Miracle-dz/UniFAR-FTUs huggingface dataset:
A high-content screen identifies the vulnerability of MYC-overexpressing cells to dimethylfasudil

A synthetic lethal effect arises when a cancer-associated change introduces a unique vulnerability to cancer cells that makes them unusually susceptible to a drug’s inhibitory activity. The synthetic lethal approach is attractive because it enables targeting of cancers harboring specific genomic alterations, the products of which may have proven refractory to direct targeting. An example is cancer driven by overexpression of MYC. Here, we conducted a high-content screen for compounds that are synthetic lethal to elevated MYC using a small-molecule library to identify compounds that are closely related to, or are themselves, regulatory-approved drugs. The screen identified dimethylfasudil, a potent and reversible inhibitor of Rho-associated kinases ROCK1 and ROCK2. Close analogs of dimethylfasudil are used clinically to treat neurologic and cardiovascular disorders. The synthetic lethal interaction was conserved in rodent and human cell lines and could be observed with activation of either MYC or its paralog MYCN. The synthetic lethality seems specific to MYC overexpressing cells as it could not be substituted by a variety of oncogenic manipulations and synthetic lethality was diminished by RNAi-mediated depletion of MYC in human cancer cell lines. Collectively, these data support investigation of the use of dimethylfasudil as a drug that is synthetic lethal for malignancies that specifically overexpress MYC. Significance Statement Synthetic lethal targeting of tumors overexpressing MYC holds promise for attacking aggressive malignancies. Here we describe a synthetic lethal interaction between dimethylfasudil and overexpression of MYC. Uniquely, this novel synthetic lethal interaction points toward an opportunity for synthetic lethality with a molecule likely to harbor favorable drug-like properties that enable systemic use.
Duplication and divergence of the retrovirus restriction gene Fv1 in Mus caroli mice allows protection from multiple retroviruses

Viruses and their hosts are locked in an evolutionary race where resistance to infection is acquired by the hosts while viruses develop strategies to circumvent these host defenses. Forming one arm of the host defense armory are cell autonomous restriction factors like Fv1. Originally described as protecting laboratory mice from infection by murine leukemia virus (MLV), Fv1s from some wild mice have also been found to restrict non-MLV retroviruses, suggesting an important role in the protection against viruses in nature. To begin to understand how restriction factors evolve, we surveyed the Fv1 genes of wild mice trapped in Thailand and characterized their restriction activities against a panel of retroviruses. An extra copy of the Fv1 gene, named Fv7, was found on chromosome 6 of three closely related Asian species of mice (Mus caroli, M. cervicolor and M. cookii). The presence of flanking repeats suggested it arose by LINE-mediated retrotransposition. A high degree of natural variation was observed in both Fv1 and Fv7, including numerous single nucleotide polymorphisms resulting in altered amino acids, as well as insertions and deletions that changed the length of the reading frames. These genes exhibited a range of restriction phenotypes with activities directed against feline foamy virus (FFV), equine infectious anemia virus (EIAV) and MLV. It seems likely, at least in the case of M. caroli, that the observed gene duplication confers protection against multiple viruses not possible with a single restriction factor. We suggest that EIAV-, FFV- and MLV-like viruses are endemic within these populations, driving the evolution of the Fv1 and Fv7 genes. Author Summary During the passage of time all vertebrates will be exposed to infection by a variety of different kinds of virus. To meet this threat, a variety of genes for natural resistance to viral infection have evolved. The prototype of such so-called restriction factors is encoded by the mouse Fv1 gene, which acts to block the life cycle of retroviruses at a stage between virus entry into the cell and integration of the viral genetic material into the nuclear DNA. We have studied the evolution of this gene in certain species of wild mice from South East Asia and describe an example where a duplication of the Fv1 gene has taken place. The two copies of the gene, initially identical, have evolved separately allowing the development of resistance to two rather different kinds of retroviruses, lentiviruses and spumaviruses. Independent selection for resistance to these two kinds of retrovirus suggests that such mice are repeatedly exposed to never-before-reported pathogenic retroviruses of these genera.
Detecting dipicolinic acid production and biosynthesis pathways in Bacilli and Clostridia

