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Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a familial cardiac disease associated with ventricular arrhythmias and an increased risk of sudden cardiac death. Currently, there are no approved treatments that address the underlying genetic cause of this disease. Mutations in desmosome gene Plakophilin-2 (PKP2) account for 45% of ARVC cases and result in reduced gene expression. Our goal is to examine the feasibility and the efficacy of adeno-associated virus 9 (AAV9)-mediated restoration of PKP2 expression in a cardiac specific knock-out mouse model of Pkp2. We demonstrated that a single-dose cardiac AAV9:PKP2 gene delivery effectively prevented disease development before overt cardiomyopathy and attenuated disease progression after overt cardiomyopathy. Restoration of PKP2 expression leads to highly coordinated and durable correction of PKP2-associated transcriptional networks beyond desmosomes, revealing a broad spectrum of biological perturbances behind ARVC disease etiology. These results indicate that cardiac AAV9:PKP2 gene therapy may be a promising therapeutic approach to treat ARVC patients with PKP2 mutations.

PurposeThe study aims to examine the impact of six events related to the escalating Indo-China border conflicts in 2020 on the Indian stock market, including the role of firm-specific variables.Design/methodology/approachThis study employs an event-study method on a sample of 481 firms from August 23, 2019 to March 3, 2022. A cross-sectional regression is employed to examine the association between event-led abnormal returns and firm characteristics.FindingsThe results show that, although the individual events reflect heterogeneous effects on stock market returns, the average impact of the event categories is negative. The study also found that net working capital, current ratio, financial leverage and operating cash flows are significant financial performance indicators and drive cumulative abnormal returns. Further, size anomaly is absent, indicating that more prominent firms are resilient to new information.Research limitations/implicationsThe ongoing conflict between Russia and Ukraine is an example of how these disagreements can devolve into a disaster for the parties to the war. Although wars have an impact on markets at the global level, the impacts of border disputes are local. Border disputes are ongoing, and the study's findings can be used to empower investors to make risk-averting decisions that make their portfolios resilient to such events.Originality/valueThis study provides firm-level insight into the impacts of border conflicts on stock markets. The authors compare the magnitude of such impacts on two types of events, namely injuries and casualties due to country-specific border tensions and a government ban on Chinese apps. Key implications for policymakers, stakeholders and academics are presented.

Dilated cardiomyopathy (DCM) is characterized by reduced cardiac output, as well as thinning and enlargement of left ventricular chambers. These characteristics eventually lead to heart failure. Current standards of care do not target the underlying molecular mechanisms associated with genetic forms of heart failure, driving a need to develop novel therapeutics for DCM. To identify candidate therapeutics, we developed an in vitro DCM model using induced pluripotent stem cell–derived cardiomyocytes (iPSC-CMs) deficient in B-cell lymphoma 2 (BCL2)-associated athanogene 3 (BAG3). With these BAG3-deficient iPSC-CMs, we identified cardioprotective drugs using a phenotypic screen and deep learning. From a library of 5500 bioactive compounds and siRNA validation, we found that inhibiting histone deacetylase 6 (HDAC6) was cardioprotective at the sarcomere level. We translated this finding to a BAG3 cardiomyocyte–knockout (BAG3 cKO ) mouse model of DCM, showing that inhibiting HDAC6 with two isoform-selective inhibitors (tubastatin A and a novel inhibitor TYA-018) protected heart function. In BAG3 cKO and BAG3 E455K mice, HDAC6 inhibitors improved left ventricular ejection fraction and reduced left ventricular diameter at diastole and systole. In BAG3 cKO mice, TYA-018 protected against sarcomere damage and reduced Nppb expression. Based on integrated transcriptomics and proteomics and mitochondrial function analysis, TYA-018 also enhanced energetics in these mice by increasing expression of targets associated with fatty acid metabolism, protein metabolism, and oxidative phosphorylation. Our results demonstrate the power of combining iPSC-CMs with phenotypic screening and deep learning to accelerate drug discovery, and they support developing novel therapies that address underlying mechanisms associated with heart disease.

In light of the COVID-19 pandemic, the demand for better UV disinfection sources has increased drastically. Recent advances in Lanthanide-based upconverting nanoparticle (UCNP) designs have led to dramatic increases in efficiency – beyond what is possible in bulk upconverting material – for generating short-wavelength light from long-wavelength photons, pushing achievable upconversion into the UV regime. Such nanoparticles represent an ultimate source of ultra-local UV light, with applications in UV photocatalysis, 3D printing and manufacturing, and perhaps most importantly, health care. The goal of this article is to provide an assessment for the application of UCNPs as local UV sources for disinfection. We map out the potential for incorporation into personal protective equipment (PPE), focusing on N95 face masks as a model system. Performance and viability are evaluated based on recent UCNP findings and extrapolating cost trends following the recent example of commercialized semiconductor quantum dot nanoparticles.

