggregation analysis, pathological analysis, and genetic testing. RESULTS: The results confirmed that these diseased animals suffered from spontaneous ankylosing spondylitis with clinical features recapitulating human ankylosing spondylitis disease progression, manifested by pathological changes and biochemical indicators similar to that of ankylosing spondylitis patients. CONCLUSION: The study offers a promising non-human primate model for spontaneous ankylosing spondylitis which may serve as an excellent substitute for its pre-clinical research.

Transcriptome and methylome changes in two contrasting mungbean genotypes in response to drought stress.

BACKGROUND: Due to drought stress, the growth, distribution, and production of mungbean is severely restricted. Previous study combining physiological and transcriptomic data indicated different genotypes of mungbean exhibited variable responses when exposed to drought stress. Aside from the genetic variation, the modifications of environmentally induced epigenetics alterations on mungbean drought-stress responses were still elusive. RESULTS: In this study, firstly, we compared the drought tolerance capacity at seedling stage by detecting physiological parameters in two contrasting genotypes wild mungbean 61 and cultivar 70 in response to drought stress. We found that wild mungbean 61 showed lower level of MDA and higher levels of POD and CAT, suggesting wild mungbean 61 exhibited stronger drought resistance. Transcriptomic analysis indicated totally 2859 differentially expressed genes (DEGs) were detected when 70 compared with 61 (C70 vs C61), and the number increased to 3121 in the comparison of drought-treated 70 compared with drought-treated 61 (D70 vs D61). In addition, when drought-treated 61 and 70 were compared with their controls, the DEGs were 1117 and 185 respectively, with more down-regulated DEGs than up-regulated in D61 vs C61, which was opposite in D70 vs C70. Interestingly, corresponding to this, after drought stress, more hypermethylated differentially methylated regions (DMRs) in 61 were detected and more hypomethylated DMRs in 70 were detected. Further analysis suggested that the main variations between 61 and 70 existed in CHH methylation in promoter. Moreover, the preference of methylation status alterations in D61 vs C61 and D70 vs C70 also fell in CHH sequence context. Further analysis of the correlation between DMRs and DEGs indicated in both D61 vs C61 and D70 vs C70, the DMRs in gene body was significantly negatively correlated with DEGs. CONCLUSIONS: The physiological parameters in this research suggested that wild mungbean 61 was more resistant to drought stress, with more hypermethylated DMRs and less hypomethylated DMRs after drought stress, corresponding to more down-regulated DEGs than up-regulated DEGs. Among the three DNA methylation contexts CG, CHG, and CHH, asymmetric CHH contexts were more dynamic and prone to be altered by drought stress and genotypic variations.

The crosstalk between viral RNA- and DNA-sensing mechanisms.

Viral infections pose a severe threat to humans by causing many infectious, even fatal, diseases, such as the current pandemic disease (COVID-19) since 2019, and understanding how the host innate immune system recognizes viruses has become more important. Endosomal and cytosolic sensors can detect viral nucleic acids to induce type I interferon and proinflammatory cytokines, subsequently inducing interferon-stimulated genes for restricting viral infection. Although viral RNA and DNA sensing generally rely on diverse receptors and adaptors, the crosstalk between DNA and RNA sensing is gradually appreciated. This minireview highlights the overlap between the RNA- and DNA-sensing mechanisms in antiviral innate immunity, which significantly amplifies the antiviral innate responses to restrict viral infection and might be a potential novel target for preventing and treating viral diseases.

Characterization of Mungbean CONSTANS-LIKE Genes and Functional Analysis of CONSTANS-LIKE 2 in the Regulation of Flowering Time in Arabidopsis.

