Bioinformatics

The complexities of social and technological policy domains, such as the economy, the environment, and public health present challenges that require a new approach to modeling and decision making. The information required for effective policy and decision making in these complex domains is massive in scale, fine-grained in resolution, and distributed over many data sources. Thus, one of the key challenges in building systems to support policy informatics is information integration. We describe our approach to this problem, and how we are building a multi-theory, multi-actor, multi-perspective system that supports continual data uptake, state assessment, decision analysis, and action assignment based on large-scale high-performance computing infrastructures. Our simulation-based approach allows rapid course-of-action analysis to bound variances in outcomes of policy interventions, which in turn allows the short time-scale planning required in response to emergencies such as epidemic ...

Introduction: Characterized by the development of hundreds to thousands of colonic adenomas, classic familial adenomatous polyposis (FAP) is one of the most common hereditary syndromes associated with an increased risk of colorectal cancer. Several studies have attempted to correlate specific APC mutations with clinical phenotype. 6 However, there is considerable variability in the expression of specific phenotypes within families and among individuals with identical mutations. 7 Case presentation: A 30 year-old Hispanic female presented to the emergency department with a 2-week history of persistent, worsening, left lower quadrant abdominal pain. She had no family history of malignancy. Sigmoidoscopy revealed innumerable polyps in the rectum and sigmoid colon and a large mass in the sigmoid colon. Biopsy of the mass revealed a moderately differentiated adenocarcinoma invading the subserosa. Endoscopy revealed innumerable polyps. Genetic testing of the patient via southern blot revealed a germline APC mutation 3927del5, resulting in a premature truncation of the APC protein at amino acid position 1312. Conclusion: Genetic information has only recently started being incorporated into clinical care. More research and randomized clinical trials need to be conducted to definitively characterize random mutations. Once these mutations are further understood, FAP patients may be able to be risk stratified and this may ultimately improve the screening, diagnosis, and treatment of this rare condition.

Asian cultivated rice Oryza sativa L. was domesticated from its wild ancestor, O. rufipogon. During domestication, the cultivated rice lost its seed-shattering behaviour. Previous studies have shown that two major quantitative trait loci (QTLs; qSH1 and sh4) are responsible for the seed-shattering degree. Here, we produced introgression lines carrying non-functional alleles from O. sativa 'Nipponbare' at the two major QTLs in the genetic background of wild rice O. rufipogon W630, and examined the effects of the two QTLs on seed shattering and abscission layer formation. The introgression lines, with Nipponbare alleles at either or both loci, showed complete or partial abscission layer formation, respectively, indicating that other unknown loci might be involved in enhancing seed shattering in wild rice. We detected a single QTL named qSH3 regulating seed-shattering degree using an F 2 population between Nipponbare and the introgression line carrying Nipponbare alleles at the two QTLs. Although we generated an introgression line for qSH3 alone, no effects on seed shattering were observed. However, a significant effect on seed-shattering degree was observed for the introgression line carrying Nipponbare alleles at qSH3 and the two QTLs, suggesting an important role of qSH3 on seed shattering in coordination with the two QTLs.

Monitoring tests form an increasing proportion of the workload in clinical biochemistry and biochemists can help by providing clinicians with information about the variability and precision of tests, the time frame for pharmacodynamic stabilisation after a treatment change, and the frequency of testing. This paper outlines the phases of monitoring, and how to decide if monitoring is beneficial, which test to use for monitoring, when a change in the test result indicates a need for the change in treatment and the length of testing intervals. We conclude with some recommendations for biochemists for future areas of research and advice that can be given to clinicians.

Cuando no sabemos a qué puerto nos dirigimos, todos los vientos son desfavorables. Yo declaro lo siguiente: He leído el Acuerdo 035 de 2003 del Consejo Académico de la Universidad Nacional. «Reglamento sobre propiedad intelectual» y la Normatividad Nacional relacionada al respeto de los derechos de autor. Esta disertación representa mi trabajo original, excepto donde he reconocido las ideas, las palabras, o materiales de otros autores. Cuando se han presentado ideas o palabras de otros autores en esta disertación, he realizado su respectivo reconocimiento aplicando correctamente los esquemas de citas y referencias bibliográficas en el estilo requerido. He obtenido el permiso del autor o editor para incluir cualquier material con derechos de autor (por ejemplo, tablas, figuras, instrumentos de encuesta o grandes porciones de texto). Por último, he sometido esta disertación a la herramienta de integridad académica, definida por la universidad.

