Texture-Induced Corrosion Resistance of Dissimilar AA7204/AA6082 Friction Stir Welded Joints.

The quasi in situ EBSD test was applied to study the effect of grain orientation on corrosion behaviors of the thermomechanically affected zone I (TMAZ I) of dissimilar AA6082/AA7204 friction stir welding (FSW) joints in this work. The results show that the structure with grain orientation close to the brass texture ({110}<112>) has excellent corrosion resistance, which contributes to the better corrosion performance of the TMAZ I of the 7204-AS joint than the 7204-RS joint. Furthermore, the brass texture around by S texture ({213}<364>) in the TMAZ I of the 7204-AS joint is slightly corroded, and the orientation of the remaining structure is closer to the ({110}<112>) than before, which indicates that the corrosion, like deformation, is carried out alongside the {110} plane for the structure with grain orientation near {110}<112>. Those findings could provide new insight into the designed FSW joints and improve the corrosion resistance of the wrought aluminum alloy.

Circulating macrophages as the mechanistic link between mosaic loss of Y-chromosome and cardiac disease.

BACKGROUND: Genetics evidences have long linked mosaic loss of Y-chromosome (mLOY) in peripheral leukocytes with a wide range of male age-associated diseases. However, a lack of cellular and molecular mechanistic explanations for this link has limited further investigation into the relationship between mLOY and male age-related disease. Excitingly, Sano et al. have provided the first piece of evidence directly linking mLOY to cardiac fibrosis through mLOY enriched profibrotic transforming growth factor ß1 (TGF-ß1) regulons in hematopoietic macrophages along with suppressed interleukin-1ß (IL-1ß) proinflammatory regulons. The results of this novel finding can be extrapolated to other disease related to mLOY, such as cancer, cardiac disease, and age-related macular degeneration. RESULTS: Sano et al. used a CRISPR-Cas9 gRNAs gene editing induced Y-chromosome ablation mouse model to assess results of a UK biobank prospective analysis implicating the Y-chromosome in male age-related disease. Using this in vivo model, Sano et al. showed that hematopoietic mLOY accelerated cardiac fibrosis and heart failure in male mice through profibrotic pathways. This process was linked to monocyte-macrophage differentiation during hematopoietic development. Mice confirmed to have mLOY in leukocytes, by loss of Y-chromosome genes Kdm5d, Uty, Eif2s3y, and Ddx3y, at similar percentages to the human population were shown to have accelerated rates of interstitial and perivascular fibrosis and abnormal echocardiograms. These mice also recovered poorly from the transverse aortic constriction (TAC) model of heart failure and developed left ventricular dysfunction at higher rates. This was attributed to aberrant proliferation of cardiac MEF-SK4 + fibroblasts promoted by mLOY macrophages enriched in profibrotic regulons and lacking in proinflammatory regulons. These pro-fibrotic macrophages localized to heart and eventually resulted in cardiac fibrosis via enhanced TGF-ß1 and suppressed IL-1ß signaling. Furthermore, treatment of mLOY mice with TGFß1 neutralizing antibody was able to improve their cardiac function. This study by Sano et al. was able to provide a causative link between the known association between mLOY and male cardiac disease morbidity and mortality for the first time, and thereby provide a new target for improving human health. CONCLUSIONS: Using a CRISPR-Cas9 induced Y-chromosome ablation mouse model, Sano et al. has proven mosaic loss of Y-chromosome in peripheral myeloid cells to have a causative effect on male mobility and mortality due to male age-related cardiac disease. They traced the mechanism of this effect to hyper-expression of the profibrotic TGF-ß1 and reduced pro-inflammatory IL-1ß signaling, attenuation of which could provide another potential strategy in improving outcomes against age-related diseases in men.

Clinical observation of autologous platelet rich fibrin assisted revascularization of mature permanent teeth.

OBJECTIVE: To investigate the clinical observation of autologous platelet-rich fibrin (PRF) assisting the revascularization of mature permanent teeth. METHODS: Twenty patients with mature permanent teeth were divided into experimental group and control group. The control group was treated with classic revascularization, and the experimental group was treated with PRF-assisted mature permanent tooth revascularization. RESULTS: After treatment, the total effective rate of the experimental group (100.00%) was higher than that of the control group (50.00%); the thickness of the root canal wall of the experimental group was higher than that of the control group, and the crown root length was lower than that of the control group; The bite degree, chewing function, color, overall aesthetic score, and satisfaction rate of the patients were higher, and the difference was statistically significant (P < 0.05). CONCLUSION: Autologous PRF assists in revascularization of mature permanent teeth, which can achieve ideal results, and promote pulp regeneration.

