Miracle-dz/UniFAR-FTUs huggingface dataset:
IDENTIFICATION OF CHROMOSOMAL REGIONS ASSOCIATED WITH INFECTIOUS DISEASES IN CATTLE

by Ricardo Zanella, Ph.D. Washington State University December 2011 Chair: Holly L. Neibergs Genetic selection for animals resistant or tolerant to a disease might yield new opportunities to improve profitability of the animal industry. Selection for animals that are able to defend themselves against pathogenic infection or animals that can tolerate infection might result in healthier and more profitable animals. In this dissertation I am reporting studies which were conducted to identify genetic regions associated with tolerance and susceptibility for Johne’s disease, bovine respiratory disease (BRD) and bovine viral diarrhea (BVD) in cattle. Johne’s disease is an incurable bacterial disease caused by infection with Mycobacterium avium subspecies paratuberculosis and accounts for annual losses of over $200 million in the dairy industry. Animals exposed to this pathogen can either become infected or tolerate the infection. In the current study we evaluated the infection
Electron transfer-based combination therapy of cisplatin with tetramethyl-p-phenylenediamine for ovarian, cervical, and lung cancers

The platinum-based chemotherapy is the standard treatment for several types of cancer. However, cancer cells often become refractory with time and most patients with serious cancers die of drug resistance. Recently, we have discovered a unique dissociative electron-transfer mechanism of action of cisplatin, the first and most widely used platinum-based anticancer drug. Here, we show that the combination of cisplatin with an exemplary biological electron donor, N,N,N′,N′-tetramethyl-p-phenylenediamine (TMPD), may overcome the resistance of cancer cells to cisplatin. Our steady-state absorption and fluorescence spectroscopic measurements confirm the effective dissociative electron-transfer reaction between TMPD and cisplatin. More significantly, we found that the combination of 100 μM TMPD with cisplatin enhances double-strand breaks of plasmid DNA by a factor of approximately 3.5 and dramatically reduces the viability of cisplatin-sensitive human cervical (HeLa) cancer cells and highly cisplatin-resistant human ovarian (NIH:OVCAR-3) and lung (A549) cancer cells. Furthermore, this combination enhances apoptosis and DNA fragmentation by factors of 2–5 compared with cisplatin alone. These results demonstrate that this combination treatment not only results in a strong synergetic effect, but also makes resistant cancer cells sensitive to cisplatin. Because cisplatin is the cornerstone agent for the treatment of a variety of human cancers (including testicular, ovarian, cervical, bladder, head/neck, and lung cancers), our results show both the potential to improve platinum-based chemotherapy of various human cancers and the promise of femtomedicine as an emerging frontier in advancing cancer therapy.
Neuroradiological correlates of neuropsychological disorders in olivopontocerebellar atrophy (OPCA)

Thirty‐two OPCA patients without cortical atrophy were studied. In addition to inspection of films by a neuroradiologist (i.e. “subjective” assessment), five neuroradiological measures were used, namely, the estimation of brainstem ratio, midbrain ratio, fourth ventricular ratio, brachium pontis ratio and bicaudate ratio. The patients were divided into two groups: one with mild and the other with moderate‐severe atrophies. The neuropsychological assessment measures were: global memory quotient, verbal learning capacities, recall and recognition, attention, abstract thinking, visuo‐spatial and visuo‐constructive functioning. Three conclusions emerged: (i) cognitive disturbances in OPCA are related to the degree of cerebellar damage; (ii) these findings are consistent with the concept of anatomic and metabolic neocerebellar → basal ganglia → associative cerebral cortex loops; and (iii) it appears that the role of the neocerebellum in cognition is not exclusive because some other structures (fastigius, vermis) and the fastigial → limbic loops seem to be involved.
Review of management and outcome in 65 patients with lentigo maligna

