Impact of the metabolic syndrome on prevalence and survival in motor neuron disease: a retrospective case series.

Metabolic dysfunction is an important factor in the pathogenesis of motor neuron disease, but its prevalence and association with survival in this disorder is unknown. We hypothesized that patients with motor neuron disease would show a higher prevalence of metabolic syndrome compared to the general New Zealand population, and that metabolic syndrome would be associated with worsened survival. We undertook a retrospective analysis in 109 motor neuron disease patients diagnosed and treated at Waikato Hospital from 2013 to 2020. Demographic, clinical, and laboratory data were collected. Survival was defined as the date of initial symptom onset to the date of death. Of 104 eligible patients, 34 patients (33%) had metabolic syndrome (33% of Europeans, 46% of Maori). Mean survival in motor neuron disease patients with metabolic syndrome was significantly reduced compared to patients without metabolic syndrome (38 vs. 61 months, P = 0.044), with a 5-year survival rate of 21% for the former and 38% for the latter (P = 0.012). Compared with the general New Zealand population, metabolic syndrome is highly prevalent amongst motor neuron disease patients in the Waikato region and it is associated with worsened survival. Metabolic dysfunction may be a key factor underlying the pathogenesis of motor neuron disease.

Generation of Red Blood Cells from Human Pluripotent Stem Cells-An Update.

Red blood cell (RBC) transfusion is a lifesaving medical procedure that can treat patients with anemia and hemoglobin disorders. However, the shortage of blood supply and risks of transfusion-transmitted infection and immune incompatibility present a challenge for transfusion. The in vitro generation of RBCs or erythrocytes holds great promise for transfusion medicine and novel cell-based therapies. While hematopoietic stem cells and progenitors derived from peripheral blood, cord blood, and bone marrow can give rise to erythrocytes, the use of human pluripotent stem cells (hPSCs) has also provided an important opportunity to obtain erythrocytes. These hPSCs include both human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs). As hESCs carry ethical and political controversies, hiPSCs can be a more universal source for RBC generation. In this review, we first discuss the key concepts and mechanisms of erythropoiesis. Thereafter, we summarize different methodologies to differentiate hPSCs into erythrocytes with an emphasis on the key features of human definitive erythroid lineage cells. Finally, we address the current limitations and future directions of clinical applications using hiPSC-derived erythrocytes.

Generation and Application of Directly Reprogrammed Endothelial Cells.

Cell-based therapy has emerged as a promising option for treating advanced ischemic cardiovascular disease by inducing vascular regeneration. However, clinical trials with adult cells turned out disappointing in general. As a newer approach, direct reprogramming has emerged to efficiently generate endothelial cells (ECs), which can promote neovascularization and vascular regeneration. This review provides recent updates on the direct endothelial reprogramming. In general, directly reprogrammed ECs can be generated by two approaches: one by transitioning through a plastic intermediate state and the other in a one-step transition without any intermediate states toward pluripotency. Moreover, the methods to deliver reprogramming factors and chemicals for the fate conversion are highlighted. Next, the therapeutic effects of the directly reprogrammed ECs on animal models are reviewed in detail. Other applications using directly reprogrammed ECs, such as tissue engineering and disease modeling, are also discussed. Lastly, the remaining questions and foremost challenges are addressed.

Human Induced Pluripotent Stem Cell-Derived Vascular Cells: Recent Progress and Future Directions.

Human induced pluripotent stem cells (hiPSCs) hold great promise for cardiovascular regeneration following ischemic injury. Considerable effort has been made toward the development and optimization of methods to differentiate hiPSCs into vascular cells, such as endothelial and smooth muscle cells (ECs and SMCs). In particular, hiPSC-derived ECs have shown robust potential for promoting neovascularization in animal models of cardiovascular diseases, potentially achieving significant and sustained therapeutic benefits. However, the use of hiPSC-derived SMCs that possess high therapeutic relevance is a relatively new area of investigation, still in the earlier investigational stages. In this review, we first discuss different methodologies to derive vascular cells from hiPSCs with a particular emphasis on the role of key developmental signals. Furthermore, we propose a standardized framework for assessing and defining the EC and SMC identity that might be suitable for inducing tissue repair and regeneration. We then highlight the regenerative effects of hiPSC-derived vascular cells on animal models of myocardial infarction and hindlimb ischemia. Finally, we address several obstacles that need to be overcome to fully implement the use of hiPSC-derived vascular cells for clinical application.