Dynamic mutations involve expansion of the number of repeat units consisting of three or more nucleotides in tandem (i.e. adjacent to one another) present in a gene or in its neighborhood. These repeats may occur in different genes and may code for different aminoacids. According to expansions sizes, it is possible to have unaffected individuals that are carriers of a pre-mutation. Instability of triplet repeat size can lead to gradual expansion through generations, a phenomenon called anticipation. Genetic anticipation is characterized by the reduction in the age of disease onset and by a worsening of symptoms in affected individuals in successive generations. This work describes dynamic mutations giving emphasis on triplet repeats diseases, making the parallel with disease anticipation. Treatment strategies that have been developed during the last years are also discussed.

IntroductionAs social animals, our health depends in part on interactions with other human beings. Yet millions suffer from chronic social isolation, including those in nursing/assisted living facilities, people experiencing chronic loneliness as well as those in enforced isolation within our criminal justice system. While many historical studies have examined the effects of early isolation on the brain, few have examined its effects when this condition begins in adulthood. Here, we developed a model of adult isolation using mice (C57BL/6J) born and raised in an enriched environment.MethodsFrom birth until 4 months of age C57BL/6J mice were raised in an enriched environment and then maintained in that environment or moved to social isolation for 1 or 3 months. We then examined neuronal structure and catecholamine and brain derived neurotrophic factor (BDNF) levels from different regions of the brain, comparing animals from social isolation to enriched environment controls.ResultsWe ...

We present the implementation of a combined digital scanned light-sheet microscope (DSLM) able to work in the linear and nonlinear regimes under either Gaussian or Bessel beam excitation schemes. A complete characterization of the setup is performed and a comparison of the performance of each DSLM imaging modality is presented using in vivo Caenorhabditis elegans samples. We found that the use of Bessel beam nonlinear excitation results in better image contrast over a wider field of view.

Direct videomicroscopic visualization of organ formation and regeneration in toto is a powerful strategy to study cellular processes that often cannot be replicated in vitro. Intravital imaging aims at quantifying changes in tissue architecture or subcellular organization over time during organ development, regeneration or degeneration. A general feature of this approach is its reliance on the optical isolation of defined cell types in the whole animals by transgenic expression of fluorescent markers. Here we describe a simple and robust method to analyze sensory hair-cell development and regeneration in the zebrafish lateral line by high-resolution intravital imaging using laser-scanning confocal microscopy (LSCM) and selective plane illumination microscopy (SPIM). The main advantage of studying hair-cell regeneration in the lateral line is that it occurs throughout the life of the animal, which allows its study in the most natural context. We detail protocols to achieve continuous videomicroscopy for up to 68 hours, enabling direct observation of cellular behavior, which can provide a sensitive assay for the quantitative classification of cellular phenotypes and cell-lineage reconstruction. Modifications to this protocol should facilitate pharmacogenetic assays to identify or validate otoprotective or reparative drugs for future clinical strategies aimed at preserving aural function in humans.

Background. Major depression is often chronic or recurrent and is usually treated within primary care. Little is known about the associated morbidity and costs. Objectives. To determine socio-demographic characteristics of people with chronic or recurrent depression in primary care and associated morbidity, service use, and costs. Method. 558 participants were recruited from 42 GP practices in the UK. All participants had a history of chronic major depression, recurrent major depression, or dysthymia. Participants completed questionnaires including the BDI-II, Work and Social Adjustment Scale, Euroquol, and Client Service Receipt Inventory documenting use of primary care, mental health, and other services. Results. The sample was characterised by high levels of depression, functional impairment, and high service use and costs. The majority (74%) had been treated with an anti-depressant, while few had seen a counsellor (15%) or a psychologist (3%) in the preceding three months. The g...

A seleção genômica ampla (GWS) aumenta a eficiência e rapidez do melhoramento genético. Essa tecnologia fundamenta-se na predição de fenótipos com base na leitura de marcadores genéticos e uso de métodos preditivos. Existem vários métodos para aplicação na GWS. O presente documento contempla mais de uma dezena desses métodos contemplando a teoria, a computação e a aplicação a dados simulados. Assim, seu conteúdo é abrangente e pode servir como um guia importante para os usuários da GWS.

Alzheimer's disease (AD) is the most common form of dementia. Several hypotheses have been put forward to explain the basis of disease onset and progression. Unfortunately, none of these seems to clarify the complexity of the pathogenesis. In fact, diverse and independent pathogenetic pathways can be disrupted at the same time, and each contributes to disease etiology. In recent years, researchers have begun studying biometals more deeply. A number of studies have shown that metal dyshomeostasis may enhance AD onset and progression. Specifically, different authors have hypothesized that alterations in metal metabolism are associated with an increased in metal-related oxidative stress and beta-amyloid oligomer formation and precipitation. Studies conducted in vivo, in vitro, in living patients and in silico studies have demonstrated that local and systemic defects in copper metabolism are characteristic signs of AD. This strongly supports the hypothesis that copper pathways may be disrupted by the disease. More specifically, a copper phenotype can be proposed for AD, based on defects found in genes involved in copper metabolism. In this review, we describe copper dyshomeostasis in AD patients and attempt to explain the basis of the AD copper phenotype. Dissecting copper pathways, we highlight mechanisms which may be at the basis of the disease. We also discuss various associated translation outcomes.

