bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficient Replication of Over 180 Genetic Associations with Self‐Reported Medical Data
Authors: Francke Uta , Naughton Brian , Naughton Joanna , Wojcicki Anne , Tung Joyce , Do Chuong , Hinds David , Kiefer Amy , Macpherson J. Michael , Eriksson Nicholas , Chowdry Arnab
Published: July 2019

While the cost and speed of generating genomic data have come down dramatically in recent years, the slow pace of collecting medical data for large cohorts continues to hamper genetic research. Here we evaluate a novel online framework for amassing large amounts of medical information in a recontactable cohort by assessing our ability to replicate genetic associations using these data. Using web‐based questionnaires, we gathered self-reported data on 50 medical phenotypes from a generally unselected cohort of over 20,000 genotyped individuals. Of a list of genetic associations curated by NHGRI, we successfully replicated about 75% of the associations that we expected to (based on the number of cases in our cohort and reported odds ratios, and excluding a set of associations with contradictory published evidence). Altogether we replicated over 180 previously reported associations, including many for type 2 diabetes, prostate cancer, cholesterol levels, and multiple sclerosis. We found significant variation across categories of conditions in the percentage of expected associations that we were able to replicate, which may reflect systematic inflation of the effects in some initial reports, or differences across diseases in the likelihood of misdiagnosis or misreport. We also demonstrated that we could improve replication success by taking advantage of our recontactable cohort, offering more in‐depth questions to refine self‐reported diagnoses. Our data suggests that online collection of self‐reported data in a recontactable cohort may be a viable method for both broad and deep phenotyping in large populations.
Protein Regge Trajectories, Phase Coexistence and Loop Aetiology in Alzheimers Disease
Authors: Niemi Antti , Krokhotin Andrey
Published: July 2019

Alzheimer's disease has a devastating impact on its victims by causing severe neurodegeneration in the brain that leads to a certain death. Only in a small number of cases can the origin be traced to a variety of genetic mutations, for the greater part the reasons for its onset are unclear.The defining factor is the formation of extracellular senile amyloid plaques in the brain, but therapeutic approaches to remove them remain to be shown effective in humans. Here we investigate physical processes that are involved in the release of the extracellular amyloid, by scrutinizing the intracellular domain of its precursor protein. We identify a phenomenon that has never before been discussed in the context of protein research: Like ice and water together, the intracellular domain of the amyloid precursor protein can form a complex of phase coexistence with another protein. This leads to an inherent instability that could well be among the missing pieces in the puzzle of Alzheimer's disease.
Openness as Infrastructure
Authors: Wilbanks John
Published: July 2019

Openness at the layer of cultural works and data is the key to the data infrastructure we need to accelerate science. This article lays out three key elements of data infrastructure - collaboration, classification, and openness - which draw us inevitably towards the long-claimed, but rarely-achieved, goal of the scientific method: to make claims that are reproducible under similar circumstances by someone other than the claimant, to be reproducible.
A decline in pollinator dependent vegetable crop productivity in India indicates pollination limitation and consequent agro-economic crises.
Authors: Basu Parthiba , Bhattacharya Ritam , Ianetta Pietro
Published: July 2019

Approximately 70% of the tropical crop species depend on pollinators for optimum yields (Roubik, 1995, Klein 2007). The economic value of such pollinated crops to India is $726 million and India is the world's second largest vegetable producer (Sidhu, 2005). This status has been underpinned by large-scale changes in land-use and pesticide dependency (Fazal, 2000; Shaw & Satish, 2007). A method (c.f. Aizen et al. 2008) that partitions crops into categories depending on their relative pollinator dependence (Index of pollinator dependence, DI) was applied to analysis of vegetable yields for India over 45 years (1963-2008) using FAO data. This has revealed that since 1993, relative yields of crop production has either flattened or declined, while pollinator non dependent crops show no similar decline. This pattern of yield limitation may be due to several factors, among which pollinator limitation would be a major factor (Kearns et al. 1998) and this risk is discussed. Pollinator decline will have serious socio-economic consequences for countries like India, which host a large population of small and marginal farms for whom falling yield level would be critical for subsistence (Kearns et al. 1998; Kremen et al., 2002; Klein et al., 2007; Potts et al., 2010). We show here for the first time any indication of pollination limitation in India, an emerging economy that is still predominantly agrarian. Detailed land use and ecological surveys are urgently required to assess the ecology of pollinating insects within and around agricultural systems in India.
Genetic Normalization of Differentiating Aneuploid Human Embryos
Authors: Brezina Paul , Barker Andrew , Benner Andrew , Ross Ric , Nguyen Khanh-Ha , Anchan Raymond , Richter Kevin , Cutting Garry , Kearns William
Published: July 2019

