Miracle-dz/UniFAR-FTUs huggingface dataset:
Estrogen receptor-α expression in the mammary epithelium is required for ductal and alveolar morphogenesis in mice

The estrogen receptor-α (ERα) is a critical transcription factor that regulates epithelial cell proliferation and ductal morphogenesis during postnatal mammary gland development. Tissue recombination and transplantation studies using the first generation of ERα knockout (ERKO) mice suggested that this steroid hormone receptor is required in the mammary stroma that subsequently exerts its effect on the epithelium through additional paracrine signaling events. A more detailed analysis revealed that ERKO mice produce a truncated ERα protein with detectable transactivation activity, and it is likely that this functional ERα variant has masked the biological significance of this steroid receptor in the mammary epithelium. In this article, we describe the generation a Cre-lox-based conditional knockout of the ERα gene to study the biological function of this steroid receptor in the epithelial compartment at defined stages of mammary gland development. The mouse mammary tumor virus (MMTV)-Cre-mediated, epithelial-specific ablation of exon 3 of the ERα gene in virgin mice severely impaired ductal elongation and side branching. The conditional knockout resulted in ablation of the ERα protein, and the progesterone receptor (PR), whose expression is under the control of ERα, was largely absent. The whey acidic protein (WAP)-Cre-mediated deletion of ERα during successive gestation cycles resulted in a loss of ductal side-branching and lobuloalveolar structures, ductal dilation, and decreased proliferation of alveolar progenitors. These abnormalities compromised milk production and led to malnourishment of the offspring by the second lactation. These observations suggest that ERα expression in the mammary epithelium is essential for normal ductal morphogenesis during puberty and alveologenesis during pregnancy and lactation.
Developmental changes of CaMKII localization, activity and function during postembryonic CNS remodelling in Manduca sexta

Insect metamorphosis is a compelling example of postembryonic remodelling of neuronal structure and synaptic connectivity as larval and adult behaviours place distinct demands on the CNS. Holometabolous insects such as the moth Manduca sexta have long served as suitable models for the study of steroid effects on CNS remodelling, but activity and calcium‐dependent mechanisms have been found to act in concert with hormonal signals. This study examines developmental changes in the localization and the activational state of CaMKII during postembryonic Manduca CNS remodelling. Western blotting, CaMKII purification and autophosphorylation with γ32P‐ATP indicate that the lepidopteran CNS may contain only one CaMKII isoform. In situ immunohistochemistry reveals developmental changes in the expression patterns of CaMKII in different types of thoracic neurons and in different neuronal compartments. Early pupal life is characterized by an increase in postsynaptic CaMKII localization, which coincides with a developmental increase in CaMKII activation. Both events correlate temporally with motoneuron dendritic filopodia collapse and rapid synaptogenesis, indicating a possible functional role for CaMKII for the postembryonic development of invertebrate motor circuitry. Substrate phosphorylation assays demonstrate that CaMKII activity in the ventral nerve cord reflects changes in calcium influx through voltage‐activated channels as occurring in vivo during normal development.
A Screen to Identify Cellular Modulators of Soluble Levels of an Amyotrophic Lateral Sclerosis (ALS)–Causing Mutant SOD1

The molecular pathology of many protein misfolding, toxic gain-of-function diseases, such as amyotrophic lateral sclerosis (ALS), is not well understood. Although protein misfolding and aggregation are common themes in these diseases, efforts to identify cellular factors that regulate this process in an unbiased fashion and on a global scale have been lacking. Using an adapted version of an extant β-gal-based protein solubility assay, an expression screen for cellular modulators of solubility of an ALS-causing mutant SOD1 was carried out in mammalian cells. Following fluorescence-activated cell sorting enrichment of a mouse spinal cord cDNA library for gene products that increased SOD1 solubility, high-throughput screening of the cDNA pools from this enriched fraction was employed to identify pools containing relevant modulators. Positive pools, containing approximately 10 cDNA clones each, were diluted and rescreened iteratively until individual clones that improved SOD1 folding/solubility were identified. Genes with profound effects in the solubility assay were selected for validation by independent biochemical assays. Six of 10 validated genes had a significant effect on SOD1 solubility and folding in a SOD1 promoter-driven β-gal assay, indicating that global screening of cellular targets using such protein solubility/folding assay is viable and can be adapted for other misfolding diseases.
Surgical Anatomy of Atrioventricular Septal Defect

