Toroidal Crystals

Crystalline assemblages of identical sub-units packed together and elastically bent in the form of a torus have been found in the past ten years in a variety of systems of surprisingly different nature, such as viral capsids, self-assembled monolayers and carbon nanomaterials. In this Letter we analyze the structural properties of toroidal crystals and we provide a unified description based on the elastic theory of defects in curved geometries. We find ground states characterized by the presence of 5-fold disclinations on the exterior of the torus and 7-fold disclinations in the interior. The number of excess disclinations is controlled primarily by the aspect ratio of the torus, suggesting a novel mechanism for creating toroidal templates with precisely controlled valency via functionalization of the defect sites.Comment: 4 pages, 4 figure

Quality and Safety Aspects of Infant Nutrition

Quality and safety aspects of infant nutrition are of key importance for child health, but oftentimes they do not get much attention by health care professionals whose interest tends to focus on functional benefits of early nutrition. Unbalanced diets and harmful food components induce particularly high risks for untoward effects in infants because of their rapid growth, high nutrient needs, and their typical dependence on only one or few foods during the first months of life. The concepts, standards and practices that relate to infant food quality and safety were discussed at a scientific workshop organized by the Child Health Foundation and the Early Nutrition Academy jointly with the European Society for Paediatric Gastroenterology, Hepatology and Nutrition, and a summary is provided here. The participants reviewed past and current issues on quality and safety, the role of different stakeholders, and recommendations to avert future issues. It was concluded that a high level of quality and safety is currently achieved, but this is no reason for complacency. The food industry carries the primary responsibility for the safety and suitability of their products, including the quality of composition, raw materials and production processes. Introduction of new or modified products should be preceded by a thorough science based review of suitability and safety by an independent authority. Food safety events should be managed on an international basis. Global collaboration of food producers, food-safety authorities, paediatricians and scientists is needed to efficiently exchange information and to best protect public health. Copyright (C) 2012 S. Karger AG, Base

Arterivirus Nsp1 Modulates the Accumulation of Minus-Strand Templates to Control the Relative Abundance of Viral mRNAs

The gene expression of plus-strand RNA viruses with a polycistronic genome depends on translation and replication of the genomic mRNA, as well as synthesis of subgenomic (sg) mRNAs. Arteriviruses and coronaviruses, distantly related members of the nidovirus order, employ a unique mechanism of discontinuous minus-strand RNA synthesis to generate subgenome-length templates for the synthesis of a nested set of sg mRNAs. Non-structural protein 1 (nsp1) of the arterivirus equine arteritis virus (EAV), a multifunctional regulator of viral RNA synthesis and virion biogenesis, was previously implicated in controlling the balance between genome replication and sg mRNA synthesis. Here, we employed reverse and forward genetics to gain insight into the multiple regulatory roles of nsp1. Our analysis revealed that the relative abundance of viral mRNAs is tightly controlled by an intricate network of interactions involving all nsp1 subdomains. Distinct nsp1 mutations affected the quantitative balance among viral mRNA species, and our data implicate nsp1 in controlling the accumulation of full-length and subgenome-length minus-strand templates for viral mRNA synthesis. The moderate differential changes in viral mRNA abundance of nsp1 mutants resulted in similarly altered viral protein levels, but progeny virus yields were greatly reduced. Pseudorevertant analysis provided compelling genetic evidence that balanced EAV mRNA accumulation is critical for efficient virus production. This first report on protein-mediated, mRNA-specific control of nidovirus RNA synthesis reveals the existence of an integral control mechanism to fine-tune replication, sg mRNA synthesis, and virus production, and establishes a major role for nsp1 in coordinating the arterivirus replicative cycle

Inflammation, insulin resistance, and diabetes-mendelian randomization using CRP haplotypes points upstream

