Graphical technique for identifying a monotonic variance stabilizing transformation for absolute gene intensity signals

BACKGROUND: The usefulness of log(2 )transformation for cDNA microarray data has led to its widespread application to Affymetrix data. For Affymetrix data, where absolute intensities are indicative of number of transcripts, there is a systematic relationship between variance and magnitude of measurements. Application of the log(2 )transformation expands the scale of genes with low intensities while compressing the scale of genes with higher intensities thus reversing the mean by variance relationship. The usefulness of these transformations needs to be examined. RESULTS: Using an Affymetrix GeneChip(® )dataset, problems associated with applying the log(2 )transformation to absolute intensity data are demonstrated. Use of the spread-versus-level plot to identify an appropriate variance stabilizing transformation is presented. For the data presented, the spread-versus-level plot identified a power transformation that successfully stabilized the variance of probe set summaries. CONCLUSION: The spread-versus-level plot is helpful to identify transformations for variance stabilization. This is robust against outliers and avoids assumption of models and maximizations

Preliminary results of subintimal angioplasty for limb salvage in lower extremities with severe chronic ischemia and limb-threatening ischemia

ObjectiveThis study examined the hypothesis that superficial femoral artery (SFA) subintimal angioplasty (SI-PTA) can maintain limb salvage with minimal complications in patients with symptomatic occlusive arterial disease.MethodsFrom March 1, 2004, until April 28, 2006, 78 patients with rest pain (62.2%), gangrene (25.6%), or severe progressive claudication (12.2%) were treated consecutively with 82 SFA SI-PTAs (4 bilateral). The mean age was 59 ± 1.2 years, and 21 (27%) of the patients were female. All patients were treated in the operating room under local anesthesia by using fluoroscopic guidance, and the percentage SFA that was occluded was measured during the diagnostic portion of the procedure. Selective stent placement was performed after successful recanalization of the occluded arterial segments. Patients were treated with chronic aspirin and clopidogrel bisulfate for 3 months and followed up at 30 days and then every 3 months with physical examination and arterial duplex scan.ResultsOf the 82 SFA SI-PTA attempts, 76 (92%) were initially successful, with an increase in the ankle-brachial index from 0.46 ± 0.02 to 0.88 ± 0.01 (P < .001). Five of the six patients with a failed SFA SI-PTA were female, two of the six had had previous bypass attempts, and one of the six had had a previous SFA SI-PTA attempt by another physician. Forty-nine (64%) of the 76 initially successful SFA SI-PTAs required placement of a stent, and 43 (56.5%) of the successful 76 SFA SI-PTAs required additional PTA of 1 or more arterial segments. The group treated with a successful SFA SI-PTA had 42.5% ± 3.5% SFA occlusion, compared with 82% ± 10% (P < .05) in the group with a failed attempt at SFA SI-PTA. Two of the six patients with initial SI-PTA failure underwent leg amputation within 30 days, three were treated with successful leg bypass surgery, and one was lost to follow-up. Of the 76 successful SFA SI-PTAs, 5 (6.5%) failed within 90 days, and the patients were treated successfully with leg bypass surgery. Of the 71 limbs with patent SI-PTAs at 90 days, 68 have remained patent with a mean follow-up 10.4 ± 0.7 months (range, 2-24 months). Three of the 71 SFA SI-PTAs failed between 4 and 7 months (mean, 5 ± 0.7 months): 1 patient was treated with successful bypass surgery, 1 patient is currently considering further intervention, and 1 patient was treated with amputation. Ten (14%) of the 71 successful SFA SI-PTAs required limited PTA for asymptomatic restenosis, as identified by the arterial duplex scan (7.4 ± 1.4 months; range, 2-16 months). There were no perioperative deaths, and three patients have died during follow-up with patent SFA SI-PTAs (9.3 ± 1.4 months).ConclusionsThese data suggest that SFA SI-PTA can be successfully used for limb salvage with minimal morbidity and mortality in a group of patients with severe lower extremity occlusive vascular disease

Genetics and genomics of moso bamboo (Phyllostachys edulis) : Current status, future challenges, and biotechnological opportunities toward a sustainable bamboo industry

