Identification of QTLs and candidate genes for high grain Fe and Zn concentration in sorghum [Sorghum bicolor (L.)Moench]

Sorghum is a major food crop in the semi-arid tropics of Africa and Asia. Enhancing the grain iron (Fe) and zinc (Zn) concentration in sorghum using genetic approaches would help alleviate micronutrient malnutrition in millions of poor people consuming sorghum as a staple food. To localize genomic regions associated with grain Fe and Zn, a sorghum F6 recombinant inbred line (RIL) population (342 lines derived from cross 296B PVK 801) was phenotyped in six environments, and genotyped with simple sequence repeat (SSR), DArT (Diversity Array Technology) and DArTSeq (Diversity Array Technology) markers. Highly significant genotype environment interactions were observed for both micronutrients. Grain Fe showed greater variation than Zn. A sorghum genetic map was constructed with 2088 markers (1148 DArTs, 927 DArTSeqs and 13 SSRs) covering 1355.52 cM with an average marker interval of 0.6 cM. Eleven QTLs (individual) and 3 QTLs (across) environments for Fe and Zn were identified. We identified putative candidate genes from the QTL interval of qfe7.1, qzn7.1, and qzn7.2 (across environments) located on SBI-07 involved in Fe and Zn metabolism. These were CYP71B34, and ZFP 8 (ZINC FINGER PROTEIN 8). After validation, the linked markers identified in this study can help in developing high grain Fe and Zn sorghum cultivars in sorghum improvement programs globally

Disordered structure for long-range charge density wave order in annealed crystals of magnetic kagome FeGe

Recently, charge density wave (CDW) has been observed well below the order of antiferromagnetism (AFM) in kagome FeGe in which magnetism and CDW are intertwined to form an emergent quantum ground state. The mechanism of CDW precipitating from an A-type AFM of Fe kagome sublattice is intensively debated. The structural distortion originating from the CDW has yet to be accurately determined in FeGe. Here we resolved the structure model of the CDW in annealed FeGe crystals through single crystal x-ray diffraction via a synchrotron radiation source. The annealed crystals exhibit strong CDW transition signals exemplified by sharp magnetic susceptibility drop and specific heat jump, as well as intense superlattice reflections from 2 $\times$ 2 $\times$ 2 CDW order. Occupational disorder of Ge atoms resulting from short-range CDW correlations above $T_\mathrm{CDW}$ has also been identified from the structure refinements. The dimerization of Ge atoms along c axis has been demonstrated to be the dominant distortion for CDW. The Fe kagome and Ge honeycomb sublattices only undergo subtle distortions. Occupational disorder of Ge atoms is also proved to exist in the CDW phase due to the random selection of partial Ge sites to be dimerized to realize the structural distortion. Our work paves the way to understanding the unconventional nature of CDW in FeGe not only by solving the structural distortion below $T_\mathrm{CDW}$ and identifying fluctuations above it but also by rationalizing the synthesis of high-quality crystals for in-depth investigations in the future.Comment: 18 pages, 4 figures. Comments are welcom

Identification of QTLs and Underlying Candidate Genes Controlling Grain Fe and Zn Concentration in Sorghum [Sorghum bicolor (L).Moench]

Biofortification is one of sustainable options for combating micronutrient-malnutrition. For identifying genomic regions associated with grain Fe and Zn in sorghum, RIL population (342 individuals) from cross 296B × PVK 801 was phenotyped for two years at three locations and genotyped with SSRs and DArTs. Highly significant genotype×environment interactions were observed for both micronutrients; grain Fe showed greater variation than Zn. Sorghum genetic map was constructed with 2088 markers (1148 DArTs, 927 DArT Seqs and 13 SSRs) covering 1355.52 cM with an average marker interval of 0.6cM. A total of 18 QTLs controlling Fe and Zn were found stable across environments. Three QTLs for Fe and 15 for Zn were identified with phenotypic variance explained (PVE) values ranging from 3.94 to 5.09% and 3.17 to 9.42%, respectively. Of these 18 stable QTLs, 11 were located on chromosome SBI-07. Favorable alleles for 11 QTLs (co-located) for Fe and Zn on chromosome SBI-07 were contributed by parent PVK801-P23. QTLs were analyzed in-silico to identify underlying candidate genes, 62 candidate genes involved in Fe/Zn metabolism were identified within QTL interval; twenty-three were found in QTL with highest phenotypic effect (PVE 9.42%). Sorghum genes underlying Fe/Zn QTLs were used to analyze gene synteny with rice and maize. Synteny sequence level between sorghum-rice ranged from 44% to 97%, while sorghum-maize ranged from 49% to 99%. QTLs/candidate/novel genes along with the marker/genetic resources identified through this study can help in developing high Fe and Zn lines in cost-effective and efficient manner

IPSS-independent prognostic value of plasma CXCL10, IL-7 and IL-6 levels in myelodysplastic syndromes