the lesion. A good result was observed after 4–5 weeks in all cases (Fig. 1b). A second cycle was completed in the lower half of the lesion with a good aesthetic result (Fig. 1c). Usually no treatment is available for these patients; only cosmetic camouflage is offered. The alexandrite laser is a wellestablished treatment for epilation whose chromophore is melanin. Melanin has a wide absorption spectrum which makes it possible to employ different wavelengths; short wavelengths (510 nm) are useful in the treatment of epidermal deposits while long wavelengths are employed for dermal lesions. From the results in these patients it is clear that alexandrite long-pulse laser is efficacious in clearing the hyperpigmentation of radiodermatitis. The treatment was well tolerated although the first patient developed cigarette paper-like skin in the centre of the lesion. We think that the elimination of the pigment could clinically reveal the atrophy that was seen on the biopsy. The skin in chronic radiodermatitis is atrophic and we prefer to treat our patients with low fluence in order to avoid radionecrotic ulceration; caution should be exercised in treating atrophied skin with a potentially injurious agent such as laser. After removal of the pigmentation no telangiectasia or ulceration was seen. The treatment was well tolerated by all patients, and a good cosmetic outcome was achieved. We therefore believe that this can increase the possible indications for the use of this laser and provide a new approach to the treatment of hyperpigmentation in radiodermatitis.
Calcium homeostasis modulator 1 (CALHM1) is the pore-forming subunit of an ion channel that mediates extracellular Ca2+ regulation of neuronal excitability

Extracellular Ca2+ (Ca2+ o) plays important roles in physiology. Changes of Ca2+o concentration ([Ca2+]o) have been observed to modulate neuronal excitability in various physiological and pathophysiological settings, but the mechanisms by which neurons detect [Ca2+]o are not fully understood. Calcium homeostasis modulator 1 (CALHM1) expression was shown to induce cation currents in cells and elevate cytoplasmic Ca2+ concentration ([Ca2+]i) in response to removal of Ca2+o and its subsequent addback. However, it is unknown whether CALHM1 is a pore-forming ion channel or modulates endogenous ion channels. Here we identify CALHM1 as the pore-forming subunit of a plasma membrane Ca2+-permeable ion channel with distinct ion permeability properties and unique coupled allosteric gating regulation by voltage and [Ca2+]o. Furthermore, we show that CALHM1 is expressed in mouse cortical neurons that respond to reducing [Ca2+]o with enhanced conductance and action potential firing and strongly elevated [Ca2+]i upon Ca2+o removal and its addback. In contrast, these responses are strongly muted in neurons from mice with CALHM1 genetically deleted. These results demonstrate that CALHM1 is an evolutionarily conserved ion channel family that detects membrane voltage and extracellular Ca2+ levels and plays a role in cortical neuronal excitability and Ca2+ homeostasis, particularly in response to lowering [Ca2+]o and its restoration to normal levels.
Nonseed plant Selaginella moellendorffii has both seed plant and microbial types of terpene synthases

Terpene synthases (TPSs) are pivotal enzymes for the biosynthesis of terpenoids, the largest class of secondary metabolites made by plants and other organisms. To understand the basis of the vast diversification of these enzymes in plants, we investigated Selaginella moellendorffii, a nonseed vascular plant. The genome of this species was found to contain two distinct types of TPS genes. The first type of genes, which was designated as S. moellendorffii TPS genes (SmTPSs), consists of 18 members. SmTPSs share common ancestry with typical seed plant TPSs. Selected members of the SmTPSs were shown to encode diterpene synthases. The second type of genes, designated as S. moellendorffii microbial TPS-like genes (SmMTPSLs), consists of 48 members. Phylogenetic analysis showed that SmMTPSLs are more closely related to microbial TPSs than other plant TPSs. Selected SmMTPSLs were determined to function as monoterpene and sesquiterpene synthases. Most of the products formed were typical monoterpenes and sesquiterpenes that have been previously shown to be synthesized by classical plant TPS enzymes. Some in vitro products of the characterized SmMTPSLs were detected in the headspace of S. moellendorffii plants treated with the fungal elicitor alamethicin, showing that they are also formed in the intact plant. The presence of two distinct types of TPSs in the genome of S. moellendorffii raises the possibility that the TPSs in other plant species may also have more than one evolutionary origin.
Giant Photoamplification in Indirect‐Bandgap Multilayer MoS2 Phototransistors with Local Bottom‐Gate Structures

Local-gate multilayer MoS2 phototransistors exhibit a photoresponsivity of up to 342.6 A W(-1) , which is higher by 3 orders of magnitude than that of global-gate multilayer MoS2 phototransistors. These simulations indicate that the gate underlap is critical for the enhancement of the photoresponsivity. These results suggest that high photoresponsivity can be achieved in indirect-bandgap multilayer MoS2 phototransistors by optimizing the optoelectronic design.
Surfactants from the gas phase may promote cloud droplet formation