Background Raised C-reactive protein (CRP) is a risk factor for type 2 diabetes. According to the Mendelian randomization method, the association is likely to be causal if genetic variants that affect CRP level are associated with markers of diabetes development and diabetes. Our objective was to examine the nature of the association between CRP phenotype and diabetes development using CRP haplotypes as instrumental variables. Methods and Findings We genotyped three tagging SNPs (CRP + 2302G > A; CRP + 1444T > C; CRP + 4899T > G) in the CRP gene and measured serum CRP in 5,274 men and women at mean ages 49 and 61 y (Whitehall II Study). Homeostasis model assessment-insulin resistance (HOMA-IR) and hemoglobin A1c (HbA1c) were measured at age 61 y. Diabetes was ascertained by glucose tolerance test and self-report. Common major haplotypes were strongly associated with serum CRP levels, but unrelated to obesity, blood pressure, and socioeconomic position, which may confound the association between CRP and diabetes risk. Serum CRP was associated with these potential confounding factors. After adjustment for age and sex, baseline serum CRP was associated with incident diabetes (hazard ratio = 1.39 [95% confidence interval 1.29-1.51], HOMA-IR, and HbA1c, but the associations were considerably attenuated on adjustment for potential confounding factors. In contrast, CRP haplotypes were not associated with HOMA-IR or HbA1c (p=0.52-0.92). The associations of CRP with HOMA-IR and HbA1c were all null when examined using instrumental variables analysis, with genetic variants as the instrument for serum CRP. Instrumental variables estimates differed from the directly observed associations (p=0.007-0.11). Pooled analysis of CRP haplotypes and diabetes in Whitehall II and Northwick Park Heart Study II produced null findings (p=0.25-0.88). Analyses based on the Wellcome Trust Case Control Consortium (1,923 diabetes cases, 2,932 controls) using three SNPs in tight linkage disequilibrium with our tagging SNPs also demonstrated null associations. Conclusions Observed associations between serum CRP and insulin resistance, glycemia, and diabetes are likely to be noncausal. Inflammation may play a causal role via upstream effectors rather than the downstream marker CRP

Nanoparticle vesicle encoding for imaging and tracking cell populations.

For phenotypic behavior to be understood in the context of cell lineage and local environment, properties of individual cells must be measured relative to population-wide traits. However, the inability to accurately identify, track and measure thousands of single cells via high-throughput microscopy has impeded dynamic studies of cell populations. We demonstrate unique labeling of cells, driven by the heterogeneous random uptake of fluorescent nanoparticles of different emission colors. By sequentially exposing a cell population to different particles, we generated a large number of unique digital codes, which corresponded to the cell-specific number of nanoparticle-loaded vesicles and were visible within a given fluorescence channel. When three colors are used, the assay can self-generate over 17,000 individual codes identifiable using a typical fluorescence microscope. The color-codes provided immediate visualization of cell identity and allowed us to track human cells with a success rate of 78% across image frames separated by 8 h

Location, location, location: Beneficial effects of autologous fat transplantation

Visceral adiposity is a risk factor for cardiovascular disorders, type 2 diabetes mellitus (T2D) and associated metabolic diseases. Sub-cutaneous fat is believed to be intrinsically different from visceral fat. To understand molecular mechanisms involved in metabolic advantages of fat transplantation, we studied a rat model of diet-induced adiposity. Adipokine genes (Adiponectin, Leptin, Resistin and Visfatin) were expressed at 10,000 to a million-fold lower in visceral fat depot as compared to peripheral (thigh/chest) fat depots. Interestingly, autologous transplantation of visceral fat to subcutaneous sites resulted in increased gene transcript abundance in the grafts by 3 weeks post-transplantation, indicating the impact of local (residence) factors influencing epigenetic memory. We show here that active transcriptional state of adipokine genes is linked with glucose mediated recruitment of enzymes that regulate histone methylation. Adipose depots have “residence memory” and autologous transplantation of visceral fat to sub-cutaneous sites offers metabolic advantage

Hydrogen sulphide-induced hypometabolism in human-sized porcine kidneys

Background Since the start of organ transplantation, hypothermia-forced hypometabolism has been the cornerstone in organ preservation. Cold preservation showed to protect against ischemia, although post-transplant injury still occurs and further improvement in preservation techniques is needed. We hypothesize that hydrogen sulphide can be used as such a new preservation method, by inducing a reversible hypometabolic state in human sized kidneys during normothermic machine perfusion. Methods Porcine kidneys were connected to an ex-vivo isolated, oxygen supplemented, normothermic blood perfusion set-up. Experimental kidneys (n = 5) received a 85mg NaHS infusion of 100 ppm and were compared to controls (n = 5). As a reflection of the cellular metabolism, oxygen consumption, mitochondrial activity and tissue ATP levels were measured. Kidney function was assessed by creatinine clearance and fractional excretion of sodium. To rule out potential structural and functional deterioration, kidneys were studied for biochemical markers and histology. Results Hydrogen sulphide strongly decreased oxygen consumption by 61%, which was associated with a marked decrease in mitochondrial activity/function, without directly affecting ATP levels. Renal biological markers, renal function and histology did not change after hydrogen sulphide treatment. Conclusion In conclusion, we showed that hydrogen sulphide can induce a controllable hypometabolic state in a human sized organ, without damaging the organ itself and could thereby be a promising therapeutic alternative for cold preservation under normothermic conditions in renal transplantation

