Bruton’s tyrosine kinase inhibitors in primary central nervous system lymphoma:New hopes on the horizon

In this editorial,we comment on the article by Wang et al.This manuscript explores the potential synergistic effects of combining zanubrutinib,a novel oral inhibitor of Bruton’s tyrosine kinase,with high-dose methotrexate(HD-MTX)as a therapeutic intervention for primary central nervous system lymphoma(PCNSL).The study involves a retrospective analysis of 19 PCNSL patients,highlighting clinicopathological characteristics,treatment outcomes,and genomic biomarkers.The results indicate the combination’s good tolerance and strong antitumor activity,with an 84.2%overall response rate.The authors emphasize the potential of zanubrutinib to modulate key genomic features of PCNSL,particularly mutations in myeloid differentiation primary response 88 and cluster of differentiation 79B.Furthermore,the study investigates the role of circulating tumor DNA in cerebrospinal fluid for disease surveillance and treatment response monitoring.In essence,the study provides valuable insights into the potential of combining zanubrutinib with HD-MTX as a frontline therapeutic regimen for PCNSL.The findings underscore the importance of exploring alternative treatment modalities and monitoring genomic and liquid biopsy markers to optimize patient outcomes.While the findings suggest promise,the study’s limitations should be considered,and further research is needed to establish the clinical relevance of this therapeutic approach for PCNSL.

Generation-expansion planning with linearized primary frequency response constraints

As renewable energy resources increasingly penetrate the electric grid,the inertia capability of power systems has become a developmental bottleneck.Nevertheless,the importance of primary frequency response(PFR)when making generation-expansion plans has been largely ignored.In this paper,we propose an optimal generation-expansion planning framework for wind and thermal power plants that takes PFR into account.The model is based on the frequency equivalent model.It includes investment,startup/shutdown,and typical operating costs for both thermal and renewable generators.The linearization constraints of PFR are derived theoretically.Case studies based on the modified IEEE 39-bus system demonstrate the efficiency and effectiveness of the proposed method.Compared with methods that ignore PFR,the method proposed in this paper can effectively reduce the cost of the entire planning and operation cycle,improving the accommodation rate of renewable energy.

Regulatory Effects of AT1R-TRAF6-MAPKs Signaling on Proliferation of Intermittent Hypoxia-induced Human Umbilical Vein Endothelial Cells

Summary： Endothelial dysfunction induced by intermittent hypoxia （IH） participates in obstructive sleep apnea syndrome （OSAS）-associated cardiovascular disorders. Myeloid differentiation primary response 88 （MyD88） and tumor necrosis factor receptor-associated factor 6 （TRAF6） regulate nu- merous downstream adaptors like mitogen-activated protein kinases （MAPKs） and the subsequent oxidative stress and inflammatory responses. This study aimed to characterize the role of MyD88/TRAF6 in IH-treated cell function and its associated signaling. Human umbilical vein endo- thelial cells （HUVECs） were randomly exposed to IH or normoxia for 0, 2, 4 and 6 h. Western blot- ting was used to detect the expression pattern of target gene proteins [angiotensin 1 receptor （AT1R）, p-ERK1/2, p-p38MAPK, MyD88 and TRAF6], and the relationships among these target genes down-regulated by the corresponding inhibitors were studied. Finally, the influence of these target genes on proliferation of HUVECs was also assessed by EdU analysis. Protein levels of AT1R, TRAF6 and p-ERK1/2 were increased after IH exposure, with a slight rise in MyD88 and a dynamic change in p-p38MAPK. The down-regulation of TRAF6 by siRNA reduced ERK1/2 phosphorylation during IH without any effects on ATIR. Blockade of AT1R with valsartan decreased TRAF6 and p-ERK1/2 protein expression after IH exposure. ERK1/2 inhibition with PD98059 suppressed only AT1R expression. IH promoted HUVECs proliferation, which was significantly suppressed by the in- hibition of TRAF6, AT1R and ERK1/2. The findings demonstrate that TRAF6 regulates the prolifera- tion of HUVECs exposed to short-term IH by modulating cell signaling involving ERK1/2 down- stream of AT1R. Targeting the AT1R-TRAF6-p-ERK1/2 signaling pathway might be helpful in re- storing endothelial function.