Our results show that all of the brown rot fungi tested produce oxalic acid in liquid as well as in semisolid cultures. Gloeophyllum trabeum , which accumulates the lowest amount of oxalic acid during decay of pine holocellulose, showed the highest polysaccharide-depolymerizing activity. Semisolid cultures inoculated with this fungus rapidly converted 14 C-labeled oxalic acid to CO 2 during cellulose depolymerization. The other brown rot fungi also oxidized 14 C-labeled oxalic acid, although less rapidly. In contrast, semisolid cultures inoculated with the white rot fungus Coriolus versicolor did not significantly catabolize the acid and did not depolymerize the holocellulose during decay. Semisolid cultures of G. trabeum amended with desferrioxamine, a specific iron-chelating agent, were unable to lower the degree of polymerization of cellulose or to oxidize 14 C-labeled oxalic acid to the extent or at the rate that control cultures did. These results suggest that both iron and oxa...

Various substituted 3-{6-fluoro-7-(substituted)-1,3-benzothiazol-2-yl-1- [(4-acetyl-5-methyl-5phenyl-4,5-dihydro-1,3,4-oxadiazol-2-yl) containing different functional groups have been synthesized by condensing anthranilic acids with substituted 2-aminobenzothiazoles in dry pyridine and then by condensing with ethylchloroacetate in presence dry acetone and K 2 CO 3 . The identity of compounds were confirmed on the basis of their spectral (UV, IR, 1 H NMR and MASS) data. Further, they have been screened for their antimicrobial activities.

Introduction: Tumor endothelial marker 1 (TEM1) is expressed by tumor vascular endothelial cells in various cancers. Methods: Here, we developed poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) PEGylated with polyethylene glycol (PEG) and functionalized with anti-TEM1 antibody fragment (78Fc) and loaded them with necroptosis-inducing agent shikonin (SHK) (78Fc-PLGA-SHK NPs). Results: The nanoformulation showed a smooth spherical shape (~120 nm; the ζ potential of -30 mV) with high drug entrapment and bioconjugation efficiencies (~92% and ~90%, respectively) and a sustained-release profile in serum. Having significant toxicity in vitro (e.g., MS1 and TC1 cells), the nanoformulation dramatically increased the cytotoxicity in the TC1 murine lung carcinoma subcutaneous and intravenous/metastatic models as aggressive tumor models. The injection of the 78Fc-PLGA-SHK NPs to the MS1-xenograft mice resulted in significantly higher accumulation and effects in the TEM1-positive tumor targets, while they were excreted via urine track without retaining in the liver/spleen. In the TC1 subcutaneous model, C57/BL6 mice treated with the 78Fc-PLGA-SHK NPs revealed a significant therapeutic effect. The mice, which were tumor-free after receiving the nanoformulation, were re-challenged with the TC1 cells to investigate the immune response. These animals became tumor-free a week after the injection of TC1 cells. Based on these findings, we propose the 78Fc-PLGA-SHK NPs as a highly effective immunostimulating nanomedicine against the TEM1-expressing cells for targeted therapy of solid tumors including ovarian cancer.

Introduction: Tumor endothelial marker 1 (TEM1) is expressed by tumor vascular endothelial cells in various cancers. Methods: Here, we developed poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) PEGylated with polyethylene glycol (PEG) and functionalized with anti-TEM1 antibody fragment (78Fc) and loaded them with necroptosis-inducing agent shikonin (SHK) (78Fc-PLGA-SHK NPs). Results: The nanoformulation showed a smooth spherical shape (~120 nm; the ζ potential of –30 mV) with high drug entrapment and bioconjugation efficiencies (~92% and ~90%, respectively) and a sustained-release profile in serum. Having significant toxicity in vitro (e.g., MS1 and TC1 cells), the nanoformulation dramatically increased the cytotoxicity in the TC1 murine lung carcinoma subcutaneous and intravenous/metastatic models as aggressive tumor models. The injection of the 78Fc-PLGA-SHK NPs to the MS1-xenograft mice resulted in significantly higher accumulation and effects in the TEM1-positive tumor t...