Early embryogenesis involves a series of dynamic processes, many of which are currently not well described or understood. Aneuploidy and aneuploid mosaicism, a mixture of aneuploid and euploid cells within one embryo, in early embryonic development are principal causes of developmental failure.^1,2^ Here we show that human embryos demonstrate a significant rate of genetic correction of aneuploidy, or "genetic normalization" when cultured from the cleavage stage on day 3 (Cleavage) to the blastocyst stage on day 5 (Blastocyst) using routine in vitro fertilization (IVF) laboratory conditions. One hundred and twenty-six human Cleavage stage embryos were evaluated for clinically indicated preimplantation genetic screening (PGS). Sixty-four of these embryos were found to be aneuploid following Cleavage stage embryo biopsy and single nucleotide polymorphism (SNP) 23 chromosome molecular karyotype (microarray). Of these, 25 survived to the Blastocyst stage of development and repeat microarray evaluation was performed. The inner cell mass (ICM), containing cells destined to form the fetus, and the trophectoderm (TE), containing cells destined to form the placenta were evaluated. Sixteen of 25 embryos (64%) [95% CI: 44-80%] possessed diploid karyotypes in both the ICM and TE cell populations. An additional three Blastocyst stage embryos showed genetic correction of the TE but not the ICM and one Blastocyst stage embryo showed the reverse. Mosaicism (exceeding 5%), was not detected in any of the ICM and TE samples analyzed. Recognizing that genetic normalization may occur in developing human embryos has important implications for stem cell biology, preimplantation and developmental genetics, embryology, and reproductive medicine.1)Hassold, T. et al. A cytogenetic study of 1000 spontaneous abortions. Ann Hum Genet. 44, 151-78 (1980).2)Menasha, J., Levy, B., Hirschhorn, K., & Kardon, N.B. Incidence and spectrum of chromosome abnormalities in spontaneous abortions: new insights from a 12-year study. Genet Med. 7, 251-63 (2005).
A novel therapeutic strategy for pancreatic neoplasia using a novel RNAi platform targeting PDX-1
Authors: Wang Zhaohui , Stehling Kelly , Gibbs Richard , Fisher William , Norman Michael , Brunicardi Charles , Templeton Nancy , Liu Shi-He , Rao Donald , Nemunaitis John , Senzer Neil , Dawson David , DeMayo Francesco , Gingras Marie-Claude
Published: July 2019

Bi-functional shRNA (bi-shRNA), a novel RNA interference (RNAi) effector platform targeting PDX-1 utilizing a systemic DOTAP-Cholesterol delivery vehicle, was studied in three mouse models of progressive pancreatic neoplasia. Species-specific bi-functional PDX-1 shRNA (bi-shRNAPDX-1) lipoplexes inhibited insulin expression and secretion while also substantially inhibiting proliferation of mouse and human cell lines via disruption of cell cycle proteins in vitro. Three cycles of either bi-shRNAmousePDX-1 or shRNAmousePDX-1 lipoplexes administered intravenously prevented death from hyperinsulinemia and hypoglycemia in a lethal insulinoma mouse model. Three cycles of shRNAmousePDX-1 lipoplexes reversed hyperinsulinemia and hypoglycemia in an immune-competent mouse model of pancreatic neoplasia. Moreover, three cycles of the bi-shRNAhumanPDX-1 lipoplexes resulted in near complete ablation of tumor volume and considerably improved survival in a human PANC-1 implanted SCID-mouse model. Human pancreatic neoplasia specimens also stained strongly for PDX-1 expression. Together, these data support the clinical development of a novel therapeutic strategy using systemic bi-shRNAPDX-1 lipoplexes against pancreatic neoplasia.
Gulf War Syndrome: A role for organophosphate induced plasticity of locus coeruleus neurons
Authors: Cao Jun-li , Varnell Andrew , Cooper Donald
Published: July 2019

Gulf War syndrome is a chronic multi-symptom illness that has affected about a quarter of the deployed veterans of the 1991 Gulf War. Exposure to prolonged low-level organophosphate insecticides and other toxic chemicals is now thought to be responsible. Chlorpyrifos was one commonly used insecticide. The metabolite of chlorpyrifos, chlorpyrifos oxon, is a potent irreversible inhibitor of acetylcholinesterase, much like the nerve agent Sarin. To date, the target brain region(s) most susceptible to the neuroactive effects of chlorpyrifos oxon have yet to be identified. To address this we tested ability of chlorpyrifos oxon to influence neuronal excitability and induce lasting changes in the locus coeruleus, a brain region implicated in anxiety, substance use, attention and emotional response to stress. Here we used an ex vivo rodent model to identify a dramatic effect of chlorpyrifos oxon on locus coeruleus noradrenergic neuronal activity. Prolonged exposure to chlorpyrifos oxon caused acute inhibition and a lasting rebound excitatory state expressed after days of exposure and subsequent withdrawal. Our findings indicate that the locus coeruleus is a brain region vulnerable to chlorpyrifos oxon-induced neuroplastic changes possibly leading to the neurological symptoms affecting veterans of the Gulf War.
Structures at the Atomic Level of Cobalt, Zinc and Lead Niobates
Authors: Heyrovska Raji
Published: July 2019

The author has found in recent years that bond lengths are exact sums of the radii of adjacent atoms and or ions, where the ions have Golden ratio based radii. This work was prompted by the exciting observation last year of the Golden ratio in the magnetic properties of cobalt niobate. It is shown here that in cobalt and zinc niobates, cobalt, zinc and oxygen ions have Golden ratio based ionic radii, whereas in lead niobate, all atoms have covalent radii. Also, the angles at the single bond oxygen anion and atom are close to 1080, as in a pentagon.
Structures at the Atomic Level of Cobalt, Zinc and Lead Niobates (with an Appendix: Atomic structure of cobalt niobate crystal)
Authors: Heyrovska Raji
Published: July 2019

