The GWAS SNP rs80207740 modulates erythrocyte traits via allele-specific binding of IKZF1 and targeting XPO7 gene.

Genome-wide association studies have identified many single nucleotide polymorphisms (SNPs) associated with erythrocyte traits. However, the functional variants and their working mechanisms remain largely unknown. Here, we reported that the SNP of rs80207740, which was associated with red blood cell (RBC) volume and hemoglobin content across populations, conferred enhancer activity to XPO7 gene via allele-differentially binding to Ikaros family zinc finger 1 (IKZF1). We showed that the region around rs80207740 was an erythroid-specific enhancer using reporter assays, and that the G-allele further enhanced activity. 3D genome evidence showed that the enhancer interacted with the XPO7 promoter, and eQTL analysis suggested that the G-allele upregulated expression of XPO7. We further showed that the rs80207740-G allele facilitated the binding of transcription factor IKZF1 in EMSA and ChIP analyses. Knockdown of IKZF1 and GATA1 resulted in decreased expression of Xpo7 in both human and mouse erythroid cells. Finally, we constructed Xpo7 knockout mouse by CRISPR/Cas9 and observed anemic phenotype with reduced volume and hemoglobin content of RBC, consistent to the effect of rs80207740 on erythrocyte traits. Overall, our study demonstrated that rs80207740 modulated erythroid indices by regulating IKZF1 binding and Xpo7 expression.

Inducing and exploiting vulnerabilities for the treatment of liver cancer.

Liver cancer remains difficult to treat, owing to a paucity of drugs that target critical dependencies1,2; broad-spectrum kinase inhibitors such as sorafenib provide only a modest benefit to patients with hepatocellular carcinoma3. The induction of senescence may represent a strategy for the treatment of cancer, especially when combined with a second drug that selectively eliminates senescent cancer cells (senolysis)4,5. Here, using a kinome-focused genetic screen, we show that pharmacological inhibition of the DNA-replication kinase CDC7 induces senescence selectively in liver cancer cells with mutations in TP53. A follow-up chemical screen identified the antidepressant sertraline as an agent that kills hepatocellular carcinoma cells that have been rendered senescent by inhibition of CDC7. Sertraline suppressed mTOR signalling, and selective drugs that target this pathway were highly effective in causing the apoptotic cell death of hepatocellular carcinoma cells treated with a CDC7 inhibitor. The feedback reactivation of mTOR signalling after its inhibition6 is blocked in cells that have been treated with a CDC7 inhibitor, which leads to the sustained inhibition of mTOR and cell death. Using multiple in vivo mouse models of liver cancer, we show that treatment with combined inhibition of of CDC7 and mTOR results in a marked reduction of tumour growth. Our data indicate that exploiting an induced vulnerability could be an effective treatment for liver cancer.

Transcriptome analysis of axillary buds in low phosphorus stress and functional analysis of TaWRKY74s in wheat.

BACKGROUND: Wheat is one of the main grain crops in the world, and the tiller number is a key factor affecting the yield of wheat. Phosphorus is an essential element for tiller development in wheat. However, due to decreasing phosphorus content in soil, there has been increasing use of phosphorus fertilizer, while imposing risk of soil and water pollution. Hence, it is important to identify low phosphorus tolerance genes and utilize them for stress resistance breeding in wheat. RESULTS: We subjected the wheat variety Kenong 199 (KN199) to low phosphorus stress and observed a reduced tiller number. Using transcriptome analysis, we identified 1651 upregulated genes and 827 downregulated of genes after low phosphorus stress. The differentially expressed genes were found to be enriched in the enzyme activity regulation related to phosphorus, hormone signal transduction, and ion transmembrane transport. Furthermore, the transcription factor analysis revealed that TaWRKY74s were important for low phosphorus tolerance. TaWRKY74s have three alleles: TaWRKY74-A, TaWRKY74-B, and TaWRKY74-D, and they all belong to the WRKY family with conserved WRKYGQK motifs. These proteins were found to be located in the nucleus, and they were expressed in axillary meristem, shoot apical meristem(SAM), young leaves, leaf primordium, and spikelet primordium. The evolutionary tree showed that TaWRKY74s were closely related to OsWRKY74s in rice. Moreover, TaWRKY74s-RNAi transgenic plants displayed significantly fewer tillers compared to wild-type plants under normal conditions. Additionally, the tiller numebr of the RNAi transgenic plants was also significantly lower than that of the wild-type plants under low-phosphorus stress, and increased the decrease amplitude. This suggestd that TaWRKY74s are related to phosphorus response and can affect the tiller number of wheat. CONCLUSIONS: The results of this research showed that TaWRKY74s were key genes in wheat response to low phosphorus stress, which might regulate wheat tiller number through abscisic acid (ABA) and auxin signal transduction pathways. This research lays the foundation for further investigating the mechanism of TaWRKY74s in the low phosphorus environments and is significant for wheat stress resistance breeding.

