Miracle-dz/UniFAR-FTUs huggingface dataset:
Drug Target Identification Using Side-Effect Similarity

Targets for drugs have so far been predicted on the basis of molecular or cellular features, for example, by exploiting similarity in chemical structure or in activity across cell lines. We used phenotypic side-effect similarities to infer whether two drugs share a target. Applied to 746 marketed drugs, a network of 1018 side effect–driven drug-drug relations became apparent, 261 of which are formed by chemically dissimilar drugs from different therapeutic indications. We experimentally tested 20 of these unexpected drug-drug relations and validated 13 implied drug-target relations by in vitro binding assays, of which 11 reveal inhibition constants equal to less than 10 micromolar. Nine of these were tested and confirmed in cell assays, documenting the feasibility of using phenotypic information to infer molecular interactions and hinting at new uses of marketed drugs.
Application of denaturing gradient gel electrophoresis for analysing the gut microflora of Lumbricus rubellus Hoffmeister under different feeding conditions

Abstract The earthworm, Lumbricus rubellus, plays an essential role in soil ecosystems as it affects organic matter decomposition and nutrient cycling. By ingesting a mixture of organic and mineral material, a variety of bacteria and fungi are carried to the intestinal tract of the earthworm. To get a better understanding of the interactions between L. rubellus and the microorganisms ingested, this study tried to reveal if the diet affects the composition of the gut microflora of L. rubellus or if its intestinal tract hosts an indigenous, species-specific microbiota. A feeding experiment with L. rubellus was set up; individuals were collected in the field, transferred to a climate chamber and fed with food sources of different quality (dwarf shrub litter, grass litter or horse dung) for six weeks. DNA was extracted from the guts of the earthworms, as well as from the food sources and the surrounding soil, and further analysed by a molecular fingerprinting method, PCR-DGGE (Polymerase Chain Reaction – Denaturing Gradient Gel Electrophoresis). We were able to demonstrate that the gut microbiota was strongly influenced by the food source ingested and was considerably different to that of the surrounding soil. Sequencing of dominant bands of the bacterial DGGE fingerprints revealed a strong occurrence of y-Proteobacteria in all gut samples, independent of the food source. A specific microflora in the intestinal tract of L. rubellus, robust against diet changes, could not be found.
Analysis of hMSH2 Mismatch Repair Protein Expression in Dysplasia, Carcinoma In Situ and Invasive Squamous Cell Carcinoma of the Vocal Folds

The expression pattern of hMSH2 mismatch repair protein during the progression of benign epithelium to vocal fold invasive squamous cell carcinoma has not been previously described. Nor has the correlation between the hMSH2 protein expression and the clinicopathologic features of the vocal fold dysplasia and carcinoma been examined. Hypothesis: “The progression of benign epithelium to invasive squamous cell carcinoma of the vocal folds is associated with reduction of the hMSH2 mismatch repair protein expression. ” Methods: Vocal fold biopsies were obtained from 20 patients with mild and moderate dysplasia: 10 patients with severe dysplasia (squamous cell carcinoma in situ) and 20 patients with invasive squamous cell carcinoma. The expression pattern of hMSH2 protein was examined by using immunoperoxidase-staining methods and mouse monoclonal antibodies. The results were scored as the percentage of hMSH2 positively stained cells. Results: The mean values of hMSH2 positively stained cells decreased gradually with the transitions from normal epithelium to dysplasia and finally to invasive squamous cell carcinoma. There was a negative correlation between the expression of hMSH2 and the degree of dysplasia, that is, as the severity of the dysplasia increases at the microscopic level, there was a decrease in the expression values of the hMSH2 protein. Conclusions: We report, for the first time, that the reduced expression of the hMSH2 mismatch repair protein is related to the progression of the benign epithelium to invasive squamous cell carcinoma of the vocal folds.
HIV and Periodontal Disease: Redemption or Resurrection