The author has found in recent years that bond lengths are exact sums of the radii of adjacent atoms and or ions, where the ions have Golden ratio based radii. This work was prompted by the exciting observation last year of the Golden ratio in the magnetic properties of cobalt niobate. It is shown here that in cobalt and zinc niobates, cobalt, zinc and oxygen ions have Golden ratio based ionic radii, whereas in lead niobate, all atoms have covalent radii. Also, the angles at the single bond oxygen anion and atom are close to 1080, as in a pentagon.
Formation of an SIR-Nucleosome Filament in vitro and Its Modulation by O-Acetyl-ADP-Ribose
Authors: Wu Yu-Yi , Hong Jia-Yang , Lee Sue-Ping , Shen Hsiao-Hsuian , Tsai Shu-Ping , Liou Gunn-Guang
Published: July 2019

It is not possible to clearly visualize how chromatin condenses to heterochromatin in vivo. However, in an in vitro system for Saccharomyces cerevisiae, the requirements for heterochromatin filament formation mirror those found in vivo. Here we report that the nucleosomes and the Sir2, Sir3 and Sir4 proteins, which are required for in vitro filament assembly, are also components of these filaments, confirming that the filaments are SIR-nucleosome filaments. We show the individual localization patterns of the Sir proteins on this SIR-nucleosome filament, and demonstrate that the metabolite, AAR, plays a specific and essential role in promoting the formation of this SIR-nucleosome filament.
Molecular-genetic analysis of Mycobacterium tuberculosis strains spread in different patient groups in St.Petersburg (Russia)
Authors: Chernyaeva Ekaterina , Dobrynin Pavel , Pestova Natalia , Matveeva Natalia , Zhemkov Vladimir , Kozlov Andrei
Published: July 2019

Molecular epidemiological features of Mycobacterium tuberculosis strains spread among different patient groups in Russia is not studied well. The aim of our study was to compare genotypes of M.tuberculosis strains circulating among TB patients from different groups: homeless, HIV-infected, prisoners and general population of St.Petersburg citizens.One hundred fifty M.tuberculosis complex isolates from different TB patient groups were studied using spoligotyping method.The majority of studied M.tuberculosis isolates in all groups belonged to Beijing family (56% among homeless; 77% among HIV-infected; 60% among general population; 83% among prisoners). There were no significant difference in Beijing family prevalence among homeless patients, HIV/TB co-infected and general population of TB patients. The lowest genetic diversity of the pathogen was detected among imprisoned patients.

Results

of our study demonstrate that M.tuberculosis strains circulating among homeless and HIV-infected people are also spread among general population of St.Petersburg citizens. Thus, we have investigated the participation of high-risk groups in the spread of TB infection in the city.
Slow in Motion but Smart in Learning and Memory: Behavioral Changes in Adult NR3A Knockout Mice
Authors: Yu Shan Ping , Song Mingke , Mohamad Osama , Wei Ling
Published: July 2019

The expression of NMDA receptor subunit NR3A is high in the neonatal brain but low in adults. However, its functional role in the adult brain is obscure. Using wild-type (WT) and NR3A knockout (KO) mice, we show here that NR3A plays imperative roles in multiple behavioral functions in adults. NR3A deletion produced a slow locomotor phenotype with enhanced memory capacities. Hippocampal slices from juvenile and adult NR3A KO mice showed greater long-term potentiation (LTP) compared to WT slices. NR3A deletion resulted in increased expression and phosphorylation of calmodulin-dependent kinase II (CaMKII). CaMKII inhibition abrogated the enhanced LTP in NR3A KO slices. NR3A KO mice were also more sensitive to acute and chronic pain. These data reveal for the first time that NR3A, despite its low expression, plays several critical roles in behavioral activities in adults and may be a therapeutic target for modulating behaviors under normal and pathological conditions.
Regrowing the adult brain: NF-κB controls functional circuit formation and tissue homeostasis in the dentate gyrus
Authors: Leske Oliver , Kaltschmidt Christian , Püschel Andreas , Kaltschmidt Barbara , Memet Sylvie , Heumann Rolf , Imielski Yvonne , Schwamborn Jens , Lüningschrör Patrick , Heimann Peter , Holzberg Magdalena , Israel Alain , Werner Hendrikje
Published: July 2019

Cognitive decline during aging is correlated with a continuous loss of cells within the brain and especially within the hippocampus, which could be regenerated by adult neurogenesis. Here we show that genetic ablation of NF-κB resulted in severe defects in the neurogenic region (dentate gyrus) of the hippocampus. Despite increased stem cell proliferation, axogenesis, synaptogenesis and neuroprotection were hampered, leading to disruption of the mossy fiber pathway and to atrophy of the dentate gyrus during aging. Here, NF-κB controls the transcription of FOXO1 and PKA, regulating axogenesis. Structural defects culminated in behavioral impairments in pattern separation. Re-activation of NF-κB resulted in integration of newborn neurons, finally to regeneration of the dentate gyrus, accompanied by a complete recovery of structural and behavioral defects. These data identify NF-κB as a crucial regulator of dentate gyrus tissue homeostasis suggesting NF-κB to be a therapeutic target for treating cognitive and mood disorders.
Huntington’s disease is a TH17 related autoimmune disorder against mutant Huntingtin coded by multiple CAG triplets
Authors: Hu Wanchung
Published: July 2019

