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Isolating Coupled Effects by Interface Editing of Intermetallic Heterostructures for Fuel Cells

Ih Shapes Pathway-Specific Inhibition in the Substantia Nigra Pars Reticulata

The substantia nigra pars reticulata (SNr) functions as the principal inhibitory output of the basal ganglia, with the timing of its spikes critically controlling downstream disinhibition required for movement initiation. The external globus pallidus (GPe) and D1-expressing medium spiny neurons (D1-MSNs) in the striatum provide GABAergic inputs to the SNr that differ in their amplitude and kinetic properties. How these inputs interact with the intrinsic membrane currents that determine SNr firing is only partially understood. Using optogenetics, computational modeling, and electrophysiology in acute mouse brain slices, 47 animals of either sex were used for measurements, and we found an unexpected interaction between GABAergic inputs and hyperpolarization-activated currents (Ih) that tunes inhibitory efficacy in a pathway-specific manner. GPe inputs evoke fast, large IPSCs that transiently suppress SNr firing within a narrow window but whose rapid decay enables depolarization from Ih to restore firing after only a brief pause. In contrast, the slower decay kinetics of striatal IPSCs enables more sustained inhibition that counters the depolarizing drive from Ih to produce longer pauses, despite their lower conductance amplitudes. Pharmacological blockade of Ih with ZD7288 eliminated the rapid recovery of firing after GPe inhibition and equalized the inhibitory efficacy between GPe and striatal pathways. These findings establish an important interplay between synaptic kinetics and intrinsic membrane conductances in establishing pathway-specific inhibitory balance in the basal ganglia.

Adaptive quantum inspired deep reinforcement learning for multi objective low carbon CCHP optimization

Final results of a randomized, controlled, phase 3 trial comparing resection and post-operative stereotactic radiation versus resection and cesium-131 tile-based radiation for treatment of newly diagnosed brain metastases.

LBA2000 Background: Post-operative stereotactic radiation (SRT) is the standard to reduce recurrence of resected brain metastases (BM). Cesium-131 tile-based radiation therapy (TBRT) (GT Medical Technologies) delivers focal radiation (RT) immediately upon resection and may offer logistical and therapeutic advantages. ROADS (NCT04365374) compared TBRT vs SRT in patients with newly diagnosed resectable BM. Methods: In this open label phase 3 trial across 32 US centers, patients requiring resection of one newly diagnosed BM were randomized 1:1 to surgery + SRT or surgery + TBRT. Up to 5 additional unresected BM were allowed and treated with SRT in both arms. Co-primary endpoints were time to surgical bed recurrence (SBR; independently centrally reviewed) and surgical bed recurrence free survival (SB-RFS), analyzed using Cox proportional hazards models with stratification factors as covariates. Multiplicity was controlled by hierarchical testing. Key secondary endpoints were overall survival (OS), leptomeningeal disease (LMD; independently centrally reviewed), radiation necrosis (RN) and treatment related adverse events (TRAEs). Exploratory endpoints were time to SBR or RN and time to total cranial management (TTCM, time from surgery to completion of all RT). Analyses used the modified intent to treat (mITT) population, defined as patients who underwent surgery and had follow up information. Results: 230 patients with balanced patient and tumor characteristics were randomized (115 per arm). 204 patients (101 SRT, 103 TBRT) comprised the mITT population. Median follow-up time was 12.9 mo (IQR:5.9-22.8 months). SBR occurred in 11.9% (SRT) vs 1.0% (TBRT). Median time to SBR was 17.4 mo in SRT and not reached in TBRT (HR: 0.06, 95% CI: 0.01-0.46, p=0.007). SB-RFS was significantly improved with TBRT: median SB-RFS was 10.9 mo in SRT vs not reached in TBRT (HR: 0.48, 95% CI: 0.30-0.76, p=0.002). OS was significantly improved with TBRT (HR: 0.59, 95% CI: 0.37-0.96; p=0.032); estimated 24-mo survival was 35.7% (SRT) vs 61.7% (TBRT). LMD occurred in 3.0% (SRT) vs 9.7% (TBRT) (p=0.146). The 24-mo probability of being alive without LMD was 35.9% (SRT) vs 57.7% (TBRT) (HR: 0.68, 95% CI: 0.43-1.08, p=0.102). RN occurred in 6.9% of patients (SRT) vs 7.8% (TBRT) (p=0.495). TBRT extended time to SBR or RN: median time was 18.3 mo in SRT vs not reached in TBRT (HR: 0.28, 95% CI: 0.12-0.66, p=0.004). Median TTCM was 30 days (SRT) vs 1 day (TBRT) (p<0.001). Grade ≥3 TRAEs were 19.3% (SRT) vs 18.1% (TBRT). Conclusions: TBRT improved surgical bed control and OS compared to SRT for patients with a newly diagnosed resectable BM. Safety was equivalent. Completing total cranial treatment faster with TBRT, coupled with fewer SBR occurrences may lead to fewer gaps in systemic therapy perhaps resulting in the observed OS benefit. Clinical trial information: NCT04365374 .