Human immunodeficiency virus (HIV) infection, a major medical crisis that has hit families, communities & nations across the world, remains a major health concern of unprecedented dimension. Mounting evidence suggests that co-infections and inflammation may result in re-activation of latent virus and blunt the success of Highly Active Anti-retroviral Therapy (HAART). Periodontal diseases are chronic multibacterial infections that can result in significant bacterial & inflammatory load in the body and HIV infection has been found to be associated with various forms of periodontal diseases. Besides Immune Reconstitution Inflammatory Syndrome (IRIS), following HAART, may also lead to increased frequency of periodontal disease among these patients. If co-infections & inflammation can increase the risk of HIV reactivation, can periodontitis in an HIV infected individual lead to HIV re-activation. This question remains unanswered, but initial evidence suggests a probable role of periodontitis in HIV re-activation. The clinical implication of such a role is that, periodontitis being most often preventable and definitely treatable, every attempt should be made to prevent and promptly treat this disease in individuals with HIV infection.
Structural plasticity of 4-α-helical bundles exemplified by the puzzle-like molecular assembly of the Rop protein

Significance The ColE1 Rop protein is a paradigm of a canonical 4-α-helical bundle and an attractive model system for protein-folding studies. This work characterizes Rop and several of its loop mutants, focusing on their extreme structural plasticity. Plasticity gives rise to new helical bundle topologies and properties and establishes a variety of native-like and molten globule states that depend on nonnative disulfide bonds. This plasticity and the capacity of the Rop mutants to assemble a large variety of different hydrophobic cores add Rop to the list of proteins that are suitable for the engineering of bio-inspired materials. Additionally, our findings have implications for the theory of protein folding and for understanding certain pathogenic mechanisms and diseases. The dimeric Repressor of Primer (Rop) protein, a widely used model system for the study of coiled-coil 4-α-helical bundles, is characterized by a remarkable structural plasticity. Loop region mutations lead to a wide range of topologies, folding states, and altered physicochemical properties. A protein-folding study of Rop and several loop variants has identified specific residues and sequences that are linked to the observed structural plasticity. Apart from the native state, native-like and molten-globule states have been identified; these states are sensitive to reducing agents due to the formation of nonnative disulfide bridges. Pro residues in the loop are critical for the establishment of new topologies and molten globule states; their effects, however, can be in part compensated by Gly residues. The extreme plasticity in the assembly of 4-α-helical bundles reflects the capacity of the Rop sequence to combine a specific set of hydrophobic residues into strikingly different hydrophobic cores. These cores include highly hydrated ones that are consistent with the formation of interchain, nonnative disulfide bridges and the establishment of molten globules. Potential applications of this structural plasticity are among others in the engineering of bio-inspired materials.
Polar location and functional domains of the Agrobacterium tumefaciens DNA transfer protein VirD4

Agrobacterium tumefaciens VirD4 is essential for DNA transfer to plants. VirD4 presumably functions as a coupling factor that facilitates communication between a substrate and the transport pore. To serve as a coupling protein, VirD4 may be required to localize near the transport apparatus. In a previous study, we observed that several constituents of the transport apparatus localize to the cell membranes. In this study, we demonstrate that VirD4 has a unique cellular location. In immunofluorescence microscopy, cells probed with anti‐VirD4 antibodies had foci of fluorescence primarily at the cell poles, indicating that VirD4 localizes to the cell pole. Polar location of VirD4 was not dependent on T‐DNA processing, the formation of the transport apparatus and the presence of other Vir proteins. VirD4 is an integral membrane protein with one periplasmic domain. The large cytoplasmic region contains a nucleotide‐binding domain. To investigate the role of these domains in DNA transfer, we introduced mutations in virD4 and studied the effect of a mutation on substrate transfer. A deletion of most of the periplasmic domain as well as the alterations of glycine 151 to serine and lysine 152 to alanine led to the complete loss of DNA transfer, indicating that both domains are essential for substrate transfer. Subcellular localization of the mutant proteins indicated that both the periplasmic and the nucleotide‐binding domains are required for polar localization of VirD4. The periplasmic domain mutant VirD4Δ36–61 was distributed throughout the cell membrane, whereas the nucleotide binding site mutant VirD4G151S localized to sites other than the cell poles. Polar location of VirD4 suggests a role for the cell pole in DNA transfer.
SYNTHESIS AND BIOLOGICAL EVALUATION OF ENDOCYCLIC 2′,3′-DIDEHYDRO- 2′,3′-DIDEOXYMETHANOCARBA ADENOSINE