MicroRNA-218-5p-Ddx41 axis restrains microglia-mediated neuroinflammation through downregulating type I interferon response in a mouse model of Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic (DA) neurons in the substantia nigra (SN). Microglia-mediated neuroinflammation has been largely considered one of main factors to the PD pathology. MicroRNA-218-5p (miR-218-5p) is a microRNA that plays a role in neurodevelopment and function, while its potential function in PD and neuroinflammation remains unclear. METHODS: We explore the involvement of miR-218-5p in the PD in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model. The miR-218-5p agomir used for overexpression was delivered into the substantia nigra (SN) by bilateral stereotaxic infusions. The loss of dopaminergic (DA) neurons and microglial inflammation in the SN was determined using Western blotting and immunofluorescence. Motor function was assessed using the rotarod test. RNA sequencing (RNA-seq) was performed to explore the pathways regulated by miR-218-5p. The target genes of miR-218-5p were predicted using TargetScan and confirmed using dual luciferase reporter assays. The effects of miR-218-5p on microglial inflammation and related pathways were verified in murine microglia-like BV2 cells. To stimulate BV2 cells, SH-SY5Y cells were treated with 1-methyl-4-phenylpyridinium (MPP+) and the conditioned media (CM) were collected. RESULTS: MiR-218-5p expression was reduced in both the SN of MPTP-induced mice and MPP+-treated BV2 cells. MiR-218-5p overexpression significantly alleviated MPTP-induced microglial inflammation, loss of DA neurons, and motor dysfunction. RNA sequence and gene set enrichment analysis showed that type I interferon (IFN-I) pathways were upregulated in MPTP-induced mice, while this upregulation was reversed by miR-218-5p overexpression. A luciferase reporter assay verified that Ddx41 was a target gene of miR-218-5p. In vitro, miR-218-5p overexpression or Ddx41 knockdown inhibited the IFN-I response and expression of inflammatory cytokines in BV2 cells stimulated with MPP+-CM. CONCLUSIONS: MiR-218-5p suppresses microglia-mediated neuroinflammation and preserves DA neurons via Ddx41/IFN-I. Hence, miR-218-5p-Ddx41 is a promising therapeutic target for PD.

Boosting Excited-State Energy Transfer by Anchoring Dipole Orientation in Binary Thermally Activated Delayed Fluorescence/J-Aggregate Assemblies.

Förster resonance energy transfer (FRET) has been widely applied in fluorescence imaging, sensing and so on, while developing useful strategy of boosting FRET efficiency becomes a key issue that limits the application. Except optimizing spectral properties, promoting orientation factor (κ2) has been well discussed but rarely utilized for boosting FRET. Herein, we constructed binary nano-assembling of two thermally activated delayed fluorescence (TADF) emitters (2CzPN and DMAC-DPS) with J-type aggregate of cyanine dye (C8S4) as doping films by taking advantage of their electrostatic interactions. Time-resolved spectroscopic measurements indicated that 2CzPN/Cy-J films exhibit an order of magnitude higher kFRET than DMAC-DPS/Cy-J films. Further quantitative analysing on kFRET and kDET indicated higher orientation factor (κ2) in 2CzPN/Cy-J films play a key role for achieving fast kFRET, which was subsequently confirmed by anisotropic measurements. Corresponding DFT/TDDFT calculation revealed strong "two-point" electrostatic anchoring in 2CzPN/Cy-J films that is responsible for highly orientated transitions. We provide a new strategy for boosting FRET in nano-assemblies, which might be inspired for designing FRET-based devices of sensing, imaging and information encryption.

Stellate ganglion block ameliorated central post-stroke pain with comorbid anxiety and depression through inhibiting HIF-1α/NLRP3 signaling following thalamic hemorrhagic stroke.

BACKGROUND: Central post-stroke pain (CPSP) is an intractable and disabling central neuropathic pain that severely affects patients' lives, well-being, and socialization abilities. However, CPSP has been poorly studied mechanistically and its treatment remains challenging. Here, we used a rat model of CPSP induced by thalamic hemorrhage to investigate its underlying mechanisms and the effect of stellate ganglion block (SGB) on CPSP and emotional comorbidities. METHODS: Thalamic hemorrhage was produced by injecting collagenase IV into the ventral-posterolateral nucleus (VPL) of the right thalamus. The up-and-down method with von Frey hairs was used to measure the mechanical allodynia. Behavioral tests were carried out to examine depressive and anxiety-like behaviors including the open field test (OFT), elevated plus maze test (EPMT), novelty-suppressed feeding test (NSFT), and forced swim test (FST). The peri-thalamic lesion tissues were collected for immunofluorescence, western blotting, and enzyme-linked immunosorbent assay (ELISA). Genetic knockdown of thalamic hypoxia-inducible factor-1α (HIF-1α) and NOD-like receptor thermal protein domain associated protein 3 (NLRP3) with microinjection of HIF-1α siRNA and NLRP3 siRNA into the VPL of thalamus were performed 3 days before collagenase injection into the same regions. Microinjection of lificiguat (YC-1) and MCC950 into the VPL of thalamus were administrated 30 min before the collagenase injection in order to inhibited HIF-1α and NLRP3 pharmacologically. Repetitive right SGB was performed daily for 5 days and laser speckle contrast imaging (LSCI) was conducted to examine cerebral blood flow. RESULTS: Thalamic hemorrhage caused persistent mechanical allodynia and anxiety- and depression-like behaviors. Accompanying the persistent mechanical allodynia, the expression of HIF-1α and NLRP3, as well as the activities of microglia and astrocytes in the peri-thalamic lesion sites, were significantly increased. Genetic knockdown of thalamic HIF-1α and NLRP3 significantly attenuated mechanical allodynia and anxiety- and depression-like behaviors following thalamic hemorrhage. Further studies revealed that intra-thalamic injection of YC-1, or MCC950 significantly suppressed the activation of microglia and astrocytes, the release of pro-inflammatory cytokines, the upregulation of malondialdehyde (MDA), and the downregulation of superoxide dismutase (SOD), as well as mechanical allodynia and anxiety- and depression-like behaviors following thalamic hemorrhage. In addition, repetitive ipsilateral SGB significantly restored the upregulated HIF-1α/NLRP3 signaling and the hyperactivated microglia and astrocytes following thalamic hemorrhage. The enhanced expression of pro-inflammatory cytokines and the oxidative stress in the peri-thalamic lesion sites were also reversed by SGB. Moreover, LSCI showed that repetitive SGB significantly increased cerebral blood flow following thalamic hemorrhage. Most strikingly, SGB not only prevented, but also reversed the development of mechanical allodynia and anxiety- and depression-like behaviors induced by thalamic hemorrhage. However, pharmacological activation of thalamic HIF-1α and NLRP3 with specific agonists significantly eliminated the therapeutic effects of SGB on mechanical allodynia and anxiety- and depression-like behaviors following thalamic hemorrhage. CONCLUSION: This study demonstrated for the first time that SGB could improve CPSP with comorbid anxiety and depression by increasing cerebral blood flow and inhibiting HIF-1α/NLRP3 inflammatory signaling.