Sustainable goals for contemporary world seek viable solutions for interconnected challenges, particularly in the fields of food and energy security and climate change. We present bamboo, one of the versatile plant species on earth, as an ideal candidate for bioeconomy for meeting some of these challenges. With its potential realized, particularly in the industrial sector, countries such as China are going extensive with bamboo development and cultivation to support a myriad of industrial uses. These include timber, fiber, biofuel, paper, food, and medicinal industries. Bamboo is an ecologically viable choice, having better adaptation to wider environments than do other grasses, and can help to restore degraded lands and mitigate climate change. Bamboo, as a crop species, has not become amenable to genetic improvement, due to its long breeding cycle, perennial nature, and monocarpic behavior. One of the commonly used species, moso bamboo (Phyllostachys edulis) is a potential candidate that qualifies as industrial bamboo. With its whole-genome information released, genetic manipulations of moso bamboo offer tremendous potential to meet the industrial expectations either in quality or in quantity. Further, bamboo cultivation can expect several natural hindrances through biotic and abiotic stresses, which needs viable solutions such as genetic resistance. Taking a pragmatic view of these future requirements, we have compiled the present status of bamboo physiology, genetics, genomics, and biotechnology, particularly of moso bamboo, to drive various implications in meeting industrial and cultivation requirements. We also discuss challenges underway, caveats, and contextual opportunities concerning sustainable development.Peer reviewe

Comparison of Effects of p53 Null and Gain-of-Function Mutations on Salivary Tumors in MMTV-Hras Transgenic Mice

p53 is an important tumor suppressor gene which is mutated in ~50% of all human cancers. Some of these mutants appear to have acquired novel functions beyond merely losing wild-type functions. To investigate these gain-of-function effects in vivo, we generated mice of three different genotypes: MMTV-Hras/p53+/+, MMTV-Hras/p53-/-, and MMTV-Hras/p53R172H/R172H. Salivary tumors from these mice were characterized with regard to age of tumor onset, tumor growth rates, cell cycle distribution, apoptotic levels, tumor histopathology, as well as response to doxorubicin treatment. Microarray analysis was also performed to profile gene expression. The MMTV-Hras/p53-/- and MMTV-Hras/p53R172H/R172H mice displayed similar properties with regard to age of tumor onset, tumor growth rates, tumor histopathology, and response to doxorubicin, while both groups were clearly distinct from the MMTV-Hras/p53+/+ mice by these measurements. In addition, the gene expression profiles of the MMTV-Hras/p53-/- and MMTV-Hras/p53R172H/R172H tumors were tightly clustered, and clearly distinct from the profiles of the MMTV-Hras/p53+/+ tumors. Only a small group of genes showing differential expression between the MMTV-Hras/p53-/- and MMTV-Hras/p53R172H/R172H tumors, that did not appear to be regulated by wild-type p53, were identified. Taken together, these results indicate that in this MMTV-Hras-driven salivary tumor model, the major effect of the p53 R172H mutant is due to the loss of wild-type p53 function, with little or no gain-of-function effect on tumorigenesis, which may be explained by the tissue- and tumor type-specific properties of this gain-of-function mutant of p53

Visualizing formation of the active site in the mitochondrial ribosome.

Funder: Agouron InstituteFunder: Louis-Jeantet FoundationRibosome assembly is an essential and conserved process that is regulated at each step by specific factors. Using cryo-electron microscopy (cryo-EM), we visualize the formation of the conserved peptidyl transferase center (PTC) of the human mitochondrial ribosome. The conserved GTPase GTPBP7 regulates the correct folding of 16S ribosomal RNA (rRNA) helices and ensures 2'-O-methylation of the PTC base U3039. GTPBP7 binds the RNA methyltransferase NSUN4 and MTERF4, which sequester H68-71 of the 16S rRNA and allow biogenesis factors to access the maturing PTC. Mutations that disrupt binding of their Caenorhabditis elegans orthologs to the large subunit potently activate mitochondrial stress and cause viability, development, and sterility defects. Next-generation RNA sequencing reveals widespread gene expression changes in these mutant animals that are indicative of mitochondrial stress response activation. We also answer the long-standing question of why NSUN4, but not its enzymatic activity, is indispensable for mitochondrial protein synthesis

The role of LTR retrotransposons in plant genetic engineering : How to control their transposition in the genome

Key message We briefly discuss that the similarity of LTR retrotransposons to retroviruses is a great opportunity for the development of a genetic engineering tool that exploits intragenic elements in the plant genome for plant genetic improvement. Long terminal repeat (LTR) retrotransposons are very similar to retroviruses but do not have the property of being infectious. While spreading between its host cells, a retrovirus inserts a DNA copy of its genome into the cells. The ability of retroviruses to cause infection with genome integration allows genes to be delivered to cells and tissues. Retrovirus vectors are, however, only specific to animals and insects, and, thus, are not relevant to plant genetic engineering. However, the similarity of LTR retrotransposons to retroviruses is an opportunity to explore the former as a tool for genetic engineering. Although recent long-read sequencing technologies have advanced the knowledge about transposable elements (TEs), the integration of TEs is still unable either to control them or to direct them to specific genomic locations. The use of existing intragenic elements to achieve the desired genome composition is better than using artificial constructs like vectors, but it is not yet clear how to control the process. Moreover, most LTR retrotransposons are inactive and unable to produce complete proteins. They are also highly mutable. In addition, it is impossible to find a full active copy of a LTR retrotransposon out of thousands of its own copies. Theoretically, if these elements were directly controlled and turned on or off using certain epigenetic mechanisms (inducing by stress or infection), LTR retrotransposons could be a great opportunity to develop a genetic engineering tool using intragenic elements in the plant genome. In this review, the recent developments in uncovering the nature of LTR retrotransposons and the possibility of using these intragenic elements as a tool for plant genetic engineering are briefly discussed.Peer reviewe