Bacterial endospores are highly resistant structures and dipicolinic acid is a key component of their resilience and stability. Due to the difficulty in controlling endospore contaminants, they are of interest in clean rooms, food processing, and production industries, while benefical endospore-formers are sought for potential utility. Dipicolinic acid production has traditionally been recognized in Bacilli, Clostridia, and Paenibacilli. Here, sixty-seven strains of aerobic and anaerobic endospore-forming bacteria belonging to the genera Bacillus, Brevibacillus, Clostridium, Fontibacillus, Lysinibacillus, Paenibacillus, Rummeliibacillus, and Terribacillus were grown axenically and sporulated biomasses were assayed for dipicolinic acid production using fluorimetric detection. Strains testing positive were sequenced and the genomes analyzed to identify dipicolinic acid biosynthesis genes. The well-characterized biosynthesis pathway was conserved in 59 strains of Bacilli and Paenibacilli as well as two strains of Clostridia; six strains of Clostridia lacked homologs to genes recognized as involved in dipicolinic acid biosynthesis. Our results confirm dipicolinic acid production across different classes and families of Firmicutes. We find that members of Clostridium (cluster I) lack recognized dipicolinic acid biosynthesis genes and propose an alternate genetic pathway in these strains. Finally, we explore why the extent and mechanism of dipicolinic acid production in endospore-forming bacteria should be fully understood. We believe that understanding the mechanism by which dipicolinic acid is produced can expand the methods to utilize endospore-forming bacteria, such as novel bacterial strains added to products, for genes to create inputs for the polymer industry and to be better equipped to control contaminating spores in industrial processes.
The effect of conspecific density, herbivory, and bamboo on seedling dynamics of a dominant oak in a Neotropical highland forest

Conspecific negative density dependence (CNDD) is one of the main mechanisms influencing diversity maintenance in tropical forests. Tropical highland forests, in contrast to most lowland forests, are commonly dominated by a few tree species, and testing the importance of density dependence effects on seedling establishment of dominant trees may provide insights on the mechanisms regulating population dynamics and forest composition of tropical highlands. We tested the effect of CNDD regulation on seedling survival and recruitment of Quercus costaricensis, a monodominant oak in the Talamanca highland forests of Costa Rica. We used Ripley's K and generalized linear mixed models to test the effects of conspecific density, distance to the nearest adult, density of Chusquea bamboo shoots, and herbivory on the annual survival probability of 3579 seedlings between 2014 and 2017. We did not find a significant effect of CNDD on seedling survival. However, bamboo density and herbivory both significantly decreased oak seedling survival. All seedlings had signs of herbivory and predator satiation may explain the lack of density dependent regulation in seedlings of this species. We argue that the lack of intraspecific density regulation at the seedling stage may contribute to explain the dominance of Q. costaricensis in the highland forests of Costa Rica. Local seedling dynamics of this endemic oak are instead regulated by herbivory and the density of Chusquea.
Productivity of Intercropped Wheat with Faba Bean under Crop Sequences and Foliar Application of Humic Acid

INTERCROPPING cereal-legume (wheat + faba bean) is essential to enhance productivity per unit area, land use efficiency and decreasing the gap between production and consumption in Egypt. Furthermore, we are trying to find the best concentration of humic acid foliar application which could improve the production of wheat and faba bean. A field experiment was set with a combination of five crop sequences and intercropping systems (clover/wheat; wheat + faba bean; clover/wheat + faba bean; sole wheat; sole faba bean) in addition to, three foliar application treatments of humic acid at the rate of control (0.0), 2.0 and 4.0g/L. Results show that foliar application of humic acid and intercropping systems affected significantly all traits of wheat and faba bean except number of branches/plant and plant height in the first season for faba bean. The highest mean values of yield and its components of wheat were obtained when wheat was sown after clover under foliar application with 4g/L humic acid as compared with sole wheat with no foliar application in both seasons. The 2g/L humic acid and wheat + faba bean give higher land equivalent ratio and the lowest values of aggressivity. whereas the highest mean values of area time equivalent ratio and monetary advantage index were obtained from 4g/L humic acid foliar application with clover/wheat + faba bean in both seasons.
Lung Biopsy after Localization of Pulmonary Nodules with Hook Wire