ABSTRACT This is the first report describing the synthesis and conformation of methanocarba nucleosides incorporating an endo (β-face) cyclopropyl at the 2′,3′ position of 2′,3′-didehydro-2′,3′-dideoxy carbocyclic nucleosides. These nucleoside isosteres have been shown to exist in a unique extreme eastern conformation. This prediction was confirmed by x-ray crystallography and high resolution NMR spectroscopy. As expected, the methanocarba adenosine compound was neither a substrate nor an inhibitor of adenosine deaminase. However, some of the compounds synthesized demonstrated moderate antiviral activity against HSV-1. The methanocarba adenosine and its triphosphate form were evaluated as inhibitors of HIV-1 reverse transcriptase.
The riskiest time for the brain: could the nighttime be the right time for intervention?

The natural circadian rhythm of blood pressure (BP) typically includes a nocturnal decrease of 10% to 20% in BP compared with daytime, awake values.1,2 However, in as many as 25% to 35% of hypertensive patients, there is a moderate-to-marked loss of this decline in nocturnal BP, a phenomenon that has been associated with excessive cardiac,3 renal,4 and cerebrovascular5 target organ damage. In addition, patients with hypertension who exhibit a nocturnal BP increase compared with daytime BP (so-called “risers”) have the worst prognosis for future stroke and cardiac events.6 In contrast, there is also some evidence that patients with marked nocturnal BP declines (so-called “extreme dippers”) are at greater risk for ischemic strokes and silent myocardial ischemia than patients whose decline in BP during sleep is normal.7 Both the etiologies and the consequences of an elevated nocturnal BP are diverse. Since Shimada et al8 first reported a study evaluating ambulatory BP monitoring in older patients with hypertension using MRI 15 years ago, there has been an ongoing issue with our general understanding of BP variability and the brain as a target organ, because most studies have had small sample sizes and have been performed in homogenous populations. In this issue of Hypertension , Schwartz et al9 have provided us with a large cross-sectional study from Minnesota and Mississippi of 263 black and 343 white subjects who underwent clinic …
Analytical and experimental analysis of optimal tilt angle of solar photovoltaic systems

Performance of PV panel depends on the tilt angle of the panel with respect to the horizontal plane. The tilt angle determines the amount of solar insolation on panel surface and intern determines quantity of energy collected. Conventionally the best tilt angle is equivalent to latitude of the location at which panel is installed. The value of optimal tilt angle at defined location depends on local atmospheric condition, altitude of region, movement of sun etc. So the value of optimal tilt angle varies over each month. In this paper the values of optimal tilt angle over each month for a PV panel installed in Kerala, India (9.55°N, 76.81°E) was theoretically estimated using geographic factor method, clearness index method and declination angle method. The results showed that the gain in the amount of solar radiation throughout the year received by the PV panel mounted at monthly optimum tilt angles with respect to seasonal optimum angles and tilt angle equal to latitude were 3.4% and 7%, respectively. The theoretically estimated values of optimal tilt angles are used as a base for experimental investigation. Experimental investigation was done for three months and it is found that the geographic factor method is the best method among three methods.
EFFECT OF THE REPLACEMENT OF MAIZE WITH WHEAT OFFAL IN BROILER FINISHER DIETS ON GROWTH PERFORMANCE AND FEED COST

An experiment was carried out to assess the effect of replacing maize with wheat offal in broiler finisher diets on bird performance and feed cost. Six rations were formulated using 0, 5, 10, 15, 20, and 25 percent wheat offal to replace maize in the rations. The formulated rations were fed to one hundred and fifty six commercial broiler finisher birds in a completely randomized experimental design. All the rations were made isocaloric and isonitrogenous with the inclusion of varying levels of palm oil. The results indicated that there were no significant differences (P > 0.05) in body weight, body weight gain, feed intake and efficiency of feed utilization and carcass characteristics amongst the treatment means. However, wheat offal replaced maize for up to 25 percent without any adverse effect on performance. More so, at 25 percent inclusion to replace maize, cost of feed per kilogram was reduced by about 15.91 percent. Such feed cost reduction could engender overall production cost reduction in broiler production especially at the finisher stage.
Thermal ageing effects on the dielectric properties and moisture content of vegetable and mineral oil used in power transformers