CONSTANS-LIKE (COL) genes play important roles in the regulation of plant growth and development, and they have been analyzed in many plant species. However, few studies have examined COL genes in mungbean (Vigna radiata). In this study, we identified and characterized 31 mungbean genes whose proteins contained B-Box domains. Fourteen were designated as VrCOL genes and were distributed on 7 of the 11 mungbean chromosomes. Based on their phylogenetic relationships, VrCOLs were clustered into three groups (I, II, and III), which contained 4, 6, and 4 members, respectively. The gene structures and conserved motifs of the VrCOL genes were analyzed, and two duplicated gene pairs, VrCOL1/VrCOL2 and VrCOL8/VrCOL9, were identified. A total of 82 cis-acting elements were found in the VrCOL promoter regions, and the numbers and types of cis-acting elements in each VrCOL promoter region differed. As a result, the expression patterns of VrCOLs varied in different tissues and throughout the day under long-day and short-day conditions. Among these VrCOL genes, VrCOL2 showed a close phylogenetic relationship with Arabidopsis thaliana CO and displayed daily oscillations in expression under short-day conditions but not long-day conditions. In addition, overexpression of VrCOL2 accelerated flowering in Arabidopsis under short-day conditions by affecting the expression of the flowering time genes AtFT and AtTSF. Our study lays the foundation for further investigation of VrCOL gene functions.

Unidirectional movement of small RNAs from shoots to roots in interspecific heterografts.

Long-distance RNA movement is important for plant growth and environmental responses; however, the extent to which RNAs move between distant tissues, their relative magnitude and functional importance remain to be elucidated on a genomic scale. Using a soybean (Glycine max)-common bean (Phaseolus vulgaris) grafting system, we identified 100 shoot-root mobile microRNAs and 32 shoot-root mobile phased secondary small interfering RNAs (phasiRNAs), which were predominantly produced in shoots and transported to roots, and, in most cases, accumulated to a level similar to that observed in shoots. Many of these microRNAs or phasiRNAs enabled cleavage of their messenger RNA targets or phasiRNA precursors in roots. In contrast, most mobile-capable mRNAs were transcribed in both shoots and roots, with only small proportions transported to recipient tissues. These findings suggest that the regulatory mechanisms for small RNA movement are different from those for mRNA movement, and that the former is more strictly regulated and, probably, more functionally important than the latter.

Functional characterization of soybean (Glycine max) DIRIGENT genes reveals an important role of GmDIR27 in the regulation of pod dehiscence.

DIRIGENT (DIR) genes play important roles in regulating plant growth and development and have been studied in many plant species. However, information on DIR genes in soybean is limited. Here, we identified and characterized 54 GmDIRs and studied the characteristics of GmDIRs. Most of the GmDIRs contained a classical gene structure, one exon; 26 conserved motifs were found among these GmDIRs. The GmDIRs were grouped into four subfamilies, DIR-a, DIR-b, DIR-e and DIR-f, based on a phylogenetic analysis, and 24 duplicated gene pairs were identified. Differences in the cis-acting elements in the GmDIR promoter regions might result in distinct expression patterns of GmDIRs in different tissues. In addition, GmDIR27 had a close relationship with the pod dehiscence gene GmPdh1, and overexpression of GmDIR27 increased pod dehiscence by affecting several pod dehiscence-related gene expressions. Generally, our results provide essential information that aids future efforts to functionally characterize soybean GmDIR genes.

VrLELP controls flowering time under short-day conditions in Arabidopsis.

Flowering time has a critically important effect on the reproduction of plants, and many components involved in flowering-time regulation have been identified in multiple plant species. However, studies of the flowering-time genes in mungbean (Vigna radiata) have been limited. Here, we characterized a novel mungbean gene, VrLELP, involved in flowering-time regulation in transgenic Arabidopsis. Subcellular localization analysis revealed that VrLELP was localized in the membrane, cytoplasm and nucleus and the nucleus and membrane contained higher signal than cytoplasm, similar to the empty vector control. The expression of VrLELP was higher in leaves and pods and lower in nodule roots relative to other tissues. The expression of VrLELP varied during flower development. The expression of VrLELP also varied during the day, reaching a peak after 12 h of illumination under long-day conditions. In contrast, under short-day conditions, the abundance of VrLELP transcripts changed little throughout the day. In addition, VrLELP delayed flowering time in transgenic Arabidopsis plants by suppressing the expression of the flowering-time genes CO and FT under short-day conditions. However, VrLELP did not affect flowering time under long-day conditions in Arabidopsis. Our study provides essential information for future studies of the molecular mechanisms of the flowering-time regulation system in mungbean.