Background: A chest computed-tomography has become more prevalent so that it is more common to detect small sized pulmonary nodules that have not been found in previous simple chest x-ray. If those detected nodules are undersized or located in pulmonary parenchyma, it is difficult to accomplish a biopsy since it is vulnerable to explore them either grossly or digitally. Thus, in our hospital, a thoracoscopic pulmonary wedge resection was performed after locating a lesion by means of hook wire with CT-guided. Material and Method: 31 patients (17 males and 14 female patients) from December in 2006 to June in 2010 became our subjects; their 34 pulmonary nodules were subjected to the thoracoscopic pulmonary wedge resection after locating a lesion by means of hook wire with CT-guided. Also we analyzed a possibility of hook wire dislocation, a frequency of conversion to open thoracotomy, time consumed to operation after location of a lesion, operation time, post operation complication, and histological diagnosis of the lesion. Result: 12 of 34 cases were ground glass lesion, whereas 22 cases of them were solitary pulmonary lesion. The median value of the lesion was 8㎜ in size (range: 3 to 23 ㎜), while the median value was 12.5 ㎜ in depth (range: 1 to 34 ㎜). The median value of time consumed from location of the lesion to anesthetic induction was 86.5 minutes (41~473 minutes); furthermore the mean value of operation time was 103 minutes (25~345 minutes). Intrathoracic wire dislocation was found in one case, but a target lesion was successfully excised. Open thoracotomy was performed in four cases due to pleural adhesion. However, there was no case of conversion to open thoracotomy due to failure to detect a target lesion. In histological diagnosis, metastatic cancer were found in 15 cases, which were the most common, primary lung cancer were in 9 cases, non-specific inflammation were in 3 cases, tuberculosis inflammation were in 2 cases, lymph nodes were in 2 cases, active tuberculosis were in 1 case, atypical adenomatous hyperplasia was in 1 case and normal lung parenchymal finding was in 1 case, respectively. Conclusion: In our hospital, in order to accomplish a precise histological diagnosis of ground-glass lesion and pulmonary nodules in lung parenchyma, location of pulmonary nodules were exactly located with hook wire under chest computed-tomography, which was followed by lung biopsy. We concluded that this was an accurate, minimally invasive and valuable method to minimize the complications and increase of cost of medical service provided.
EVALUATION OF SOME ESSENTIAL OILS FOR CONTROLLING VARROA MITES AND THEIR EFFECTS ON BROOD REARING ACTIVITY IN HONEY BEE COLONIES.

This study was carried out to assess the efficacy of controlling essential oils i.eThymol, Cinnamon and Anise oils with different concentrations compared to 65% Formic acid in controlling Varroa destructor mites infesting colonies of Apismellifera during the winter and summer of 2013 season. Randomized complete block design was applied at this study. The apiary was divided into 7 groups (3 colonies / group). Three application of the oils. Average of Varroa infestation level before treatment ranged between 21–29 in winter and from 37-47 in summer. The treatments were significantly effective when applied in summer than the winter season and when used at 30% concentration than those obtained at 15% concentration compared to the control treatment. Average efficacies percentage ranged between 80.95% (Cinnamon oil 30%) to 86.99 (Thymol 30%) in winter and from 67.46 %(Thymol 30%) to 82.16% (Cinnamon 30%). Thymol oil was the best in winter, however, Cinnamon was the best in summer. Anise oil 30% was intermediate 80.00 and 77.11% in winter and summer treatments respectively. In concern with the effect of the tested oils on brood rearing activity, Anise and Cinnamon oils at 30% concentration were the best (74.54 and 74.35 %. respectively) during January – February. However, in significant differences were found between the tested oils at 30% concentration during August–September. Thymol was the best at 15 % concentration ( 55.38%). However, Cinnamon oil 30% was the best (64.54%) followed by Thymol(56.52%) .
Growth, Critical N Concentration and Crop N Demand in Butterhead and Crisphead Lettuce Grown under Mediterranean Conditions