The Intricate Nonadiabatic Dynamics of NO ⁺ and NO ₃ ^– Mutual Neutralization

Inflammatory Monocyte-Derived Macrophages Drive Pain via Their Production of Nerve Growth Factor after Peripheral Nerve Injury in Mice

Immune cells are vital to regeneration and repair processes in the nervous system. We previously reported that myeloid cells play a critical role in nerve regeneration and locomotor recovery after peripheral nerve injury (PNI) by facilitating the clearance of inhibitory myelin debris, promoting angiogenesis, and producing neurotrophins (NTs) such as nerve growth factor (NGF), brain-derived neurotrophic factor, NT-3, and NT-4/5. Here, we show that NTs are synthesized by various types of myeloid cells after PNI, including neutrophils, macrophages, and dendritic cells. Notably, we found that within the first week of PNI in male and female mice, monocyte-derived Cd11b + Cd68 + Ly6B + Ly6C hi macrophages infiltrate the sciatic nerve in an interleukin-1-dependent but CC chemokine receptor 2-independent manner and then locally produce mature NGF. Accordingly, depletion of circulating monocytes using PLX73086, a CSF1R inhibitor unable to cross blood–nervous system barriers, reduced NGF mRNA levels in the sciatic nerve distal stump. When polarized toward a proinflammatory phenotype in vitro, mouse macrophages rapidly release the cleaved form of NGF. Further analysis revealed that systemic administration of an anti-NGF-neutralizing antibody reduced mechanical pain in mice with PNI. Together with our previous work, these results suggest that infiltrating monocyte-derived macrophages release NGF, thereby promoting both peripheral nerve regeneration and pain following injury.

Bulk and single-cell transcriptomics reveal prognostic signatures of phosphoinositide metabolism in lung adenocarcinoma

Abstract Lung adenocarcinoma (LUAD) is one of the most severe malignant tumors. Phosphoinositides metabolism (PIM) plays an important role in maintaining the normal life activities of the organism and regulating tumor development. This study aimed to comprehensively investigate the association between LUAD and PIM. Data on LUAD and PIM-related genes (PIM-RGs) were sourced from public databases. Differential expression, univariate Cox regression analyses, and machine learning were conducted to identify prognostic genes. A risk model was subsequently developed, and LUAD patients were categorized into a high-risk group (HRG) and a low-risk group (LRG). Independent prognostic factors for LUAD were identified, and a nomogram was constructed. Functional enrichment, tumor microenvironment, mutations, and drug sensitivity analyses were also conducted to investigate the molecular mechanisms underlying LUAD. Additionally, single-cell RNA sequencing (scRNA-seq) data analysis was employed to identify key cells and clarify the dynamics of prognostic genes’ expression. Ultimately, prognostic gene expression was investigated in clinical samples. MTMR7, GDPD1, MTMR4, and MTMR10 were recognized as prognostic genes. The risk model and nomogram (incorporating risk score and Stage) had good predictive performance. Notably, LUAD’s malignant progression might be closely associated with biological processes including cellular protein synthesis, abnormal activation of neuroactive ligand-receptor interactions, and anti-tumor immune responses. Additionally, there was a general positive correlation between the differentially infiltrated immune cells of HRG and LRG. Moreover, TP53 and TTN had relatively high mutation frequencies in both HRG and LRG, and 142 drugs exhibited differential sensitivity between the 2 groups. Interestingly, epithelial cells were identified as LUAD’s key cell type, with prognostic gene expression showing dynamic changes as these cells differentiated. Consistently, compared with the control group, GDPD1 and MTMR4 were upregulated, MTMR10 was downregulated, and MTMR7 showed no statistical difference but a certain upward trend in the LUAD group. This study identified 4 prognostic genes and constructed an effective risk model, providing a new perspective on the treatment of LUAD.

Safety and performance results from PATHFINDER 2, a registrational study of a multi-cancer early detection (MCED) test in an intended-use population.

LBA10509 Background: The MCED test (Galleri) detects a shared cancer signal from cell-free DNA in blood and predicts a cancer signal origin (CSO) to guide diagnostic (dx) workup. PF2 (NCT05155605) is a large, prospective, multicenter, interventional study of the MCED test’s performance and safety in a diverse US intended-use population. Methods: PF2 enrolled participants aged ≥50y without clinical suspicion of cancer or cancer diagnosis/treatment within 3y of enrollment. Primary objectives were MCED performance and safety in terms of dx testing triggered by a positive (cancer signal detected) MCED test result. Participants with a positive MCED test underwent targeted dx workup guided by the predicted CSO(s). Participant-reported anxiety was assessed with the State Trait Anxiety Inventory. Results: PF2 enrolled 35,878 participants; 32,007 with a 12m cancer assessment were analyzable for performance. Of 287 (0.9%) with a positive MCED test, 173 were diagnosed with cancer within 12m, for a cancer detection rate of 0.5% (95% CI 0.5-0.6%) and positive predictive value of 60.3% (54.5-65.8%). Specificity was 99.6% (99.6-99.7%). 12m episode sensitivity was 69.8% (62.8-76.0%) in a prespecified subgroup of 12 cancers responsible for ⅔ of US cancer deaths, 66.2% (55.1-75.8%) in a subgroup of 6 aggressive cancers with low 5y survival, and 39.3% (34.9-44.0%) across all cancers. Overall CSO prediction accuracy was 91.3% (86.2-94.7%) across all cancers. The MCED test detected 151 new primary and 22 recurrent cancers; additional cancers detected by screening were those with USPSTF A/B (n=31) and C (n=60) recommended screening. Of 151 MCED-detected new primaries, 80 (53.0%) were clinical stage I-II; 107 (70.9%) were stage I-III. Of 80 MCED-detected stage I-II cancers, 71.2% had no USPSTF A/B screening recommendation. Of 35,335 participants analyzable for safety, 213 (0.6%) had invasive procedure(s) to evaluate a positive MCED test result, of which 90% were nonsurgical and 1.8x more likely for participants with vs without cancer diagnosis. Most (87.6%) had a CSO-guided dx evaluation. There were 5 study-related adverse events during the time of dx workup; none were serious. Anxiety temporarily increased for participants with a positive MCED test and cancer diagnosed, and returned to baseline by 12m. Of participants with a positive MCED test, median time from test result to dx resolution was 48d (95% CI 43-56). Few participants (7/63 [11.1%]) had cancer found by dx PET/CT after a targeted dx workup that did not reveal cancer. Conclusion: The MCED test demonstrated robust performance with a favorable safety profile. When MCED testing was added to USPSTF A/B screening, 6.5x more cancers were detected by screening, most at early stages. The diverse, representative PF2 participant population supports the generalizability of these findings to the US intended-use population. Clinical trial information: NCT05155605 .