This review aims to describe the anatomic spectrum of hearts classified with the collective term atrioventricular septal defect. Despite their anatomical variety, hearts with the stigmata of atrioventricular septal defect share the characteristic feature of a common atrioventricular junction guarded by a 5-leaflet valve. The lack of normal atrioventricular septation makes the aorta un-wedged, resulting in an elongated outlet length on the left ventricular surface (known as inlet-outlet disproportion). The major determinant of anatomic variations is the relationship of the bridging leaflets to the septal structures. This important relationship determines not only the level of intracardiac shunting (interatrial only, interventricular only, or both) but also the propensity for left ventricular outflow tract obstruction. Furthermore, the location of the atrioventricular node, which is posteroinferiorly displaced from the tip of the triangle of Koch, is also affected by this relationship. Understanding the cardiac anatomy in this malformation is an absolute prerequisite for successful surgery, and should be facilitated by recognizing the fundamental nature of the morphology.
Hypertension in Delhi: prevalence, awareness, treatment and control

Two cross-sectional, population-based studies were conducted to assess the prevalence, awareness, treatment and control of hypertension, among people aged 20-59 years and those over 60 years in Delhi. Study 1 (20-59 years): in total,1213 subjects from 120 clusters spread across Delhi were studied. The prevalence of hypertension was 27.5%. Of the hypertensives, 53.3% were aware of their diagnosis; 42.8% were taking treatment and only10.5% had controlled blood pressure. About 9.0% of the hypertensives had coexisting diabetes mellitus and 8.4% were suffering from coronary disease. The prevalence of hypertension was significantly higher in urban areas, but there was no significant difference in levels of awareness, treatment and control between urban and slum areas. The prevalence of hypertension was comparable in both sexes. Women, however, were more likely to be aware of their condition. Study 2 (6-10 years): in total,1105 subjects from 110 clusters were studied. Prevalence of hypertension was 63.8%. Isolated systolic hypertension (ISH) was found in 15.3% of the subjects. About 54% of the hypertensives were aware of their diagnosis; 43.4% were taking treatment and only 8.5% had controlled blood pressure. Prevalence of hypertension and ISH were comparable among sexes. Women were more aware and better treated. About 21.3% hypertensives had coexisting diabetes mellitus, and 14.3% were suffering from coronary disease. There was no significant difference between sexes. Urban and slum areas were also found to be comparable. Over 3% of the elderly were controlling their raised blood pressure by non-pharmacological measures. They belonged to the 'aware' category yet could not be labelled as 'hypertensives', highlighting an operational fault in the Joint National Committee definition.
Reduced base-base interactions between the DNA seed and RNA target are the major determinants of a significant reduction in the off-target effect due to DNA-seed-containing siRNA

Previously, we showed that DNA replacement of the seed-containing region of class I siRNAs significantly reduced the off-target effect without substantial loss of target gene silencing activity (Ui-Tei et al, Nucleic Acids Res., 36, 2136–2151, 2008). Separately, we also showed that the level of the off-target effect due to non-modified class I siRNA is determined primarily by the calculated melting temperature (Tm) of the seed-target duplex, indicating that, at least in class I-siRNA-mediated gene silencing, Tm or thermodynamic stability of the complex between the siRNA seed and target mRNA is the most important factor determining the degree of off-target effects (Ui-Tei et al., Nucleic Acids Res., 36, 7100–7109, 2008). Here, using non-modified siRNAs other than class I siRNAs and DNA-seed-containing siRNAs, we examined the relationship between the thermodynamic stability of the seed-target duplex and the degree of the off-target effect. We found that the degree of the off-target effects is generally determined primarily by the Tm of the corresponding seed-target duplex, indicating that its thermodynamic stability is the most important general determinant of the degree of the off-target effect in gene silencing.
Control of neural precursor specification by proneural proteins in the CNS of Drosophila.