Excessive nitrogen (N) fertilizers are applied in lettuce causing both environmental issues and N crop luxury consumption. In order to improve the N use efficiency (NUE) by defining optimal crop growth and N requirements of butterhead and crisphead lettuce, two field experiments were conducted using 0, 50, and 100 kg ha−1 of N fertilizer to study (i) the growth and productivity, (ii) the NUE, (iii) the critical N dilution curve, and (iv) the N demand. Nitrogen supply enhanced dry weight (DW) accumulation in the butterhead (from 295 to 410 g m−2), but not in the crisphead type (251 g m−2). The NUE indices underlined the poor ability of the crisphead type in absorbing soil N and also in the utilization of the absorbed N for producing DW. The critical N dilution curves %Nc = 3.96 DW−0.205 and %Nc = 3.65 DW−0.115 were determined for crisphead and butterhead lettuce, respectively. Based on these type-specific %Nc curves, the estimated N demand was 125 kg ha−1 in the butterhead and 80 kg ha−1 in the crisphead lettuce for producing 4.3 and 2.5 Mg ha−1 of DW, respectively, under Mediterranean climate. Neither N fertilization nor genotype affected crop productivity.
Daughterless, the Drosophila orthologue of TCF4, is required for associative learning and maintenance of synaptic proteome

Mammalian Transcription Factor 4 (TCF4) has been linked to schizophrenia and intellectual disabilities like Pitt-Hopkins syndrome (PTHS). Here we show that similarly to mammalian TCF4, fruit fly orthologue Daughterless (Da) is expressed in the Drosophila brain structures associated with learning and memory, the mushroom bodies. Furthermore, silencing of da in mushroom body neurons impairs appetitive associative learning of the larvae and leads to decreased levels of the synaptic proteins Synapsin (Syn) and discs large 1 (dlg1) suggesting the involvement of Da in memory formation. Here we demonstrate that Syn and dlg1 are direct target genes of Da in adult Drosophila heads, since Da binds to the regulatory regions of these genes and the modulation of Da levels alter the levels of Syn and dlg1 mRNA. Silencing of da also affects negative geotaxis of the adult flies suggesting the impairment of locomotor function. Overall, our findings suggest that Da regulates Drosophila larval memory and adult negative geotaxis possibly via its synaptic target genes Syn and dlg1. These behavioural phenotypes can be further used as a PTHS model to screen for therapeutics. Summary statement Human TCF4, a bHLH transcription factor, is associated with intellectual disability and schizophrenia. Here we propose a Drosophila model for human disease studies using TCF4 orthologue in fruit fly, Daughterless.
EVALUATION OF LETROZOLE THERAPEUTIC EFFECT IN INFERTILE WOMEN

Combination therapy with clomiphene citrate plus gonadotropin (clomiphene citrate plus HMG) in induction ovulation reduce the gonadotropins dose but antiestrogenic effect of c.c. can decrease pregnancy rate. In a randomized clinical trial we compared 3 treatment protocol for induction ovulation and intra uterine insemination (I/o plus IUI) in women with infertility history more than one year, normal hysterosalpingogram (HSG), normal spermiogram and follicular stimulating hormone (FSH) P P
HIV risk behaviour among public primary healthcare patients with tuberculosis in South Africa

Objective. To identify factors associated with HIV in tuberculosis (TB) patients in a public primary healthcare (PHC) setting in South Africa (SA). Method. Among 4 900 consecutively selected TB patients (54.5% men; women 45.5%) from 42 public PHC clinics in 3 districts in SA, a cross-sectional survey was performed to assess new TB and new TB retreatment patients within one month of anti-TB treatment. Results. The sample comprised 76.6% new TB patients and 23.4% TB retreatment patients. Of those who had tested for HIV, 59.9% were HIV-positive; 9.6% had never tested for HIV. In multivariate analysis, older age (odds ratio (OR) 5.86; confidence interval (CI) 4.07 - 8.44), female gender (OR 0.47; CI 0.37 - 0.59), residing in an informal settlement (OR 1.55; CI 1.13 - 2.12), being a TB retreatment patient (OR 0.55; CI 0.42 - 0.72), occasions of sexual intercourse with condom use (OR 1.07; CI 1.02 - 1.13) and having a sexual partner receiving antiretroviral treatment (ART) (OR 7.09, CI 4.35 - 11.57) were associated with an HIV-positive status in TB patients. Conclusion. This study revealed high HIV risk behaviour (e.g. unprotected last sexual intercourse and alcohol and drug use in the context of sexual intercourse) among TB patients in SA. Various factors were associated with HIV risk behaviour. Condom use and substance use risk reduction need to be considered as HIV-prevention measures when planning such strategies for TB patients.
Body Mass Index and Outcome of Gastrectomy with D2 Lymphadenectomy.

