Substantial Similarity Research Articles

Balancing Tumor Immunotherapy and Immune-Related Adverse Events: Unveiling the Key Regulators.

Tumor immunotherapy has emerged as a promising approach in cancer treatment in recent years, offering vast potential. This method primarily involves targeting and inhibiting the suppressive checkpoints present in different immune cells to enhance their activation, ultimately leading to tumor regression. However, tumor cells exploit the surrounding immune cells and tissues to establish a tumor microenvironment (TME) that supports their survival and growth. Within the TME, the efficacy of effector immune cells is compromised, as tumor cells exploit inhibitory immune cells to suppress their function. Furthermore, certain immune cells can be co-opted by tumor cells to facilitate tumor growth. While significantly enhancing the body's tumor immunity can lead to tumor regression, it can also result in severe toxic side effects and an inflammatory factor storm. As a consequence, patients often discontinue treatment due to immune-related adverse events (irAEs) or, in extreme cases, succumb to toxic side effects before experiencing tumor regression. In this analysis, we examined several remission regimens for irAEs, each with its own drawbacks, including toxic side effects or suppression of tumor immunotherapy, which is undesirable. A recent research study, specifically aimed at downregulating intestinal epithelial barrier permeability, has shown promising results in reducing the severity of inflammatory bowel disease (IBD) while preserving immune function. This approach effectively reduces the severity of IBD without compromising the levels of TNF-α and IFN-γ, which are crucial for maintaining the efficacy of tumor immunotherapy. