Sports data analysis and prediction are essential for gaining a competitive advantage in today’s sports. Artificial Neural Networks (ANNs) have shown promising outcomes in several disciplines, ...including sports analytics. Sports data is dynamic and complex, making it difficult for standard ANNs to identify minute patterns in it. We introduce a new Puzzle-Optimized Artificial Neural Network (PO-ANN) in this work, which is intended for sports data processing and prediction. The PO-ANN is optimized using a puzzle-inspired method to enhance the network’s ability to identify and comprehend complex patterns in the data. The technique constantly modifies the weights and network topology, enabling the model to better react to the shifting dynamics of sports competitions. The Indian Premier League provided the dataset, which consists of 950 matches and 20 variables (IPL). We implemented our proposed PO-ANN and forecast accuracy in sports data analysis and prediction using Python. We performed a comparison analysis between our suggested PO-ANN approach and other existing methods, using numerous metrics, including MSE, MAE, and MAPE. The suggested POANN technique produced better outcomes than the previous approaches.
Cancer therapy has traditionally focused on eliminating fast-growing populations of cells. Yet, an increasing body of evidence suggests that small subpopulations of cancer cells can evade strong ...selective drug pressure by entering a 'persister' state of negligible growth. This drug-tolerant state has been hypothesized to be part of an initial strategy towards eventual acquisition of bona fide drug-resistance mechanisms. However, the diversity of drug-resistance mechanisms that can expand from a persister bottleneck is unknown. Here we compare persister-derived, erlotinib-resistant colonies that arose from a single, EGFR-addicted lung cancer cell. We find, using a combination of large-scale drug screening and whole-exome sequencing, that our erlotinib-resistant colonies acquired diverse resistance mechanisms, including the most commonly observed clinical resistance mechanisms. Thus, the drug-tolerant persister state does not limit--and may even provide a latent reservoir of cells for--the emergence of heterogeneous drug-resistance mechanisms.
The pervasive influence of secreted Wnt signaling proteins in tissue homeostasis and tumorigenesis has galvanized efforts to identify small molecules that target Wnt-mediated cellular responses. By ...screening a diverse synthetic chemical library, we have discovered two new classes of small molecules that disrupt Wnt pathway responses; whereas one class inhibits the activity of Porcupine, a membrane-bound acyltransferase that is essential to the production of Wnt proteins, the other abrogates destruction of Axin proteins, which are suppressors of Wnt/beta-catenin pathway activity. With these small molecules, we establish a chemical genetic approach for studying Wnt pathway responses and stem cell function in adult tissue. We achieve transient, reversible suppression of Wnt/beta-catenin pathway response in vivo, and we establish a mechanism-based approach to target cancerous cell growth. The signal transduction mechanisms shown here to be chemically tractable additionally contribute to Wnt-independent signal transduction pathways and thus could be broadly exploited for chemical genetics and therapeutic goals.
Opioid withdrawal generates extremely unpleasant physical symptoms and negative affective states. A rapid relief of opioid withdrawal-induced anxiety has obvious clinical relevance but has been ...rarely reported. We have shown that injection of ketamine metabolite (2R,6R)-hydroxynorketamine (HNK) leads to a rapid alleviation of anxiety-like behaviors in male mice undergoing chronic morphine withdrawal. Here we investigated the contribution of nucleus accumbens shell (sNAc) parvalbumin (PV)-neurons to this process. Chronic morphine withdrawal was associated with higher intrinsic excitability of sNAc PV-neurons via reduced voltage-dependent potassium currents. Chemogenetic inhibition of sNAc PV-neurons reversed the enhanced excitability of PV-neurons and anxiety-like behaviors in these morphine withdrawal male mice, while activation of sNAc PV-neurons induced anxiety-like behaviors in naive male mice. (2R,6R)-HNK reversed the altered potassium currents and intrinsic excitability of sNAc PV-neurons. Our findings demonstrate an important contribution of sNAc PV-neurons to modulating morphine withdrawal-induced anxiety-like behaviors and rapid relief of anxiety-like behaviors by (2R,6R)-HNK, this newly identified target may have therapeutic potentials in treating opioid addiction and anxiety disorders.
•sNAc PV-neuron excitability is higher in mice undergoing morphine withdrawal.•Inhibiting sNAc PV-neurons improves morphine withdrawal-induced anxiety-like behaviors.•Activating sNAc PV-neurons elicits anxiety-like behaviors in naïve mice.•(2R,6R)-HNK alleviates morphine withdrawal-induced anxiety-like behaviors in mice.•(2R,6R)-HNK increases K+ currents and reduces excitability of sNAc PV-neurons.
•The A allele of ADRA1A rs1048101 is associated with a shorter duration transition from first use to addiction.•Individuals carrying the C allele of ADRA1A rs3808585 are more susceptible to memory ...impairment after heroin use disorder.•Subjects with G allele of COMT rs769224 are more likely to take a higher dose of heroin every day.
Heroin use disorder is a chronic relapsing brain disease containing multiple phenotypes. These phenotypes vary among heroin users and might be influenced by genetic factors. Single-nucleotide polymorphisms (SNPs) of catechol-O-methyltransferase (COMT) and alpha-1-adrenergic receptor (ADRA1A) genes are associated with heroin use disorder. However, it has not been clarified which phenotypes of heroin use disorder are related to these genes. To address this question, we recruited 801 unrelated heroin users and divided them into different subgroups according to four important phenotypes of heroin use disorder. Then 7 SNPs in the functional region of these genes were systematically screened and genotyped using a SNaPshot assay. We found that the A allele of ADRA1A rs1048101 was associated with a shorter duration of transition from first use to addiction. Subjects with the C allele of ADRA1A rs3808585 were more susceptible to memory impairment after heroin use disorder. Subjects with the G allele of COMT rs769224 were more likely to take a higher dose of heroin every day. Our study confirmed the association between polymorphisms of COMT and ADRA1A with those specific phenotypes of heroin use disorder, which will be instructive for the precise treatment of the disease.
Tumorous stem mustard is a characteristic vegetable in Southeast Asia, as are its sprouts. The purple color of the purple variety ‘Zi Ying’ leaves is because of anthocyanin accumulation. The ways in ...which this anthocyanin accumulation is affected by the environment and hormones has remained unclear. Here, the impacts of sucrose, methyl jasmonate (MeJA), light, and dark on the growth and anthocyanin production of ‘Zi Ying’ sprouts were explored. The results showed that anthocyanins can be enhanced by sucrose in sprouts under light condition, and MeJA can promote anthocyanins production under light and dark conditions in sprouts. The anthocyanin biosynthetic regulatory genes BjTT8, BjMYB1, BjMYB2 and BjMYB4, and the EBGs and LBGs were upregulated under light conditions, while BjTT8, BjMYB1, and BjMYB2 and anthocyanin biosynthetic genes BjF3H and BjF3′H were upregulated under DM condition. These results indicate that sucrose and methyl jasmonate can stimulate the expression of genes encoding components of the MBW complex (MYB, bHLH, and WD40) and that they transcriptional activated the expression of LBGs and EBGs to promote the accumulation of anthocyanins in ‘Zi Ying’ sprouts. Our findings enhance our understanding of anthocyanin accumulation regulated by sucrose and MeJA in ‘Zi Ying’, which will help growers to produce anthocyanin-rich foods with benefits to human health.
A shot in the arm for damaged tissue
Tissue damage can be caused by injury, disease, and even certain medical treatments. There is great interest in identifying drugs that accelerate tissue ...regeneration and recovery, especially drugs that might benefit multiple organ systems. Zhang
et al.
describe a compound with this desired activity, at least in mice (see the Perspective by FitzGerald). SW033291 promotes recovery of the hematopoietic system after bone marrow transplantation, prevents the development of ulcerative colitis in the intestine, and accelerates liver regeneration after hepatic surgery. It acts by inhibiting an enzyme that degrades prostaglandins, lipid signaling molecules that have been implicated in tissue stem cell maintenance.
Science
, this issue
10.1126/science.aaa2340
; see also p.
1208
A compound that inhibits prostaglandin degradation enhances tissue regeneration in multiple organs in mice.
Also see Perspective by
FitzGerald
INTRODUCTION
Agents that promote tissue regeneration could be beneficial in a variety of clinical settings, such as stimulating recovery of the hematopoietic system after bone marrow transplantation. Prostaglandin PGE2, a lipid signaling molecule that supports expansion of several types of tissue stem cells, is a candidate therapeutic target for promoting tissue regeneration in vivo. To date, therapeutic interventions have largely focused on targeting two PGE2 biosynthetic enzymes, cyclooxygenase-1 and cyclooxygenase-2 (COX-1 and COX-2), with the aim of reducing PGE2 production. In this study, we take the converse approach: We examine the role of a prostaglandin-degrading enzyme, 15-hydroxyprostaglandin dehydrogenase (15-PGDH), as a negative regulator of tissue repair, and we explore whether inhibition of this enzyme can potentiate tissue regeneration in mouse models.
RATIONALE
We used 15-PGDH knockout mice to elucidate the role of 15-PGDH in regulating tissue levels of PGE2 and tissue repair capacity in multiple organs. We then developed SW033291, a potent small-molecule inhibitor of 15-PGDH with activity in vivo. We used SW033291 to investigate the therapeutic potential of 15-PGDH inhibitors in tissue regeneration and to identify a 15-PGDH–regulated hematopoietic pathway within the bone marrow niche.
RESULTS
We found that in comparison with wild-type mice, 15-PGDH–deficient mice display a twofold increase in PGE2 levels across multiple tissues—including bone marrow, colon, and liver—and that they show increased fitness of these tissues in response to damage. The mutant mice also show enhanced hematopoietic capacity, with increased neutrophils, increased bone marrow SKL (Sca-1
+
C-kit
+
Lin
−
) cells (enriched for stem cells), and greater capacity to generate erythroid and myeloid colonies in cell culture. The 15-PGDH–deficient mice respond to colon injury from dextran sulfate sodium (DSS) with a twofold increase in cell proliferation in colon crypts, which confers resistance to DSS-induced colitis. The mutant mice also respond to partial hepatectomy with a greater than twofold increase in hepatocyte proliferation, which leads to accelerated and more extensive liver regeneration. SW033291, a potent small-molecule inhibitor of 15-PGDH (inhibitor dissociation constant
K
i
~0.1 nM), recapitulates in mice the phenotypes of 15-PGDH gene knockout, inducing increased hematopoiesis, resistance to DSS colitis, and more rapid liver regeneration after partial hepatectomy. Moreover, SW033291-treated mice show a 6-day-faster reconstitution of hematopoiesis after bone marrow transplantation, with accelerated recovery of neutrophils, platelets, and erythrocytes, and greater recovery of bone marrow SKL cells. This effect is mediated by bone marrow CD45
–
cells, which respond to increased PGE2 with a fourfold increase in production of CXCL12 and SCF, two cytokines that play key roles in hematopoietic stem cell homing and maintenance.
CONCLUSIONS
Studying mouse models, we have shown that 15-PGDH negatively regulates tissue regeneration and repair in the bone marrow, colon, and liver. Of most direct utility, our observations identify 15-PGDH as a therapeutic target and provide a chemical formulation, SW033291, that is an active 15-PGDH inhibitor in vivo and that potentiates repair in multiple tissues. SW033291 or related compounds may merit clinical investigation as a strategy to accelerate recovery after bone marrow transplantation and other tissue injuries.
Inhibiting 15-PGDH accelerates tissue repair.
(
A
) The enzyme 15-PGDH degrades and negatively regulates PGE2. (
B
) SW033291 inhibits 15-PGDH, increases tissue levels of PGE2, and induces CXCL12 and SCF expression from CD45
–
bone marrow cells. This in turn accelerates homing of transplanted hematopoietic stem cells (HSC), generation of mature blood elements, and post-transplant recovery of normal blood counts. Inhibiting 15-PGDH similarly stimulates cell proliferation after injury to colon or liver, accelerating repair of these tissues.
Agents that promote tissue regeneration could be beneficial in a variety of clinical settings, such as stimulating recovery of the hematopoietic system after bone marrow transplantation. Prostaglandin PGE2, a lipid signaling molecule that supports expansion of several types of tissue stem cells, is a candidate therapeutic target for promoting tissue regeneration in vivo. Here, we show that inhibition of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), a prostaglandin-degrading enzyme, potentiates tissue regeneration in multiple organs in mice. In a chemical screen, we identify a small-molecule inhibitor of 15-PGDH (SW033291) that increases prostaglandin PGE2 levels in bone marrow and other tissues. SW033291 accelerates hematopoietic recovery in mice receiving a bone marrow transplant. The same compound also promotes tissue regeneration in mouse models of colon and liver injury. Tissues from 15-PGDH knockout mice demonstrate similar increased regenerative capacity. Thus, 15-PGDH inhibition may be a valuable therapeutic strategy for tissue regeneration in diverse clinical contexts.
Although most people living with HIV (PLWH) receiving antiretroviral therapy (ART) achieve continuous viral suppression, some show detectable HIV RNA as low-level viremia (LLV) (50-999 copies/mL). ...Drug resistance mutations (DRMs) in PLWH with LLV is of particular concern as which may lead to treatment failure. In this study, we investigated the prevalence of LLV and LLV-associated DRMs in PLWH in Zhengzhou City, China. Of 3616 ART-experienced PLWH in a long-term follow-up cohort from Jan 2022 to Aug 2023, 120 were identified as having LLV. Of these PLWH with LLV, we obtained partial pol and integrase sequences from 104 (70 from HIV-1 RNA and 34 from proviral DNA) individuals. DRMs were identified in 44 individuals. Subtyping analysis indicated that the top three subtypes were B (48.08%, 50/104), CRF07_BC (31.73%, 33/104), and CRF01_AE (15.38%, 16/104). The proportions of nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), and integrase strand transfer inhibitors (INSTIs) associated DRMs were 23.83% (24/104), 35.58% (37/104), 5.77% (6/104), and 3.85% (4/104), respectively, which contributed to an overall prevalence of 42.31% (44/104). When analyzed by individual DRMs, the most common mutation(s) were V184 (18.27%, 19/104), followed by V179 (11.54%, 12/104), K103 (9.62%, 10/104), Y181 (9.62%, 10/104), M41 (7.69%, 8/104), and K65R (7.69%, 8/104). The prevalence of DRMs in ART-experienced PLWH with LLV is high in Zhengzhou City and continuous surveillance can facilitate early intervention and provision of effective treatment.
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•The cancer cell membrane (CM) coated calcium carbonate (CC) nanoparticles was successfully constructed.•The multidrug resistant was reversed by miR-451.•Combination of miR-451 and ...Adriamycin was proposed to treat bladder cancer.
The outcome of current cancer therapy is usually impeded by complicated extracellular and intracellular barriers. Most importantly, untargeted distribution and multidrug resistance (MDR) are considered as two important difficulties responsible for the poor performance of many currently available drug delivery systems (DDS). As a result, in our study, we developed a cancer cell membrane (CM) coated calcium carbonate (CC) nanoparticles to co-delivery miR-451 with adriamycin (Adr) to address the dilemma occurred in the therapy of bladder cancer (MCC/R-A). The homologous CCM from MDR bladder cancer cells (BIU-87/Adr) was employed to increase targeted retention of DDS within the tumor tissue and to bypass the extracellular barriers. Moreover, the MDR of cancer cells was conquered through downregulation of P-gp expression using miR-451 since it was confirmed by previous reports that miR-451 could significantly downregulate the level of P-gp in MDR cells, which in turn elevated the cellular drug retention in BIU-87/Adr. Our in vitro and in vivo experiments have revealed that MCC/R-A showed a greatly enhanced therapeutic effect on BIU-87/Adr, which was superior than applying miR-451 or Adr alone. The preferable effect of MCC/R-A on conquering the MDR in bladder cancer provides a novel alternative for effective chemotherapy of MDR cancers.
This paper proposes a novel coupling structure wireless power transfer (WPT) technology for improving the charging and recharging efficiency between electric vehicles (EVs) in the case that the ...transmitting and receiving coils are not exactly aligned. During the process of wireless power transmission, if the relative position of the coils located on each objective is randomly changed, a change in the mutual inductance occurs, which critically leads to fluctuation in the WPT system output. In order to improve the tolerance of the EV WPT system, considering coupling structure misalignment and the deflection caused by relative location changes, a double-layer coupling structure with solenoid pads and double-D pads (SP-DDP coupling structure) is designed for deployment on the side of EVs. Then, the coupling structure is developed through parametrized optimization. Finally, the established coupling structure is evaluated through simulations and an experiment using a prototype, the results of which demonstrate that the proposed coupling structure can achieve good anti-misalignment and anti-deflection performance, realizing a system efficiency of 92.65% and an output power of 192.02 W for the designed EV WPT system.
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