Purpose: The effectiveness of D2 lymph node dissection in gastric cancer operation is controversial in Western countries because of the relatively high complication and mortality rates in contrast to those of Japanese studies. A generally high body mass index (BMI) of the European patients was assumed to be one of the major causes for postoperative complication. The aim of this study is to clarify the relationship between patient BMI and operative outcomes. Methods: We studied 201 consecutive Korean patients who had undergone gastrectomy with D2 lymph node dissection for gastric cancer between Jan 2002 and Apr 2003. They were assigned to four groups according to BMI: group A, with BMI; group B, with BMI of 18.5 to 23 kg/; group C, with BMI of 23 to 25 kg/; and group D, with BMI>25 kg/. We analyzed differences in the length of operation time, numbers of examined lymph nodes, numbers of transfused patients, postoperative hospital stay, and postoperative complications in the four groups. Results: No significant differences were found with regard to the length of operation time, the numbers of examined lymph nodes, the numbers of transfused patients, the postoperative hospital stay, and the postoperative complications in four groups. Conclusion: High BMI was not associated with increased operative risk or morbidity.
Populations of genetic circuits are unable to find the fittest solution in a multilevel genotype-phenotype map

The evolution of gene regulatory networks (GRNs) is of great relevance for both evolutionary and synthetic biology. Understanding the relationship between GRN structure and its function can allow us to understand the selective pressures that have shaped a given circuit. This is especially relevant when considering spatiotemporal expression patterns, where GRN models have been shown to be extremely robust and evolvable. However, previous models that studied GRN evolution did not include the evolution of protein and genetic elements that underlie GRN architecture. Here we use toyLIFE, a multilevel genotype-phenotype map, to show that not all GRNs are equally likely in genotype space and that evolution is biased to find the most common GRNs. toyLIFE rules create Boolean GRNs that, embedded in a one-dimensional tissue, develop a variety of spatiotemporal gene expression patterns. Populations of toyLIFE organisms choose the most common GRN out of a set of equally fit alternatives and, most importantly, fail to find a target pattern when it is very rare in genotype space. Indeed, we show that the probability of finding the fittest phenotype increases dramatically with its abundance in genotype space. This phenotypic bias represents a mechanism that can prevent the fixation in the population of the fittest phenotype, one that is inherent to the structure of genotype space and the genotype-phenotype map.
The desmosomal cadherin Desmoglein-3 regulates YAP and phospho-YAP in keratinocyte responses to mechanical forces

Desmoglein 3 (Dsg3), plays a crucial role in cell-cell adhesion and tissue integrity. Increasing evidence suggests that Dsg3 acts as a regulator of cellular mechanotransduction, but little is known about its direct role in mechanical force transmission. The present study investigated the impact of cyclic strain and substrate stiffness on Dsg3 expression and its role in mechanotransduction. A direct comparison was made with E-cadherin, a well-characterized mechanosensor, in human keratinocytes. Exposure of oral and skin keratinocytes to equiaxial cyclic strain promoted changes in expression and localization of junction assembly proteins. Knockdown of Dsg3 by siRNA blocked strain-induced junctional remodeling of E-cadherin and Myosin IIa. Importantly, the study demonstrated that Dsg3 regulates the expression and localization of YAP, a mechanosensor and an effector of the Hippo pathway. Furthermore, we showed that Dsg3 forms a complex with phospho-YAP and sequestered it to the plasma membrane, while Dsg3 depletion had an impact on both YAP and phospho-YAP in their response to mechanical forces, increasing the sensitivity of keratinocytes to both strain-or substrate rigidity-induced nuclear relocalization of YAP and phospho-YAP. We showed that PKP1 seemed to be the key in such a complex formation since its silencing resulted in Dsg3 disruption at the junctions with concomitant loss of pYAP in the peripheral cytoplasm. Finally, we demonstrated that this Dsg3/YAP pathway has an influence on the expression of YAP1 target genes as well as cell proliferation in keratinocytes. Together, these findings provide evidence of a novel role for Dsg3 in keratinocyte mechanotransduction.