The operational safety of transmission and distribution grids depends essentially on the power transformers' state. Lately, there is a tendency to replace mineral oils with vegetable oils because vegetable oils provide a higher explosion safety aspect for transformers due to their higher fire points. Further, vegetable oils are favorable for the environment due to their higher biodegradability. The focus of the present paper is to study the properties of mineral and vegetable after these oils are exposed to accelerated thermal ageing. Vegetable and mineral oil samples were subjected to accelerated thermal ageing (with and without cellulosic paper) at three different temperatures: 135 °C, 155 °C and 175 °C. The dielectric properties of the samples (relative permittivity, loss factor and resistivity) and their water content were determined for different ageing durations. The results show that in the case of mineral oil samples, there is a direct relation between the water content values and the dielectric properties. However, the obtained results indicate that the water content does not fully characterize the ageing condition of vegetable oil.
Nucleotide Excision Repair-dependent DNA Double-strand Break Formation and ATM Signaling Activation in Mammalian Quiescent Cells*

Background: In quiescent human cells, UV induces histone H2AX phosphorylation by ATR in a nucleotide excision repair (NER)-dependent manner. Results: UV also activates ATM in response to NER-mediated DNA double-strand break (DSB). Conclusion: The NER reaction in quiescent cells potentially generates multiple types of secondary DNA damage. Significance: This work highlights the importance of our understanding of the DNA damage response in quiescent cells. Histone H2A variant H2AX is phosphorylated at Ser139 in response to DNA double-strand break (DSB) and single-stranded DNA (ssDNA) formation. UV light dominantly induces pyrimidine photodimers, which are removed from the mammalian genome by nucleotide excision repair (NER). We previously reported that in quiescent G0 phase cells, UV induces ATR-mediated H2AX phosphorylation plausibly caused by persistent ssDNA gap intermediates during NER. In this study, we have found that DSB is also generated following UV irradiation in an NER-dependent manner and contributes to an earlier fraction of UV-induced H2AX phosphorylation. The NER-dependent DSB formation activates ATM kinase and triggers the accumulation of its downstream factors, MRE11, NBS1, and MDC1, at UV-damaged sites. Importantly, ATM-deficient cells exhibited enhanced UV sensitivity under quiescent conditions compared with asynchronously growing conditions. Finally, we show that the NER-dependent H2AX phosphorylation is also observed in murine peripheral T lymphocytes, typical nonproliferating quiescent cells in vivo. These results suggest that in vivo quiescent cells may suffer from NER-mediated secondary DNA damage including ssDNA and DSB.
Clinical and imaging characterization of a patient with idiopathic progressive ataxia and palatal tremor

We describe clinical and imaging features of a patient with sporadic progressive ataxia and palatal tremor (PAPT) of unknown etiology. There was hypertrophy of bilateral inferior olivary nuclei with hyperintense T2‐weighted signal and mild cerebellar atrophy at brain magnetic resonance imaging. 18F‐fluoro‐2‐desoxy‐d‐glucose positron emission tomography scanning (FDG‐PET) showed hypometabolism in the red nucleus, external globus pallidus and precuneus while FP‐CIT‐SPECT imaging revealed mild and progressive loss of striatal dopaminergic terminals. Our findings suggest that in idiopathic PAPT involvement of the dentato‐rubro‐olivary pathway occurs along with some dopaminergic dysfunction.
Stimulation of Open Complex Formation by Nicks and Apurinic Sites Suggests a Role for Nucleation of DNA Melting in Escherichia coli Promoter Function*

We report the effects of depurination and prenicking at various positions of the phage λprmup-1Δ265 promoter DNA on the rate of open complex formation. We have found that depurination and prenicking at positions around the −10 region strongly stimulated the rate of open complex formation. Since nicking and depurination are known to destabilize DNA helical structure, our observations indicate that the instability of the −10 region is important for open complex formation. We further infer that (i) the nucleation of DNA melting, which occurs during the isomerization from the closed complex into the open complex, contributes to the rate of open complex formation; (ii) the nucleation of melting occurs around the −10 region; and (iii) the propagation of DNA melting from the nucleation region is not rate-limiting. In addition, we have found that depurination at several positions inhibited open complex formation. We used dimethyl sulfate modification protection studies to show that most of the guanine bases that are among these positions are in contact with RNA polymerase in the open complex.
Use in current clinical practice of 70‐gene signature in early breast cancer