α-Synuclein induces Th17 differentiation and impairs the function and stability of Tregs by promoting RORC transcription in Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons (DA) and the accumulation of Lewy body deposits composed of alpha-Synuclein (α-Syn), which act as antigenic epitopes to drive cytotoxic T-cell responses in PD. Increased T helper 17 (Th17) cells and dysfunctional regulatory T cells (Tregs) have been reported to be associated with the loss of DA in PD. However, the mechanism underlying the Th17/Treg imbalance remains unknown. METHODS: Here, we examined the percentage of Th17 cells, the percentage of Tregs and the α-Syn level and analysed their correlations in the peripheral blood of PD patients and in the substantia nigra pars compacta (SNpc) and spleen of MPTP-treated mice and A53 transgenic mice. We assessed the effect of α-Syn on the stability and function of Tregs and the differentiation of Th17 cells and evaluated the role of retinoid-related orphan nuclear receptor (RORγt) upregulation in α-Syn stimulation in vivo and in vitro. RESULTS: We found that the α-Syn level and severity of motor symptoms were positively correlated with the increase in Th17 cells and decrease in Tregs in PD patients. Moreover, α-Syn stimulation led to the loss of Forkhead box protein P3 (FOXP3) expression in Tregs, accompanied by the acquisition of IL-17A expression. Increased Th17 differentiation was detected upon α-Syn stimulation when naïve CD4+ T cells were cultured under Th17-polarizing conditions. Mechanistically, α-Syn promotes the transcription of RORC, encoding RORγt, in Tregs and Th17 cells, leading to increased Th17 differentiation and loss of Treg function. Intriguingly, the increase in Th17 cells, decrease in Tregs and apoptosis of DA were suppressed by a RORγt inhibitor (GSK805) in MPTP-treated mice. CONCLUSION: Together, our data suggest that α-Syn promotes the transcription of RORC in circulating CD4+ T cells, including Tregs and Th17 cells, to impair the stability of Tregs and promote the differentiation of Th17 cells in PD. Inhibition of RORγt attenuated the apoptosis of DA and alleviated the increase in Th17 cells and decrease in Tregs in PD.

Factors associated with negative conversion of viral RNA in hospitalized children infected with SARS-CoV-2 Omicron variant in Shanghai, China: a retrospective analysis.

OBJECTIVES: This study aimed to identify the related risk factors and potential predictors of SARS-CoV-2 RNA negative conversion by describing the dynamics of viral shedding in infected children admitted to two hospitals from Shanghai during the Omicron variant outbreak. METHODS: This retrospective cohort included laboratory-confirmed cases of SARS-CoV-2 infection from Shanghai between March 28 and May 31, 2022. Clinical characteristics, personal vaccination, and household vaccination rates were collected through electronic health records and telephone interviews. RESULTS: A total of 603 paediatric patients confirmed to have COVID-19 were included in this study. Both univariate and multivariate analyses were performed to filter independent factors for the duration to viral RNA negative conversion. Data on the redetection of SARS-CoV-2 in the patients after they showed negative results on the RT‒PCR test (intermittent negative status) were also analysed. The median duration of virus shedding was 12 (interquartile range, IQR: 10-14) days. The severity of clinical outcome, personal vaccination-2doses, household vaccination rates, and abnormal defecation were factors indecently affecting negative conversion of SARS-CoV-2 RNA, suggesting that patients who had abnormal defecation or with more severe conditions would have delayed virological clearance, while patients who previously had 2 doses of vaccination or had higher household vaccination rates would have accelerated virological clearance. Loss of appetite (odds ratio (OR): 5.343; 95% CI: 3.307-8.632) and abnormal defecation (OR: 2.840; 95% CI: 1.736-4.645) were significantly associated with intermittent negative status. CONCLUSION: These findings could provide clues for the early identification of paediatric patients with prolonged viral shedding and could enrich the evidence for the development of prevention and control strategies, especially vaccination policies for children and adolescents.

Trends in public interest in shopping and point-of-sales of JUUL and Puff Bar 2019-2021.

INTRODUCTION: We investigated public interest in shopping and point-of-sales (POS) of JUUL and Puff Bar products in the context of five regulatory, company sales policy and other events of interest that may have influenced the trajectory of these products during 2019-2021. METHODS: Outcome variables included relative search volume (RSV) from Google search queries indicative of shopping interest in and aggregate dollar sales from Nielsen POS for JUUL and Puff Bar in the USA from March 2019 to May 2021. Adjusted autoregressive integrated moving average assessed the observed and predicted trends and adjusted linear regression analysis measured the relative rate of change in the outcome variables for each time period of interest. RESULTS: After the Trump administration announced its plans to ban flavoured e-cigarettes and JUUL Labs, Inc.'s decided to suspend the sales of its sweet and fruity flavoured products, JUUL's shopping interest RSV and sales declined while Puff Bar's shopping interest RSV peaked, and its sales increased. From the period following FDA's announcement of its enforcement guidance policy on unauthorised flavoured cartridge-based e-cigarettes until May 2021, JUUL's shopping interest RSV and sales continued to decline. Puff Bar's shopping interest RSV increased, and its sales peaked until the House approved the flavoured e-cigarette ban bill. Puff Bar's sales steeply declined following suspension of its sales in February 2020. The decline, however, slowed after Puff Bar products were relaunched as 'synthetic nicotine' e-cigarettes. CONCLUSIONS: Puff Bar's unprecedented peak in the shopping interest and sales of Puff Bar warrants continued surveillance.

