An Intentionalist Proposal to Reform the Transformative Use Doctrine

Courts have not reached consensus on how to apply the transformative use standard, which is a major factor in copyright law’s fair use analysis. Many courts implicitly rely on aesthetic theories for interpreting art when judging transformative use, but inconsistent application of these theories creates confusion about what constitutes transformative use. This Article analyzes the aesthetic theories, such as intentionalism and reader response theory, used by courts in landmark transformative use cases. The Article explores issues of unpredictability and subjectivity caused by the use of contradictory aesthetic theories. Ultimately, the Article proposes that courts adopt a moderate intentionalist framework for the transformative use analysis to standardize the inquiry and increase its objectivity

Accelerating Peripheral Nerve Regeneration Using Electrical Stimulation of Selected Power Spectral Densities

Peripheral nerve injuries are common consequences of extremity trauma or chronic compression with a prevalence of 43.8 per 1 million people (on average) reported in the United States annually, accompanied by a yearly increase in cost of care. Patients suffering from these injuries require surgical procedures and rehabilitative strategies to reinforce their extensive recovery. Several studies have found that the application of electrical stimulation can accelerate peripheral nerve regeneration, thus shortening the time of peripheral nerve growth and reducing the cost of care (Willand et al., 2016). The electrical stimulation paradigms that effectively enhanced functional recovery in most studies employed signals of sinusoidal waves delivered at higher frequencies (50–100 Hz) or pulsed waves delivered at lower frequencies (\u3c 20 Hz). As it would be impractical to try to pinpoint the exact stimulation parameter (i.e., frequency or waveform) that will enhance the healing procedure, our task at hand is to conduct a series of experiments with the objective of identifying an optimal arrangement of stimulation parameters for clinical applications. Indeed, the goal of our research is to identify an improved stimulation strategy by precisely determining the contribution of different stimulation parameters and factoring in the possible contribution of these parameters to the response of peripheral glial cells

Correlated decoding of logical algorithms with transversal gates

Quantum error correction is believed to be essential for scalable quantum computation, but its implementation is challenging due to its considerable space-time overhead. Motivated by recent experiments demonstrating efficient manipulation of logical qubits using transversal gates (Bluvstein et al., Nature 626, 58-65 (2024)), we show that the performance of logical algorithms can be substantially improved by decoding the qubits jointly to account for physical error propagation during transversal entangling gates. We find that such correlated decoding improves the performance of both Clifford and non-Clifford transversal entangling gates, and explore two decoders offering different computational runtimes and accuracies. By considering deep logical Clifford circuits, we find that correlated decoding can significantly improve the space-time cost by reducing the number of rounds of noisy syndrome extraction per gate. These results demonstrate that correlated decoding provides a major advantage in early fault-tolerant computation, and indicate it has considerable potential to reduce the space-time cost in large-scale logical algorithms.Comment: 7+12 pages, 5+3 figure

Metabolomic profiles of arsenic (+3 oxidation state) methyltransferase knockout mice: effect of sex and arsenic exposure

Arsenic (+3 oxidation state) methyltransferase (As3mt) is the key enzyme in the pathway for methylation of inorganic arsenic (iAs). Altered As3mt expression and AS3MT polymorphism have been linked to changes in iAs metabolism and in susceptibility to iAs toxicity in laboratory models and in humans. As3mt-knockout mice have been used to study the association between iAs metabolism and adverse effects of iAs exposure. However, little is known about systemic changes in metabolism of these mice and how these changes lead to their increased susceptibility to iAs toxicity. Here, we compared plasma and urinary metabolomes of male and female wild-type (WT) and As3mt-KO (KO) C57BL6 mice and examined metabolomic shifts associated with iAs exposure in drinking water. Surprisingly, exposure to 1 ppm As elicited only small changes in the metabolite profiles of either WT or KO mice. In contrast, comparisons of KO mice with WT mice revealed significant differences in plasma and urinary metabolites associated with lipid (phosphatidylcholines, cytidine, acyl-carnitine), amino acid (hippuric acid, acetylglycine, urea), and carbohydrate (L-sorbose, galactonic acid, gluconic acid) metabolism. Notably, most of these differences were sex-specific. Sex-specific differences were also found between WT and KO mice in plasma triglyceride and lipoprotein cholesterol levels. Some of the differentially changed metabolites (phosphatidylcholines, carnosine, and sarcosine) are substrates or products of reactions catalyzed by other methyltransferases. These results suggest that As3mt KO alters major metabolic pathways in a sex-specific manner, independent of iAs treatment, and that As3mt may be involved in other cellular processes beyond iAs methylation

A randomized phase 2 study of neoadjuvant carboplatin and paclitaxel with or without atezolizumab in triple negative breast cancer (TNBC) - NCI 10013

