In the observations, El Niño events initiated by a subtropical Pacific mechanism (SP-onset El Niños) show larger uncertainty in their decay evolution patterns than those initiated by a tropical Pacific mechanism. A 2,200-year simulation of Community Earth System Model reproduces this observed feature and its SP-onset El Niños are analyzed to understand the cause of the large uncertainty. Results show that the onset location of SP-onset El Niño, which interacts with the eastern edge of the western Pacific warm pool, is a key factor controlling its decay evolution. When the onset is located east (west) of 155°E, the event has a strong tendency to reverse (maintain) its phase, leading to cyclic (multiyear) evolution. These two onset locations respectively activate Indo-Pacific and tropical-subtropical Pacific interactions to give rise to the different evolution patterns. The findings offer a potential way to predict the evolution of SP-onset El Niños using their onset locations.

To understand the unique temporal evolution of the 2014–2016 multiyear El Niño event, which can be characterized as a successive and reintensified event preceded by a weak El Niño, this study examines similar events in a 2,200-yr simulation of Community Earth System Model, version 1. By contrasting multiyear El Niño events with single-year ones, we find that the succession characteristics of multiyear El Niño events are primarily caused by a negative North Pacific Oscillation (NPO) in the first-year winter via subtropical Pacific coupling processes. By contrasting reintensified multiyear El Niño events with lingering ones, we find that the reintensification characteristics are caused by a negative Indian Ocean Dipole (IOD) in the first-year fall via tropical interbasin coupling processes. The phase information of the preceding winter NPO and fall IOD together can be used to project the evolution characteristics of El Niño events, particularly the reintensified multiyear and transitional single-year events.

Capicua (CIC) is a highly conserved transcriptional repressor that is differentially regulated through mitogen-activated protein kinase (MAPK) signaling or genetic alteration across human cancer. CIC contributes to tumor progression and metastasis through direct transcriptional control of effector target genes. Recent findings indicate that CIC dysregulation is mechanistically linked and restricted to specific cancer subtypes, yet convergence on key downstream transcriptional nodes are critical for CIC-regulated oncogenesis across these cancers. In this review, we focus on how differential regulation of CIC through functional and genetic mechanisms contributes to subtype-specific cancer phenotypes and we propose new therapeutic strategies to effectively target CIC-altered cancers.

Previous studies have emphasized the significance of a strong El Niño preceding La Niña (LN) in the formation of multi-year LN events due to the slow recharge-discharge ocean heat content process. However, observational analyses from 1900 to 2022 reveal that the majority (64%) of multi-year LN events did not necessitate a preceding strong El Niño to generate their second LN, suggesting an overemphasis on traditional views. Instead, here we show that a negative phase of the North Pacific Meridional Mode (PMM) during spring, when the first LN begins to decay, activates the mechanism responsible for triggering another LN and producing a multi-year event. The westward extension of the first LNs cold anomalies, which interact directly with the eastern edge of the western Pacific warm pool, is highlighted as a crucial factor in the occurrence of a negative PMM. Additionally, the PMM mechanism can create a third LN, leading to triple-dip events.

Heat shock proteins (HSPs) are chaperones that catalyze the refolding of denatured proteins. In addition to their ability to prevent protein denaturation and aggregation, the HSPs have also been shown to modulate many signaling pathways. Among HSPs, the inducible 70 kDa HSP (HSP70) has especially been shown to improve neurological outcome in experimental models of brain ischemia and injury. HSP70 can modulate various aspects of the programmed cell death pathways and inflammation. This review will focus on potential mechanisms of the neuroprotective effects of HSP70 in stroke and brain trauma models. We also comment on potential ways in which HSP70 could be translated into clinical therapies.

Transcription factor fusions (TFFs) are present in ∼30% of soft-tissue sarcomas. TFFs are not readily "druggable" in a direct pharmacologic manner and thus have proven difficult to target in the clinic. A prime example is the CIC-DUX4 oncoprotein, which fuses Capicua (CIC) to the double homeobox 4 gene, DUX4. CIC-DUX4 sarcoma is a highly aggressive and lethal subtype of small round cell sarcoma found predominantly in adolescents and young adults. To identify new therapeutic targets in CIC-DUX4 sarcoma, we performed chromatin immunoprecipitation sequencing analysis using patient-derived CIC-DUX4 cells. We uncovered multiple CIC-DUX4 targets that negatively regulate MAPK-ERK signaling. Mechanistically, CIC-DUX4 transcriptionally up-regulates these negative regulators of MAPK to dampen ERK activity, leading to sustained CIC-DUX4 expression. Genetic and pharmacologic MAPK-ERK activation through DUSP6 inhibition leads to CIC-DUX4 degradation and apoptotic induction. Collectively, we reveal a mechanism-based approach to therapeutically degrade the CIC-DUX4 oncoprotein and provide a precision-based strategy to combat this lethal cancer.