Huntington’s disease is an inherited neurodegenerative disorder. It belongs to the polyQ accumulation disease with mutant Huntington protein. The mutant Huntington has expanded CAG triplet repeats which make it easy to accumulate. However, the exact mechanism causing Huntington’s disease pathophysiology is unknown. Here, I propose that Huntington’s disease is an autoimmune disease. During childhood, there are Treg cells from the thymus to prevent autoimmune reaction against mutant Huntington. When the patient grows older with thymus atrophy, the accumulated mutant Huntington triggers TH17 related inflammatory reaction via heat shock proteins and toll-like receptor activation. Then, TH17 related cytokines such as TNFα, IL1, and IL6 cause neuron degeneration by activating apoptotic cascade. Once we know the pathogenesis of Huntington’s disease, we can use immunological knowledge to develop preventive or therapeutic strategies to cope with this detrimental disorder.
Molecular Modeling study of Protein Kinase PKnB from Mycobacterium Tuberculosis with derivatives of 1, 3, 4- Thiadiazoles
Authors: Gupta Vivek , Naqvi Asif , Tanwar Jayendra , Mishra Kaushlesh
Published: July 2019

Tuberculosis causes more than two million deaths per year. Faced with this global threat it is crucial to better understand the physiology of the causative organism, Mycobacterium Tuberculosis, in order to develop efficient therapeutic strategies. PKnB from Mycobacterium tuberculosis is a crucial receptor-like protein kinase involved in signal transduction. M. tuberculosis PKnB is a trans-membrane Ser/Thr protein kinase (STPK) highly conserved in Gram-positive bacteria and apparently essential for Mycobacterial viability. We have attempted with the help of virtual screening and docking approaches to expound the extent of specificity of protein kinase B towards different classes of Thiadiazoles (an anti-tubercular agent). The selected Thiadiazoles were selected on the basis of the structural specificity to the enzyme towards its substrate and inhibitors. Total number of Thiadiazoles were 5000 in number with the minimum binding energy of -10.46 kcal/mol with 10 molecules showing hydrogen bonds with the active site residue. The protein kinase B peptide contains two types of structural elements (Valine 95, Arginine 97) and the basic residue ring consisted of glycine rich residues. The structure of the protein-ligand complex reveals that Thiadiazoles partially occupies the adenine-binding pocket in PKnB, providing a framework for the design of compounds with potential therapeutic applications. The study provides hints for the future design of new derivatives with higher potency and specificity.
Plants switch photosystem at high temperature to protect photosystem II
Authors: Yamauchi Yasuo , Kimura Yukihiro , Akimoto Seiji , Marutani Yoko , Mizutani Masaharu , Sugimoto Yukihiro
Published: July 2019

Plants are often exposed to temperatures of around 40^o^C. These temperatures can cause serious damage to photosystems, yet plants can survive with minimum damage. Here, we show that plants switch photosystem to protect photosystem II (PSII) at 40^o^C. Using wheat and Arabidopsis seedlings, we investigated the mechanisms of heat-derived damage in the dark and avoidance of damage in the light. Heat treatment at 40^o^C in the dark caused serious damage to PSII: the maximum quantum yield of PSII (Fv/Fm) and oxygen evolution rapidly decreased. The damage was due to the degradation of the D1 protein (shown by immuno-chemical analysis) and the disturbance of energy transfer in PSII core chlorophyll-binding proteins CP43 and CP47 (shown by time-resolved fluorescence measurement). The damage to PSII might be due to enhanced introduction of electrons from the reducing power of the stroma into thylakoid membranes, causing subsequent electron backflow to PSII. Plants treated at 40^o^C in the light avoided PSII damage and showed preferential excitation of photosystem I (PSI), phosphorylation and migration of light-harvesting complex II (LHCII), which indicate state transition of the photosystem to enhance thermal dispersion and light-driven cyclic electron flow around PSI. These results suggest that heat damage to PSII is probably due to a backflow of reducing power from the stroma to PSII, and that light causes a state transition of photosystem, driving cyclic electron flow and thus protecting PSII from damage.
mGluR5 knockout mice exhibit normal conditioned place-preference to cocaine
Authors: Fowler Melissa , Varnell Andrew , Cooper Donald
Published: July 2019

Metabotropic glutamate receptor 5 (mGluR5) null mutant (-/-) mice have been reported to totally lack the reinforcing or locomotor stimulating effects of cocaine. We tested mGluR5 -/- and +/+ mice for their locomotor and conditioned place- preference response to cocaine. Unlike the previous finding, here we show that compared to mGluR5 +/+ mice, -/- mice exhibit no difference in the locomotor response to low to moderate doses of cocaine (10 or 20 mg/kg). A high dose of cocaine (40 mg/kg) resulted in a blunted rather than absent locomotor response. We tested mGluR5 -/- and +/+ mice for conditioned place-preference to cocaine and found no group differences at a conditioning dose of 10 mg/kg, suggesting normal conditioned rewarding properties of cocaine. These results differ substantially from Chiamulera et al. (2001) and replicates Olsen et al., (2010), who found normal cocaine place-preference in mGluR5 -/- mice at 5 mg/kg. Our results indicate mGluR5 receptors exert a modulatory rather than necessary role in cocaine-induced locomotor stimulation and exert no effect on the conditioned rewarding effects of cocaine.
Natural Radiation Induced Developmental Disability: An Avian Model
Authors: Padua Jeni Chandar , MR Basil Rose
Published: July 2019