Ligand-Symmetry-Driven Metal-Cluster Rotation for Accessing Compressed Pore Regimes in Metal–Organic Frameworks

Distinct Roles of CaMKII in Synaptic Vesicle Dynamics at Zebrafish Retinal Rod Bipolar Ribbon Synapses

Calcium (Ca 2+ ) not only serves as a fundamental trigger for neurotransmitter release but also participates in shaping neurotransmitter release (NTR) during prolonged presynaptic stimulation via multiple Ca 2+ -dependent processes. The Ca 2+ /calmodulin (CaM)-dependent protein kinase II (CaMKII) is enriched at various presynaptic terminals, including ribbon synapses, where it associates with synaptic ribbons and thus may contribute to the modulation of Ca 2+ -dependent NTR. This could arise via its ability to influence one or more steps that control either the Ca 2+ signal, the release process, or synaptic vesicle dynamics, affecting available pools. Yet, recent studies have yielded conflicting results regarding the ability of CaMKII to influence NTR at rod bipolar cell (RBC) ribbon synapses. To address this, we acutely manipulated CaMKII activity in synaptic terminals of zebrafish RBCs from both sexes by infusion of either inhibitory peptides targeting CaMKII or CaM, or a constitutively active CaMKII, while using a combination of imaging and electrophysiological approaches. Neither inhibiting nor enhancing CaMKII activity affects presynaptic Ca 2+ channel activity. However, capacitance measurements revealed that inhibition of either CaMKII or CaM reduces exocytosis. CaMKII inhibition also reduces synaptic vesicle replenishment. Surprisingly, elevation of CaMKII activity also diminished vesicle fusion, similar to the effect of CaMKII inhibition, suggesting that CaMKII activity naturally exists at optimal levels to support neurotransmitter release. In contrast to CaMKII inhibition, CaMKII activity elevation did not impair vesicle replenishment. Collectively, these data suggest that distinct synaptic vesicle populations are differentially reliant on the level of CaMKII activity.

Structural diversity and chemical space analysis of a PROTAC database using unsupervised machine learning

Abstract Targeted protein degradation (TPD) mediated by proteolysis-targeting chimeras (PROTACs) has emerged as a powerful therapeutic strategy, enabling the catalytic and selective elimination of disease-relevant proteins via the ubiquitin–proteasome system. Despite their ability to overcome drug resistance and address traditionally undruggable targets, the structural complexity and vast chemical diversity of PROTACs present challenges for systematic analysis and rational design. Here, we present a systematic unsupervised machine-learning framework that represents the first large-scale similarity-driven clustering and scaffold-centric analysis of the PROTAC chemical space, to comprehensively characterize the structural, functional, and physicochemical landscape of PROTAC molecules and to support data-driven lead optimization and next-generation degrader design. An initial dataset of 9,380 compounds was curated from the publicly available PROTACs Database (PROTAC-DB 3.0), followed by rigorous standardization and filtering, resulting in 6,113 unique, chemically valid compounds. The chemical space was explored using a multi-step computational pipeline involving dimensionality reduction and a comparative evaluation of diverse clustering algorithms. Among the evaluated approaches, a refined clustering strategy demonstrated superior performance in partitioning the dataset into structurally coherent groups. Structural analysis revealed a pronounced convergence around canonical PROTAC architectures, characterized by conserved E3 ligase-binding motifs, diverse target-binding frameworks, and heterogeneous linker designs. Functional group profiling and physicochemical analysis further demonstrated that these compounds predominantly occupy a specialized chemical space beyond traditional drug-like limits, marked by high molecular weight and substantial conformational flexibility. Collectively, these findings provide data-driven design guidance for PROTAC optimization by highlighting frequent scaffold architectures and preferred property ranges, thereby informing the development of next-generation degraders.