The prokineticins (PKs) were discovered approximately 20 years ago as small peptides inducing gut contractility. Today, they are established as angiogenic, anorectic, and proinflammatory cytokines, chemokines, hormones, and neuropeptides involved in variety of physiologic and pathophysiological pathways. Their altered expression or mutations implicated in several diseases make them a potential biomarker. Their G-protein coupled receptors, PKR1 and PKR2, have divergent roles that can be therapeutic target for treatment of cardiovascular, metabolic, and neural diseases as well as pain and cancer. This article reviews and summarizes our current knowledge of PK family functions from development of heart and brain to regulation of homeostasis in health and diseases. Finally, the review summarizes the established roles of the endogenous peptides, synthetic peptides and the selective ligands of PKR1 and PKR2, and nonpeptide orthostatic and allosteric modulator of the receptors in preclinical disease models. The present review emphasizes the ambiguous aspects and gaps in our knowledge of functions of PKR ligands and elucidates future perspectives for PK research.

Background: Acute myeloid leukemia, as most cancers, results from exposure to carcinogens and an impaired inherited individual capacity to eliminate xenobiotics. The present case-control study measures the relationship between glutathione S-transferase (GST) T1 and M1 null genotypes and the risk of acute myeloid leukemia. Methods: We identified the GSTT1 and GSTM1 genotypes by multiplex polymerase chain reaction in 129 acute myeloid leukemia patients and 129 controls. Results: Individuals that carried GSTT1 null had a risk of acute myeloid leukemia when compared to GSTT1 present carriers (OR: 2.80; 95% CI: 1.63-4.80, P=0.00036). However, GSTM1 null did not influence the risk for acute myeloid leukemia (OR: 1.20; 95% CI: 0.72-1.97, P=0.53). The combined GSTT1 null/GSTM1 present genotype showed an association with the risk for acute myeloid leukemia compared to those that carried both functional genotypes (OR: 8.85; 95% CI: 3.09-23.8, P=0.0001). The double null genotype also showed an association with the risk for acute myeloid leukemia (OR: 2.32, 95% CI: 1.15-4.66, P=0.019). Conclusion: Both GSTT1 null and GST double-null genotypes may be risk factors for acute myeloid leukemia. Further studies are needed to confirm these results.

Dilated cardiomyopathy (DCM) is a clinical diagnosis characterized by left ventricular or biventricular dilation and systolic dysfunction. In most cases, DCM is progressive, leading to heart failure (HF) and death. This cardiomyopathy has been considered a common and final phenotype of several entities. DCM occurs when cellular pathways fail to maintain the pumping function. The etiology of this disease encompasses several factors, such as ischemia, infection, autoimmunity, drugs or genetic susceptibility. Although the prognosis has improved in the last few years due to red flag clinical follow-up, early familial diagnosis and ongoing optimization of treatment, due to its heterogeneity, there are no targeted therapies available for DCM based on each etiology. Therefore, a better understanding of the mechanisms underlying the pathophysiology of DCM will provide novel therapeutic strategies against this cardiac disease and their different triggers. MicroRNAs (miRNAs) are a group of sm...

The palaeontological sites of Riba de Santiuste and Sienes (Riba de Santiuste area) are located in the province of Guadalajara, Spain. They include a stratigraphic interval in Muschelkalk facies belonging to the "Cuesta del Castillo Sandstones" Formation and "Royuela Dolostones, Marls and Mudstones" Formation. These sites include numerous fossil plants, direct vertebrate remains, and vertebrate swim traces. The vertebrate remains correspond to a multitude of anatomical elements of Sauropterygia (Nothosauroidea, Placodontia) and possible Archosauria (Rauisuchia) remains. The fossil material attributed to nothosaurs includes teeth, coracoids, a thoracic vertebra, some isolated vertebral centra, humerus, rib fragments, and some dorsal and caudal vertebrae. The remains attributed to placodonts correspond to fragments of skull, quadrate, teeth and osteoderms. Other undetermined sauropterygian remains, such as ulnas, fragments of long bones, fragments of ribs, and articular facets of ribs have been also recovered. Additionally, a fragment of mandible and an intervertebral disk of indeterminate reptiles whose size could be compatible with archosaurs are also described. These bones are exceptionally wellpreserved because the fossilization processes have preserved the microstructure of the tissues. The sites also show vertebrate traces, with parallel scratch impressions interpreted as swim traces. The relative stratigraphic position and the palaeontological content of these sites suggest a Ladinian age (Middle Triassic). The interpretation of the sedimentary facies here described also suggests that the sites could correspond to detrital-carbonate mixed deposits of coastal intertidal to supratidal environments.