Cardiac-Specific Expression of Cre Recombinase Leads to Age-Related Cardiac Dysfunction Associated with Tumor-like Growth of Atrial Cardiomyocyte and Ventricular Fibrosis and Ferroptosis.

Transgenic expression of Cre recombinase driven by a specific promoter is normally used to conditionally knockout a gene in a tissue- or cell-type-specific manner. In αMHC-Cre transgenic mouse model, expression of Cre recombinase is controlled by the myocardial-specific α-myosin heavy chain (αMHC) promoter, which is commonly used to edit myocardial-specific genes. Toxic effects of Cre expression have been reported, including intro-chromosome rearrangements, micronuclei formation and other forms of DNA damage, and cardiomyopathy was observed in cardiac-specific Cre transgenic mice. However, mechanisms associated with Cardiotoxicity of Cre remain poorly understood. In our study, our data unveiled that αMHC-Cre mice developed arrhythmias and died after six months progressively, and none of them survived more than one year. Histopathological examination showed that αMHC-Cre mice had aberrant proliferation of tumor-like tissue in the atrial chamber extended from and vacuolation of ventricular myocytes. Furthermore, the αMHC-Cre mice developed severe cardiac interstitial and perivascular fibrosis, accompanied by significant increase of expression levels of MMP-2 and MMP-9 in the cardiac atrium and ventricular. Moreover, cardiac-specific expression of Cre led to disintegration of the intercalated disc, along with altered proteins expression of the disc and calcium-handling abnormality. Comprehensively, we identified that the ferroptosis signaling pathway is involved in heart failure caused by cardiac-specific expression of Cre, on which oxidative stress results in cytoplasmic vacuole accumulation of lipid peroxidation on the myocardial cell membrane. Taken together, these results revealed that cardiac-specific expression of Cre recombinase can lead to atrial mesenchymal tumor-like growth in the mice, which causes cardiac dysfunction, including cardiac fibrosis, reduction of the intercalated disc and cardiomyocytes ferroptosis at the age older than six months in mice. Our study suggests that αMHC-Cre mouse models are effective in young mice, but not in old mice. Researchers need to be particularly careful when using αMHC-Cre mouse model to interpret those phenotypic impacts of gene responses. As the Cre-associated cardiac pathology matched mostly to that of the patients, the model could also be employed for investigating age-related cardiac dysfunction.

microRNA-142-3p regulates osteogenic differentiation of human periodontal ligament stem cells via mediating SGK1.

OBJECTIVE: Human periodontal ligament stem cells (hPDLSCs) refer to one kind of somatic stem cells that are capable of differentiating into multiple cell kinds and undergoing robust clonal self-renewal. This work was unearthed to elucidate the possible molecular mechanism of miR-142-3p in mediating osteogenic differentiation of hPDLSCs by targeting SGK1. METHODS: The hPDLSCs were isolated, cultured, and identified. hPDLSCs were identified by immunofluorescence staining and multiple differentiation ability detection. Cell proliferation ability was assessed by CCK-8 assay. hPDLSCs were induced using osteogenic differentiation medium. ALP activity was detected by alkaline phosphatase (ALP) staining  and ALP activity assay, and mineralized nodule formation was determined by alizarin red staining. The expression levels of osteogenic differentiation marker proteins ALP, RUNX2, and OCN were measured by RT-qPCR. miR-142-3p candidate targets were obtained through bioinformatics analysis. The relationship between miR-142-3p and SKG1 was verified. RESULTS: miR-142-3p in hPDLSCs after osteogenic induction was down-regulated. Elevated miR-142-3p restricted hPDLSCs proliferation, and diminished ALP activity and mineralized nodule formation, as well as the expression of ALP, RUNX2, and OCN, while miR-142-3p inhibition led to inverse results. miR-142-3p inhibited SKG1 expression. SKG1 overexpression promoted hPDLSC proliferation and osteogenic differentiation, and reversed the inhibitory function of miR-142-3p on hPDLSCs. CONCLUSION: This study highlights that miR-142-3p represses osteogenic differentiation of hPDLSCs by reducing SGK1 expression.

The Prognostic Significance of FKBP1A and Its Related Immune Infiltration in Liver Hepatocellular Carcinoma.

Liver hepatocellular carcinoma (LIHC) remains a global health challenge with poor prognosis and high mortality. FKBP1A was first discovered as a receptor for the immunosuppressant drug FK506 in immune cells and is critical for various tumors and cancers. However, the relationships between FKBP1A expression, cellular distribution, tumor immunity, and prognosis in LIHC remain unclear. Here, we investigated the expression level of FKBP1A and its prognostic value in LIHC via multiple datasets including ONCOMINE, TIMER, GEPIA, UALCAN, HCCDB, Kaplan-Meier plotter, LinkedOmics, and STRING. Human liver tissue microarray was employed to analyze the characteristics of FKBP1A protein including the expression level and pathological alteration in cellular distribution. FKBP1A expression was significantly higher in LIHC and correlated with tumor stage, grade and metastasis. The expression level of the FKBP1A protein was also increased in LIHC patients along with its accumulation in endoplasmic reticulum (ER). High FKBP1A expression was correlated with a poor survival rate in LIHC patients. The analysis of gene co-expression and the regulatory pathway network suggested that FKBP1A is mainly involved in protein synthesis, metabolism and the immune-related pathway. FKBP1A expression had a significantly positive association with the infiltration of hematopoietic immune cells including B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells. Moreover, M2 macrophage infiltration was especially associated with a poor survival prognosis in LIHC. Furthermore, FKBP1A expression was significantly positively correlated with the expression of markers of M2 macrophages and immune checkpoint proteins such as PD-L1, CTLA-4, LAG3 and HAVCR2. Our study demonstrated that FKBP1A could be a potential prognostic target involved in tumor immune cell infiltration in LIHC.

Mosaic loss of chromosome Y in peripheral blood cells is associated with age-related macular degeneration in men.

BACKGROUND: Age-related macular degeneration (AMD) is the leading cause of severe vision loss in patients over 55 years old in the industrialized world. In the past 20 years, approximately 288 million patents have been affected by this disease. Despite this high prevalence, the molecular mechanism for AMD remains unclear, and there remains no effective treatment for this disease. The mosaic loss of Y chromosome (mLOY) has been identified as a common phenomenon in multiple age-related disease (i.e., oncogenesis and cardiovascular disease) has recently been identified by genome-wide analysis to be linked to AMD as well. As the Y chromosome mainly possesses three genomic functions, sister chromatin cohesion, cell cycle mitosis, and apoptotic signaling, here we characterize the Y chromosome euchromatic genes and non-chromosome AMD genes in relevance to cellular proliferation and apoptotic signaling of leukocytes. RESULTS: Using STRING, a publically available database of all protein-protein interaction, Grassmann et al. found the genes on the Y chromosome is mainly believed to take part in three major cellular genomic functions- sister chromatin cohesion, cell cycle mitosis, and apoptotic signaling. Based on data from the Ensembl Genome database, we focus on our discussion on coding genes found in the euchromatins but not the PAR1 and PAR2 regions of the Y chromosomes. All 14 known euchromatic genes on the Y chromosome short arm and all 31 known euchromatic genes on the Y chromosome long arm (Yq) are directly or indirectly involved in the cell cycle (meiosis and mitosis) and proliferation. We sorted non-Y chromosome AMD associated genes into these three categories to identify signaling pathways that may compound with cellular dysregulation due to mLOY. Of the genes associated with AMD, complement pathway genes such as C2, C9 and CFH/ARMD4 are associated with proliferation, receptor-mediated endocytosis genes such as APOE, DAB2 and others associated with apoptotic signaling. Because nucleated cells found in peripheral circulation are mainly composed of leukocytes with reduced expression of CD99, a protein essential for leukocytes adhesion, translocation, and function, mLOY in these cells likely affect retinal degeneration through altered immunological surveillance. In fact, there is precedence that circulating macrophage can stabilize and modify the cardiac rhythm and contractility post ischemic damage. Therefore, the most likely mechanism through which peripheral mLOY affects AMD development in men is through the role affected leukocytes play in retinal proliferation and apoptosis. CONCLUSIONS: mLOY in peripheral blood is newly discovered in AMD by Grassmann et al. as it is a common phenomenon in oncogenesis and cardiac dysfunction. Here the recent data conclude the possible mechanism for the newly identified link between mLOY and AMD, and provide support that mLOY in circulating macrophage-monocyte of affected male patients promotes AMD by targeting the retina and causing macular degeneration.