Randomized crossover trial of a modified ketogenic diet in Alzheimer's disease.

BACKGROUND: Brain energy metabolism is impaired in Alzheimer's disease (AD), which may be mitigated by a ketogenic diet. We conducted a randomized crossover trial to determine whether a 12-week modified ketogenic diet improved cognition, daily function, or quality of life in a hospital clinic of AD patients. METHODS: We randomly assigned patients with clinically confirmed diagnoses of AD to a modified ketogenic diet or usual diet supplemented with low-fat healthy-eating guidelines and enrolled them in a single-phase, assessor-blinded, two-period crossover trial (two 12-week treatment periods, separated by a 10-week washout period). Primary outcomes were mean within-individual changes in the Addenbrookes Cognitive Examination - III (ACE-III) scale, AD Cooperative Study - Activities of Daily Living (ADCS-ADL) inventory, and Quality of Life in AD (QOL-AD) questionnaire over 12 weeks. Secondary outcomes considered changes in cardiovascular risk factors and adverse effects. RESULTS: We randomized 26 patients, of whom 21 (81%) completed the ketogenic diet; only one withdrawal was attributed to the ketogenic diet. While on the ketogenic diet, patients achieved sustained physiological ketosis (12-week mean beta-hydroxybutyrate level: 0.95 ± 0.34 mmol/L). Compared with usual diet, patients on the ketogenic diet increased their mean within-individual ADCS-ADL (+ 3.13 ± 5.01 points, P = 0.0067) and QOL-AD (+ 3.37 ± 6.86 points, P = 0.023) scores; the ACE-III also increased, but not significantly (+ 2.12 ± 8.70 points, P = 0.24). Changes in cardiovascular risk factors were mostly favourable, and adverse effects were mild. CONCLUSIONS: This is the first randomized trial to investigate the impact of a ketogenic diet in patients with uniform diagnoses of AD. High rates of retention, adherence, and safety appear to be achievable in applying a 12-week modified ketogenic diet to AD patients. Compared with a usual diet supplemented with low-fat healthy-eating guidelines, patients on the ketogenic diet improved in daily function and quality of life, two factors of great importance to people living with dementia. TRIAL REGISTRATION: This trial is registered on the Australia New Zealand Clinical Trials Registry, number ACTRN12618001450202 . The trial was registered on August 28, 2018.

Does the implementation of smoke-free laws and smoking culture affect exposure to tobacco smoking? Results from 3 hospitality settings in South Korea.

OBJECTIVES: It is especially difficult for hospitality workers to avoid secondhand smoke (SHS), meaning that they are likely particularly vulnerable to the effects of SHS. The authors aimed to determine the degree to which smoke-free laws protect hospitality workers from SHS exposure, by examining biochemical markers of such exposure. MATERIAL AND METHODS: This was a cross-sectional study examining SHS exposure in non-smoking employees working in hospitality settings where smoking is prohibited or permitted. The following biomarkers were selected: cotinine and tobaccospecific nitrosamines, which are known to measure SHS exposure, and 2 representative carcinogens: 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). The authors compared these biomarkers between 3 hospitality settings. A descriptive analysis was performed. In addition, they conducted 1-way and 2-way analysis of covariance (ANCOVA) to compare the biochemical markers. RESULTS: Smoking substances were identified by smoking ban levels. In the case of hair nicotine and urine cotinine, their concentrations were lower in areas with a complete smoking ban than in both areas with a separate smoking room and no smoking ban; however, there was no statistically significant difference between these. In the case of dust NNK, its level was the lowest in areas with a complete smoking ban. To confirm the smoking ban effect by hospitality settings, the authors checked the results of the 2-way ANCOVA. In karaoke and billiard halls, the dust NNK concentrations were significantly higher in areas with no smoking ban than in areas with a separate smoking room. CONCLUSIONS: Exposure to SHS is more prevalent in places that are more lenient when it comes to smoking (e.g., Internet cafés) than in places that are not (e.g., restaurants and cafés), even when smoking is similarly prohibited in both types of places. Int J Occup Med Environ Health. 2021;34(1):53-67.

Facile extraction of cellulose nanocrystals.

A simple process for extracting cellulose nanocrystals (CNCs) is proposed that only uses high-pressure homogenization (HPH) controlling a process temperature. The proposed process was assessed and compared with normal production through acidic hydrolysis. Temperature-controlled HPH produced CNCs with high crystallinity, which linearly increased with increasing process temperature over 20 passes. The CNCs had uniform widths and lengths in the ranges of 4-14 nm and 60-320 nm, respectively. Undesirable chemical reaction can be avoided with the proposed process because no chemical was used to promote the CNC extraction. This method is an efficient and sustainable green approach to CNC production.

Towards smoke-free cars in the Republic of Korea: Evidence from environmental and biochemical monitoring of third-hand smoke exposure in taxis.

INTRODUCTION: To evaluate the level of tobacco smoke exposure in taxis in Korea using tobacco specific environmental markers. METHODS: From June to September 2012, cross-sectional measurements of air nicotine levels and dust nicotine-derived nitrosamine ketone (NNK) concentrations were conducted in 17 taxis in Goyang, Korea. Field investigators completed an observational questionnaire on building characteristics, smoking policies and evidence of smoking. Descriptive statistics including geometric means (GMs) ± standard deviations were produced for air nicotine levels and dust NNK concentrations. RESULTS: There was no evidence of active smoking in the 17 taxis monitored, despite the fact that 10 drivers were current smokers. The overall GMs of air nicotine and dust NNK concentration were 0.42 µg/m3 and 6.78 pg/mg, respectively. These levels were 3.4-fold and 2.6-fold higher in taxis whose drivers were current smokers compared to the taxis of nonsmokers (GM of air nicotine: 0.65 µg/m3 vs 0.19 µg/m3; GM of dust NNK: 10.07 pg/mg vs 3.85 pg/mg). CONCLUSIONS: The present study shows that air nicotine and dust NNK were detected in all taxis regardless of whether the taxi driver was smoking or not, which indicates the potential for exposure to SHS or THS. It suggests that an appreciable level of SHS and TSH exposure might occur if the environment is not completely smoke-free and enforcement is lacking. ABBREVIATIONS: THS: third-hand smoke, SHS: second-hand smoke, FCTC: Framework Convention Alliance for Tobacco Control, NNK: 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, LOD: limit of detection, GM: geometric mean, GSD: geometric standard deviation.

Epigenetic control of juvenile-to-adult phase transition by the Arabidopsis SAGA-like complex.

During growth and development, plants undergo a series of phase transitions from the juvenile-to-adult vegetative phase to the reproductive phase. In Arabidopsis, vegetative phase transitions and flowering are regulated by SQUAMOSA PROMOTER BINDING PROTEIN-LIKE (SPL) factors. SPL mRNAs are post-transcriptionally regulated by miR156 in an age-dependent manner; however, the role of other mechanisms in this process is not known. In this study, we demonstrate that the HAG1/GCN5- and PRZ1/ADA2b-containing SAGA-like histone acetyltransferase (HAT) complex directly controls the transcription of SPLs and determines the time for juvenile-to-adult phase transition. Thus, epigenetic control by the SAGA-like HAT complex determines the transcriptional output of SPLs, which might be a prerequisite for the subsequent post-transcriptional regulation by miR156. Importantly, this epigenetic control mechanism is also crucial for miR156-independent induction of SPLs and acceleration of phase transition by light and photoperiod or during post-embryonic growth.

A nuclear factor kappa B-derived inhibitor tripeptide inhibits UVB-induced photoaging process.

