A putative phosphatase, LSF1 (for LIKE SEX4; previously PTPKIS2), is closely related in sequence and structure to STARCH-EXCESS4 (SEX4), an enzyme necessary for the removal of phosphate groups from ...starch polymers during starch degradation in Arabidopsis (Arabidopsis thaliana) leaves at night. We show that LSF1 is also required for starch degradation: lsf1 mutants, like sex4 mutants, have substantially more starch in their leaves than wild-type plants throughout the diurnal cycle. LSF1 is chloroplastic and is located on the surface of starch granules. lsf1 and sex4 mutants show similar, extensive changes relative to wild-type plants in the expression of sugar-sensitive genes. However, although LSF1 and SEX4 are probably both involved in the early stages of starch degradation, we show that LSF1 neither catalyzes the same reaction as SEX4 nor mediates a sequential step in the pathway. Evidence includes the contents and metabolism of phosphorylated glucans in the single mutants. The sex4 mutant accumulates soluble phospho-oligosaccharides undetectable in wild-type plants and is deficient in a starch granule-dephosphorylating activity present in wild-type plants. The lsf1 mutant displays neither of these phenotypes. The phenotype of the lsf1/sex4 double mutant also differs from that of both single mutants in several respects. We discuss the possible role of the LSF1 protein in starch degradation.
Emerging molecular and precision medicine makes nuclear medicine a de facto choice of imaging, especially in the era of target-oriented medical care. Nuclear medicine is minimally invasive, ...four-dimensional (space and time or dynamic space), and functional imaging using radioactive biochemical tracers in evaluating human diseases on an anatomically configured image. Many radiopharmaceuticals are also used in therapies. However, there have been concerns over the emission of radiation from the radionuclides, resulting in wrongly neglecting the potential benefits against little or any risks at all of imaging to the patients. The sound concepts of radiation and radiation protection are critical for promoting the optimal use of radiopharmaceuticals to patients, and alleviating concerns from caregivers, nuclear medicine staff, medical colleagues, and the public alike.
With the introduction of large-scale molecular profiling methods and high-throughput sequencing technologies, the genomic features of most lymphoid neoplasms have been characterized at an ...unprecedented scale. Although the principles for the classification and diagnosis of these disorders, founded on a multidimensional definition of disease entities, have been consolidated over the past 25 years, novel genomic data have markedly enhanced our understanding of lymphomagenesis and enriched the description of disease entities at the molecular level. Yet, the current diagnosis of lymphoid tumors is largely based on morphological assessment and immunophenotyping, with only few entities being defined by genomic criteria. This paper, which accompanies the International Consensus Classification of mature lymphoid neoplasms, will address how established assays and newly developed technologies for molecular testing already complement clinical diagnoses and provide a novel lens on disease classification. More specifically, their contributions to diagnosis refinement, risk stratification, and therapy prediction will be considered for the main categories of lymphoid neoplasms. The potential of whole-genome sequencing, circulating tumor DNA analyses, single-cell analyses, and epigenetic profiling will be discussed because these will likely become important future tools for implementing precision medicine approaches in clinical decision making for patients with lymphoid malignancies.
Shorea parvifolia
(Dipterocarpaceae) is a widely distributed tree species which is important in terms of ecosystem functioning as well as forestry in Southeast Asia. During glacial periods, ...substantial precipitation decline is believed to have occurred in Southeast Asia, which considerably changed the distribution of the species. Repeated glacial and inter-glacial fluctuations were found to have influenced the genetic structure of the species, which is important to know for conservation and sustainable use. Leaf samples were collected from 18 populations covering most of the natural distribution of this species including the Malay Peninsula, Sumatra, and Borneo Islands. We investigated these samples using sequence data for eight chloroplast DNA (cpDNA) regions and 14 nuclear EST-SSR loci. The nucleotide diversity of cpDNA is higher in Malay Peninsula populations but the genetic diversity of nuclear DNA is higher in Borneo populations. The genetic structure revealed by nuclear DNA clearly separated Borneo populations from the rest, with an
F
ST
value of 0.150, while the genetic structure obtained from cpDNA was less pronounced (
F
ST
value = 0.136). Tajima’s
D
and Fu and Li’s
D
* for cpDNA showed statistical significance only in populations from Borneo. These results suggested that there has been recent population expansion of
S
.
parvifolia
in Borneo.