Radiation exposure during gestation causes mutation in the fetus leading to birth defects in the newborn. On a survey of the coastal villages of Kanyakumari District, Tamilnadu, India, high levels of background radiation were detected, which was suggestive of inducing mutations, and congenital abnormalities in the exposed population. To substantiate the dangerous impact of such natural radioactive emissions, we have established an avian model of irradiation-induced birth defect in chicks hatched from eggs exposed to natural radioactive beach sand. The hatched experimental chicks exhibited severe locomotor disability and extreme malformations. Our study proves for the first time, that natural beach sand radiation induces severe developmental abnormalities. The results of this experiment brings to light, the importance of radiation-protection during gestation and also the need for monitoring and cleaning of radioactive sand deposits in beaches all over the world.
3D models of lamprey corticoid receptor complexed with 11-deoxycortisol and deoxycorticosterone
Authors: Baker Michael , Uh Kayla , Asnaashari Paiyuam
Published: July 2019

The serum of Atlantic sea lamprey, a basal vertebrate, contains two corticosteroids, 11-deoxycortisol and deoxycorticosterone. Only 11-deoxycortisol has high affinity [Kd~3 nM] for the corticoid receptor [CR] in lamprey gill cytosol. To investigate the binding of 11-deoxycortisol to the CR, we constructed 3D models of lamprey CR complexed with 11-deoxycortisol and deoxycorticosterone. These 3D models reveal that Leu-220 and Met-299 in lamprey CR have contacts with the 17[alpha]-hydroxyl on 11-deoxycortisol. Lamprey CR is the ancestor of the mineralocorticoid receptor [MR] and glucocorticoid receptor [GR]. Unlike human MR and human GR, the 3D model of lamprey CR finds a van der Waals contact between Cys-227 in helix 3 and Met-264 in helix 5. Mutant human MR and GR containing a van der Waals contact between helix 3 and helix 5 display enhanced responses to progesterone and glucocorticoids, respectively. We propose that this interaction was present in the CR and lost during the evolution of the MR and GR, leading to changes in their response to progesterone and corticosteroids, respectively.
Intraspecific variability drives diversity in food webs
Authors: Melian Carlos , Vilas Cesar , Baldo Francisco , Gonzalez-Ortegon Enrique , Drake Pilar , Williams Richard
Published: July 2019

Biodiversity theories neglect individual-level variability in ecological interactions even though empirical work has revealed considerable genetic and phenotypic variation among individuals in natural populations. This impedes assessing the impact of individual-level variability on biodiversity in multi-trophic ecosystems. Here we use a density-dependent and individual-based food web model, tested against the largest individual-based food web to date, to show that non-random intraspecific variation in prey selection alters species diversity in food webs. Predators consuming many prey increase diversity by preferentially selecting common prey; predators consuming few prey inhibit diversity by preferentially selecting rare prey, putting them at risk of extinction. Thus species-level patterns cannot be explained by species-level averages, but instead must consider individual-level variation in prey selection. Individual-level variation occurs in many biological and social contexts, suggesting that analyses of individual-level interaction data will be relevant in a wide range of fields.
Reduction of adipose tissue mass by the angiogenesis inhibitor ALS-L1023
Authors: Lee Hee , Park Eun kyu , Hahm Jong Cheon , Kim Min-Young , Yoon Michung , Lee Hyunhee , Hong Yeonhee , Park Dongmin , Oh Jaeho , Park Byung-Young
Published: July 2019

Objective:

Angiogenesis has been demonstrated to modulate adipogenesis and obesity. This study was undertaken to determine whether the botanical drug ALS-L1023 (ALS), which exhibits antiangiogenic activity, can regulate adipose tissue growth in high-fat-diet-induced obese mice.

Materials and Methods:

The effects of ALS on angiogenesis and extracellular matrix remodeling were measured using in vitro assays. The effects of ALS on adipose tissue growth was investigated in nutritionally obese mice.

Results:

ALS inhibited angiogenesis in a concentration-dependent manner in the tube formation assay and the VEGF-induced proliferation assay using human umbilical vein endothelial cells. ALS also suppressed matrix metalloproteinase (MMP) activity in vitro. ALS administration to high-fat-diet-induced obese mice significantly reduced body weight gain, adipose tissue mass, and adipocyte size compared with the findings in the controls. ALS treatment decreased blood vessel density and MMP activity in adipose tissues. ALS reduced the mRNA levels of angiogenic factors (VEGFs and FGF-2) and MMPs (MMP-2 and MMP-9), whereas it increased the mRNA levels of angiogenic inhibitors (TSP-1 and TIMPs) in adipose tissues. Conclusion: These results suggest that in vivo and in vitro treatment with ALS, which has antiangiogenic and MMP inhibitory activities, reduces adipose tissue mass in nutritionally induced obese mice, providing evidence that adipose tissue growth can be regulated by angiogenesis inhibitors.
Comparison of Efficiency of Photodynamic Diagnostics with Topical Use of the 3% and 15% Aminolevulinic Acid in the Detection of Vulvar Lesions
Authors: Mazdziarz Agnieszka , Alkhalayla Habib , Zielinska Aleksandra , Spiewankiewicz Beata
Published: July 2019