Dicynodontia represent the most diverse tetrapod group during the Late Permian. They survived the Permo-Triassic extinction and are central to understanding Permo-Triassic terrestrial ecosystems. Although extensively studied, several aspects of dicynodont paleobiology such as, neuroanatomy, inner ear morphology and internal cranial anatomy remain obscure. Here we describe a new dicynodont (Therapsida, Anomodontia) from northern Mozambique: Niassodon mfumukasi gen. et sp. nov. The holotype ML1620 was collected from the Late Permian K5 formation, Metangula Graben, Niassa Province northern Mozambique, an almost completely unexplored basin and country for vertebrate paleontology. Synchrotron radiation based micro-computed tomography (SRmCT), combined with a phylogenetic analysis, demonstrates a set of characters shared with Emydopoidea. All individual bones were digitally segmented allowing a 3D visualization of each element. In addition, we reconstructed the osseous labyrinth, endocast, cranial nerves and vasculature. The brain is narrow and the cerebellum is broader than the forebrain, resembling the conservative, ''reptilian-grade'' morphology of other non-mammalian therapsids, but the enlarged paraflocculi occupy the same relative volume as in birds. The orientation of the horizontal semicircular canals indicates a slightly more dorsally tilted head posture than previously assumed in other dicynodonts. In addition, synchrotron data shows a secondary center of ossification in the femur. Thus ML1620 represents, to our knowledge, the oldest fossil evidence of a secondary center of ossification, pushing back the evolutionary origins of this feature. The fact that the specimen represents a new species indicates that the Late Permian tetrapod fauna of east Africa is still incompletely known.

Metastatic squamous cell carcinoma of the gastrointestinal tract is relatively uncommon. It is associated with a poor prognosis and behaves more aggressively. We report a case of metastatic growth in the ascending flexure of the colon that had eroded into the anterior abdominal wall muscles and resulted in a large parietal abscess. She had undergone radical hysterectomy followed by radiation therapy for stage II carcinoma of the uterine cervix 14 months back. Ultrasound guided drainage of the abscess was done as an emergency procedure to control the sepsis. After 3 days an extended Right Hemicolectomy with stapled ileo colic anastomosis was done with resection of a part of abdominal wall adherent to the growth with a grossly normal margin. Histopathological examination confirmed metastatic squamous cell carcinoma. She is disease free 2 months after surgery. Surgical management of the metastatic tumour was palliative but necessary to prevent intestinal obstruction in future.

Background and Objective: Urinary Tract Infections (UTIs) are mostly caused by Escherichia coli. The appropriate therapy demands a current knowledge on the antimicrobial susceptibility pattern amongst these pathogens, as an inappropriate use of antibiotics may lead to complications and treatment failure. The UTIs which are caused by multidrug resistant Extended-Spectrum Beta-Lactamase (ESBL) producing bacteria further pose a severe problem, as the treatment options are limited. The aim of this study was to identify the pattern of multi drug resistance amongst the uropathogenic E. coli (UPEC) isolates which were obtained from hospitalized patients. Forty UPEC were isolated from 200 urine samples of hospitalized patients who were clinically suspected for UTIs. Antimicrobial susceptibility screening was performed by using 16 antibiotics, by the Kirby Bauer disk diffusion technique. The isolates which were resistant to the third generation cephalosporins were subjected to the ESBL confirmatory test by using drug and drug-inhibitor combination disks by following the CLSI guidelines. Results: All the 40 isolates except three were multidrug resistant. They showed the highest sensitivities for nitrofurantoin (72.5%) and amikacin (70%). A high level of resistance was observed against ampicillin (97.5%), nalidixic acid and cefelexin (95%), amoxicillin (92.5%), cotrimoxazole (82.5%) and ciprofloxacin (80%) respectively. Thirty different antibiotic resistance patterns were observed against the different antibiotics. Twenty-eight out of the 40 isolates were resistant to the third generation cephalosporins. However, the phenotypic test for the ESBL confirmation indicated that eighteen out of the twenty-eight isolates were ESBL producers and that eleven different drug resistance patterns were observed amongst them. Conclusions: Therefore, this study accounts for the varied multidrug resistance pattern amongst the uropathogenic E. coli which were isolated from hospitalized patients in Kolkata, an eastern region of India. Nitrofurantoin and amikacin should be assigned as potent drugs to treat this infection in this region of the country. These varied resistance patterns present major therapeutic and infection control challenges and they suggest a heterogeneous population of the uropathogenic E. coli isolates which circulate in this sector of India.

Pigeonpea (Cajanus cajan) is an important grain legume of the Indian subcontinent, South-East Asia and East Africa. More than eighty five percent of the world pigeonpea is produced and consumed in India where it is a key crop for food and nutritional security of the people. Here we present the first draft of the genome sequence of a popular pigeonpea variety 'Asha'. The genome was assembled using long sequence reads of 454 GS-FLX sequencing chemistry with mean read lengths of >550 bp and >10-fold genome coverage, resulting in 510,809,477 bp of high quality sequence. Total 47,004 protein coding genes and 12,511 transposable elements related genes were predicted. We identified 1,213 disease resistance/defense response genes and 152 abiotic stress tolerance genes in the pigeonpea genome that make it a hardy crop. In comparison to soybean, pigeonpea has relatively fewer number of genes for lipid biosynthesis and larger number of genes for cellulose synthesis. The sequence contigs were arranged in to 59,681 scaffolds, which were anchored to eleven chromosomes of pigeonpea with 347 genic-SNP markers of an intra-species reference genetic map. Eleven pigeonpea chromosomes showed low but significant synteny with the twenty chromosomes of soybean. The genome sequence was used to identify large number of hypervariable 'Arhar' simple sequence repeat (HASSR) markers, 437 of which were experimentally validated for PCR amplification and high rate of polymorphism among pigeonpea varieties. These markers will be useful for fingerprinting and diversity analysis of pigeonpea germplasm and molecular breeding applications. This is the first plant genome sequence completed entirely through a network of Indian institutions led by the Indian Council of Agricultural Research and provides a valuable resource for the pigeonpea variety improvement.