Accelerator or Brake: Immune Regulators in Malaria.

Malaria is a life-threatening infectious disease, affecting over 250 million individuals worldwide each year, eradicating malaria has been one of the greatest challenges to public health for a century. Growing resistance to anti-parasitic therapies and lack of effective vaccines are major contributing factors in controlling this disease. However, the incomplete understanding of parasite interactions with host anti-malaria immunity hinders vaccine development efforts to date. Recent studies have been unveiling the complexity of immune responses and regulators against Plasmodium infection. Here, we summarize our current understanding of host immune responses against Plasmodium-derived components infection and mainly focus on the various regulatory mechanisms mediated by recent identified immune regulators orchestrating anti-malaria immunity.

Characterization and Comparative Analysis of RWP-RK Proteins from Arachis duranensis, Arachis ipaensis, and Arachis hypogaea.

RWP-RK proteins are important factors involved in nitrate response and gametophyte development in plants, and the functions of RWP-RK proteins have been analyzed in many species. However, the characterization of peanut RWP-RK proteins is limited. In this study, we identified 16, 19, and 32 RWP-RK members from Arachis duranensis, Arachis ipaensis, and Arachis hypogaea, respectively, and investigated their evolution relationships. The RWP-RK proteins were classified into two groups, RWP-RK domain proteins and NODULE-INCEPTION-like proteins. Chromosomal distributions, gene structures, and conserved motifs of RWP-RK genes were compared among wild and cultivated peanuts. In addition, we identified 12 orthologous gene pairs from the two wild peanut species, 13 from A. duranensis and A. hypogaea, and 13 from A. ipaensis and A. hypogaea. One, one, and seventeen duplicated gene pairs were identified within the A. duranensis, A. ipaensis, and A. hypogaea genomes, respectively. Moreover, different numbers of cis-acting elements in the RWP-RK promoters were found in wild and cultivated species (87 in A. duranensis, 89 in A. ipaensis, and 92 in A. hypogaea), and as a result, many RWP-RK genes showed distinct expression patterns in different tissues. Our study will provide useful information for further functional and evolutionary analysis of the RWP-RK genes.

A mathematic model to reveal delicate cross-regulation between MAVS/STING, inflammasome and MyD88-dependent type I interferon signalling.

Early type I interferon is essential for antagonizing against malaria infection, which remains a significant global infectious disease. After Plasmodium yoelii YM infection, the activation of MAVS-, STING- and inflammasome-IRF3-mediated pathway could trigger the Socs1 expression to inhibit the TLR7-MyD88-IRF7-induced type I interferon production. However, the dynamic regulatory mechanisms of type I interferon response to YM infection and delicate cross-regulation of these signalling are far from clear. In current study, we established a mathematical model to systematically demonstrate that the MAVS-, STING- and inflammasome-mediated signalling pathways play distinct roles in regulating type I interferon response after YM infection; and the YM dose could significantly affect the difference of resistance to YM infection among MAVS, STING and inflammasome deficiency. Collectively, our study systematically elucidated the precise regulatory mechanisms of type I interferon signalling after YM infection and advanced the research on therapy of plasmodium infection by incorporating multiple signalling pathways at diverse time.

Molecular and transcriptional characterization of phosphatidyl ethanolamine-binding proteins in wild peanuts Arachis duranensis and Arachis ipaensis.