The first applications of luminescent nanocrystals to bioimaging were semiconductor quantum dots with optoelectronic properties that largely mirror those of organics and proteins, but with substantially increased stability and brightness that have enabled single molecule and other challenging imaging applications. Building on this success, newer nanocrystals have been engineered with optical properties unlike anything found in traditional probes, including perfect photostability,1,2 anti-Stokes emission a billion-fold more efficient than 2-photon excitation,3 and most recently, photon avalanches hosted within nanostructures.4 Avalanches are steeply nonlinear events in which outsized responses arise from a series of minute inputs. With light, photon avalanching (PA) had been observed only in bulk materials and aggregates, often at cryogenic temperatures, preventing its application to bioimaging. We recently reported the realization of PA at room temperature in sub-30 nm Tm3+-doped NaYF4 upconverting nanoparticles (UCNPs) and demonstrated their use in high-resolution imaging at wavelengths that fall within NIR spectral windows of maximal biological transparency. Avalanching nanoparticles (ANPs) can be pumped by either continuous-wave or pulsed lasers and exhibit all of the defining features of PA: clear excitation power thresholds, exceptionally long rise time at threshold, and a dominant excited-state absorption that is >10,000 times larger than ground-state absorption. Beyond the avalanching threshold, ANP emission scales with up to the 31st power of pump intensity, an extreme nonlinearity caused by the induced positive optical feedback within each nanocrystal. This enables sub-70 nm spatial resolution using only simple scanning confocal microscopy and before any computational data analysis. NaYF4 ANPs with 8-20% Tm3+content can be excited at either 1064 or 1450 nm, with avalanching emission at 800 nm. Pairing the steep nonlinearity of ANPs with existing superresolution techniques and computational methods allows for imaging with higher resolution and at ca. 100-fold lower excitation intensities than is possible with other probes. For application of ANPs to live-cell imaging, we have developed synthetic chemistry-free methods for conjugating engineered antibodies to NP-surface SpyCatcher proteins,5 which bind and spontaneously form covalent isopeptide bonds with cognate SpyTag peptides. This enables controlled and irreversible attachment of antibodies to nanoparticle surfaces, for specific targeting of cell-surface receptors in quantitative live-cell study of their distribution, trafficking, and physiology. Wu, S. et al. Non-blinking and photostable upconverted luminescence from single lanthanide-doped nanocrystals. Proc. Natl. Acad. Sci. 106, 10917–10921 (2009). Fernandez-Bravo, A. et al. Continuous-wave upconverting nanoparticle microlasers. Nat. Nanotechnol. 13, 572–577 (2018). Tian, B. et al. Low irradiance multiphoton imaging with alloyed lanthanide nanocrystals. Nat. Commun. 9, 3082 (2018). Lee, C. et al. Giant nonlinear optical responses from photon-avalanching nanoparticles. Nature 589, 230–235 (2021). Pedroso, C. C. S. et al. Immunotargeting of nanocrystals by SpyCatcher conjugation of engineered antibodies. ACS Nano 15, 18374–18384 (2021). Figure 1

Heart failure affects an estimated 38 million people worldwide and is typically caused by cardiomyocyte (CM) loss or dysfunction. Although CMs have limited ability to regenerate, a large pool of non-myocytes, including cardiac fibroblasts (CFs), exist in the postnatal heart. In vivo reprogramming of non-myocytes into functional CMs is emerging as a potential new approach to treat heart failure and substantial proof-of-concept has been achieved in this new field. However, challenges remain in terms of clinical application. First, reported human reprogramming cocktails often consist of five to seven factors that require multiple AAV vectors for delivery. Thus, a less complex cocktail that is able to fit into one AAV vector is needed for this technology to impact human health. Second, the lack of specificity in AAV tropism further complicates the safety and regulatory landscape. A means to limit the expression of reprogramming factors to target cells is critical for maximizing long-term safety. Lastly, although promising studies in small animals have already been reported, safety and efficacy results in large animal MI models are critical to justify cardiac reprogramming in human clinical trials. We have developed a novel human cardiac reprogramming cocktail that consists of only two transcription factors and one miRNA. This new cocktail has been engineered into a single AAV cassette to efficiently reprogram human CFs into cardiomyocytes. We also substantially improved transduction of hCFs through AAV capsid engineering and eliminated CMs expression through a microRNA de-targeting method. Moreover, our novel cardiac reprogramming gene therapy improved cardiac function in both rat and swine MI models upon delivery at various time-points after MI without inducing arrhythmias. Given these promising safety and efficacy results in larger animals, we endeavor to translate direct cardiac reprogramming for clinical application.