Dietary restriction (DR) increases life span and delays the onset of age-related diseases across species. However, the molecular mechanisms have remained relatively unexplored in terms of gene regulation. InC. elegans, a popular model for aging studies, the FOXA transcription factor PHA-4 is a robust genetic regulator of DR, although little is known about how it regulates gene expression. We profiled the transcriptome and miRNAome of an eat-2 mutant, a genetic surrogate of DR, by Next Generation sequencing and find that most of the miRNAs are upregulated in the young-adult worms, none significantly downregulated. Interestingly, PHA-4 can potentially regulate the expression of most of these miRNA genes. Remarkably, many of the PHA-4-regulated genes that are induced during DR are also targets of the PHA-4-upregulated miRNAs, forming a large feed-forward gene regulatory network. The genes targeted by the feed-forward loops (FFLs) are enriched for functions related to ubiquitin-mediated...

Polycystic kidney disease (PKD) is a significant cause of end-stage kidney failure and there are few effective drugs for treating this inherited condition. Numerous aberrantly expressed non-coding RNAs (ncRNAs), particularly microRNAs (miRNAs), may contribute to PKD pathogenesis by participating in multiple intracellular and intercellular functions through post-transcriptional regulation of protein-encoding genes. Insights into the mechanisms of miRNAs and other ncRNAs in the development of PKD may provide novel therapeutic strategies. In this review, we discuss the current knowledge about the roles of dysregulated miRNAs and other ncRNAs in PKD. These roles involve multiple aspects of cellular function including mitochondrial metabolism, proliferation, cell death, fibrosis and cell-to-cell communication. We also summarize the potential application of miRNAs as biomarkers or therapeutic targets in PKD, and briefly describe strategies to overcome the challenges of delivering RNA to the kidney, providing a better understanding of the fundamental advances in utilizing miRNAs and other non-coding RNAs to treat PKD.

Cell-free microRNAs in plasma and serum have become a promising source of biomarkers for various diseases. Despite rapid progress in this field, there remains a lack of consensus regarding optimal quantification methods, reference genes, and quality control of samples. Recent studies have shown that hemolysis occurring during blood collection has substantial impact on the microRNA content in plasma/serum. To date, the impact of hemolysis has only been investigated for a limited number of microRNAs, mainly the red blood cell (RBC)-enriched miRs-16 and -451. In contrast, the effect of hemolysis on other microRNAs - in particular those proposed as biomarkers - has not been addressed. In this study we profiled the microRNA content of hemolyzed and non-hemolyzed plasma as well as RBCs to obtain a profile of microRNAs in the circulation affected or unaffected by hemolysis. Profiling by TaqMan Array Microfluidic Cards was used to compare three pairs of hemolyzed and non-hemolyzed plasma (w...

A combined computational and experimental study was conducted to examine the effect of extended benzannelation orientation on C-C and C-C cyclization of acyclic quinoxalenediynes. Calculations (mPW1PW91/cc-pVTZ//mPW1PW91/6-31G(d,p)) on terminal and phenylethynyl-substituted 5,6-diethynylquinoxaline and 6,7-diethynylquinoxaline showed C-C Bergman cyclization as the favored thermodynamic reaction pathway, with larger C-C preference for the angular quinoxalenediynes due to gain of a new aromatic sextet. Kinetic studies, as a function of 1,4-cyclohexadiene concentration, revealed retro-Bergman ring opening predominates over hydrogen atom abstraction (k > k) for 6,7-diethynylquinoxaline while 5,6-diethynylquinoxaline undergoes irreversible Bergman cyclization indicative of a large retro-Bergman ring opening barrier (k > k). The effect of extended linear versus angular benzannelation on reaction pathway shows in the contrasting photocyclizations of phenylethynyl derivatives. While a...