Atezolizumab with chemotherapy has shown improved progression-free and overall survival in patients with metastatic PD-L1 positive triple negative breast cancer (TNBC). Atezolizumab with anthracycline- and taxane-based neoadjuvant chemotherapy has also shown increased pathological complete response (pCR) rates in early TNBC. This trial evaluated neoadjuvant carboplatin and paclitaxel with or without atezolizumab in patients with clinical stages II-III TNBC. The co-primary objectives were to evaluate if chemotherapy and atezolizumab increase pCR rate and tumor infiltrating lymphocyte (TIL) percentage compared to chemotherapy alone in the mITT population. Sixty-seven patients (ages 25-78 years; median, 52 years) were randomly assigned - 22 patients to Arm A, and 45 to Arm B. Median follow up was 6.6 months. In the modified intent to treat population (all patients evaluable for the primary endpoints who received at least one dose of combination therapy), the pCR rate was 18.8% (95% CI 4.0-45.6%) in Arm A, and 55.6% (95% CI 40.0-70.4%) in Arm B (estimated treatment difference: 36.8%, 95% CI 8.5-56.6%; p = 0.018). Grade 3 or higher treatment-related adverse events occurred in 62.5% of patients in Arm A, and 57.8% of patients in Arm B. One patient in Arm B died from recurrent disease during the follow-up period. TIL percentage increased slightly from baseline to cycle 1 in both Arm A (mean ± SD: 0.6% ± 21.0%) and Arm B (5.7% ± 15.8%) (p = 0.36). Patients with pCR had higher median TIL percentages (24.8%) than those with non-pCR (14.2%) (p = 0.02). Although subgroup analyses were limited by the small sample size, PD-L1-positive patients treated with chemotherapy and atezolizumab had a pCR rate of 75% (12/16). The addition of atezolizumab to neoadjuvant carboplatin and paclitaxel resulted in a statistically significant and clinically relevant increased pCR rate in patients with clinical stages II and III TNBC. (Funded by National Cancer Institute)

Developing an Extracellular Vesicle Based Treatment for Osteoarthritis

Osteoarthritis (OA) is a disease characterized by the degradation of articular cartilage. Extracellular vesicles (EVs) are cargo-filled bodies that mediate intercellular communication and are influential in OA pathogenesis. This study utilized parallel methodologies to investigate whether EV signaling can be manipulated to combat OA. The first approach aimed to identify cells lines that produce EVs with therapeutic activity against OA, while the second introduced miRNA in EVs to induce cartilage regeneration. EVs derived from synovial fibroblasts (SFBs) induced further inflammation. Moreover, miRNA did not impact MMP-13 production. While SFB-EVs were pro-inflammatory, increasing the amount of MMP-13 present, human bone marrow-derived mesenchymal stem cell (BM-hMSC) EVs did not stimulate a change in MMP-13 production. Future studies should further characterize these results to maximize therapeutic impact

Prevalence and diversity of type VI secretion systems in a model beneficial symbiosis

The type VI secretion system (T6SS) is widely distributed in diverse bacterial species and habitats where it is required for interbacterial competition and interactions with eukaryotic cells. Previous work described the role of a T6SS in the beneficial symbiont, Vibrio fischeri, during colonization of the light organ of Euprymna scolopes squid. However, the prevalence and diversity of T6SSs found within the distinct symbiotic structures of this model host have not yet been determined. Here, we analyzed 73 genomes of isolates from squid light organs and accessory nidamental glands (ANGs) and 178 reference genomes. We found that the majority of these bacterial symbionts encode diverse T6SSs from four distinct classes, and most share homology with T6SSs from more distantly related species, including pathogens of animals and humans. These findings indicate that T6SSs with shared evolutionary histories can be integrated into the cellular systems of host-associated bacteria with different effects on host health. Furthermore, we found that one T6SS in V. fischeri is located within a genomic island with high genomic plasticity. Five distinct genomic island genotypes were identified, suggesting this region encodes diverse functional potential that natural selection can act on. Finally, analysis of newly described T6SSs in roseobacter clade ANG isolates revealed a novel predicted protein that appears to be a fusion of the TssB-TssC sheath components. This work underscores the importance of studying T6SSs in diverse organisms and natural habitats to better understand how T6SSs promote the propagation of bacterial populations and impact host health

Dominant-negative variant in SLC1A4 causes an autosomal dominant epilepsy syndrome.

SLC1A4 is a trimeric neutral amino acid transporter essential for shuttling L-serine from astrocytes into neurons. Individuals with biallelic variants in SLC1A4 are known to have spastic tetraplegia, thin corpus callosum, and progressive microcephaly (SPATCCM) syndrome, but individuals with heterozygous variants are not thought to have disease. We identify an 8-year-old patient with global developmental delay, spasticity, epilepsy, and microcephaly who has a de novo heterozygous three amino acid duplication in SLC1A4 (L86_M88dup). We demonstrate that L86_M88dup causes a dominant-negative N-glycosylation defect of SLC1A4, which in turn reduces the plasma membrane localization of SLC1A4 and the transport rate of SLC1A4 for L-serine

An Intentionalist Proposal to Reform the Transformative Use Doctrine

Courts have not reached consensus on how to apply the transformative use standard, which is a major factor in copyright law’s fair use analysis. Many courts implicitly rely on aesthetic theories for interpreting art when judging transformative use, but inconsistent application of these theories creates confusion about what constitutes transformative use. This Article analyzes the aesthetic theories, such as intentionalism and reader response theory, used by courts in landmark transformative use cases. The Article explores issues of unpredictability and subjectivity caused by the use of contradictory aesthetic theories. Ultimately, the Article proposes that courts adopt a moderate intentionalist framework for the transformative use analysis to standardize the inquiry and increase its objectivity