Both SEPT2 and MLL are down-regulated in MLL-SEPT2 therapy-related myeloid neoplasia

<p>Abstract</p> <p>Background</p> <p>A relevant role of septins in leukemogenesis has been uncovered by their involvement as fusion partners in <it>MLL</it>-related leukemia. Recently, we have established the <it>MLL-SEPT2 </it>gene fusion as the molecular abnormality subjacent to the translocation t(2;11)(q37;q23) in therapy-related acute myeloid leukemia. In this work we quantified <it>MLL </it>and <it>SEPT2 </it>gene expression in 58 acute myeloid leukemia patients selected to represent the major AML genetic subgroups, as well as in all three cases of <it>MLL-SEPT2</it>-associated myeloid neoplasms so far described in the literature.</p> <p>Methods</p> <p>Cytogenetics, fluorescence in situ hybridization (FISH) and molecular studies (RT-PCR, qRT-PCR and qMSP) were used to characterize 58 acute myeloid leukemia patients (AML) at diagnosis selected to represent the major AML genetic subgroups: <it>CBFB-MYH11 </it>(n = 13), <it>PML-RARA </it>(n = 12); <it>RUNX1-RUNX1T1 </it>(n = 12), normal karyotype (n = 11), and <it>MLL </it>gene fusions other than <it>MLL-SEPT2 </it>(n = 10). We also studied all three <it>MLL-SEPT2 </it>myeloid neoplasia cases reported in the literature, namely two AML patients and a t-MDS patient.</p> <p>Results</p> <p>When compared with normal controls, we found a 12.8-fold reduction of wild-type <it>SEPT2 </it>and <it>MLL-SEPT2 </it>combined expression in cases with the <it>MLL-SEPT2 </it>gene fusion (p = 0.007), which is accompanied by a 12.4-fold down-regulation of wild-type <it>MLL </it>and <it>MLL-SEPT2 </it>combined expression (p = 0.028). The down-regulation of <it>SEPT2 </it>in <it>MLL-SEPT2 </it>myeloid neoplasias was statistically significant when compared with all other leukemia genetic subgroups (including those with other <it>MLL </it>gene fusions). In addition, <it>MLL </it>expression was also down-regulated in the group of <it>MLL </it>fusions other than <it>MLL-SEPT2</it>, when compared with the normal control group (p = 0.023)</p> <p>Conclusion</p> <p>We found a significant down-regulation of both <it>SEPT2 </it>and <it>MLL </it>in <it>MLL-SEPT2 </it>myeloid neoplasias. In addition, we also found that <it>MLL </it>is under-expressed in AML patients with <it>MLL </it>fusions other than <it>MLL-SEPT2</it>.</p

Proteogenetic drug response profiling elucidates targetable vulnerabilities of myelofibrosis

Myelofibrosis is a hematopoietic stem cell disorder belonging to the myeloproliferative neoplasms. Myelofibrosis patients frequently carry driver mutations in either JAK2 or Calreticulin (CALR) and have limited therapeutic options. Here, we integrate ex vivo drug response and proteotype analyses across myelofibrosis patient cohorts to discover targetable vulnerabilities and associated therapeutic strategies. Drug sensitivities of mutated and progenitor cells were measured in patient blood using high-content imaging and single-cell deep learning-based analyses. Integration with matched molecular profiling revealed three targetable vulnerabilities. First, CALR mutations drive BET and HDAC inhibitor sensitivity, particularly in the absence of high Ras pathway protein levels. Second, an MCM complex-high proliferative signature corresponds to advanced disease and sensitivity to drugs targeting pro-survival signaling and DNA replication. Third, homozygous CALR mutations result in high endoplasmic reticulum (ER) stress, responding to ER stressors and unfolded protein response inhibition. Overall, our integrated analyses provide a molecularly motivated roadmap for individualized myelofibrosis patient treatment