Using observational data and model hindcasts produced by a coupled climate model, we examine the response of the East Asian winter monsoon (EAWM) to three types of El Niño: eastern Pacific (EP) and central Pacific I (CP-I) and II (CP-II) El Niños. The observational analysis shows that all three El Niño types weaken the EAWM with varying degrees of impact. The EP El Niño has the largest weakening effect, while the CP-II El Niño has the second largest, and the CP-I El Niño has the smallest. We find that diverse El Niño types impact the EAWM by altering the responses of two anomalous anticyclones during El Niño mature winter: the western North Pacific anticyclone (WNPAC) and Kuroshio anticyclone (KAC). The WNPAC responses are controlled by the Gill response and Indian Ocean warming processes that both respond to the eastern-to-central tropical Pacific precipitation anomalies. The KAC responses are controlled by a poleward wave propagation responding to the northwestern tropical Pacific precipitation anomalies. We find that the model hindcasts significantly underestimate the weakening effect during the EP and CP-II El Niños. These underestimations are related to a model deficiency in which it produces a too-weak WNPAC response during the EP El Niño and completely misses the KAC response during both types of El Niño. The too-weak WNPAC response is caused by the model deficiency of simulating too-weak eastern-to-central tropical Pacific precipitation anomalies. The lack of KAC response arises from the unrealistic response of the model’s extratropical atmosphere to the northwestern tropical Pacific precipitation anomalies.

Inactivation of Capicua (CIC) or upregulation of yes-associated protein 1, YAP1, leads to broad RAS-RAF-MEK-ERK inhibitor resistance and tumor progression in multiple human cancers. Despite these shared malignant phenotypes, it remains unclear whether CIC and YAP1 are mechanistically linked. Here, we show that the ERK-regulated transcription factor CIC can directly repress YAP1 expression through non-consensus GGAAGGAA DNA-binding motifs in a proximal YAP1 regulatory element. Through binding at GGAA repeats, CIC regulates YAP1 transcriptional output in both normal and human cancer cells. Silencing YAP1 in CIC-deficient cells restores MAPK inhibitor sensitivity and suppresses tumor growth. Thus, we uncover a molecular link between the MAPK-ERK effector CIC and YAP1 in human cells and established YAP inhibition as a strategy to target CIC-deficient cancers.

Polychlorinated biphenyls (PCBs), and in particular non-dioxin-like (NDL) congeners, continue to pose a significant risk to the developing nervous system. PCB 95, a prevalent NDL congener in the human chemosphere, promotes dendritic growth in rodent primary neurons by activating calcium-dependent transcriptional mechanisms that normally function to link activity to dendritic growth. Activity-dependent dendritic growth is also mediated by calcium-dependent translational mechanisms involving mechanistic target of rapamycin (mTOR), suggesting that the dendrite-promoting activity of PCB 95 may also involve mTOR signaling. Here, we test this hypothesis using primary neuron-glia co-cultures derived from the hippocampi of postnatal day 0 Sprague Dawley rats. PCB 95 (1 nM) activated mTOR in hippocampal cultures as evidenced by increased phosphorylation of mTOR at ser2448. Pharmacologic inhibition of mTOR signaling using rapamycin (20 nM), FK506 (5 nM), or 4EGI-1 (1 µM), and siRNA knockdown of mTOR, or the mTOR complex binding proteins, raptor or rictor, blocked PCB 95-induced dendritic growth. These data identify mTOR activation as a novel molecular mechanism contributing to the effects of PCB 95 on dendritic arborization. In light of clinical data linking gain-of-function mutations in mTOR signaling to neurodevelopmental disorders, our findings suggest that mTOR signaling may represent a convergence point for gene by environment interactions that confer risk for adverse neurodevelopmental outcomes.

Human prostate cancer can result from chromosomal rearrangements that lead to aberrant ETS gene expression. The mechanisms that lead to fusion-independent ETS factor upregulation and prostate oncogenesis remain relatively unknown. Here, we show that two neighboring transcription factors, Capicua (CIC) and ETS2 repressor factor (ERF), which are co-deleted in human prostate tumors can drive prostate oncogenesis. Concurrent CIC and ERF loss commonly occur through focal genomic deletions at chromosome 19q13.2. Mechanistically, CIC and ERF co-bind the proximal regulatory element and mutually repress the ETS transcription factor, ETV1. Targeting ETV1 in CIC and ERF-deficient prostate cancer limits tumor growth. Thus, we have uncovered a fusion-independent mode of ETS transcriptional activation defined by concurrent loss of CIC and ERF.