The objective of the study was evaluating the efficiency of the photodynamic method PDD (photodynamic diagnosis) in the detection of vulvar lesions when two concentrations of the photosensitizer were used ( 3%- and 15%-aminolevulinic acid ), as well as evaluating the efficiency of this method when compared to the efficiency of vulvoscopy, against the result of histological examination. Two concentrations of the 5-ALA cream ( aminolevulinic acid ) - 3% and 15% - were used in the PDD testing. The study group was divided into two subgroups A and B. In subgroup A the 15% eucerine - based cream was used. In subgroup B the 3% ALA gel with addition of 2% DMSO was used. The photosensitizer was applied to the vulva four to six hours before the examination. In order to obtain fluorescence, energy in the form of light whose wavelength was approximately 405 nm, and whose source was a SLED diode, was transmitted to vulvar tissue. The positive result of the exam was obtaining tissue fluorescence. All patients underwent vulvoscopy and a histological examination of tissue samples was performed in all cases. The efficiency of the photodynamic testing in subgroups A and B was compared with the efficiency of vulvoscopy, against the result of histological examination. Sensitivity, specificity, as well as positive and negative predictive values of the PDD examination and vulvoscopy in both subgroups, were evaluated. When the 15% ALA was used in detecting vulvar lesions, the photodynamic diagnostics was characterized by sensitivity of 100%, specificity of 92%, positive predictive value of 80%, negative predictive value of 100%, and correlation with the histopathological examination of 93.9%. When the 3% ALA was used, we observed: sensitivity of 100%, specificity of 91.4%, positive predictive value of 78.5%, negative predictive value of 100%, and correlation with the histopathological examination of 93.4%. Differences in the two subgroups were not statistically significant.
Early Diagnosis of Alzheimer's disease by NIRF Spectroscopy and Nuclear Medicine-v.4.0
Authors: Baianu I
Published: July 2019

There is an urgent need for the early detection of diseases such as Alzheimer’s (AD) and Cancers in order to enable their successful treatment. Cancer is the second major cause of death after Heart Disease, and AD is the third major cause of death with major, human and financial/economics trillion dollar consequences for the society. Nuclear Medicine is concerned with applications in Medicine of Nuclear Science and Engineering techniques and knowledge. Three major Nuclear Medicine techniques that are established for diagnostic and research purposes are: Positron Emission Tomography (PET) and CAT/CT, Nuclear Magnetic Resonance Imaging (NMRI/MRI). However, these three techniques have also major limitations in terms of either cost or image resolution, as well as patient irradiation in the case of CAT/CT and PET. On the other hand, Near Infrared Chemical Imaging Microspectroscopy and certain Fluorescence spectroscopic techniques are capable of single cancer cell and/or single molecule detection and/or imaging. Such powerful capabilities, combined with low cost of diagnostics, make these novel techniques very attractive means for early detection of diseases such as cancer and Alzheimer’s, that are promising to reduce the fatality rate of patients through adequate diagnosis and treatment of such diseases at early stages.Currently NIH provides only inadequate funding for the clinical and research aspects of these novel investigation and clinical diagnostic techniques by FT-NIRS and Fluorescence spectrocopy for early detection of Alzheimer’s and Cancers.
Endothelin-Induced Sarcoplasmic Reticulum Calcium Depletion Waves in Vascular Smooth Muscle Cells
Authors: Esfandiarei Mitra , Choi Yohan , Tehrani Arash , Hoskins Jeremy , Fameli Nicola , van Breemen Cornelis
Published: July 2019

Agonist-stimulated waves of elevated cytoplasmic Ca2+ concentration ([Ca2+]i ) regulate blood vessel tone and vasomotion in vascular smooth muscle. Previous studies employing cytoplasmic Ca2+ indicators revealed that these Ca2+ waves were generated by a combination of inositol 1,4,5-trisphosphate (IP3) and Ca2+ induced Ca2+ release (CICR) from the sarcoplasmic reticulum (SR); although, some of the mechanistic details remain uncertain. However, these findings were derived indirectly from observing agonist-induced [Ca2+]i fluctuations in the cytoplasm.Here, for the first time, we have recorded Endothelin-1 (ET-1) induced waves of Ca2+ depletion from the SR lumen in vascular smooth muscle cells (VSMCs) using a calsequestrin-targeted Ca2+ indicator. Our findings show that these waves: (1) are due to regenerative CICR by the receptors for IP3 (IP3R), (2) have a marked latency period, (3) are characterized by a transient increase in SR Ca2+ ([Ca2+]SR ) both at the point of origin and at the wave front, (4) proceed with diminishing velocity, and (5) are arrested by the nuclear envelope. Our quantitative model indicates that the gradual decrease in the velocity of the SR depletion wave, in the absence of external Ca2+, results from continuity of the SR luminal network.
Atomic and molecular structures of positronium, dipositronium and positronium hydride
Authors: Heyrovska Raji
Published: July 2019

The three positron based chemical entities, analogous to hydrogen atom, hydrogen molecule and hydride, are drawing increasing attention in the literature. While a lot is known about the binding energies, not much is known about the radii of the atoms and ions and bond lengths and structures of these exotic entities. This article brings for the first time exact values of these structural properties which are comparable with known data. It is hoped that the results will be of help for a better understanding and further development of the chemistry and physics of these exotic compounds and of their possible role as intermediates in chemical and interfacial processes.
Vermiculiphily: Larvae Pollinating Orchids!
Authors: Kumar Pankaj , Rawat Gopal
Published: July 2019

Orchids are truly extraordinary organisms exhibiting a wide range of pollination mechanism, many of which awaits discovery. Epipactis veratrifolia is a terrestrial orchid that has been reported to be pollinated by various species of hoverflies in Israel1,2. This orchid is known to emit the smell of aphid pheromone that attracts hoverflies, which lay eggs inside the flower and in the process pollinate them. Recently, we observed a species of hoverfly (Ischiodon scutellaris) pollinate the same orchid species in the Western Himalaya while laying eggs inside the flowers. Ischiodon scutellaris is being reported for the first time as pollinator of this orchid. However, all flowers don’t get pollinated, even though insects visit them and lay eggs inside. In this communication we reveal the fate of those orchid flowers which are visited by the flies but are left unpollinated.
The Calbindin-D28k binding site on inositol monophosphatase may allow inhibition independent of the lithium site of action
Authors: Hoffman Amnon , Talgan Yftah , Fanous Joseph , Agam Galila , Eisenstein Miriam , Levi Itshak , Askira Yael , Almog Orna , Gilon Chaim
Published: July 2019