Association between cigarette sales in the USA and FDA's announcement of its intention to prohibit menthol as a characterising flavour in cigarettes.

INTRODUCTION: On 29 April 2021, the US Food and Drug Administration (FDA) announced its intention to prohibit menthol as a characterising flavour in cigarettes. METHODS: We assessed the changes in cigarette sales associated with the FDA's announcement using interrupted time series analysis based on monthly retail point-of-sale data on cigarettes from the NielsenIQ Local Trade Area (LTA) data from September 2019 to April 2022. Main outcome variables included LTA-level monthly menthol and non-menthol cigarette sales per 1000-persons. RESULTS: Monthly cigarette sales were declining before the FDA's announcement (menthol vs non-menthol: -1.68 (95% CI -1.92, -1.45) vs -3.14 (95% CI -3.33, -2.96) packs per 1000-persons). Monthly menthol cigarette sales increased immediately in May 2021 after the FDA's announcement by 6.44 packs per 1000-persons (95% CI 3.83, 9.05). Analysis stratified by LTA-level racial/ethnic compositions showed that LTAs with a relatively higher proportion of non-Hispanic Black population (>8.94%) experienced higher spike in menthol cigarette sales in May 2021 immediately after the announcement and higher post-announcement 12-month menthol cigarette sales than expected. CONCLUSIONS: Areas with a relatively higher proportion of non-Hispanic Black population are potentially at risk of experiencing increased burden of menthol cigarette consumption. Targeted community level cessation support in non-Hispanic Black majority areas may help mitigate the growing burden of menthol cigarette smoking and improve health equity. The findings of this study also suggest that FDA's prompt finalisation and enforcement of such ban may help avoid extending the increased burden of menthol cigarette consumptions in non-Hispanic Black majority areas.

Association of nicotine replacement therapy product sales with menthol cigarette sales restriction in Massachusetts.

BACKGROUND: Massachusetts was the first to implement a state-wide menthol cigarette sales restriction in the USA. Following its implementation in June 2020, evidence showed declines in cigarette sales in Massachusetts; however, changes in nicotine replacement therapy (NRT) product sales are unknown. METHODS: This cohort study analysed NRT products sold by US-based retailers available in 26 states from the Nielsen Retail Scanner Data. Outcomes were state-level 4-week aggregate sales of gum, lozenge and patch NRT products converted into pieces per 1000 adults (aged ≥18 years) who smoke cigarettes based on smoking rates from the Behavioral Risk Factor Surveillance System and corresponding population from the US Census Bureau. We used a difference-in-differences method to compare changes in NRT product sales in Massachusetts before (1 January 2017 to 13 June 2020) and after (14 June 2020 to 4 December 2021) the policy with sales in 25 states. RESULTS: The analysis included 1664 observations for each NRT product, with 1170 from before and 494 from after the policy change. The 4-week NRT product sales per 1000 adults who smoke cigarettes in Massachusetts compared with the comparison states increased for gums by 643.11 (95% CI 365.33 to 920.89; p<0.001) pieces or 12.9% and for lozenges by 436.97 (95% CI 292.88 to 581.06; p<0.001) pieces or 17.9% but no statistically significant change in patches after implementing the policy. CONCLUSION: The increases in sales of gum and lozenge NRT products in Massachusetts after implementing the policy suggest that a nationwide ban on menthol cigarettes can increase NRT product use; therefore, interventions are needed to strengthen cessation support for adults who smoke cigarettes but intend to quit.

Delta computed tomography radiomics features-based nomogram predicts long-term efficacy after neoadjuvant chemotherapy in advanced gastric cancer.