Perioperative (neoadjuvant and adjuvant) apalutamide (APA) + androgen deprivation therapy (ADT) vs placebo (PBO) + ADT with radical prostatectomy (RP) in high-risk localized or locally advanced prostate cancer (HR LPC/LAPC): Final analysis of the PROTEUS phase 3 study.

LBA1 Background: RP is potentially curative for patients (pts) with HR LPC/LAPC, yet ≈50% of pts relapse. PROTEUS evaluated whether APA + ADT vs PBO + ADT before and after RP with pelvic lymph node dissection (henceforth, RP) improves pathologic complete response/minimal residual disease (pCR/MRD) and metastasis-free survival (MFS) in HR LPC/LAPC. Methods: Pts with newly diagnosed HR LPC/LAPC (histology, prostate-specific antigen [PSA], and cN0/cN1 on conventional imaging) were randomized 1:1 to blinded APA (240 mg/d) or PBO as neoadjuvant treatment (tx) for 6 mo + ADT, with a 2-wk break prior to and a 4-wk break post RP, followed by 6 mo of assigned tx. Dual primary end points, pCR/MRD (≤ypT2, ≤5 mm tumor diameter) and MFS based on conventional or prostate-specific membrane antigen positron emission tomography (PSMA PET) imaging, were assessed by blinded independent central review (BICR). Secondary end points included event-free survival (EFS), time to first subsequent tx (TTST1), time to distant metastasis (TTDM), and safety. Exploratory end points included residual cancer burden (RCB/MRD; ≤ypT2, ≤0.25 cm 3 ) and investigator-assessed MFS. Results: Of 2109 pts randomized (APA + ADT [1057] or PBO + ADT [1052]), median (range) age was 66.0 (41-89) years (y); PSA, 14.8 (0.0-2798.0) ng/mL; GS ≥8, 95.8%. Median follow-up was 61.7 mo. Both primary end points were met with APA + ADT vs PBO + ADT: pCR/MRD rate was significantly higher, 8.9% vs 1.0% (odds ratio [OR] 10.17; 95% CI 5.27-19.64; p<0.0001); MFS by BICR was significantly improved with HR 0.80; 95% CI 0.67-0.96; p=0.0169 and 5-y MFS rate of 78.2% vs 73.5%; median not reached [NR]. Investigator-assessed MFS favored APA + ADT, with HR 0.74; 95% CI 0.62-0.87; nominal p=0.0004. EFS, TTST1, TTDM were all significantly improved with APA + ADT (Table), as was RCB/MRD: MRD 30.6% vs 11.7%; OR 3.36; 95% CI 2.67-4.23; nominal p<0.0001. Grade 3/4 tx-emergent adverse events (TEAEs) for APA + ADT vs PBO + ADT were 39.6% vs 31.0%, with discontinuation due to TEAEs 7.4% vs 2.7%, respectively. Conclusions: APA + ADT significantly increased the curative success of RP in pts with HR LPC/LAPC, with a 10-fold higher odds of pCR/MRD and a clinically meaningful 20% reduction in risk of distant metastasis or death. Secondary end points all favored APA + ADT. These results support combined APA + ADT and RP as a new standard of care for pts with HR LPC/LAPC. Clinical trial information: NCT03767244 . HR(95% CI) p Value a APA + ADTn=1057Median (mo) PBO + ADTn=1052Median (mo) EFS 0.71(0.63-0.80) <0.0001 57.1 38.4 TTST1 (local, regional, or systemic, including ADT reinitiation) 0.65(0.57-0.73) <0.0001 74.2 41.5 TTDM (conventional or PSMA PET imaging) 0.68(0.55-0.83) 0.0002 NR NR a Stratified by GS (7, ≥8), nodal status, and geographic region (North America, European Union, rest of world).