Sustained delivery of rhMG53 promotes diabetic wound healing and hair follicle development.

MG53 is an essential component of the cell membrane repair machinery, participating in the healing of dermal wounds. Here we develop a novel delivery system using recombinant human MG53 (rhMG53) protein and a reactive oxygen species (ROS)-scavenging gel to treat diabetic wounds. Mice with ablation of MG53 display defective hair follicle structure, and topical application of rhMG53 can promote hair growth in the mg53 -/- mice. Cell lineage tracing studies reveal a physiological function of MG53 in modulating the proliferation of hair follicle stem cells (HFSCs). We find that rhMG53 protects HFSCs from oxidative stress-induced apoptosis and stimulates differentiation of HSFCs into keratinocytes. The cytoprotective function of MG53 is mediated by STATs and MAPK signaling in HFSCs. The thermosensitive ROS-scavenging gel encapsulated with rhMG53 allows for sustained release of rhMG53 and promotes healing of chronic cutaneous wounds and hair follicle development in the db/db mice. These findings support the potential therapeutic value of using rhMG53 in combination with ROS-scavenging gel to treat diabetic wounds.

In-vitro characterization and evaluation of mesoporous titanium dioxide composite hydroxyapatite and its effectiveness in occluding dentine tubules.

BACKGROUND: To synthesize mesoporous titanium dioxide composite hydroxyapatite (TiO2-HAP) and to evaluate its effectiveness in sealing of occluding dentine tubules. METHODS: TiO2-HAP was synthesized by chemical precipitation method and characterized using infrared absorption spectrometer, X-ray diffraction, scanning electron microscope, and specific surface area detector. Forty completely extracted molars were prepared and randomly assigned into Control group, Gluma group, HAP group and TiO2-HAP group according to different treatments. The characteristics of HAP and TiO2-HAP and the sealing effectiveness of dentine tubules in these four groups, including infrared spectrum, surface contact angle, pore size distribution, and re-mineralized enamel surface profiles, were analyzed by suitable characterized techniques. The cytotoxicity of the synthesized TiO2-HAP was tested and compared using 3-(4,5)-dimethylthiahiazo(-z-y1)-3,5-di-phenytetrazoliumromide (MTT) colorimetry. RESULTS: Our results showed TiO2-HAP group had significantly lower contact angle, higher specific surface area, and wider range of pore size distribution than other groups. The majority of dentinal tubules in the TiO2-HAP group were blocked by white matter in a uniformed manner, and the crystals arranged in order grew along the axial direction. In addition, no significant difference in optical density (OD) value was found between control group and TiO2-HAP group (P > 0.05), and cell growth was good in TiO2-HAP group, indicating no cytotoxicity of TiO2-HAP. CONCLUSIONS: The MTT assay identified that TiO2-HAP had little effect on the L929 cell line. We showed TiO2-HAP might be used as a remineralization agent in enamel caries-like lesions.

Overexpression of long noncoding RNA MCM3AP-AS1 promotes osteogenic differentiation of dental pulp stem cells via miR-143-3p/IGFBP5 axis.

MCM3AP-AS1 regulates the cartilage repair in osteoarthritis, but how it regulates osteogenic differentiation of dental pulp stem cells (DPSCs) remains to be determined. DPSCs were isolated and induced for osteogenic differentiation. MCM3AP-AS1 expression was increased along with the osteogenic differentiation of DPSCs, whose expression was positive correlated with those of OCN, alkaline phosphatase (ALP) and RUNX2. On contrary, miR-143-3p expression was decreased along with the osteogenic differentiation and was negatively correlated with those of OCN, ALP and RUNX2. Dual-luciferase reporter gene assay showed that miR-143-3p can be negatively regulated by MCM3AP-AS1 and can regulate IGFBP5. MCM3AP-AS1 overexpression increased the expression levels of osteogenesis-specific genes, ALP activity and mineralized nodules during DPSC osteogenic differentiation, while IGFBP5 knockdown or miR-143-3p overexpression counteracted the effect of MCM3AP-AS1 overexpression in DPSCs. Therefore, this study demonstrated the role of MCM3AP-AS1/miR-143-3p/IGFBP5 axis in regulating DPSC osteogenic differentiation.

Membrane-delimited signaling and cytosolic action of MG53 preserve hepatocyte integrity during drug-induced liver injury.

BACKGROUND & AIMS: Drug-induced liver injury (DILI) remains challenging to treat and is still a leading cause of acute liver failure. MG53 is a muscle-derived tissue-repair protein that circulates in the bloodstream and whose physiological role in protection against DILI has not been examined. METHODS: Recombinant MG53 protein (rhMG53) was administered exogenously, using mice with deletion of Mg53 or Ripk3. Live-cell imaging, histological, biochemical, and molecular studies were used to investigate the mechanisms that underlie the extracellular and intracellular action of rhMG53 in hepatoprotection. RESULTS: Systemic administration of rhMG53 protein, in mice, can prophylactically and therapeutically treat DILI induced through exposure to acetaminophen, tetracycline, concanavalin A, carbon tetrachloride, or thioacetamide. Circulating MG53 protects hepatocytes from injury through direct interaction with MLKL at the plasma membrane. Extracellular MG53 can enter hepatocytes and act as an E3-ligase to mitigate RIPK3-mediated MLKL phosphorylation and membrane translocation. CONCLUSIONS: Our data show that the membrane-delimited signaling and cytosolic dual action of MG53 effectively preserves hepatocyte integrity during DILI. rhMG53 may be a potential treatment option for patients with DILI. LAY SUMMARY: Interventions to treat drug-induced liver injury and halt its progression into liver failure are of great value to society. The present study reveals that muscle-liver cross talk, with MG53 as a messenger, serves an important role in liver cell protection. Thus, MG53 is a potential treatment option for patients with drug-induced liver injury.

Multiple functions of autophagy in vascular calcification.

BACKGROUND: Vascular calcification is a closely linked to cardiovascular diseases, such as atherosclerosis, chronic kidney disease, diabetes, hypertension and aging. The extent of vascular calcification is closely correlate with adverse clinical events and cardiovascular all-cause mortality. The role of autophagy in vascular calcification is complex with many mechanistic unknowns. METHODS: In this review, we analyze the current known mechanisms of autophagy in vascular calcification and discuss the theoretical advantages of targeting autophagy as an intervention against vascular calcification. RESULTS: Here we summarize the functional link between vascular calcification and autophagy in both animal models of and human cardiovascular disease. Firstly, autophagy can reduce calcification by inhibiting the osteogenic differentiation of VSMCs related to ANCR, ERα, ß-catenin, HIF-1a/PDK4, p62, miR-30b, BECN1, mTOR, SOX9, GHSR/ERK, and AMPK signaling. Conversely, autophagy can induce osteoblast differentiation and calcification as mediated by CREB, degradation of elastin, and lncRNA H19 and DUSP5 mediated ERK signaling. Secondly, autophagy also links apoptosis and vascular calcification through AMPK/mTOR/ULK1, Wnt/ß-catenin and GAS6/AXL synthesis, as apoptotic cells become the nidus for calcium-phosphate crystal deposition. The failure of mitophagy can activate Drp1, BNIP3, and NR4A1/DNA­PKcs/p53 mediated intrinsic apoptotic pathways, which have been closely linked to the formation of vascular calcification. Additionally, autophagy also plays a role in osteogenesis by regulating vascular calcification, which in turn regulates expression of proteins related to bone development, such as osteocalcin, osteonectin, etc. and regulated by mTOR, EphrinB2 and RhoA. Furthermore, autophagy also promotes vitamin K2-induced MC3T3 E1 osteoblast differentiation and FGFR4/FGF18- and JNK/complex VPS34-beclin-1-related bone mineralization via vascular calcification. CONCLUSION: The interaction between autophagy and vascular calcification are complicated, with their interaction affected by the disease process, anatomical location, and the surrounding microenvironment. Autophagy activation in existent cellular damage is considered protective, while defective autophagy in normal cells result in apoptotic activation. Identifying and maintaining cells at the delicate line between these two states may hold the key to reducing vascular calcification, in which autophagy associated clinical strategy could be developed.

MG53, A Tissue Repair Protein with Broad Applications in Regenerative Medicine.

Under natural conditions, injured cells can be repaired rapidly through inherent biological processes. However, in the case of diabetes, cardiovascular disease, muscular dystrophy, and other degenerative conditions, the natural repair process is impaired. Repair of injury to the cell membrane is an important aspect of physiology. Inadequate membrane repair function is implicated in the pathophysiology of many human disorders. Recent studies show that Mitsugumin 53 (MG53), a TRIM family protein, plays a key role in repairing cell membrane damage and facilitating tissue regeneration. Clarifying the role of MG53 and its molecular mechanism are important for the application of MG53 in regenerative medicine. In this review, we analyze current research dissecting MG53's function in cell membrane repair and tissue regeneration, and highlight the development of recombinant human MG53 protein as a potential therapeutic agent to repair multiple-organ injuries.