BACKGROUND AND OBJECTIVE: No effective preoperative tool is available for predicting the prognosis of advanced gastric cancer (AGC) treated by neoadjuvant chemotherapy (NAC). We aimed to explore the association between change values ("delta") in the radiomic signatures of computed tomography (CT) (delCT-RS) before and after NAC for AGC and overall survival(OS). METHODS AND DESIGN: A total of 132 AGC patients with AGC were studied as a training cohort in our center, and 45 patients from another center were used as an external validation set. A radiomic signatures-clinical-nomogram(RS-CN) was established using delCT-RS and preoperative clinical variables. The prediction performance of RS-CN was evaluated using the area under the receiver operating characteristic (ROC)curve (AUC values), time-dependent ROC, decision curve analysis(DCA) and C-index. RESULTS: Multivariable Cox regression analyses showed that delCT-RS, cT-stage, cN-stage, Lauren-type and the value of variation of carcinoma embryonic antigen (CEA) between NAC were independent risk factors for 3-year OS of AGC. In the training cohort, RS-CN had a good prediction performance for OS (C-Index 0.73) and AUC values were significantly better than those of delCT-RS, ypTNM-stage and tumor regression grade(TRG) (0.827 vs 0.704 vs 0.749 vs 0.571, p < 0.001). DCA and time-dependent ROC of RS-CN were better than those of ypTNM stage, TRG grade and delCT-RS. The prediction performance of the validation set was equivalent to that of the training set. The cut-off (177.2) of RS-CN score was obtained from X-Tile software, a score of > 177.2 was defined as high-risk group(HRG), and scores of ≤ 177.2 were defined as the low-risk group(LRG). The 3-year OS and disease free survival(DFS) of patients in the LRG were significantly better than those in the HRG. Adjuvant chemotherapy(AC) can only significantly improve the 3-year OS and DFS of the LRG. (p < 0.05). CONCLUSIONS: Our nomogram based on delCT-RS has good prediction of prognosis before surgery and helps identify patients that are most likely to benefit from AC. It works well in precise and individualised NAC in AGC.

Enhanced vitamin K2 production by engineered Bacillus subtilis during leakage fermentation.

Menaquinone-7 (MK-7), a valuable member of the vitamin K2 series, is an essential nutrient for humans. It is used for treating coagulation disorders, and osteoporosis, promoting liver function recovery, and preventing cardiovascular diseases. In this study, to further improve the metabolic synthesis of MK-7 by the mutant strain, the effect of surfactants on the metabolic synthesis of MK-7 by the mutant strain Bacillus subtilis 168 KO-SinR (BS168 KO-SinR) was analyzed. The scanning electron microscopy and flow cytometry results showed that the addition of surfactants changed the permeability of the cell membrane of the mutant strain and the structural components of the biofilm. When 0.7% Tween-80 was added into the medium, the extracellular and intracellular synthesis of MK-7 reached 28.8 mg/L and 59.2 mg/L, respectively, increasing the total synthesis of MK-7 by 80.3%. Quantitative real-time PCR showed that the addition of surfactant significantly increased the expression level of MK-7 synthesis-related genes, and the electron microscopy results showed that the addition of surfactant changed the permeability of the cell membrane. The research results of this paper can serve as a reference for the industrial development of MK-7 prepared by fermentation.

Advances in regulating vitamin K2 production through metabolic engineering strategies.

Vitamin K2 (menaquinone, VK2, MK) is an essential lipid-soluble vitamin that plays critical roles in inhibiting cell ferroptosis, improving blood clotting, and preventing osteoporosis. The increased global demand for VK2 has inspired interest in novel production strategies. In this review, various novel metabolic regulation strategies, including static and dynamic metabolic regulation, are summarized and discussed. Furthermore, the advantages and disadvantages of both strategies are analyzed in-depth to highlight the bottlenecks facing microbial VK2 production on an industrial scale. Finally, advanced metabolic engineering biotechnology for future microbial VK2 production will also be discussed. In summary, this review provides in-depth information and offers an outlook on metabolic engineering strategies for VK2 production.

Upregulated hexokinase 2 expression induces the apoptosis of dopaminergic neurons by promoting lactate production in Parkinson's disease.