Formation of neural precursors in Drosophila is determined by proneural genes. The distinctive pattern of expression of some genes of the achaete‐scute complex in the embryonic neuroectoderm has prompted the speculation that they could also function in the specification of neural precursor identity in the CNS. To test this hypothesis, we have analysed the capacity of different proneural proteins to promote the development of a particular CNS precursor, the MP2 precursor. Our results indicate that: (i) all known proneural proteins are similarly able to support the formation of a neural precursor at the position of MP2; (ii) different proneural proteins promote the expression of different characteristics of MP2; and (iii) a totally normal specification of the MP2 fate can only be attained by the proneural genes achaete or scute.
Defining New Colorectal Cancer Syndromes in a Population-based Cohort of the Disease.

BACKGROUND/AIM Most known cancer syndromes confer an increased risk of more than one tumour types, and families with more than one colorectal cancer often segregate other cancers as well. The aim of this study was to examine if there is a general increased risk of other cancers in colorectal cancer families, which are defined as having two or more cases of colorectal cancer in close relatives. MATERIALS AND METHODS The study used a detailed family history of cancer diagnoses in a cohort of more than 3,000 consecutive colorectal cancer cases. A comparison was made between families with sporadic and those with familial colorectal cancer cases. Detailed morphology data were used to find further support for putative syndromes. RESULTS There were significantly more non-colorectal cancers in the family history of the familial CRC cases (p<0.001), with significantly more gastric cancers (p<0.001), prostate cancers (p<0.001), urinary bladder cancers (p<0.001) and melanomas (p=0.002), leukaemia/lymphomas (p=0.004), gynaecological cancers (p=0.007) and breast cancers (p=0.023). There was also some support for different morphological profiles for four of the five tested syndromes. CONCLUSION This study found support for a general increased risk of one or more different cancer syndromes involving families with colorectal cancer and other cancers. Further studies will define the different possible syndromes and determine the genetic background.
Anticancer effect and immune induction by hyperthermia of malignant melanoma using magnetite cationic liposomes

&NA; The hyperthermic effect of magnetic particles was examined in an in vivo study of mouse B16 melanoma. Magnetite cationic liposomes (MCLs) have a positive surface charge and generate heat under an alternating magnetic field (AMF) by hysteresis loss. MCLs were injected into melanoma nodules, which were then subjected to an AMF. The mice were divided into four groups: group I (control), group II (hyperthermia at 43°C for 30 min, once), group III (hyperthermia at 46°C for 30 min, once) and group IV (hyperthermia at 46°C for 30 min, twice). Complete tumour regression was observed in 90% of the mice in group IV, while no mice in groups I and II and only 40% in group III showed regression. To examine whether hyperthermia caused immune induction in B16 melanoma, in vitro cytotoxicity assays and rechallenge experiments were performed. Cytotoxic activity was observed in the spleen cells of the cured mice in group IV. In the rechallenge experiment, 66% of the cured mice rejected melanoma cells. These results suggest that hyperthermia using MCLs is an effective therapy for melanoma, since this treatment can kill the tumour cells not only by heat but also by inducing an immune response.
Mesenchymal stem cells inhibit the formation of cytotoxic T lymphocytes, but not activated cytotoxic T lymphocytes or natural killer cells