BACKGROUND: Ultraviolet (UV) irradiation on the skin induces photoaging which is characterized by keratinocyte hyperproliferation, generation of coarse wrinkles, worse of laxity and roughness. Upon UV irradiation, nuclear factor kappa B (NF-κB) is activated which plays a key role in signaling pathway leading to inflammation cascade and this activation stimulates expression of pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF-α), interleukin-1alpha (IL-1α) and a stress response gene cyclooxygenase-2 (COX-2). In addition, activation of NF-κB up-regulates the expression of matrix metalloprotease-1 (MMP-1) and consequently collagen in dermis is degraded. OBJECTIVE: In this study, the effects of a NF-κB-derived inhibitor tripeptide on the UVB-induced photoaging and inflammation were investigated in vitro and in vivo. METHODS: A NF-κB-derived inhibitor tripeptide (NF-κB-DVH) was synthesized based on the sequence of dimerization region of the subunit p65 of NF-κB. Its inhibitory activity was confirmed using chromatin immunoprecipitation assay and in situ proximate ligation assay. The effects of anti-photoaging and anti-inflammation were analyzed by Enzyme-linked immunosorbent assay (ELISA), immunoblotting and immunochemistry. RESULTS: NF-κB-DVH significantly decreased UV-induced expression of TNF-α, IL-1α, MMP-1 and COX-2 while increased production of type I procollagen. CONCLUSION: Results showed NF-κB-DVH had strong anti-inflammatory activity probably by inhibiting NF-κB activation pathway and suggested to be used as a novel agent for anti-photoaging.

Inhibition of mouse brown adipocyte differentiation by second-generation antipsychotics.

Brown adipose tissue is specialized to burn lipids for thermogenesis and energy expenditure. Second-generation antipsychotics (SGA) are the most commonly used drugs for schizophrenia with several advantages over first-line drugs, however, it can cause clinically-significant weight gain. To reveal the involvement of brown adipocytes in SGA-induced weight gain, we compared the effect of clozapine, quetiapine, and ziprasidone, SGA with different propensities to induce weight gain, on the differentiation and the expression of brown fat-specific markers, lipogenic genes and adipokines in a mouse brown preadipocyte cell line. On Oil Red-O staining, the differentiation was inhibited almost completely by clozapine (40 µM) and partially by quetiapine (30 µM). Clozapine significantly down-regulated the brown adipogenesis markers PRDM16, C/EBPß, PPARγ2, UCP-1, PGC-1α, and Cidea in dose- and time-dependent manners, whereas quetiapine suppressed PRDM16, PPARγ 2, and UCP-1 much weakly than clozapine. Clozapine also significantly inhibited the mRNA expressions of lipogenic genes ACC, SCD1, GLUT4, aP2, and CD36 as well as adipokines such as resistin, leptin, and adiponectin. In contrast, quetiapine suppressed only resistin and leptin but not those of lipogenic genes and adiponectin. Ziprasidone (10 µM) did not alter the differentiation as well as the gene expression patterns. Our results suggest for the first time that the inhibition of brown adipogenesis may be a possible mechanism to explain weight gain induced by clozapine and quetiapine.

A dual role for MYB60 in stomatal regulation and root growth of Arabidopsis thaliana under drought stress.

In response to environmental challenges, plant cells activate several signaling pathways that trigger the expression of transcription factors. Arabidopsis MYB60 was reported to be involved in stomatal regulation under drought conditions. Here, two splice variants of the MYB60 gene are shown to play a crucial role in stomatal movement. This role was demonstrated by over-expressing each variant, resulting in enhanced sensitivity to water deficit stress. The MYB60 splice variants, despite the fact that one of which lacks the first two exons encoding the first MYB DNA binding domain, both localize to the nucleus and promote guard cell deflation in response to water deficit. Moreover, MYB60 expression is increased in response to a low level of ABA and decreased in response to high level of ABA. At initial stage of drought stress, the plant system may modulate the root growth behavior by regulating MYB60 expression, thus promotes root growth for increased water uptake. In contrast, severe drought stress inhibits the expression of the MYB60 gene, resulting in stomatal closure and root growth inhibition. Taken together, these data indicate that MYB60 plays a dual role in abiotic stress responses in Arabidopsis through its involvement in stomatal regulation and root growth.