Single-Atom Synergy of Luminescence and Catalytic Stability in Silver-Encapsulated Gold Nanoclusters

Illusory-Causal Impression Attenuates the Detection of Event Boundaries

The art of film editing bridges the transitions between discrete events to build a coherent, immersive experience for viewers. However, how the brain integrates seemingly separate moments into a coherent whole remains poorly understood. We hypothesized that causal impression—even when illusory—acts as a powerful heuristic to attenuate the neural representation of event boundaries, thereby facilitating a smoother transition across events. Using high-resolution electroencephalography, we presented 34 participants (24 women) with a sequence of images sourced from concatenated visual clips, where action–outcome continuity across the event boundary was manipulated to induce or break illusory causality. Behaviorally, we found that illusory-causal impression delayed the detection of event boundaries. Neurally, this boundary attenuation effect was marked by a reduced N2 amplitude, indicating mitigated cognitive conflict associated with a context shift. Multivariate analyses further showed that this causal impression reshaped the event representation by increasing neural similarity between generic cross-boundary states, thereby overcoming the typical boundary-induced impairment of cross-event association. Critically, this neural representational change was linked to behavior: the greater and more stable the neural separability in posterior brain regions across the boundary, the faster participants detected the event change. These findings suggest that illusory-causal impression mitigates event segmentation by maintaining more coherent neural patterns across the boundary, providing a neuroscientific basis for intuitive editing techniques used in filmmaking.

A self-biased optoelectronic methane sensor based on Fano resonance in a cryptophane-A-infiltrated GaAs photonic crystal integrated with an InGaAs/InP photodiode

Rise and Fall of Neoadjuvant Carboplatin for Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer

The One Ring: A Monocycle Producing Class II Diterpene Cyclase from <i>Isodon leucophyllus</i>

Molecular Mechanism of the Oxidative Cleavage of Alkenes by Photoexcited Nitroarenes

Micropropagation and ISSR-based genetic fidelity assessment of the medicinal legume Butea monosperma (Lam.) Taub

Reduced circulating 20-hydroxyeicosatetraenoic acid and ACE2 in acute coronary syndrome with exploratory cell-based observations

Abstract Progression of ischemic heart disease to acute coronary syndrome (ACS) is fueled by endothelial dysfunction and disruptions in vascular signaling pathways. The relationship between the angiotensin-converting enzyme 2 (ACE2)/renin-angiotensin system (RAS) axis and eicosanoid metabolism is still not fully understood. This study aimed to investigate whether changes in circulating ACE2 and 20-hydroxyeicosatetraenoic acid (20-HETE) reflect dysregulation of a combined ACE2/RAS–eicosanoid axis in ACS and to evaluate the diagnostic and functional significance of 20-HETE. We studied 122 patients with ischemic heart disease (including stable coronary artery disease (SCAD) and ACS) and 54 controls. Levels of circulating ACE2 and 20-HETE were measured using ELISA. Additionally, in vitro experiments with cell culture models were conducted to evaluate how pharmacological modulation of the ACE2/RAS axis affects nitric oxide (NO) production, inflammatory signaling, and CYP4F2 expression. Both ACE2 and 20-HETE levels were significantly lower in ACS compared to SCAD and controls ( p  &lt; 0.001). Circulating 20-HETE effectively distinguished ACS from SCAD with an AUC of 0.91. In endothelial cells, altering the ACE2/RAS axis impacted NO availability and inflammatory gene expression, correlating with changes in CYP4F2 levels. 20-HETE affected cellular metabolic activity and GPR75 signaling, indicating a functional connection between RAS signaling and eicosanoid pathways. Lower circulating 20-HETE levels are associated with disruption of the integrated ACE2/RAS–eicosanoid axis, which is linked to endothelial dysfunction in ACS. These results suggest that 20-HETE may serve not only as a biomarker but also as part of a broader vascular signaling network related to acute coronary instability.