Background. Mesenchymal stem cells (MSCs) can reduce the incidence of graft-versus-host disease because of their ability to inhibit T-lymphocyte proliferation. There are no publications on the effect that MSCs have on cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells, effector cells vital for the graft-versus-leukemia effect. Methods. Cytotoxic T cells were primed in mixed lymphocyte culture (MLC) against irradiated stimulator lymphocytes, and irradiated third-party MSCs were added at different time points. The CTLs were collected, and their cytotoxic potential was analyzed in a chromium-release assay against the same stimulator cells as in the MLC. Purified NK cells were mixed with irradiated MSCs, and the lysis was measured in chromium-release assay against K562 target cells. Results. We found that MSCs inhibited CTL-mediated lysis by 70% if added at the beginning of the 6-day MLC. The lysis was not affected on day 3 or in the cytotoxic phase. Furthermore, MSCs inhibited the formation of cytotoxic lymphocytes when the cells were separated in a transwell system, which indicates that the effect is mediated by a soluble factor. NK cell-mediated lysis of K562 cells was not inhibited by MSCs. MSCs did not induce proliferation of allogeneic lymphocytes, and they were not lysed by allogeneic CTLs or NK cells. Conclusion. Our findings indicate that MSCs escape recognition by CTLs and alloreactive NK cells, and inhibit the formation of cytotoxic T cells by secreting a soluble factor, but that they do not interfere with CTLs and NK cell lysis.
Outcomes of elderly patients undergoing cytoreductive surgery and perioperative intraperitoneal chemotherapy for colorectal cancer peritoneal carcinomatosis

The combined treatment of cytoreductive surgery (CRS) and perioperative chemotherapy (PIC) for colorectal peritoneal carcinomatosis (PC) is a rigorous surgical treatment most suited for fit and young patients. With technical maturity and improved perioperative care, we examined the outcomes of elderly patients undergoing CRS and PIC for colorectal PC.
A phosphatidylinositol 3‐kinase of Candida albicans: molecular cloning and characterization

A phosphatidylinositol (PI) 3‐kinase gene (CaVPS34) of the human pathogenic yeast Candida albicans was cloned by a PCR‐based homology approach. The open reading frame encodes a 1020 amino acid protein with a calculated molecular weight of 118 kDa and a relative isoelectric point of 6.9. It shares 47% sequence identity with Saccharomyces cerevisiae Vps34p. Southern pattern indicated that CaVPS34 is probably present as a single copy gene per haploid genome in C. albicans. We localized the CaVPS34 gene on chromosome 1. Under all conditions tested a major CaVPS34 transcript of approximately 3.5 kb could be detected. CaVPS34 mRNA levels increased during exponential growth up to 12‐fold followed by a decline upon entry into stationary phase. The size of a 6×His tag–CaVps34p fusion protein purified from Escherichia coli is in agreement with the calculated molecular mass of CaVps34p. It exhibits in vitro PI 3‐kinase activity and produces only phosphatidylinositol 3‐phosphate. The CaVPS34 gene under the control of its own promoter were not able to complement the temperature‐sensitive growth of S. cerevisiae vps34. However, overexpression of CaVPS34 was sufficient to rescue the temperature‐sensitive vps34 phenotype, suggesting a functional conservation in C. albicans. The EMBL Accession No. for the sequence reported in this paper is Y09043. Copyright © 2000 John Wiley & Sons, Ltd.
Myositis associated with a newly described microsporidian, Trachipleistophora hominis, in a patient with AIDS

Microsporidia are zoonotic protozoa which were rare human pathogens prior to 1985, when Enterocytozoon bieneusi was described in human immunodeficiency virus-infected patients with chronic diarrhea. Another species, Encephalitozoon (Septata) intestinalis, is associated with diarrhea and chronic sinusitis, and approximately 25 cases have been reported in the literature. However, other microsporidial infections in human immunodeficiency virus-infected patients remain extremely rare. We report the first case of a Pleistophora sp. -like microsporidian infection presenting as a progressive severe myosotis associated with fever and weight loss. The organism was demonstrated by light microscopy and electron microscopy in corneal scrapings, skeletal muscle, and nasal discharge. Electron microscopy showed an electron-dense surface coat with "sunflare"-like projections surrounding all stages of development of meronts (two to four nuclei, dividing by binary fission), sporonts, and sporoblasts. Division of sporonts, in which sporonts separate from the thick outer coat, creating a sporophorous vesicle, is by binary fission, differentiating this organism from Pleistophora sp. The spore measures 4.0 by 2.5 microns and has a rugose exospore. A new genus and species, Trachipleistophora hominis, has been established for this parasite. The patient was treated with albendazole, sulfadiazine, and pyrimethamine, and the clinical symptoms resolved.
Pathogenesis of Chimeric MHV4/MHV-A59 Recombinant Viruses: the Murine Coronavirus Spike Protein Is a Major Determinant of Neurovirulence

