We have used the metal/amorphous silicon/metal tunnel junction as a Inodel system to explore the role of localized states in electron transport through thin insulating layers. We measured the tunneling conductance as a function of temperature T, bias voltage V, and barrier thickness d. The data show marked deviations from the classical WKB tunneling theory in the limit of low T and V with d intermediate between the decay length in the barrier and the Mott variable range hopping length. The data are instead consistent with directed inelastic hopping along statistically rare but highly conductive "chains" of localized states. The most effective chains for a given set of conditions (T, V, d) contain a definite number of localized states, N & 1, configured in a nearly optimal way in space and energy. The conductance of the lowest-order hopping channel (all chains with N=2) exhibits the characteristic voltage and temperature dependences 6&'"(V)~V ', and 62' (T)~T ', respectively, as predicted by theory. Higher-order channels (N & 2) also conform to the theoretical predictions remarkably well. The physical nature of these highly conductive channels and their implications for conduction through thick tunnel barriers and thin dielectrics is discussed.

We consistently observe a magnetic-field-dependent conductance peak at zero-bias voltage in a wide range of superconductor/noble-metal junctions fabricated from oxide superconductors ͑YBa 2 Cu 3 O 7Ϫ␦ and Tl 2 Ba 2 CaCu 2 O͒ that have been reported to exhibit d-wave pairing behavior; however, no measurable peak appears in similar junctions made from an s-wave oxide superconductor (Nd 1.85 Ce 0.15 CuO 4 ). Explanations of this correlation are considered in terms of the Appelbaum-Anderson model for magnetic interface scattering and the midgap-state model for d-wave interface states.

Although immune checkpoint inhibitors (ICIs), such as anti–programmed cell death protein–1 (PD-1), can deliver durable antitumor effects, most patients with cancer fail to respond. Recent studies suggest that ICI efficacy correlates with a higher load of tumor-specific neoantigens and development of vitiligo in patients with melanoma. Here, we report that patients with low melanoma neoantigen burdens who responded to ICI had tumors with higher expression of pigmentation-related genes. Moreover, expansion of peripheral blood CD8+ T cell populations specific for melanocyte antigens was observed only in patients who responded to anti–PD-1 therapy, suggesting that ICI can promote breakdown of tolerance toward tumor-lineage self-antigens. In a mouse model of poorly immunogenic melanomas, spreading of epitope recognition toward wild-type melanocyte antigens was associated with markedly improved anti–PD-1 efficacy in two independent approaches: introduction of neoantigens by ultraviolet (UV) B radiation mutagenesis or the therapeutic combination of ablative fractional photothermolysis plus imiquimod. Complete responses against UV mutation-bearing tumors after anti–PD-1 resulted in protection from subsequent engraftment of melanomas lacking any shared neoantigens, as well as pancreatic adenocarcinomas forcibly overexpressing melanocyte-lineage antigens. Our data demonstrate that somatic mutations are sufficient to provoke strong antitumor responses after checkpoint blockade, but long-term responses are not restricted to these putative neoantigens. Epitope spreading toward T cell recognition of wild-type tumor-lineage self-antigens represents a common pathway for successful response to ICI, which can be evoked in neoantigen-deficient tumors by combination therapy with ablative fractional photothermolysis and imiquimod.

It has long been held as scientific fact that soon after birth, cardiomyocytes cease dividing, thus explaining the limited restoration of cardiac function after a heart attack. Recent demonstrations of cardiac myocyte differentiation observed in vitro or after in vivo transplantation of adult stem cells from blood, fat, skeletal muscle, or heart have challenged this view. Analysis of these studies has been complicated by the large disparity in the magnitude of effects seen by different groups and obscured by the recently appreciated process of in vivo stem-cell fusion. We now show a novel population of nonsatellite cells in adult murine skeletal muscle that progress under standard primary cell-culture conditions to autonomously beating cardiomyocytes. Their differentiation into beating cardiomyocytes is characterized here by video microscopy, confocal-detected calcium transients, electron microscopy, immunofluorescent cardiac-specific markers, and single-cell patch recordings of cardiac action potentials. Within 2 d after tail-vein injection of these marked cells into a mouse model of acute infarction, the marked cells are visible in the heart. By 6 d they begin to differentiate without fusing to recipient cardiac cells. Three months later, the tagged cells are visible as striated heart muscle restricted to the region of the cardiac infarct.

Triple-negative breast cancer (TNBC) is a particularly aggressive subtype known for its extremely high drug resistance, progression, poor prognosis, and lack of clear therapeutic targets. Researchers are aiming to advance TNBC treatment worldwide. In the past 2–3 years, more positive results have emerged in the clinical research on TNBC treatment. Based on the results, several impressive drugs have been approved to benefit patients with TNBC, including the PARP inhibitors olaparib and talazoparib for germline BRCA mutation-associated breast cancer (gBRCAm-BC) and immunotherapy using the checkpoint inhibitor atezolizumab in combination with nab-paclitaxel for programmed cell death-ligand 1-positive (PD-L1+) advanced TNBC. Although neoadjuvant therapy has focused on combinations of systemic agents to optimize pathologically complete response, metastatic TNBC still has a poor prognosis. Innovative multidrug combination systemic therapies based on neoadjuvants and adjuvants have led to significant improvements in outcomes, particularly over the past decade.