Loss of Purkinje cells in the PKCγ H101Y transgenic mouse

Spinocerebellar ataxia type 14 (SCA14) is an autosomal, dominant neurodegenerative disorder caused by mutations in PKCγ. The objective of this study was to determine effects of PKCγ H101Y SCA14 mutation on Purkinje cells in the transgenic mouse. Results demonstrated that wild type PKCγ-like Purkinje cell localization of HA-tagged PKCγ H101Y mutant proteins, altered morphology and loss of Purkinje cells were observed in the PKCγ H101Y SCA14 transgenic mouse at four weeks of age. Failure of stereotypical clasping responses in the hind limbs of transgenic mice was also observed. Further, PKCγ H101Y SCA14 mutation caused lack of total cellular PKCγ enzyme activity, loss of connexin 57 phosphorylation on serines, and activation of caspase-12 in the PKCγ H101Y SCA14 transgenic mouse. Results clearly demonstrate a need for PKCγ control of gap junctions for maintenance of Purkinje cells. This is the first transgenic mouse to our knowledge which models a human SCA14 mutation.     

An additional step in the transmission of Yersinia pestis?

Plague, caused by the bacterium Yersinia pestis, is a mammalian vector-borne disease, transmitted by fleas that serve as the vector between rodent hosts. For many pathogens, including Y. pestis, there are strong evolutionary pressures that lead to a reduction in ‘useless genes'', with only those retained that reflect function in the specific environment inhabited by the pathogen. Genetic traits critical for survival and transmission between two environments, the rodent and the flea, are conserved in epizootic/epidemic plague strains. However, there are genes that remain conserved for which no function in the flea–rodent cycle has yet been observed, indicating an additional environment may exist in the transmission cycle of plague. Here, we present evidence for highly conserved genes that suggests a role in the persistence of Y. pestis after death of its host. Furthermore, maintenance of these genes points to Y. pestis traversing a post-mortem path between, and possibly within, epizootic periods and offering insight into mechanisms that may allow Y. pestis an alternative route of transmission in the natural environment.     

Loss of heterozygosity at the dilute-short ear (Myo5a-Bmp5) region of the mouse: mitotic recombination or double non-disjunction?

The occurrence of homozygous-viable dilute-short ear (Myo5a-Bmp5) double mutants in mouse specific locus mutation experiments has generally been assumed to be the result of double non-disjunction such that the mutant inherits two copies of chromosome 9 carrying the recessive alleles from the test-stock. A homozygous viable Myo5a-Bmp5 double mutant was recovered recently in our laboratory. We were able to genetically analyse both the Myo5a-Bmp5 region and proximal and distal markers in the original mutant as well as in offspring of the original mutant. Our results indicate the mutational event to be due to mitotic recombination and not double non-disjunction.     

Telomerase activation. One step on the road to cancer?

Ever since the discovery that telomeres are short in cancer cells and telomerase is activated in immortal cells, telomerase has been an oncogene wannabe. Oncogenes have been the glamour genes of molecular biology for 20 years, garnering flashy headlines and name recognition. More recently, tumor-suppressor genes have joined oncogenes on center stage. Recent evidence has shown that MYC upregulates the catalytic subunit of telomerase, TERT, and that TERT cooperates with HPV E7 in cell immortalization. This evidence now supports the placement of telomerase among the cancer gene elite.     

Tumour-initiating cells vs. cancer 'stem' cells and CD133: what's in the name?

Recent evidence suggests that a subset of cells within a tumour have 'stem-like' characteristics. These tumour-initiating cells, distinct from non-malignant stem cells, show low proliferative rates, high self-renewing capacity, propensity to differentiate into actively proliferating tumour cells, resistance to chemotherapy or radiation, and they are often characterised by elevated expression of the stem cell surface marker CD133. Understanding the molecular biology of the CD133(+) cancer cells is now essential for developing more effective cancer treatments. These may include drugs targeting organelles, such as mitochondria or lysosomes, using highly efficient and selective inducers of apoptosis. Alternatively, agents or treatment regimens that enhance sensitivity of these therapy-resistant "tumour stem cells" to the current or emerging anti-tumour drugs would be of interest as well.     

Hallmarks of cancer: of all cancer cells,all the time?

In two landmark articles, Hanahan and Weinberg synthesized into one conceptual framework 'the hallmarks of cancer', a massive amount of information describing the characteristics of a cancer cell. Although this is neither the intention nor the belief of the authors, hallmarks are often interpreted as applying to a canonic cancer cell, or equally to all cells within a cancer. In this article, we clarify the separate concepts of causes, oncogenic events, signal transduction programs, and hallmarks to show that there is no unimodal relation between these concepts but a complex network of interrelations that vary in different cells, between cells, and at different times in any given cell. We consider cancer as an evolving, dynamic, and heterogeneous system, explaining, at least in part, the difficulty of treating cancer and supporting the use of simultaneous, multitarget therapies.     