Hartmann's procedure is the resection of the rectosigmoid colon with an end colostomy formation and closure of the anorectal stump (1). Its reversal has a morbidity rate up to 58% (2, 3) with an ...incidence of fistulae formation of 4.08% (1). Herein, we present a robotic-assisted repair of a complex fistula that occurred as complication of Hartmann's reversal when the stapler was introduced inadvertently through the vaginal canal.
Eighty-three-year-old female with past medical history of hysterectomy and ischemic colitis that required colectomy and colostomy placement in December 2020. In March 2022, the patient underwent a colostomy takedown, after which she reported fecaluria, urine leakage per vagina, and recurrent urinary tract infections. Cystoscopy and vaginoscopy revealed a large colovesical fistula, a staple in the bladder trigone, and several staples in the anterior vaginal wall. Robotically, extensive adhesiolysis was performed, the sigmoid was separated from the bladder, and the intact rectal stump was dissected free. The staple from the bladder trigone was removed. Bladder was closed in two layers with 3-0 V-Loc. Colorectal anastomosis was not feasible due to the short length of both ends. Therefore, a permanent colostomy was placed.
Operative time was 454min., and estimated blood loss was 100cc. Discharged on postoperative day 4 with a JP drain and a 20Fr Foley catheter. Drain, and Foley were removed on postoperative days 9 and 23, respectively. No postoperative complications were reported.
Robotic-assisted repair represents an effective approach for the management of colovesical fistulae after Hartmann's reversal.
Medulloblastoma, the most common malignant pediatric brain tumor, often harbors MYC amplifications. Compared to high-grade gliomas, MYC-amplified medulloblastomas often show increased photoreceptor ...activity and arise in the presence of a functional ARF/p53 suppressor pathway. Here, we generate an immunocompetent transgenic mouse model with regulatable MYC that develop clonal tumors that molecularly resemble photoreceptor-positive Group 3 medulloblastoma. Compared to MYCN-expressing brain tumors driven from the same promoter, pronounced ARF silencing is present in our MYC-expressing model and in human medulloblastoma. While partial Arf suppression causes increased malignancy in MYCN-expressing tumors, complete Arf depletion promotes photoreceptor-negative high-grade glioma formation. Computational models and clinical data further identify drugs targeting MYC-driven tumors with a suppressed but functional ARF pathway. We show that the HSP90 inhibitor, Onalespib, significantly targets MYC-driven but not MYCN-driven tumors in an ARF-dependent manner. The treatment increases cell death in synergy with cisplatin and demonstrates potential for targeting MYC-driven medulloblastoma.
Abstract
Aims
Acute myocardial infarction causes lethal cardiomyocyte injury during ischaemia and reperfusion (I/R). Histones have been described as important Danger Associated Molecular Proteins ...(DAMPs) in sepsis. The objective of this study was to establish whether extracellular histone release contributes to myocardial infarction.
Methods and results
Isolated, perfused rat hearts were subject to I/R. Nucleosomes and histone-H4 release was detected early during reperfusion. Sodium-β-O-Methyl cellobioside sulfate (mCBS), a newly developed histone-neutralizing compound, significantly reduced infarct size whilst also reducing the detectable levels of histones. Histones were directly toxic to primary adult rat cardiomyocytes in vitro. This was prevented by mCBS or HIPe, a recently described, histone-H4 neutralizing peptide, but not by an inhibitor of TLR4, a receptor previously reported to be involved in DAMP-mediated cytotoxicity. Furthermore, TLR4-reporter HEK293 cells revealed that cytotoxicity of histone H4 was independent of TLR4 and NF-κB. In an in vivo rat model of I/R, HIPe significantly reduced infarct size.
Conclusion
Histones released from the myocardium are cytotoxic to cardiomyocytes, via a TLR4-independent mechanism. The targeting of extracellular histones provides a novel opportunity to limit cardiomyocyte death during I/R injury of the myocardium.
Graphical Abstract
Gadolinium-based contrast agents were not approved in the United States for detecting coronary artery disease (CAD) prior to the current studies.
The purpose of this study was to determine the ...sensitivity and specificity of gadobutrol for detection of CAD by assessing myocardial perfusion and late gadolinium enhancement (LGE) imaging.
Two international, single-vendor, phase 3 clinical trials of near identical design, “GadaCAD1” and “GadaCAD2,” were performed. Cardiovascular magnetic resonance (CMR) included gadobutrol-enhanced first-pass vasodilator stress and rest perfusion followed by LGE imaging. CAD was defined by quantitative coronary angiography (QCA) but computed tomography coronary angiography could exclude significant CAD.