Thesium longiperianthium (Santalaceae), a new replacement name for T. brevibracteatum P.C.Tam.

BACKGROUND: Thesium brevibracteatum P.C.Tam was described, based on the specimen L.C.Chiu 5128 collected from Inner Mongolia, China. The name Thesium brevibracteatum Sumnev. is validly published and described for the type (Korotkova E. E. et Titov V. S. 1502) collected from Uzbekistan. T. brevibracteatum P.C.Tam is a later homonym of T. brevibracteatum Sumnev. NEW INFORMATION: We propose T. longiperianthium as the replacemen name for T. brevibracteatum P.C. Tam.

Nonalcoholic fatty liver disease experiences accumulation of hepatic liquid crystal associated with increasing lipophagy.

BACKGROUND: In the past 30 years, incidences of non-alcoholic fatty liver disease (NAFLD) has risen by 30%. However, there is still no clear mechanism or accurate method of anticipating liver failure. Here we reveal the phase transitions of liquid crystalline qualities in hepatic lipid droplets (HLDs) as a novel method of anticipating prognosis. METHODS: NAFLD was induced by feeding C57BL/6J mice on a high-fat (HiF) diet. These NAFLD livers were then evaluated under polarized microscopy, X-ray diffraction and small-angle scattering, lipid component chromatography analysis and protein expression analysis. Optically active HLDs from mouse model and patient samples were both then confirmed to have liquid crystal characteristics. Liver MAP1LC3A expression was then evaluated to determine the role of autophagy in liquid crystal HLD (LC-HLD) formation. RESULTS: Unlike the normal diet cohort, HiF diet mice developed NAFLD livers containing HLDs exhibiting Maltese cross birefringence, phase transition, and fluidity signature to liquid crystals. These LC-HLDs transitioned to anisotropic crystal at 0 °C and remain crystalline. Temperature increase to 42 °C causes both liquid crystal and crystal HLDs to convert to isotropic droplet form. These isotropic HLDs successfully transition to anisotropic LC with fast temperature decrease and anisotropic crystal with slow temperature decrease. These findings were duplicated in patient liver. Patient LC-HLDs with no inner optical activity were discovered, hinting at lipid saturation as the mechanism through which HLD acquire LC characteristics. Downregulation of MAP1LC3A in conjunction with increased LC-HLD also implicated autophagy in NAFLD LC-HLD formation. CONCLUSIONS: Increasing concentrations of amphiphilic lipids in HLDs favors organization into alternating hydrophilic and hydrophobic layers, which present as LC-HLDs. Thus, evaluating the extent of liquid crystallization with phase transition in HLDs of NAFLD patients may reveal disease severity and predict impending liver damage.

Calcium-dependent Protein Kinases in Malaria Parasite Development and Infection.

Apicomplexan parasites have challenged researchers for nearly a century. A major challenge to developing efficient treatments and vaccines is the parasite's ability to change its cellular and molecular makeup to develop intracellular and extracellular niches in its hosts. Ca2+ signaling is an important messenger for the egress of the malaria parasite from the infected erythrocyte, gametogenesis, ookinete motility in the mosquito, and sporozoite invasion of mammalian hepatocytes. Calcium-dependent protein kinases (CDPKs) have crucial functions in calcium signaling at various stages of the parasite's life cycle; this therefore makes them attractive drug targets against malaria. Here, we summarize the functions of the various CDPK isoforms in relation to the malaria life cycle by emphasizing the molecular mechanism of developmental progression within host tissues. We also discuss the current development of anti-malarial drugs, such as how specific bumped kinase inhibitors (BKIs) for parasite CDPKs have been shown to reduce infection in Toxoplasma gondii, Cryptosporidium parvum, and Plasmodium falciparum. Our suggested combinations of BKIs, artemisinin derivatives with peroxide bridge, and inhibitors on the Ca(2+)-ATPase PfATP6 as a potential target should be inspected further as a treatment against malaria.

Influence of Minor Zn Addition on Precipitation Behavior and Intergranular Corrosion Properties of Al-Mg-Si Alloy.