We construct a measure of the pairwise relatedness of firms’ human capital to examine whether human capital relatedness is a key factor in mergers and acquisitions. We find that mergers are more likely and merger returns and postmerger performance are higher when firms have related human capital. These relations are stronger or only present in acquisitions where the merging firms do not operate in the same industries or product markets. Reductions in employment and wages following mergers with high human capital relatedness suggest that the merged firm has greater ability to layoff low quality and/or duplicate employees and reduce labor costs. We further show in a falsification test that human capital relatedness has no effect on acquiring firm returns in asset sales when little or no labor is transferred, which helps validate our measure of human capital relatedness.

We examine the valuation effects of cross-border merger and acquisition (M&A) waves. Like domestic M&As, cross-border M&As cluster by industry and time. Cross-border M&A waves create value overall: acquirer announcement returns, combined acquirer and target announcement returns, and post-merger operating performance within waves are significantly higher than those outside of waves. Unlike domestic M&A waves, deals undertaken later in waves outperform those earlier in waves. The late entrants' outperformance is stronger when target countries differ from acquirer countries in terms of culture, financial development, and legal system. Overall, the results suggest that cross-border acquisitions promote efficient redeployment of corporate assets.

Avalanche phenomena leverage steeply nonlinear dynamics to generate disproportionately high responses from small perturbations and are found in a multitude of events and materials, enabling technologies including optical phase-conjugate imaging, infrared quantum counting, and efficient upconverted lasing. However, the photon avalanching (PA) mechanism underlying these optical innovations has been observed only in bulk materials and aggregates, and typically at cryogenic temperatures, limiting its utility and impact. Here, we report the realization of PA at room temperature in single nanostructures--small, Tm-doped upconverting nanocrystals--and demonstrate their use in superresolution imaging at near-infrared (NIR) wavelengths within spectral windows of maximal biological transparency. Avalanching nanoparticles (ANPs) can be pumped by continuous-wave or pulsed lasers and exhibit all of the defining features of PA. These hallmarks include excitation power thresholds, long rise time at threshold, and a dominant excited-state absorption that is >13,000x larger than ground-state absorption. Beyond the avalanching threshold, ANP emission scales nonlinearly with the 26th power of pump intensity. This enables the realization of photon-avalanche single-beam superresolution imaging (PASSI), achieving sub-70 nm spatial resolution using only simple scanning confocal microscopy and before any computational analysis. Pairing their steep nonlinearity with existing superresolution techniques and computational methods, ANPs allow for imaging with higher resolution and at ca. 100-fold lower excitation intensities than is possible with other probes. The low PA threshold and exceptional photostability of ANPs also suggest their utility in a diverse array of applications including sub-wavelength bioimaging, IR detection, temperature and pressure transduction, neuromorphic computing, and quantum optics., 14 pages, 4 figures

We study how firms adjust their corporate retention policies to their employees’ local job opportunities. The more similarities between the firm’s labor-skill profile and the local labor market’s—a measure we label LEO—the greater are the employees’ outside options. We show that, when LEO is high, firms grant more rank-and-file stock options, provide a more employee-friendly work environment, and maintain higher financial flexibility. The relation between LEO and retention policies is stronger for firms with high-skill workers and high R&D. Two quasi-natural experiments, the staggered adoption of the Inevitable Disclosure Doctrine and Hurricane Katrina, support a causal relation.

This is the Online Appendix to accompany the paper "Human Capital Relatedness and Mergers and Acquisitions". This appendix contains additional results that are referred to but not contained in the paper. Original paper available at: https://ssrn.com/abstract=2996878

Aim: To develop a theranostic nanoemulsion (TNE) that can codeliver the conjugates of a hydrophobic drug paclitaxel (PTX) and a hydrophilic imaging probe sulforhodamine B (SRB). Materials & methods: The TNE was established using core-matched technology, and can achieve high encapsulation efficiency and synchronized release of the loaded cargo. It has been examined for a correlation between the dynamic uptake of PTX and the intensity of SRB imaging signal in different organs. Results & discussion: Our data demonstrate that the TNE, with improved circulation time, increases therapeutic efficacy and imaging efficiency in both drug-sensitive and drug-resistant cancer. The TNE could not satisfy the demand of visual diagnosis in the living animal because of interference. We therefore formulated a long-circulating theranostic nanoemulsion (LCTNE). Results showed that the LCTNE can meet imaging requirements in vivo. Conclusion: The LCTNE plays a good therapeutic and diagnostic role for subcutaneous tumors in the living animal.