Clouds, a key component of the climate system, form when water vapor condenses upon atmospheric particulates termed cloud condensation nuclei (CCN). Variations in CCN concentrations can profoundly impact cloud properties, with important effects on local and global climate. Organic matter constitutes a significant fraction of tropospheric aerosol mass, and can influence CCN activity by depressing surface tension, contributing solute, and influencing droplet activation kinetics by forming a barrier to water uptake. We present direct evidence that two ubiquitous atmospheric trace gases, methylglyoxal (MG) and acetaldehyde, known to be surface-active, can enhance aerosol CCN activity upon uptake. This effect is demonstrated by exposing acidified ammonium sulfate particles to 250 parts per billion (ppb) or 8 ppb gas-phase MG and/or acetaldehyde in an aerosol reaction chamber for up to 5 h. For the more atmospherically relevant experiments, i.e., the 8-ppb organic precursor concentrations, significant enhancements in CCN activity, up to 7.5% reduction in critical dry diameter for activation, are observed over a timescale of hours, without any detectable limitation in activation kinetics. This reduction in critical diameter enhances the apparent particle hygroscopicity up to 26%, which for ambient aerosol would lead to cloud droplet number concentration increases of 8–10% on average. The observed enhancements exceed what would be expected based on Köhler theory and bulk properties. Therefore, the effect may be attributed to the adsorption of MG and acetaldehyde to the gas–aerosol interface, leading to surface tension depression of the aerosol. We conclude that gas-phase surfactants may enhance CCN activity in the atmosphere.
Widely accessible method for superresolution fluorescence imaging of living systems

Superresolution fluorescence microscopy overcomes the diffraction resolution barrier and allows the molecular intricacies of life to be revealed with greatly enhanced detail. However, many current superresolution techniques still face limitations and their implementation is typically associated with a steep learning curve. Patterned illumination-based superresolution techniques [e.g., stimulated emission depletion (STED), reversible optically-linear fluorescence transitions (RESOLFT), and saturated structured illumination microscopy (SSIM)] require specialized equipment, whereas single-molecule–based approaches [e.g., stochastic optical reconstruction microscopy (STORM), photo-activation localization microscopy (PALM), and fluorescence-PALM (F-PALM)] involve repetitive single-molecule localization, which requires its own set of expertise and is also temporally demanding. Here we present a superresolution fluorescence imaging method, photochromic stochastic optical fluctuation imaging (pcSOFI). In this method, irradiating a reversibly photoswitching fluorescent protein at an appropriate wavelength produces robust single-molecule intensity fluctuations, from which a superresolution picture can be extracted by a statistical analysis of the fluctuations in each pixel as a function of time, as previously demonstrated in SOFI. This method, which uses off-the-shelf equipment, genetically encodable labels, and simple and rapid data acquisition, is capable of providing two- to threefold-enhanced spatial resolution, significant background rejection, markedly improved contrast, and favorable temporal resolution in living cells. Furthermore, both 3D and multicolor imaging are readily achievable. Because of its ease of use and high performance, we anticipate that pcSOFI will prove an attractive approach for superresolution imaging.
Awareness, practices, and prevalence of hypertension among rural Nigerian women

Background: High blood pressure is on the rise globally, affecting more women than men in many developing countries. It is the leading cause of mortality worldwide, and hospitalization in sub-Saharan Africa. Many known risk factors to hypertension, though prevalent in Nigeria, are controllable. Prevention, however, is difficult where there is poor awareness, attitude, and practices. Objectives: The study aims at determining the level of knowledge of hypertension and its associated factors, attitudes, practices, and prevalence among rural Nigerian women. Materials and Methods: Cross-sectional design was used to study 252 subjects in Sanga Local Government Area. Subject selection was by purposive and stratified sampling techniques. Data were collected using self-administered, semi-structured questionnaire after informed consents were obtained both verbally and in writing. Data were analyzed using SPSS statistical package. Level of significant was taken at 0.05. Results: Prevalence of hypertension was 24.2%. Average level of risk factor awareness was 65.4% with excessive salt intake (77.4%) being the most recognized. Asymptomatic nature of hypertension was recognized by 61.5% of the respondents, while 44.4% only knew the standard method for hypertension detection. While 17.5% strongly believed that hypertension can be managed effectively with drugs, it was only 9.1% that strongly disagreed that it could be caused by evil spirits. The average number of those with good preventive life style practices was 61.3%. Knowledge was associated with several factors and seems to affect practices (P < 0.05). Conclusion: Fair but inadequate level of knowledge and attitudes affected by several factors, as well as moderately high prevalence was recorded.
Acetylated STAT3 is crucial for methylation of tumor-suppressor gene promoters and inhibition by resveratrol results in demethylation

