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Nonlinear two-photon photoemission electron microscopy is used to image surface plasmon polariton (SPP) wave packets excited by an obliquely incident laser pulse (~10 fs) at a single slit fabricated in a thin silver film. We image the forward propagating polarization grating formed by the coherent superposition of the external excitation pulse and the SPP wave packet fields. By systematically varying the coupling slit width from sub-to multiple-wavelength scale, we observe a modulated increase of the grating intensity, which is phenomenologically accounted for by distinct contributions to the forward coupling efficiency from the incident to the SPP waves. Full-wave, vectorial finite-difference time-domain (FDTD) simulation of the experiments is in good agreement with the experimental observations and explains their origin. In particular, the FDTD simulation illustrates detailed spatial variation of the polarization grating as a function of the geometry of the slit under excitation by ultrafast laser pulses at an oblique incidence.2

Objective The peripheral myelin protein-22 (PMP22) gene is associated with the most common types of inherited neuropathies, including hereditary neuropathy with liability to pressure palsies (HNPP) caused by PMP22 deficiency. However, the function of PMP22 has yet to be defined. Our previous study has shown that PMP22 deficiency causes an impaired propagation of nerve action potentials in the absence of demyelination. In the present study, we tested an alternative mechanism relating to myelin permeability. Methods Utilizing Pmp22+/− mice as a model of HNPP, we evaluated myelin junctions and their permeability using morphological, electrophysiological, and biochemical approaches. Results We show disruption of multiple types of cell junction complexes in peripheral nerve, resulting in increased permeability of myelin and impaired action potential propagation. We further demonstrate that PMP22 interacts with immunoglobulin domain–containing proteins known to regulate tight/adherens junctions and/or transmembrane adhesions, including junctional adhesion molecule-C (JAM-C) and myelin-associated glycoprotein (MAG). Deletion of Jam-c or Mag in mice recapitulates pathology in HNPP. Interpretation Our study reveals a novel mechanism by which PMP22 deficiency affects nerve conduction not through removal of myelin, but through disruption of myelin junctions.

Triple negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, but an effective targeted therapy has not been well-established so far. Considering the lack of effective targets, where do we go next in the current TNBC drug development? A promising intervention for TNBC might lie in de novo small-molecule drugs that precisely target different molecular characteristics of TNBC. However, an ideal single-target drug discovery still faces a huge challenge. Alternatively, other new emerging strategies, such as dual-target drug, drug repurposing, and combination strategies, may provide new insight into the improvement of TNBC therapeutics. In this review, we focus on summarizing the current situation of a series of candidate small-molecule drugs in TNBC therapy, including single-target drugs, dual-target drugs, as well as drug repurposing and combination strategies that will together shed new light on the future directions targeting TNBC vulnerabilities with small-molecule drugs for future therapeutic purposes.

Mitochondrial dysfunction and metabolic remodeling are pivotal in the development of cardiomyopathy. Here, we show that myocardial COUP-TFII overexpression causes heart failure in mice, suggesting a causal effect of elevated COUP-TFII levels on development of dilated cardiomyopathy. COUP-TFII represses genes critical for mitochondrial electron transport chain enzyme activity, oxidative stress detoxification and mitochondrial dynamics, resulting in increased levels of reactive oxygen and lower rates of oxygen consumption in mitochondria. COUP-TFII also suppresses the metabolic regulator PGC-1 network and decreases expression of key glucose and lipid utilization genes, leading to a reduction in both glucose and oleate oxidation in hearts. These data suggest that COUP-TFII affects mitochondrial function, impairs metabolic remodeling and plays a key role in dilated cardiomyopathy. Lastly, COUP-TFII haploinsufficiency attenuates the progression of cardiac dilation and improves survival in a calcineurin transgenic mouse model, indicating that COUP-TFII may serve as a therapeutic target for treatment of dilated cardiomyopathy.

Mitochondrial pyruvate carrier 1 (MPC1) and MPC 2 form a transporter complex in cells to control pyruvate transportation into mitochondria. Reduced expression of MPC1 disrupts the transporter function, induces metabolic shift to increase glycolysis, and thus plays important roles in several diseases, including cancer. However, the role of MPC1 in prostate cancer and the underlying mechanism causing the down-regulation of MPC1 in tumor cells remain to be defined. Here, we show that MPC1 serves as a critical regulator of glycolysis in prostate cancer cells, which in turn controls cancer cell growth, invasion, and the tumorigenic capability. More importantly, we identified that chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII), a steroid receptor superfamily member, transcriptionally regulates the expression of MPC1. We further demonstrate that COUP-TFII, which is upregulated in the prostate cancer patient, regulates MPC1 and glycolysis to promote tumor growth and metastasis. Our findings reveal that COUP-TFII represses MPC1 expression in prostate cancer cells to facilitate a metabolism switch to increase glycolysis and promote cancer progression. This observation raises an intriguing possibility of targeting COUP-TFII to modulate cancer cell metabolism for prostate cancer intervention.

Recent findings have shown that inhibitors targeting bromodomain and extraterminal domain (BET) proteins, such as the small molecule JQ1, are potent growth inhibitors of many cancers and hold promise for cancer therapy. However, some reports have also revealed that JQ1 can activate additional oncogenic pathways and may affect epithelial-to-mesenchymal transition (EMT). Therefore, it is important to address the potential unexpected effect of JQ1 treatment, such as cell invasion and metastasis. Here, we showed that in prostate cancer, JQ1 inhibited cancer cell growth but promoted invasion and metastasis in a BET protein-independent manner. Multiple invasion pathways including EMT, bone morphogenetic protein (BMP) signaling, chemokine signaling, and focal adhesion were activated by JQ1 to promote invasion. Notably, JQ1 induced upregulation of invasion genes through inhibition of Forkhead box protein A1 (FOXA1), an invasion suppressor in prostate cancer. JQ1 directly interacted with FOXA1 and inactivated FOXA1 binding to its interacting repressors TLE3, HDAC7, and NFIC, thereby blocking FOXA1-repressive function and activating the invasion genes. Our findings indicate that JQ1 has an unexpected effect of promoting invasion in prostate cancer. Thus, the ill effect of JQ1 or its derived therapeutic agents cannot be ignored during cancer treatment, especially in FOXA1-related cancers.

We combine photoemission electron microscopy and electromagnetic simulations to describe the surface plasmon polariton dynamics following interaction of an ultrafast optical pulse with a slit coupling structure in a silver film. Through analysis of interference phenomena that lead to photoelectron emission from the silver film, we establish the universal contributions of a nanoscale asperity to the scattered surface field. Our results reveal the important role of surface cylindrical waves within the slit in the excitation of surface plasmon.