Reliable biomarkers for amyotrophic lateral sclerosis (ALS) are needed, given the clinical heterogeneity of the disease. Here, we provide proof-of-concept for using multimodal magnetic resonance imaging (MRI) as a diagnostic biomarker for ALS. Specifically, we evaluated the added diagnostic utility of proton magnetic resonance spectroscopy (MRS) to diffusion tensor imaging (DTI). Twenty-nine patients with ALS and 30 age- and gender-matched healthy controls underwent brain MRI which used proton MRS including spectral editing techniques to measure γ-aminobutyric acid (GABA) and DTI to measure fractional anisotropy of the corticospinal tract. Data were analyzed using logistic regression, t-tests, and generalized linear models with leave-one-out analysis to generate and compare the resulting receiver operating characteristic (ROC) curves. The diagnostic accuracy is significantly improved when the MRS data were combined with the DTI data as compared to the DTI data only (area under the R...

The interaction of actin filaments with myosin is crucial to cell motility, muscular contraction, cell division and other processes. The in vitro motility assay involves the motion of actin filaments on a substrate coated with myosin, and is used extensively to investigate the dynamics of the actomyosin system. Following on from previous work, we propose a new mechanical model of actin motility on myosin, wherein a filament is modeled as a chain of beads connected by harmonic springs. This imposes a limitation on the ‘stretching’ of the filament. The rotation of one bead with respect to its neighbors is also constrained in similar way. We implemented this model and used Monte Carlo simulations to determine whether it can predict the directionality of filament motion. The principal advantages of this model are that we have removed the empirically correct but artificial assumption that the filament moves like a ‘worm’ i.e. the head determines the direction of movement and the rest of ...

Many areas of biochemistry and molecular biology, both fundamental and applications-orientated, require an accurate construction, representation and understanding of the protein molecular surface and its interaction with other, usually small, molecules. There are however many situations when the protein molecular surface gets in physical contact with larger objects, either biological, such as membranes, or artificial, such as nanoparticles. The contribution presents a methodology for describing and quantifying the molecular properties of proteins, by geometrical and physico-chemical mapping of the molecular surfaces, with several analytical relationships being proposed for molecular surface properties. The relevance of the molecular surface-derived properties has been demonstrated through the calculation of the statistical strength of the prediction of protein adsorption. It is expected that the extension of this methodology to other phenomena involving proteins near solid surfaces, in particular the protein interaction with nanoparticles, will result in important benefits in the understanding and design of protein-specific solid surfaces.

Neocarus proteus sp. n., is described from caves and the surrounding epigean environment of ferruginous outcrops (Cangas) in Minas Gerais, Brazil. In addition, some notes about development in this species are presented. Neocarus proteus is the only species in the genus that has smooth or barbed genital setae and that carries coronidia on the basitarsi, tibiae and genua of legs II-III. Females carry additional setae with rounded tips on the subcapitulum, and are, on average, larger than males. This distinct sexual dimorphism appears in the tritonymphal instar and is maintained in the adults.

The biological control of inorganic crystal formation, morphology and assembly is of interest to biologists and biotechnologists studying hard tissue growth and regeneration, as well as to materials scientists using biomimetic approaches for control of inorganic material fabrication and assembly. Biomimetics requires an accurate understanding of natural mechanisms at the molecular level. Such understanding can be derived from the use of metal surfaces to study surface recognition by proteins together with combinatorial genetics techniques for selection of suitable peptides. Polymerization of these peptides produces engineered polypeptides large enough to encode their own folding information with low structural complexity while enhancing binding affinity to surfaces. The low complexity of such polypeptides can aid in analyses leading to modeling and eventual manipulation of the structure of the folded polypeptide. Here we present structure predictions for gold-binding protein sequences, originally selected by combinatorial techniques. Molecular dynamics simulations lasting 5 ns were carried out using solvated polypeptides at the gold surface to assess the dynamics of the binding process and the effects of surface topography on the specificity of protein binding.

The biological control of inorganic crystal formation, morphology and assembly is of interest to biologists and biotechnologists studying hard tissue growth and regeneration, as well as to materials scientists using biomimetic approaches for control of inorganic material fabrication and assembly. Biomimetics requires an accurate understanding of natural mechanisms at the molecular level. Such understanding can be derived from the use of metal surfaces to study surface recognition by proteins together with combinatorial genetics techniques for selection of suitable peptides. Polymerization of these peptides produces engineered polypeptides large enough to encode their own folding information with low structural complexity while enhancing binding affinity to surfaces. The low complexity of such polypeptides can aid in analyses leading to modeling and eventual manipulation of the structure of the folded polypeptide. Here we present structure predictions for gold-binding protein sequences, originally selected by combinatorial techniques. Molecular dynamics simulations lasting 5 ns were carried out using solvated polypeptides at the gold surface to assess the dynamics of the binding process and the effects of surface topography on the specificity of protein binding.