The mechanisms underlying hypermethylation of tumor-suppressor gene promoters in cancer is not well understood. Here, we report that lysine acetylation of the oncogenic transcription factor STAT3 is elevated in tumors. We also show that genetically altering STAT3 at Lys685 reduces tumor growth, which is accompanied by demethylation and reactivation of several tumor-suppressor genes. Moreover, mutating STAT3 at Lys685 disrupts DNA methyltransferase 1–STAT3 interactions in cultured tumor cells and in tumors. These observations are confirmed by treatment with an acetylation inhibitor, resveratrol. Furthermore, reduction of acetylated STAT3 in triple-negative breast cancer cells leads to demethylation and activation of the estrogen receptor-α gene, sensitizing the tumor cells to antiestrogens. Our results also demonstrate a correlation between STAT3 acetylation and methylation of estrogen receptor-α in melanoma, which predicts melanoma progression. Taken together, these results suggest a role of STAT3 acetylation in regulating CpG island methylation, which may partially explain aberrant gene silencing in cancer. These findings also provide a rationale for targeting acetylated STAT3 for chemoprevention and cancer therapy.
Toll-like receptor 4-activated B cells out-compete Toll-like receptor 9-activated B cells to establish peripheral immunological tolerance

B-cell–induced peripheral T-cell tolerance is characterized by suppression of T-cell proliferation and T-cell–dependent antibody production. However, the cellular interactions that underlie tolerance induction have not been identified. Using two-photon microscopy of lymph nodes we show that tolerogenic LPS-activated membrane-bound ovalbumin (mOVA) B cells (LPS B cells) establish long-lived, highly motile conjugate pairs with responding antigen-specific OTII T cells but not with antigen-irrelevant T cells. Treatment with anti–CTLA-4 disrupts persistent B-cell–T-cell (B–T) contacts and suppresses antigen-specific tolerance. Nontolerogenic CpG-activated mOVA B cells (CpG B cells) also form prolonged, motile conjugates with responding OTII T cells when transferred separately. However, when both tolerogenic and nontolerogenic B-cell populations are present, LPS B cells suppress long-lived CpG B–OTII T-cell interactions and exhibit tolerogenic dominance. Contact of LPS B cells with previously established B–T pairs resulted in partner-swapping events in which LPS B cells preferentially migrate toward and disrupt nontolerogenic CpG mOVA B-cell–OTII T-cell pairs. Our results demonstrate that establishment of peripheral T-cell tolerance involves physical engagement of B cells with the responding T-cell population, acting in a directed and competitive manner to alter the functional outcome of B–T interactions.
RAB-10-GTPase–mediated regulation of endosomal phosphatidylinositol-4,5-bisphosphate

Caenorhabditis elegans RAB-10 and mammalian Rab10 are key regulators of endocytic recycling, especially in the basolateral recycling pathways of polarized epithelial cells. To understand better how RAB-10 contributes to recycling endosome function, we sought to identify RAB-10 effectors. One RAB-10-binding partner that we identified, CNT-1, is the only C. elegans homolog of the mammalian Arf6 GTPase-activating proteins ACAP1 and ACAP2. Arf6 is known to regulate endosome-to-plasma membrane transport, in part through activation of type I phophatidylinositol-4-phosphate 5 kinase. Here we show that CNT-1 binds to RAB-10 through its C-terminal ankyrin repeats and colocalizes with RAB-10 and ARF-6 on recycling endosomes in vivo. Furthermore, we find that RAB-10 is required for the recruitment of CNT-1 to endosomal membranes in the intestinal epithelium. Consistent with negative regulation of ARF-6 by RAB-10 and CNT-1, we found overaccumulation of endosomal phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] in cnt-1 and rab-10 mutants and reduced endosomal PI(4,5)P2 levels in arf-6 mutants. These mutants produced similar effects on endosomal recruitment of the PI(4,5)P2-dependent membrane-bending proteins RME-1/Ehd and SDPN-1/Syndapin/Pacsin and resulted in endosomal trapping of specific recycling cargo. Our studies identify a RAB-10–to–ARF-6 regulatory loop required to regulate endosomal PI(4,5)P2, a key phosphoinositide in membrane traffic.
Small-molecule histone methyltransferase inhibitors display rapid antimalarial activity against all blood stage forms in Plasmodium falciparum