The ethylene signaling pathway has a negative impact on sucrose-induced anthocyanin accumulation in Arabidopsis.

In an attempt to understand the complex regulatory mechanisms underlying sucrose-induced flavonoid biosynthesis, we examined several Arabidopsis mutants with altered anthocyanin accumulation. We determined that disruption of ethylene signaling results in a dramatic increase in sucrose-induced anthocyanin accumulation. Furthermore, we investigated why the ein2-1 (ethylene insensitive) Arabidopsis mutant accumulates higher levels of anthocyanin in response to sucrose than wild-type Arabidopsis. An increased level of PAP1 transcript in the ein2-1 mutant appears to be the main factor responsible for the increased accumulation of anthocyanin in response to sucrose. Therefore, our results indicate that the ethylene signaling pathway plays a negative role in sucrose-induced anthocyanin accumulation. We believe that the explanation for this observation may be related to the initiation of the senescence program in plants.

DNA on a tube: electrostatic contribution to stiffness.

Two simple models are used to estimate the electrostatic contributions to the stiffness of short DNA fragments. The first model views DNA as two strands that are appropriately parametrized and are wrapped helically around a straight cylinder radius equal to the radius of the DNA molecule. The potential energy of the DNA due to phosphate-phosphate electrostatic interactions is evaluated assuming that the charges interact through Debye-Hückel potentials. This potential energy is compared with the potential energy as computed using our second model in which DNA is viewed as two helical strands wrapping around a curved tube whose cross-section is a disk of radius equal to the radius of the DNA. We find that the electrostatic persistence length for B-DNA molecules in the range of 105-130 bp is 125.64 angstroms (37 bp) and 76.05 angstroms (23 bp) at 5 and 10 mM monovalent salt concentration, respectively. If the condensed fraction theta is taken to be 0.715 at 10 mM, then the electrostatic persistence length is 108.28 angstroms (32 bp), while that based on taking into account end effects is 72.87 angstroms (21 bp). At 5 mM monovalent salt, the total persistence length for DNA fragments in this length range is approximately 575.64 angstroms (171 bp), using the best estimate for nonelectrostatic contribution to persistence length. Electrostatic effects thus contribute 21.8% to DNA stiffness at 5 mM for fragments between 105- to 130-bp. In contrast, electrostatics are calculated to make a negligible contribution to the DNA persistence length at physiological monovalent cation concentration. The results are compared with counterion condensation models and experimental data.

Arabidopsis hot2 encodes an endochitinase-like protein that is essential for tolerance to heat, salt and drought stresses.

The Arabidopsis hot2 mutant was originally identified based on its lack of thermotolerance, but pleiotropic abnormal phenotypes are also exhibited under normal conditions, including semi-dwarfism, ethylene overproduction and aberrant cell shape with incomplete cell walls. Here we present additional characterization of the hot2 mutant, and the map-based cloning of HOT2. Mutants of hot2 had an aberrant tolerance to salt and drought stresses, and accumulated high levels of Na(+) in cells under either normal or NaCl stress conditions. Expression of the stress-inducible COR15A and KIN1 gene in hot2 mutants in response to increased NaCl concentrations was normal. HOT2 encoded a chitinase-like protein (AtCTL1) that has not previously been shown to be involved in tolerance to salt stress. Ten-day-old seedlings of wild-type plants exhibited constitutive expression of the AtCTL1 transcript, the level of which was unaffected by treatment with NaCl, mannitol or mild heat. These observations provide genetic evidence that a chitinase-like protein prevents the overaccumulation of Na(+) ions, thereby contributing to the salt tolerance in Arabidopsis. A possible role for this chitinase-like protein in Arabidopsis tolerance to abiotic stress is discussed.