Macrophage fusion: are somatic and cancer cells possible partners?

The fusion of cells is a fundamental biological event that plays a central role in a variety of developmental and homeostatic processes. Macrophages are present in all tissues and can initiate interaction and fusion. The putative macrophage-fusion machinery is still poorly understood, but some of its components have been identified. Macrophages recognize each other as < self > in order to fuse but some essential questions remain: do macrophages fuse with somatic cells to repair tissues and organs? Do macrophages fuse with tumor cells to trigger metastasis? Agnès Vignery discusses these novel and challenging ideas in this review.     

How important is differentiation in the therapeutic effect of mesenchymal stromal cells in liver disease?

Background aimsThe protocols for differentiation of hepatocyte-like cells (HLCs) from mesenchymal stromal cells (MSCs) have been well established. Previous data have shown that MSCs and their derived HLCs were able to engraft injured liver and alleviate injuries induced by carbon tetrachloride. The goal of the current study was to determine the differences of MSCs and their derived HLCs in terms of therapeutic functions in liver diseases.MethodsAfter hepatic differentiation of umbilical cord–derived MSCs in vitro, we detected both MSC and HLC expressions of adhesion molecules and chemokine receptor CXCR4 by flow cytometry; immunosuppressive potential and hepatocyte growth factor expression were determined by means of enzyme-linked immunosorbent assay. We compared the therapeutic effect for fulminant hepatic failure in a mouse model.ResultsMSC-derived-HLCs expressed lower levels of hepatocyte growth factor, accompanied by impaired immunosuppression in comparison with MSCs. Furthermore, undifferentiated MSCs showed rescuing potentials superior to those in HLCs for the treatment of fulminant hepatic failure.ConclusionsAfter differentiation, HLCs lost several major properties in comparison with undifferentiated MSCs, which are beneficial for their application in liver diseases. Undifferentiated MSCs may be more appropriate than are HLCs for the treatment of liver diseases.     

Macrophage fusion: are somatic and cancer cells possible partners?

Macrophages are present in all tissues and can fuse with themselves to differentiate into multinucleate osteoclasts or giant cells that play a central role in osteoporosis and chronic inflammatory diseases, respectively. Yet, the mechanism by which they fuse remains uncharacterized. The macrophage fusion receptor (MFR) and its ligand CD47 might mediate homotypic fusion of macrophages and allow for their recognition as 'self' before fusion. Although a novel process and controversial idea, macrophages might exploit a similar mechanism for fusion with somatic cells or tumor cells, with resultant organ repair or metastasis, respectively. Hence, macrophages might be the 'double-edged swords' of tissues.     

How important are the common factors in psychotherapy? An update

The common factors have a long history in the field of psychotherapy theory, research and practice. To understand the evidence supporting them as important therapeutic elements, the contextual model of psychotherapy is outlined. Then the evidence, primarily from meta‐analyses, is presented for particular common factors, including alliance, empathy, expectations, cultural adaptation, and therapist differences. Then the evidence for four factors related to specificity, including treatment differences, specific ingredients, adherence, and competence, is presented. The evidence supports the conclusion that the common factors are important for producing the benefits of psychotherapy.     

Diagnostic and Prognostic Biomarkers in ovarian cancer and the potential roles of cancer stem cells – An updated review

Ovarian carcinomas relate to highest death rate in gynecologic malignancies as absence of symptoms shield the disease in the early stage. Current evidences have been devoted to discovering early effective screening mechanism prior to the onset of clinical symptoms. Therefore, biomarkers are the crucial tools that are capable of predicting progression, risk stratification and overall therapeutic benefit to fight against this deadly disease. Although recent studies have revealed serum protein markers, CA-125, HE4, mesothelin etc. have higher sensitivity and specificity at the early stages of the cancer; the critical questions arise regarding the applicability and reproducibility of genomic profiling across different patient groups. Hence, our hypothesis is that the panels of signature biomarkers will be much more effective to improve the diagnosis and prediction of patient survival outcome with high sensitivity and specificity. Ovarian cancer is heterogeneous in nature and contain a sub-population of stem cell-like characteristics that has the ability to grow as anchorage-independent manner and subsequently is able to metastasize. Highly tumorigenic and chemotherapy-resistant cancer stem cells (CSCs)-specific biomarkers therefore reflects the interesting possibilities to be targeted to minimize the high frequency of relapse and resistance to drugs. Several putative ovarian CSC markers such as CD24, CD44, CD133, SSEA have already been proposed in recent studies, yet, a large panel of updated biomarkers have high clinical relevance to define the prospective isolation of viable circulating CSCs. Therefore, this review highlights current evidence based updated ovarian cancer specific prognostic and diagnostic biomarkers and potential importance of CSCs in context of tumorigenicity and metastatic activity for fundamental biological and clinical implications.     