Parkinson's disease (PD) is characterized by impaired mitochondrial function and decreased ATP levels. Aerobic glycolysis and lactate production have been shown to be upregulated in dopaminergic neurons to sustain ATP levels, but the effect of upregulated glycolysis on dopaminergic neurons remains unknown. Since lactate promotes apoptosis and α-synuclein accumulation in neurons, we hypothesized that the lactate produced upon upregulated glycolysis is involved in the apoptosis of dopaminergic neurons in PD. In this study, we examined the expression of hexokinase 2 (HK2) and lactate dehydrogenase (LDH), the key enzymes in glycolysis, and lactate levels in the substantia nigra pars compacta (SNpc) of a MPTP-induced mouse model of PD and in MPP+-treated SH-SY5Y cells. We found that the expression of HK2 and LDHA and the lactate levels were markedly increased in the SNpc of MPTP-treated mice and in MPP+-treated SH-SY5Y cells. Exogenous lactate treatment led to the apoptosis of SH-SY5Y cells. Intriguingly, lactate production and the apoptosis of dopaminergic neurons were suppressed by the application of 3-bromopyruvic acid (3-Brpa), a HK2 inhibitor, or siRNA both in vivo and in vitro. 3-Brpa treatment markedly improved the motor behaviour of MPTP-treated mice in pole test and rotarod test. Mechanistically, lactate increases the activity of adenosine monophosphate-activated protein kinase (AMPK) and suppresses the phosphorylation of serine/threonine kinase 1 (Akt) and mammalian target of rapamycin (mTOR). Together, our data suggest that upregulated HK2 and LDHA and increased lactate levels prompt the apoptosis of dopaminergic neurons in PD. Inhibition of HK2 expression attenuated the apoptosis of dopaminergic neurons by downregulating lactate production and AMPK/Akt/mTOR pathway in PD.

The Chinese Parkinson's Disease Registry (CPDR): Study Design and Baseline Patient Characteristics.

BACKGROUND: There is a lack of large multicenter Parkinson's disease (PD) cohort studies and limited data on the natural history of PD in China. OBJECTIVES: The objective of this study was to launch the Chinese Parkinson's Disease Registry (CPDR) and to report its protocol, cross-sectional baseline data, and prospects for a comprehensive observational, longitudinal, multicenter study. METHODS: The CPDR recruited PD patients from 19 clinical sites across China between January 2018 and December 2020. Clinical data were collected prospectively using at least 17 core assessment scales. Patients were followed up for clinical outcomes through face-to-face interviews biennially. RESULTS: We launched the CPDR in China based on the Parkinson's Disease & Movement Disorders Multicenter Database and Collaborative Network (PD-MDCNC). A total of 3148 PD patients were enrolled comprising 1623 men (51.6%) and 1525 women (48.4%). The proportions of early-onset PD (EOPD, age at onset ≤50 years) and late-onset PD (LOPD) were 897 (28.5%) and 2251 (71.5%), respectively. Stratification by age at onset showed that EOPD manifested milder motor and nonmotor phenotypes and was related to increased probability of dyskinesia. Comparison across genders suggested a slightly older average age at PD onset, milder motor symptoms, and a higher rate of developing levodopa-induced dyskinesias in women. CONCLUSIONS: The CPDR is one of the largest multicenter, observational, longitudinal, and natural history studies of PD in China. It offers an opportunity to expand the understanding of clinical features, genetic, imaging, and biological markers of PD progression. © 2022 International Parkinson and Movement Disorder Society.

Tobacco 21 adoption decreased sales of cigarette brands purchased by young people: a translation of population health survey data to gain insight into market data for policy analysis.

INTRODUCTION: Policies raising the minimum age of sale of tobacco products to 21 (T21) proliferated at state and local levels across the USA before a federal policy was adopted. Evidence of the effectiveness of these policies is building and lags implementation. This study exploits demographic patterns of cigarette brand purchasing to evaluate the effectiveness of T21. METHODS: To capture the effect of T21 implementation on cigarette sales, we used universal product code-level data from Nielsen Scantrack data covering January 2015 to October 2019. We used the 2015 to 2018 National Survey on Drug Use and Health to identify cigarette brands where smokers under 21 comprised a disproportionately high (young) and low (old) share of consumption. We fit fixed-effects linear regressions in Nielsen designated market areas to test if sales of young or old cigarette brands were changed by T21. Unadjusted models controlled for time and T21 implementation date. Adjusted models controlled for price, seasonality and unemployment. A permutation test of 5000 randomised placebo T21 policies were fit to determine how well the true date of implementation fit sales data stratified by brand group. RESULTS: Sales of disproportionately young brands declined after T21 implementation. T21 policy implementation dates fit disproportionately young brand sales trends better than 99% of adjusted randomised placebo models. T21 implementation fit disproportionately old brand sales trends better than just 1% of adjusted randomised placebo models. CONCLUSION: This study adds compelling empirical evidence that T21 decreased purchases of the cigarette brands consumed disproportionately by young people, the policy's target demographic.