The effect of 0.2 wt.% Zn addition on microstructure, age hardening and intergranular corrosion (IGC) properties of Al-Mg-Si alloy were investigated by scanning electron microscope, transmission electron microscope, hardness testing, and electrochemistry testing. The results showed that the addition of Zn can accelerate the transformation of GP zones into ß″, and make the intragranular precipitates become smaller and with higher density. This is beneficial to the precipitation strengthening of the alloy, leading to obtaining higher hardness and enhancing the age hardening response. The peak hardness of the alloy with the addition of Zn is 125.8 HV which means increasing the hardness by 12.7 HV, compared with the alloy without Zn. However, the addition of Zn makes the precipitate-free zone (PFZ) of the alloy wider, and coarsens the grain boundary precipitates slightly, which result in the reduction of IGC resistance of Al-Mg-Si alloy. The maximum corrosion depth of the Zn-containing alloy is 121.3 µm in the peak age condition, which is 35.7 µm deeper than the alloy without Zn. The result of the potentiodynamic polarization curves also demonstrated the increase of IGC sensitivity. The corrosion current density of the alloy with added Zn is 0.595 µA/cm2 in the peak age condition, while that for the alloy without Zn is 0.199 µA/cm2.

Physical exercise: bulking up neurogenesis in human adults.

Whether neurogenesis occurs in the adult human brain has been a long-debated topic fueled by conflicting data both for and against neurogenesis in the mature brain. Recent reports from two independent teams may have indubitably proven that adult, hippocampal neurogenesis persists throughout the human lifespan. Llorens-Martín et al. found that thousands of immature, neurogenesis related, doublecortin-positive (DCX+) labelled neurons can be detected in the human dentate gyrus (DG) up to the eighth decade of life. While the presence of these DCX+ neurons decrease with age, they are significantly decrease in patient with Alzheimer's disease. Another group have also found mammalian embryonic Hopx+ precursors to persist beyond the early development stage as quiescent Hopx+ radial glial-like neural progenitors during early postnatal period, then as Hopx+ adult dentate neural progenitors. Together, the findings from these two groups suggest that unlike the previously thought, neurogenesis and neuroplasticity can occur well into adulthood in some capacity, at least in the hippocampus. These recent findings that neurogenesis can occur beyond development have brought into questions whether physical exercise can be shown to promote neurogenesis and brain health, as it has been shown to promote the function of other organ systems. Some data has already shown physical exercise to induce adult hippocampal neurogenesis (AHN) as demonstrated by restoration of cognitive functions, improvement of synaptic plasticity, and enhancement of angiogenesis. A large-scale meta-analysis has also demonstrated that 45-60 min of moderate-intensity physical exercise to dramatically improve cognitive functions in human subjects over the age of 50. Given these convergent developments in our understanding of neurogenesis and exercise induced improvement in cognitive function, we speculate that hippocampal neurogenesis can be promoted by physical exercise and discuss the current molecular evidence supporting the likely molecular pathways involved.

Exercise-induced myokine FNDC5/irisin functions in cardiovascular protection and intracerebral retrieval of synaptic plasticity.

Physical exercise is well known to benefit human health at every age. However, the exact mechanism through which physical exercise improves health remains unknown. Recent studies into exercise-induced myokine FNDC5/irisin, a newly discovered hormone, have begun to shed light on this mystery. Exercise-induced myokine FNDC5/irisin have been shown to be protective against cardiovascular damage post ischemic event, improve function in the neurons of Alzheimer's disease patients, and have been implicated in macrophage and adipocyte regulation. Elegantly designed experiments have shown FNDC5/irisin to promote Nkx2.5+ cardiac progenitor cell dependent cardiac regeneration, neovascularization, and reduce cardiac fibrosis. It has also been shown to improve macrophage function, which may protect against injuries to the cardiac conduction system. Similarly, FNDC5/irisin knockout mice have been shown to have reduced memory performance, while peripheral overexpression of FNDC5/irisin has been shown to improve memory impairment in a murine Alzheimer's disease model. Finally, FNDC5/irisin has been linked to regulation of osteocytes and adipocytes by signaling through the cytoplasmic membrane integrated protein aV/b5 integrin, the first known receptor for this newly discovered hormone. Although these recent discoveries have cemented the importance of FNDC5/irisin, many details regarding how FNDC5/irisin fits into the physiology of exercise benefits remain unknown and are deserving of future inquiry.