Among numerous reported biochemical effects the lithium-inhibitable enzyme inositol-monophosphatase (IMPase) remains a viable target for lithium's therapeutic mechanism of action. Calbindin-D28k (calbindin) interacts with IMPase enhancing its activity. In the present study in silico modeling of IMPase-calbindin binding using the program MolFit indicated that the 55-66 amino acid segment of IMPase anchors calbindin via Lys59 and Lys61 with a glutamate in between (Lys-Glu-Lys motif). The model further suggested that the Lys-Glu-Lys motif interacts with residues Asp24 and Asp26 of calbindin. Indeed, we found that differently from wildtype calbindin, IMPase was not activated by mutated calbindin in which Asp24 and Asp26 were replaced by alanine. Calbindin's effect was significantly reduced by a peptide with the sequence of amino acids 58-63 of IMPase (peptide 1) and by six amino-acid peptides including at least part of the Lys-Glu-Lys motif. The three amino-acid peptide Lys-Glu-Lys or five amino-acid peptides containing this motif were ineffective. Intracerebroventricular administration of peptide 1 resulted in a significant antidepressant-like reduced immobility in the Porsolt forced swim test (FST) compared with mice treated with a scrambled peptide or artificial cerebrospinal fluid. Based on the sequence of peptide 1, and to potentially increase the peptide's stability, cyclic and linear pre-cyclic analog peptides were synthesized. One cyclic and one linear pre-cyclic analog peptides exhibited an inhibitory effect on calbindin-activated brain IMPase activity in vitro. These findings may lead to the development of molecules capable of inhibiting IMPase activity at an alternative site than that of lithium.
Pachydermoperiostosis-Like Disease In Captive Red Ruffled Lemurs (Varecia Variegatus Rubra)
Authors: Rothschild Bruce , Neiffer Donald , Marks Steve
Published: July 2019

Pachydermatoperiostosis, a rare form of hypertrophic osteoarthropathy, is of unknown etiology and previously thought limited to humans. The only periosteal reaction previously reported in prosimians is related to renal disease. Notation of hypertrophic osteoarthritis in three prosimians led to recognition that this was the first non-human documentation of the disease. Three related red ruffed lemurs (Varecia variegatus rubra) had diaphyseal periosteal reaction classic for hypertrophic osteoarthropathy. Workup was negative for known underlying causes and for the secondary hyperparathyroidism which produces bone alterations in black Eulemur macao, black and white Varecia variegatatus varigatus and ringtail Lemur catta lemurs. Recognition of facial coarsening allows identification of the primary form of hypertrophic osteoarthropathy, categorized in humans as primary hypertrophic osteoarthropathy. This is the first recognition of the phenomenon in the order primates, exclusive of humans, and represents a new model for this rare disease.
Circulating Neutrophils from Trauma Patients Induce Apoptosis Through Dephosphorylation of Epithelial Cell Caspase-8
Authors: Kapus Andras , Marshall John , Jia Songhui , Parodo Jean , Battisti-Charbonney Emmanuel , Tsang Jennifer , Jia Sangyang , Rotstein Ori
Published: July 2019

Activated neutrophils can cause oxidant-mediated bystander injury to host cells. This injury has previously been ascribed to the direct effects of oxidants on membrane phospholipids. We show here that oxidants released by neutrophils activated in vivo in survivors of multiple trauma or in vitro by exposure to bacterial lipopolysaccharide (LPS) can also promote the apoptotic death of epithelial cells, through the SHP-1-mediated dephosphorylation of epithelial cell caspase-8. Neutrophils from a cohort of patients who sustained serious injury induced the apoptotic death of cultured epithelial cells in a manner that was dependent on the activity of the NADPH oxidase and the generation of neutrophil-derived reactive oxygen intermediates. Caspase-8 is constitutively tyrosine phosphorylated in a panel of resting epithelial cells, but undergoes dephosphorylation in response to hydrogen peroxide (H2O2), activated neutrophils, or inhibition of Src kinases. Mutation of either of 2 key caspase-8 tyrosine residues, Y397 and Y465 to a non-phosphorylatable phenylalanine accelerates the apoptosis of epithelial cells transfected with caspase-8, while mutation of the same tyrosine residues to the phosphomimetic glutamic acid, or transfection with the Src kinases Lyn or c-Src inhibits H2O2-induced apoptosis. Exposure to either H2O2 or LPS-stimulated neutrophils, increases the phosphorylation and activity of the phosphatase SHP-1, increases the activity of caspases-8 and -3, and accelerates epithelial cell apoptosis. Together these data reveal a novel mechanism for neutrophil-mediated tissue injury through oxidant-dependent SHP-1-mediated dephosphorylation of caspase-8 resulting in enhanced epithelial cell apoptosis.
Arrhenius' theory of partial dissociation and hydration of electrolytes in solutions replaces existing activity concepts
Authors: Heyrovska Raji
Published: July 2019