CD4^＋ T-cell dependence of primary CD8^＋ T-cell response against vaccinia virus depends upon route of infection and viral dose

CD4^＋ T-cell help （CD4 help） plays a pivotal role in CD8^＋ T-cell responses against viral infections. However, the role in primary CD8^＋ T-cell responses remains controversial. We evaluated the effects of infection route and viral dose on primary CD8^＋ T-cell responses to vaccinia virus （VACV） in MHC class II^-/- mice. CD4 help deficiency diminished the generation of VACV-specific CD8^＋ T cells after intraperitoneal （i.p.） but not after intranasal （i.n.） infection. A large viral dose could not restore normal expansion of VACV-specific CD8^＋ T cells in i.p. infected MHC II-/- mice. In contrast, dependence on CD4 help was observed in i.n. infected MHC II-/- mice when a small viral dose was used. These data suggested that primary CD8~ T-cell responses are less dependent on CD4 help in i.n. infection compared to i.p. infection. Activated CD8~ T cells produced more I FN-y, TNF-a and granzyme B in i.n. infected mice than those in i.p. infected mice, regardless of CD4 help. IL-2 signaling via CD25 was not necessary to drive expansion of VACV-specific CD8~ T cells in i.n. infection, but it was crucial in i.p. infection. VACV-specific CD8^＋ T cells underwent increased apoptosis in the absence of CD4 help, but proliferated normally and had cytotoxic potential, regardless of infection route. Our results indicate that route of infection and viral dose are two determinants for CD4 help dependence, and intranasal infection induces more potent effector CD8^＋ T cells than i.D. infection.

A transceptor-channel complex couples nitrate sensing to calcium signaling in Ambidopsis

Nitrate-induced Ca^(2+) signaling is crucial for the primary nitrate response in plants.However,the molecular mechanism underlying the generation of the nitrate-specific calcium signature remains unknown.We report here that a cyclic nucleotide-gated channel(CNGC)protein,CNGC15,and the nitrate transceptor(NRT1.1)constitute a molecular switch that controls calcium influx depending on nitrate levels.The expression of CNGC15 is induced by nitrate,and its protein is localized at the plasma membrane after establishment of young seedlings.We found that disruption of CNGC15 results in the loss of the nitrate-induced Ca^(2+) signature(primary nitrate response)and retards root growth,reminiscent of the phenotype observed in the nrt1.1 mutant.We further showed that CNGC15 is an active Ca^(2+)-permeable channel that physically interacts with the NRT1.1 protein in the plasma membrane.Importantly,we discovered that CNGC15-NRT1.1 interaction silences the channel activity of the heterocomplex,which dissociates upon a rise in nitrate levels,leading to reactivation of the CNGC15 channel.The dynamic interactions between CNGC15 and NRT1.1 therefore control the channel activity and Ca^(2+) influx in a nitrate-dependent manner.Our study reveals a new nutrient-sensing mechanism that utilizes a nutrient transceptor-channel complex assembly to couple nutrient status to a specific Ca^(2+) signature.

Optimal generation mix for frequency response adequacy in future power system

Strict enforcement of government policies to integrate high generation share from renewable energy sources(RES)like wind and PV would create inevitable operational challenges for the utilities to deliver Frequency Response(FR)services.Uncertain RES generation characteristics would worsen the situation for SO,to detain initial frequency deviation following the largest generation outage.This necessitates investigation of optimal generator combination for securing PFR adequacy with simultaneous characterization of uncertainty.In this regard,this paper proposes a novel Modified Interval(MI)based optimal generation mix formulation for operation cost minimization and FR adequacy.RES uncertainty is characterised by forecasted upper and lower bound,while hourly ramp needs are based on the net load scenarios.Proposed model is assessed on one area IEEE reliability test system.Rate of change of frequency(ROCOF)and frequency deviation are considered as network security limits to obtain optimal generation mix.Results obtained provide,overall cost performance,PFR and optimal generation mix,without violating system security criteria.This model would certainly assist SO,to enhance system’s inertia and PFR adequacy at short-term system operations and could be extended for long-term planning framework.