Epigenetic factors such as histone methylation control the developmental progression of malaria parasites during the complex life cycle in the human host. We investigated Plasmodium falciparum histone lysine methyltransferases as a potential target class for the development of novel antimalarials. We synthesized a compound library based upon a known specific inhibitor (BIX-01294) of the human G9a histone methyltransferase. Two compounds, BIX-01294 and its derivative TM2-115, inhibited P. falciparum 3D7 parasites in culture with IC50 values of ∼100 nM, values at least 22-fold more potent than their apparent IC50 toward two human cell lines and one mouse cell line. These compounds irreversibly arrested parasite growth at all stages of the intraerythrocytic life cycle. Decrease in parasite viability (>40%) was seen after a 3-h incubation with 1 µM BIX-01294 and resulted in complete parasite killing after a 12-h incubation. Additionally, mice with patent Plasmodium berghei ANKA strain infection treated with a single dose (40 mg/kg) of TM2-115 had 18-fold reduced parasitemia the following day. Importantly, treatment of P. falciparum parasites in culture with BIX-01294 or TM2-115 resulted in significant reductions in histone H3K4me3 levels in a concentration-dependent and exposure time-dependent manner. Together, these results suggest that BIX-01294 and TM2-115 inhibit malaria parasite histone methyltransferases, resulting in rapid and irreversible parasite death. Our data position histone lysine methyltransferases as a previously unrecognized target class, and BIX-01294 as a promising lead compound, in a presently unexploited avenue for antimalarial drug discovery targeting multiple life-cycle stages.
Brain conditioning is instrumental for successful microglia reconstitution following hematopoietic stem cell transplantation

The recent hypothesis that postnatal microglia are maintained independently of circulating monocytes by local precursors that colonize the brain before birth has relevant implications for the treatment of various neurological diseases, including lysosomal storage disorders (LSDs), for which hematopoietic cell transplantation (HCT) is applied to repopulate the recipient myeloid compartment, including microglia, with cells expressing the defective functional hydrolase. By studying wild-type and LSD mice at diverse time-points after HCT, we showed the occurrence of a short-term wave of brain infiltration by a fraction of the transplanted hematopoietic progenitors, independently from the administration of a preparatory regimen and from the presence of a disease state in the brain. However, only the use of a conditioning regimen capable of ablating functionally defined brain-resident myeloid precursors allowed turnover of microglia with the donor, mediated by local proliferation of early immigrants rather than entrance of mature cells from the circulation.
Relative mortality risk in chronic kidney disease and end-stage renal disease: the effect of age, sex and diabetes.

6 months of initiating PD and another has one peritonitis episode 2 years after starting PD, a relative risk analysis would consider these patients to be equivalent with respect to the outcome because the occurrence of peritonitis is registered only as a ‘yes/no event’ (despite the fact that most clinicians would agree that these patients are quite different from one another). Based on these concerns, we would argue that relative risk is not a meaningful way to assess the association of any variable with peritonitis. With regard to the authors’ conclusion that APD is associated with a lower peritonitis rate than CAPD, we note that this conclusion is based on only two randomized controlled trials. Of these trials, the study by Bro et al. [2] reported only three total episodes of peritonitis (one on APD, two on CAPD), likely related to the relatively short (6 month) follow-up time in this study. Since so few peritonitis episodes occurred in this trial, the results of the ‘review’ of the effect CAPD versus APD on peritonitis are almost entirely driven by the findings of the other trial by De Fijter et al. from 1994, showing a lower peritonitis rate with APD. The conclusions of the review with respect to peritonitis should therefore be interpreted with caution. While we commend the authors for trying to synthesize the existing literature on CAPD versus APD into a systematic review, the paucity of data available from randomized trials with respect to peritonitis limits the value of this exercise.