Effect of Cerebral Microbleeds on Cognitive Function and Quality of Life in Parkinson Disease.

BACKGROUND This study aimed to investigate the risk factors and patterns of cerebral microbleeds (CMBs) in Parkinson disease (PD) and the impact of CMBs on cognitive function and quality of life (QoL). MATERIAL AND METHODS Patients with PD that underwent susceptibility-weighted imaging were recruited and divided into CMB-free, lobar-CMB, deep-CMB, and mixed-CMB groups according to CMB location. Motor function (MDS-UPDRS III), cognitive abilities (MoCA, MMSE), and QoL (PDQ-39) were compared among groups. The risk factors for CMBs in patients with PD and the association between CMBs and cognition and QoL were analyzed using multivariable logistic regression models and linear regression models. RESULTS Among the 209 patients with PD, 42 (20.1%) had CMBs. Lobar, deep, and mixed CMBs were observed in 15 (35.7%), 17 (40.5%), and 10 (23.8%) patients, respectively. A higher frequency of hypertension was independently associated with deep CMBs (odds ratio [OR]=4.379, 95% CI: 1.405-13.643, P=0.011). The deep-CMB and mixed-CMB groups had lower MoCA scores and MMSE scores than the CMB-free group, especially in domains of naming, attention, and orientation (P<0.05). Additionally, the presence of CMBs was associated with lower MMSE (R²=0.140, ß=-0.301, P<0.001) and MoCA (R²=0.104, ß=-0.289, P<0.001) and higher PDQ-39 (R²=0.052, ß=0.227, P<0.05) scores, while the association between CMBs and PDQ-39 disappeared after adjustment of MMSE or MoCA as a covariate. CONCLUSIONS The results suggest that hypertension was associated with the occurrence of deep CMBs. Comorbidity with CMBs may impair cognitive function and indirectly reduce the QoL in patients with PD.

Comparison of the lesion formation and safety in ex vivo porcine heart study: Using ThermoCool SmartTouch and ThermoCool SmartTouch-SF catheters.

BACKGROUND: The study was performed to compare the efficacy and safety during radiofrequency ablation (RFA) using ThermoCool SmartTouch (ST) and ThermoCool SmartTouch-SF (STSF) catheters in the porcine heart. METHODS AND RESULTS: RFA was performed on the porcine myocardium by using two irrigated ablation catheters. Three groups were divided based on the different contact forces (CFs): low contact force (LCF) (1-3 g), medium contact force (MCF) (5-10 g), and high contact force (HCF) (15-20 g). In each group, RFA was delivered at four power settings of 30, 40, 50, 60 W. At each power, RFA was applied to reach the target ablation index (AI) of 350, 450, and 500. Altogether, 360 RF lesions were created by using 72 ablation conditions. AI value was positively correlated with lesion size using ST and STSF catheters. At a fixed power, lesion dimensions significantly smaller in the LCF group, whereas did not differ between MCF and HCF groups. Furthermore, at a fixed CF, lesion dimensions increased with power set at 40 W compared with 30 W but decreased with high-power RF energy (50 and 60 W). Although the average lesion surface diameter and the maximum diameter was increased using the STSF catheter, there were no significant differences in LV between the two catheters. The steam pop provoked more frequently using ST catheter and showed a negative correlation with CF and positive correlation with high-power energy. CONCLUSION: The STSF catheter is safer and equally effective in lesion formation compared with the ST catheter. LV was increased along with the early increase of CF and power, whereas a further increase of CF and power significantly reduces the lesion size.

Continuous-Variable Assisted Thermal Quantum Simulation.

Simulation of a quantum many-body system at finite temperatures is crucially important but quite challenging. Here we present an experimentally feasible quantum algorithm assisted with continuous variable for simulating quantum systems at finite temperatures. Our algorithm has a time complexity scaling polynomially with the inverse temperature and the desired accuracy. We demonstrate the quantum algorithm by simulating a finite temperature phase diagram of the quantum Ising and Kitaev models. It is found that the important crossover phase diagram of the Kitaev ring can be accurately simulated by a quantum computer with only a few qubits and thus the algorithm may be implementable on current quantum processors. We further propose a protocol with superconducting or trapped ion quantum computers.