Recent studies suggest a powerful prognostic value for plasma cytokine levels in primary myelofibrosis (interleukin (IL)-2R, IL-8, IL-12, IL-15 and C–X–C motif chemokine 10 (CXCL10)) and large-cell lymphoma (IL-2R, IL-8, IL-10, IL-12, CXCL9 and CXCL10). To examine the possibility of a similar phenomenon in myelodysplastic syndromes (MDS), we used multiplex enzyme-linked immunosorbent assay to measure 30 plasma cytokines in 78 patients with primary MDS. Compared with normal controls (n=35), the levels of 19 cytokines were significantly altered. Multivariable analysis identified increased levels of CXCL10 (P<0.01), IL-7 (P=0.02) and IL-6 (P=0.07) as predictors of shortened survival; the survival association remained significant when the Cox model was adjusted for the International Prognostic Scoring System, age, transfusion-need or thrombocytopenia. MDS patients with normal plasma levels of CXCL10, IL-7 and IL-6 lived significantly longer (median survival 76 months) than those with elevated levels of at least one of the three cytokines (median survival 25 months) (P<0.01). Increased levels of IL-6 were associated with inferior leukemia-free survival, independent of other prognostic factors (P=0.01). Comparison of plasma cytokines between MDS (n=78) and primary myelofibrosis (n=127) revealed a significantly different pattern of abnormalities. These observations reinforce the concept of distinct and prognostically relevant plasma cytokine signatures in hematological malignancies

Possible molecular mechanisms underlying the development of atherosclerosis in cancer survivors

Cancer survivors undergone treatment face an increased risk of developing atherosclerotic cardiovascular disease (CVD), yet the underlying mechanisms remain elusive. Recent studies have revealed that chemotherapy can drive senescent cancer cells to acquire a proliferative phenotype known as senescence-associated stemness (SAS). These SAS cells exhibit enhanced growth and resistance to cancer treatment, thereby contributing to disease progression. Endothelial cell (EC) senescence has been implicated in atherosclerosis and cancer, including among cancer survivors. Treatment modalities for cancer can induce EC senescence, leading to the development of SAS phenotype and subsequent atherosclerosis in cancer survivors. Consequently, targeting senescent ECs displaying the SAS phenotype hold promise as a therapeutic approach for managing atherosclerotic CVD in this population. This review aims to provide a mechanistic understanding of SAS induction in ECs and its contribution to atherosclerosis among cancer survivors. We delve into the mechanisms underlying EC senescence in response to disturbed flow and ionizing radiation, which play pivotal role in atherosclerosis and cancer. Key pathways, including p90RSK/TERF2IP, TGFβR1/SMAD, and BH4 signaling are explored as potential targets for cancer treatment. By comprehending the similarities and distinctions between different types of senescence and the associated pathways, we can pave the way for targeted interventions aim at enhancing the cardiovascular health of this vulnerable population. The insights gained from this review may facilitate the development of novel therapeutic strategies for managing atherosclerotic CVD in cancer survivors

Galectin-3C Inhibits Tumor Growth and Increases the Anticancer Activity of Bortezomib in a Murine Model of Human Multiple Myeloma

Galectin-3 is a human lectin involved in many cellular processes including differentiation, apoptosis, angiogenesis, neoplastic transformation, and metastasis. We evaluated galectin-3C, an N-terminally truncated form of galectin-3 that is thought to act as a dominant negative inhibitor, as a potential treatment for multiple myeloma (MM). Galectin-3 was expressed at varying levels by all 9 human MM cell lines tested. In vitro galectin-3C exhibited modest anti-proliferative effects on MM cells and inhibited chemotaxis and invasion of U266 MM cells induced by stromal cell-derived factor (SDF)-1α. Galectin-3C facilitated the anticancer activity of bortezomib, a proteasome inhibitor approved by the FDA for MM treatment. Galectin-3C and bortezomib also synergistically inhibited MM-induced angiogenesis activity in vitro. Delivery of galectin-3C intravenously via an osmotic pump in a subcutaneous U266 cell NOD/SCID mouse model of MM significantly inhibited tumor growth. The average tumor volume of bortezomib-treated animals was 19.6% and of galectin-3C treated animals was 13.5% of the average volume of the untreated controls at day 35. The maximal effect was obtained with the combination of galectin-3C with bortezomib that afforded a reduction of 94% in the mean tumor volume compared to the untreated controls at day 35. In conclusion, this is the first study to show that inhibition of galectin-3 is efficacious in a murine model of human MM. Our results demonstrated that galectin-3C alone was efficacious in a xenograft mouse model of human MM, and that it enhanced the anti-tumor activity of bortezomib in vitro and in vivo. These data provide the rationale for continued testing of galectin-3C towards initiation of clinical trials for treatment of MM

Lenalidomide reduces microglial activation and behavioral deficits in a transgenic model of Parkinson’s disease

BACKGROUND: Parkinson’s disease (PD) is one of the most common causes of dementia and motor deficits in the elderly. PD is characterized by the abnormal accumulation of the synaptic protein alpha-synuclein (α-syn) and degeneration of dopaminergic neurons in substantia nigra, which leads to neurodegeneration and neuroinflammation. Currently, there are no disease modifying alternatives for PD; however, targeting neuroinflammation might be a viable option for reducing motor deficits and neurodegeneration. Lenalidomide is a thalidomide derivative designed for reduced toxicity and increased immunomodulatory properties. Lenalidomide has shown protective effects in an animal model of amyotrophic lateral sclerosis, and its mechanism of action involves modulation of cytokine production and inhibition of NF-κB signaling. METHODS: In order to assess the effect of lenalidomide in an animal model of PD, mThy1-α-syn transgenic mice were treated with lenalidomide or the parent molecule thalidomide at 100 mg/kg for 4 weeks. RESULTS: Lenalidomide reduced motor behavioral deficits and ameliorated dopaminergic fiber loss in the striatum. This protective action was accompanied by a reduction in microgliosis both in striatum and hippocampus. Central expression of pro-inflammatory cytokines was diminished in lenalidomide-treated transgenic animals, together with reduction in NF-κB activation. CONCLUSION: These results support the therapeutic potential of lenalidomide for reducing maladaptive neuroinflammation in PD and related neuropathologies. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12974-015-0320-x) contains supplementary material, which is available to authorized users