ABSTRACT The mouse hepatitis virus (MHV) spike glycoprotein, S, has been implicated as a major determinant of viral pathogenesis. In the absence of a full-length molecular clone, however, it has been difficult to address the role of individual viral genes in pathogenesis. By using targeted RNA recombination to introduce the S gene of MHV4, a highly neurovirulent strain, into the genome of MHV-A59, a mildly neurovirulent strain, we have been able to directly address the role of the S gene in neurovirulence. In cell culture, the recombinants containing the MHV4 S gene, S4R22 and S4R21, exhibited a small-plaque phenotype and replicated to low levels, similar to wild-type MHV4. Intracranial inoculation of C57BL/6 mice with S4R22 and S4R21 revealed a marked alteration in pathogenesis. Relative to wild-type control recombinant viruses (wtR13 and wtR9), containing the MHV-A59 S gene, the MHV4 S gene recombinants exhibited a dramatic increase in virulence and an increase in both viral antigen staining and inflammation in the central nervous system. There was not, however, an increase in the level of viral replication in the brain. These studies demonstrate that the MHV4 S gene alone is sufficient to confer a highly neurovirulent phenotype to a recombinant virus deriving the remainder of its genome from a mildly neurovirulent virus, MHV-A59. This definitively confirms previous findings, suggesting that the spike is a major determinant of pathogenesis.
Validation of surgical site infection registration in colorectal surgery*

Abstract Background: Surgical site infection (SSI) represents almost 40% of nosocomial infections. Risk for SSI is most prominent following colorectal surgery. There is no Swedish standard SSI classification or surveillance. We have failed to find validation of SSI surveillance programs presently in use. This study investigates SSI registration routines at Halmstad County Hospital, Sweden (HCH) as well as Swedish surgery departments’ SSI classification and reporting practices. Methods: We requested information regarding SSI surveillance routines from all surgical departments performing colorectal surgery in Sweden. The reliability of SSI data collected routinely at HCH between 1999 and 2008 was approximated by comparing routine reports with data from a prospective study on infection prophylaxis. We calculate how much the reported SSI frequency must change for detection with current surveillance routines. Results: In all, 36 of 56 surgical departments answered a questionnaire; 24 have active SSI registration. Most commonly, SSI is detected with a combination of postoperative control in the outpatient unit and review of medical records after discharge. The department of surgery at HCH reported, from 1999 to 2008, an average SSI rate of 12.7% including emergency surgery. Compared to prospective registration, the routine provided a sensitivity of 0.56 and a specificity of 1.0. A reported frequency of 26% is required to detect a statistically significant increase in SSI. Conclusion: Swedish hospital SSI rates cannot be compared, there is neither uniform SSI surveillance nor classification system. The SSI monitoring routine explored in this study is uncertain. Methods must be developed further to obtain reliable data.
A nine-arm modular multilevel converter (9A-MMC) for six-phase medium voltage motor drives

Dual three-phase (asymmetrical six-phase) induction motors have received significant attention in high power medium voltage drive applications. Typically, two three-phase voltage source converters are needed to feed such a drive system. In medium voltage applications, multilevel inverters are preferred as they provide a stepped output voltage waveform that reduces dv/dt stresses and provides a better output current waveform, which reflects positively on the machine developed torque and overall drive performance. Among different multilevel inverters, the Modular Multilevel Converter (MMC) has recently shown promise in medium and high voltage applications. For a dual three-phase machine, two MMCs with 6 arms each, are needed. This paper proposes a nine-arm MMC (9A-MMC) to drive such a motor. The proposed approach reduces the number of involved arms by 25%, i.e. reduces the number of required dc capacitors, semiconductor devices and their gate drive circuits, which reduces system complexity and cost. A complete analysis of the proposed system is presented and a simulation model is used to verify the proposed concept.