An 18-year-old male presented with a nonhealing wound on left lower limb, pain and swelling over multiple joints, weight loss, and yellowish discoloration of eyes and urine for the past 4 years. On examination, the patient had pallor, icterus, and generalized lymphadenopathy with a nonhealing unhealthy ulcer over left medial malleolus. He had deformed joints with hepatomegaly and splenomegaly. His laboratory investigations were positive for antinuclear antibody (ANA) and anticardiolipin antibody (ACLA). Synovial fluid analysis showed inflammatory findings. Biopsy of margin of the ulcer showed findings consistent with Acroangiodermatitis of Mali. The patient was treated with disease-modifying antirheumatic drugs (DMARDs) and aspirin for juvenile idiopathic arthritis and secondary antiphospholipid antibody syndrome (APS), respectively. The ulcer was managed conservatively with systemic antibiotics and topical steroids along with limb elevation and compression elastic stockings. The patient's symptoms improved significantly, and he is in our followup.

Discrete trial teaching (DTT) is a common instructional method incorporated into intensive behavioral intervention programs for children diagnosed with autism. Errorless learning strategies are frequently recommended during DTT because they often result in more efficient and effective instruction. The purpose of the present study was to conduct a sequential analysis of the efficacy of three methods for teaching errorless DTT procedures to novice instructors: (a) a self-instruction manual, (b) an instructional video, (c) and brief performance feedback. Three participants mastered DTT following self-instruction and the remaining three participants required all three interventions. The present study extends the literature on training DTT skills by (a) illustrating an efficient, sequential method of staff training, (b) introducing an improved self-instruction manual, and (c) clearly delineating guidelines for implementing an errorless prompt fading strategy during DTT.

The purpose of this series of experiments was to evaluate the effects of mixed mand-tact arrangements on the acquisition of mands and tacts in preschool-aged children. In Experiment 1, the effects of three training arrangements (mand-only training, tact-only training, and mand-tact training) were investigated with 3 typically developing children. Rates of acquisition in single (mand-only and tact-only) versus mixed (mand-tact) presentation were comparable, in contrast to earlier investigations. Experiment 2 attempted to clarify the equivocal findings of Experiment 1 by directly replicating the Carroll and Hesse (1987) investigation with 2 typically developing children. Results again demonstrated no clear benefit of mixed verbal operant training on tact acquisition. In Experiment 3, these same arrangements were evaluated with a boy with autism and included assessments to determine that a relevant establishing operation was in effect prior to each mand training session. Experiment 3 again failed to demonstrate the facilitative effects of mand-tact training on the acquisition of mands or tacts. Taken together, the data from these three experiments fail to support the improved efficiency of mand-tact training suggested by prior studies. Findings are discussed in the context of future research investigating mixed verbal operant arrangements.

Discrete trial teaching (DTT) is a common instructional method incorporated into intensive behavioral intervention programs for children diagnosed with autism. Errorless learning strategies are frequently recommended during DTT because they often result in more efficient and effective instruction. The purpose of the present study was to conduct a sequential analysis of the efficacy of three methods for teaching errorless DTT procedures to novice instructors: (a) a self-instruction manual, (b) an instructional video, (c) and brief performance feedback. Three participants mastered DTT following self-instruction and the remaining three participants required all three interventions. The present study extends the literature on training DTT skills by (a) illustrating an efficient, sequential method of staff training, (b) introducing an improved self-instruction manual, and (c) clearly delineating guidelines for implementing an errorless prompt fading strategy during DTT.

The present paper deals with addition of two new flowering plants records from different parts of the Satpuda ranges of Jalgaon district, Maharashtra are new distributional records for the first time. These species are Peristylus constrictus (Lindl.) Lindl. and Begonia picta Sm. are reported for the first time for Satpuda ranges of Jalgaon district, Maharashtra. The study provides a detailed taxonomic description, photographs and relevant information based on fresh collections.

Contact angle dependence of the resonant properties of sessile drops 1 JAMES SHARP, University of Nottingham -A simple optical deflection technique was used to monitor the vibrations of microlitre sessile drops of glycerol/water mixtures with glycerol compositions ranging from 0% to 75%. A photodiode was used to detect time dependent variations in the intensity of laser light reflected from the droplets. The intensity variations were Fourier transformed to obtain information about the resonant properties of the drops (frequency and width of the resonance). These experiments were performed on a range of different substrates where the contact angle formed by the droplets varied between 38 ± 2 • and 160 ± 4 • . The measured resonant frequency values were found to be in agreement with a recently developed theory of vibrations which considers standing wave states along the profile length of the droplet. The widths of the resonances were also compared with theories which predict the influence of substrate effects, surface contamination effects and bulk viscous effects on the damping of capillary waves at the free surface of the droplets. These experiments indicate that the dominant source of damping in sessile liquid droplet is due to bulk viscous effects but that for small contact angles damping due to the droplet/substrate interaction becomes more important.