on 21 early breast cancer patients. All patients gavewritten informed consent approved by the Ethic Committee.After the breast tumor was removed, a tumor sample wasstored by pathologist and sent to Agendia for MammaPrint test.Nine patients had a MammaPrint result which is not use-ful for clinical decision about adjuvant chemotherapy because3 were ductal carcinoma in situ, 4 (22%) had quality of sam-ples not sufﬁcient to perform the MammaPrint assay and 2had both oestrogen- and progesterone-receptors negative andthen patients were candidates for chemotherapy regardlessthe MammaPrint results.In the remaining 12 cases (67%) both clinical risk (deﬁnedby clinical-pathological parameters) and MammaPrint riskwere considered for decision-making about adjuvant treat-ment. All cases were discussed in the Breast Disease Manage-ment Team with the presence of medical oncologists, sur-geons and pathologists. Characteristics of the 12 patients areshowed in Table 1.In ﬁve (42%) cases (2, 4, 5, 6, 11) clinical risk was dis-cordant with the risk estimated by MammaPrint. In thesecases decision about chemotherapy was based on clinical-pathological factors and disagreed with MammaPrint risk. Infact, in our Institute we recommend chemotherapy in endo-crine-responsive patients with node-positive (2 and 5) or T2tumor or G3 or age 35 years. Conversely, we do not recom-mend usually chemotherapy in endocrine-responsive patientswith age 70 years (4 and 6). Patient 11 had a lobular inva-sive carcinoma and, although she had a T2, we did not rec-ommend chemotherapy because lobular invasive carcinomaappeared to be less responsive to chemotherapy.
Provenance Variability during Damuda Sedimentation in the Talchir Gondwana Basin, India – A Statistical Assessment

The Talchir Gondwana basin houses the Talchir Formation at the base, succeeded by the Damuda Group and the Kamthi Formation in upward progression. The present study is an attempt to determine the provenance of the Damuda Group and its variability in terms of location, climate and tectonism through time from the composition of sandstone grains and detritus of the constituent Karharbari, Barakar and Barren Measures formations. The Damuda sandstones are composed of variable amounts of monocrystalline undulatory, nonundulatory and polycrystalline quartz grains, potash and plagioclase feldspars as well as metamorphic and sedimentary rock fragments in addition to heavy accessories. Palaeocurrent studies suggest that the Eastern Ghats Supergroup lying to the south of the basin served as the source area of the Damuda sediments. Plots of sandstone composition in tectonic setting discrimination diagrams suggest derivation of the detritus from craton interior, continental block and recycled orogen provinces. Statistical analyses indicate significant differences in the detrital modes of the sandstones of the Karharbari, Barakar and Barren Measures formations, which may be attributed to temporal and spatial variation of the provenance coupled with climate change in commensurate with Damuda sedimentation.
New Insights on the Role of Residue 673 of APP in Alzheimer's Disease

Alzheimer's disease (AD) is the most common neurodegenerative disorder and its two major pathological hallmarks are neuritic plaques and neurofibrillary tangles ([Benilova et al., 2012][1]; [Ward et al., 2012][2]). The formation of neuritic plaques through the aggregation of amyloid-β (Aβ)
Manifestations of Autonomy and Relatedness in Mothers' Accounts of Their Ethnotheories Regarding Child Care Across Five Cultural Communities

This study analyzes how autonomy and relatedness manifest in mothers' accounts of their ethnotheories regarding child care. Mothers came from two independent samples from urban middle-class in Germany and California, two autonomous-relational samples from urban middle-class in India and Cameroon, and one interdependent sample from rural Cameroon. Transcriptions of picture-based interviews are coded for discourse elements indicative of both orientations. Mothers from independent and autonomous-relational samples use more I statements and direct references to themselves. Mothers from interdependent and autonomous-relational samples contextualize and refer to authorities more often. Generally, differences between the urban and rural samples in terms of discourse elements related to autonomy are less pronounced than differences in associated socialization goals. This indicates that consciously held beliefs are more sensitive to changes in the families' sociocultural environment than their discourse.