The Effect of Travel Burden on Depression and Anxiety in African American Women Living with Systemic Lupus

The United States has a deficit of rheumatology specialists. This leads to an increased burden in accessing care for patients requiring specialized care. Given that most rheumatologists are located in urban centers at large hospitals, many lupus patients must travel long distances for routine appointments. The present work aims to determine whether travel burden is associated with increased levels of depression and anxiety among these patients. Data for this study were collected from baseline visits of patients participating in a lupus study at MUSC. A travel/economic burden survey was assessed as well as the 8-item Patient Health Questionnaire (PHQ-8) and the 7-item Generalized Anxiety Disorder (GAD-7) survey as measures of depression and anxiety, respectively. Linear regression models were used to assess the relationship between travel burden and depression and anxiety. Frequency of healthcare visits was significantly associated with increased depression (β = 1.3, p = 0.02). Significant relationships were identified between anxiety and requiring time off from work for healthcare appointments (β = 4, p = 0.02), and anxiety and perceived difficulty in traveling to primary care providers (β = 3.1, p = 0.04). Results from this study provide evidence that travel burden can have an effect on lupus patients’ anxiety and depression levels

Genome-wide association study for type 2 diabetes in Indians identifies a new susceptibility locus at 2q21.

Indians undergoing socioeconomic and lifestyle transitions will be maximally affected by epidemic of type 2 diabetes (T2D). We conducted a two-stage genome-wide association study of T2D in 12,535 Indians, a less explored but high-risk group. We identified a new type 2 diabetes-associated locus at 2q21, with the lead signal being rs6723108 (odds ratio 1.31; P = 3.32 × 10⁻⁹). Imputation analysis refined the signal to rs998451 (odds ratio 1.56; P = 6.3 × 10⁻¹²) within TMEM163 that encodes a probable vesicular transporter in nerve terminals. TMEM163 variants also showed association with decreased fasting plasma insulin and homeostatic model assessment of insulin resistance, indicating a plausible effect through impaired insulin secretion. The 2q21 region also harbors RAB3GAP1 and ACMSD; those are involved in neurologic disorders. Forty-nine of 56 previously reported signals showed consistency in direction with similar effect sizes in Indians and previous studies, and 25 of them were also associated (P < 0.05). Known loci and the newly identified 2q21 locus altogether explained 7.65% variance in the risk of T2D in Indians. Our study suggests that common susceptibility variants for T2D are largely the same across populations, but also reveals a population-specific locus and provides further insights into genetic architecture and etiology of T2D

Common variants in CLDN2 and MORC4 genes confer disease susceptibility in patients with chronic pancreatitis

A recent Genome-wide Association Study (GWAS) identified association with variants in X-linked CLDN2 and MORC4 and PRSS1-PRSS2 loci with Chronic Pancreatitis (CP) in North American patients of European ancestry. We selected 9 variants from the reported GWAS and replicated the association with CP in Indian patients by genotyping 1807 unrelated Indians of Indo-European ethnicity, including 519 patients with CP and 1288 controls. The etiology of CP was idiopathic in 83.62% and alcoholic in 16.38% of 519 patients. Our study confirmed a significant association of 2 variants in CLDN2 gene (rs4409525—OR 1.71, P = 1.38 x 10-09; rs12008279—OR 1.56, P = 1.53 x 10-04) and 2 variants in MORC4 gene (rs12688220—OR 1.72, P = 9.20 x 10-09; rs6622126—OR 1.75, P = 4.04x10-05) in Indian patients with CP. We also found significant association at PRSS1-PRSS2 locus (OR 0.60; P = 9.92 x 10-06) and SAMD12-TNFRSF11B (OR 0.49, 95% CI [0.31–0.78], P = 0.0027). A variant in the gene MORC4 (rs12688220) showed significant interaction with alcohol (OR for homozygous and heterozygous risk allele -14.62 and 1.51 respectively, P = 0.0068) suggesting gene-environment interaction. A combined analysis of the genes CLDN2 and MORC4 based on an effective risk allele score revealed a higher percentage of individuals homozygous for the risk allele in CP cases with 5.09 fold enhanced risk in individuals with 7 or more effective risk alleles compared with individuals with 3 or less risk alleles (P = 1.88 x 10-14). Genetic variants in CLDN2 and MORC4 genes were associated with CP in Indian patients