An error catastrophe in cancer?

A comparison between the evolution of cancer cell populations and RNA viruses reveals a number of remarkable similarities. Both display high levels of plasticity and adaptability as a consequence of high degrees of genetic variation. It has been suggested that, as it occurs with RNA viruses, there is a threshold in the levels of genetic instability affordable by cancer cells in order to be able to overcome selection barriers (Trends Genet. 15 (1999) M57). Here we explore this concept by means of a simple mathematical model. It is shown that an error threshold exists in this model, which investigates both competition between cancer cell populations and its impact on overall tumor growth dynamics. Once the threshold is reached, the highly unstable tumor cell populations, which were sustaining malignant growth, become unable to maintain their genetic information, which in turn triggers a slowed down overall tumor growth regime.     

Was the initiation of translation in early eukaryotes IRES-driven?

The initiation of translation in eukaryotes generally involves the recognition of a 'cap' structure at the 5' end of the mRNA. However, for some viral and cellular mRNAs, a cap-independent mechanism occurs through an mRNA structure known as the internal ribosome entry site (IRES). Here, I postulate that the first eukaryotic mRNAs were translated in a cap-independent, IRES-driven manner that was then superseded in evolution by the cap-dependent mechanism, rather than vice versa. This hypothesis is supported by the following observations: (i) IRES-dependent, but not cap-dependent, translation can take place in the absence of not only a cap, but also many initiation factors; (ii) eukaryotic initiation factor 4E (eIF4E) and eIF4G, molecules absolutely required for cap-dependent translation, are among the most recently evolved translation factors; and (iii) functional similarities suggest the evolution of IRESs from spliceosomal introns. Thus, the contemporary cellular IRESs might be relics of the past.     

An expression profile of human α-lactalbumin in the milk of transgenic mouse

Five female transgenic mice were produced by microinjection using a construct made up of a 7.3-kb-5′ flanking region and a 2.0-kb coding region of human α-lactalbumin, as well as a 227-bp 3′-flanking region from bovine growth hormone gene. A founder female expressed human α-lactalbumin as much as 0.3 g per liter of its milk, approximately a 3-fold increase in the total α-lactalbumin concentration of the transgenic mouse milk. Compared with the normal mice, the expression profile of thehα-Lac transgene in the transgenics is different during the lactation, showing low level in the first 3 days and becoming increased from day 4, then gradually reaching and stabilizing at the highest level from day 13. In addition, the milk yielding volume in the transgenics tended to be higher than in normal mice, suggesting higher concentrations of α-lactalbumin might boost more milk output.     

An expression profile of human α-lactalbumin in the milk of transgenic mouse

Five female transgenic mice were produced by microinjection using a construct made up of a 7.3-kb-5′ flanking region and a 2.0-kb coding region of human α-lactalbumin, as well as a 227-bp 3′-flanking region from bovine growth hormone gene. A founder female expressed human α-lactalbumin as much as 0.3 g per liter of its milk, approximately a 3-fold increase in the total α-lactalbumin concentration of the transgenic mouse milk. Compared with the normal mice, the expression profile of the hα-Lac transgene in the transgenics is different during the lactation, showing low level in the first 3 days and becoming increased from day 4, then gradually reaching and stabilizing at the highest level from day 13. In addition, the milk yielding volume in the transgenics tended to be higher than in normal mice, suggesting higher concentrations of α-lactalbumin might boost more milk output.     

An expression profile of human α-lactalbumin in the milk of transgenic mouse

a-lactalbumin(a-Lac),amajorwheyprotein,isacalciummetalloprotein,thathasbeenfoundinallmilksstudiedsofar.ItinteractswithUDP-galactosyl-transferasetoformthelactosesynthetaseandthusmightbeakeyproteinforlactogenesis.Lactosesyn-thetaseispostulatedtobetherate-limitingenzymeforlactosebiosynthesis.Theincreaseda-Lacactivitycanproducesufficientlactosesynthetaseforthesynthesisoflactose,andinmilkyieldbydrawingwaterintomilk,sincelactoseisanosmoreactivemolecule.Transgenicswineoverexpressingbovinea-lactalbu…