Because the design and results for GadaCAD1 (n = 376) and GadaCAD2 (n = 388) were very similar, results were summarized as a fixed-effect meta-analysis (n = 764). The prevalence of CAD was 27.8% defined by a ≥70% QCA stenosis. For detection of a ≥70% QCA stenosis, the sensitivity of CMR was 78.9%, specificity was 86.8%, and area under the curve was 0.871. The sensitivity and specificity for multivessel CAD was 87.4% and 73.0%. For detection of a 50% QCA stenosis, sensitivity was 64.6% and specificity was 86.6%. The optimal threshold for detecting CAD was a ≥67% QCA stenosis in GadaCAD1 and ≥63% QCA stenosis in GadaCAD2.
Vasodilator stress and rest myocardial perfusion CMR and LGE imaging had high diagnostic accuracy for CAD in 2 phase 3 clinical trials. These findings supported the U.S. Food and Drug Administration approval of gadobutrol-enhanced CMR (0.1 mmol/kg) to assess myocardial perfusion and LGE in adult patients with known or suspected CAD.
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Current status and trends in forest genomics Borthakur, Dulal; Busov, Victor; Cao, Xuan Hieu ...
Forestry research (Fayetteville, Ga.),
2022, Letnik:
2, Številka:
1
Journal Article
Odprti dostop
Forests are not only the most predominant of the Earth's terrestrial ecosystems, but are also the core supply for essential products for human use. However, global climate change and ongoing ...population explosion severely threatens the health of the forest ecosystem and aggravtes the deforestation and forest degradation. Forest genomics has great potential of increasing forest productivity and adaptation to the changing climate. In the last two decades, the field of forest genomics has advanced quickly owing to the advent of multiple high-throughput sequencing technologies, single cell RNA-seq, clustered regularly interspaced short palindromic repeats (CRISPR)-mediated genome editing, and spatial transcriptomes, as well as bioinformatics analysis technologies, which have led to the generation of multidimensional, multilayered, and spatiotemporal gene expression data. These technologies, together with basic technologies routinely used in plant biotechnology, enable us to tackle many important or unique issues in forest biology, and provide a panoramic view and an integrative elucidation of molecular regulatory mechanisms underlying phenotypic changes and variations. In this review, we recapitulated the advancement and current status of 12 research branches of forest genomics, and then provided future research directions and focuses for each area. Evidently, a shift from simple biotechnology-based research to advanced and integrative genomics research, and a setup for investigation and interpretation of many spatiotemporal development and differentiation issues in forest genomics have just begun to emerge.
The olfactory epithelium undergoes neuronal regeneration from basal stem cells and is susceptible to olfactory neuroblastoma (ONB), a rare tumor of unclear origins. Employing alterations in ...Rb1/Trp53/Myc (RPM), we establish a genetically engineered mouse model of high-grade metastatic ONB exhibiting a NEUROD1+ immature neuronal phenotype. We demonstrate that globose basal cells (GBCs) are a permissive cell of origin for ONB and that ONBs exhibit cell fate heterogeneity that mimics normal GBC developmental trajectories. ASCL1 loss in RPM ONB leads to emergence of non-neuronal histopathologies, including a POU2F3+ microvillar-like state. Similar to small-cell lung cancer (SCLC), mouse and human ONBs exhibit mutually exclusive NEUROD1 and POU2F3-like states, an immune-cold tumor microenvironment, intratumoral cell fate heterogeneity comprising neuronal and non-neuronal lineages, and cell fate plasticity—evidenced by barcode-based lineage tracing and single-cell transcriptomics. Collectively, our findings highlight conserved similarities between ONB and neuroendocrine tumors with significant implications for ONB classification and treatment.
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•Rb1/Trp53/Myc alterations promote high-grade metastatic NEUROD1+ ONB•Mouse and human ONBs exhibit transcriptional similarity to neuroendocrine tumors•ONB harbors intratumoral cell fate heterogeneity and lineage plasticity•ASCL1 suppresses non-neuronal lineages including POU2F3+ microvillar-like states
Finlay et al. generate mouse models of olfactory neuroblastoma (ONB) that demonstrate striking similarities to human ONB and other neuroendocrine tumors, including expression of lineage-related oncogenes ASCL1, NEUROD1, and POU2F3, an immune-cold tumor microenvironment, intratumoral cell fate heterogeneity and plasticity, and shared expression of therapeutic targets.
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