The author shows that Arrhenius's theory of partial electrolytic dissociation was immaturely displaced about eight decades ago by the empirical concept of ionic activities and the assumption of complete dissociation of electrolytes at all concentrations. The latter brought the theory of electrolytes over the next decades into a complicated state without any physical significance. Therefore, the author started a systematic investigation of the available data and could completely restore the original theory of partial dissociation. Now solution properties can be easily understood and quantitatively explained in terms of absolute concentrations and volumes of ions and ion pairs and hydration.
Firing statistics and correlations in spiking neurons: a level-crossing approach
Authors: Badel Laurent
Published: July 2019

We present a time-dependent level-crossing theory for linear dynamical systems perturbed by colored Gaussian noise. We apply these results to approximate the firing statistics of conductance-based integrate-and-fire neurons receiving excitatory and inhibitory Poissonian inputs. Analytical expressions are obtained for three key quantities characterizing the neuronal response to time-varying inputs: the mean firing rate, the linear response to sinusoidally-modulated inputs, and the pairwise spike-correlation for neurons receiving correlated inputs. The theory yields tractable results that are shown to accurately match numerical simulations, and provides useful tools for the analysis of interconnected neuronal populations.
The Strauss-Kahn Syndrome
Authors: Skopec Robert
Published: July 2019

Accumulating evidence shows that the central nervous system (CNS) regulates the activity of the immune system. Concerning the role of immune system in cancer, psychosocial influences on immune function provide a mechanism of association between psychosocial factors (like interpersonal aggression) and cancer prognosis. Social conflicts between males, involving high aggression stress and threat (psychosocial conflicts) produce both an allostatic state and allostatic load. The costs for aggressors (Hawks) and victims (losers) tested under semi laboratory conditions are quite different. Testosterone does not cause aggression, only exaggerates the pre-existing pattern and response to environmental triggers of aggression. The individual's personality type (authoritarian Hawk or Dove) has major impact on psychoneuroimmune mechanisms linking aggression stress through inflammation to cancer. Due to the latest connotations we propose this personality phenomenon label as "the Strauss-Kahn syndrome".
Involvement of proteasome b1i subunit, LMP2, on uterine leiomyosarcma tumorigenesis
Authors: Hayashi Takuma , Horiuchi Akiko , Konishi Ikuo
Published: July 2019

Although the majority of smooth muscle neoplasms found in the uterus are benign, uterine leiomyosarcoma (LMS) is extremely malignant, with high rates of recurrence and metastasis. The development of gynecologic tumors is often correlated with secretion of female hormone; however, the development of human uterine LMS is not substantially correlated with hormonal conditions, and the risk factors are unclearly understood. Importantly, a diagnostic-biomarker, which distinguishes malignant human uterine LMS from benign tumor leiomyoma (LMA) is yet to be established. Accordingly, it is necessary to analyze risk factors associated with human uterine LMS, in order to establish a clinical treatment method. Homozygous deficient mice for a proteasome subunit　b1i/LMP2 spontaneously develop uterine LMS, with a disease prevalence of ~40% by 14 months of age. Defective LMP2 expression in human uterine LMS was demonstrated, but present in human LMA. Therefore, loss in LMP2 expression may be one of the risk factors for human uterine LMS. LMP2 may be a potential diagnostic-biomarker and targeted- molecule for a new therapeutic approach.
Preservation of C Hexagons in C Allotrope Transformations
Authors: Bucknum Michael , Castro Eduardo
Published: July 2019

In this Letter is described the analogous hexagon preserving C allotrope transformations of graphite to diamond, as a packing of C spheres on the one hand, and alternatively C nanotubes to the C allotrope hexagonite, as a packing of C cylinders on the other hand.
The carbon allotrope glitter as n-diamond and i-carbon nanocrystals
Authors: Bucknum Michael , Castro Eduardo
Published: July 2019

Diffraction data taken from nanocrystalline n-diamond and i-carbon forms is fit to a so-called glitter model, in which the geometry of the C lattice has been optimized by density functional theory (DFT). A calculated theoretical diffraction pattern for glitter is shown to be a close fit to the experimental data for these novel C forms.
Accurate estimation of homologue-specific DNA concentration-ratios in cancer samples allows long-range haplotyping
Authors: Carter Scott , Meyerson Matthew , Getz Gad
Published: July 2019

Interpretation of allelic copy measurements at polymorphic markers in cancer samples presents distinctive challenges and opportunities. Due to frequent gross chromosomal alterations occurring in cancer (aneuploidy), many genomic regions are present at homologous-allele imbalance. Within such regions, the unequal contribution of alleles at heterozygous markers allows for direct phasing of the haplotype derived from each individual parent. In addition, genome-wide estimates of homologue specific copy- ratios (HSCRs) are important for interpretation of the cancer genome in terms of fixed integral copy-numbers. We describe HAPSEG, a probabilistic method to interpret bi- allelic marker data in cancer samples. HAPSEG operates by partitioning the genome into segments of distinct copy number and modeling the four distinct genotypes in each segment. We describe general methods for fitting these models to data which are suit- able for both SNP microarrays and massively parallel sequencing data. In addition, we demonstrate a specially tailored error-model for interpretation of systematic variations arising in microarray platforms. The ability to directly determine haplotypes from cancer samples represents an opportunity to expand reference panels of phased chromosomes, which may have general interest in various population genetic applications. In addition, this property may be exploited to interrogate the relationship between germline risk and cancer phenotype with greater sensitivity than is possible using unphased genotype. Finally, we exploit the statistical dependency of phased genotypes to enable the fitting of more elaborate sample-level error-model parameters, allowing more accurate estimation of HSCRs in cancer samples.