BACKGROUND: Phosphatidyl ethanolamine-binding proteins (PEBPs) are involved in the regulation of plant architecture and flowering time. The functions of PEBP genes have been studied in many plant species. However, little is known about the characteristics and expression profiles of PEBP genes in wild peanut species, Arachis duranensis and Arachis ipaensis, the diploid ancestors of cultivated peanuts. RESULTS: In this study, genome-wide identification methods were used to identify and characterize a total of 32 peanut PEBP genes, 16 from each of the two wild peanut species, A. duranensis and A. ipaensis. These PEBP genes were classified into 3 groups (TERMINAL FLOWER1-like, FLOWERING LOCUS T-like, and MOTHER OF FT AND TFL1-like) based on their phylogenetic relationships. The gene structures, motifs, and chromosomal locations for each of these PEBPs were analyzed. In addition, 4 interchromosomal duplications and 1 tandem duplication were identified in A. duranensis, and 2 interchromosomal paralogs and 1 tandem paralog were identified in A. ipaensis. Ninety-five different cis-acting elements were identified in the PEBP gene promoter regions and most genes had different numbers and types of cis-elements. As a result, the transcription patterns of these PEBP genes varied in different tissues and under long day and short day conditions during different growth phases, indicating the functional diversities of PEBPs in different tissues and their potential functions in plant photoperiod dependent developmental pathways. Moreover, our analysis revealed that AraduF950M/AraduWY2NX in A. duranensis, and Araip344D4/Araip4V81G in A. ipaensis are good candidates for regulating plant architecture, and that Aradu80YRY, AraduYY72S, and AraduEHZ9Y in A. duranensis and AraipVEP8T in A. ipaensis may be key factors regulating flowering time. CONCLUSION: Sixteen PEBP genes were identified and characterized from each of the two diploid wild peanut genomes, A. duranensis and A. ipaensis. Genetic characterization and spatio-temporal expression analysis support their importance in plant growth and development. These findings further our understanding of PEBP gene functions in plant species.

Inflammasome activation negatively regulates MyD88-IRF7 type I IFN signaling and anti-malaria immunity.

The inflammasome plays a critical role in inflammation and immune responses against pathogens. However, whether or how inflammasome activation regulates type I interferon (IFN-I) signaling in the context of malaria infection remain unknown. Here we show mice deficient in inflammasome sensors AIM2, NLRP3 or adaptor Caspase-1 produce high levels of IFN-I cytokines and are resistant to lethal Plasmodium yoelii YM infection. Inactivation of inflammasome signaling reduces interleukin (IL)-1ß production, but increases IFN-I production. Mechanistically, we show inflammsome activation enhances IL-1ß-mediated MyD88-TRAF3-IRF3 signaling and SOCS1 upregulation. However, SOCS1 inhibits MyD88-IRF7-mediated-IFN-I signaling and cytokine production in plasmacytoid dendritic cells. By contrast, ablation of inflammsome components reduces SOCS1 induction, and relieves its inhibition on MyD88-IRF7-dependent-IFN-I signaling, leading to high levels of IFN-α/ß production and host survival. Our study identifies a previously unrecognized role of inflammasome activation in the negative regulation of IFN-I signaling pathways and provides potential targets for developing effective malaria vaccines.

Parallel domestication with a broad mutational spectrum of determinate stem growth habit in leguminous crops.

Stem growth habit is a key plant architecture trait determining yield potential in grain legumes, and the phenotypic change from the indeterminate stem growth habit of wild mungbeans (Vigna radiata) to the determinate stem growth habit of cultivated mungbeans is a critical domestication transition. Here we show that indeterminate stem growth in wild mungbean is modulated by a single gene, VrDet1, which encodes a signaling protein of shoot apical meristems. The transition from an indeterminate to a determinate stem growth habit was achieved by selection of two linked point mutations in two putative cis-regulatory elements, resulting in a significant reduction in gene expression. Both the wild-type nucleotides corresponding to the two point mutations were essential for VrDet1 function. In addition, two highly diverse haplotypes of Vrdet1 were found in cultivated mungbeans, suggesting dual domestication of Vrdet1. VrDet1 was orthologous to Dt1 in wild soybean and PvTFL1y in wild common bean, where multiple loss-of-function mutations altering the coding sequences of individual genes were selected to produce determinate stems in cultivated accessions. Interspecific comparison of these orthologs in the wild and cultivated accessions reveals the most conservative interspecific and intraspecific parallel domestication events with the broadest mutational spectrum of a domestication trait in leguminous crops. We also found that interspecifically and functionally conserved promoters possess cis-regulatory elements that are highly conserved in kind but greatly variable in number and order, demonstrating the evolutionary dynamics of regulatory sequences. This work provides insights into the origins of cultivated mungbean and exemplifies the conservativeness and plasticity of the domestication processes of related crops.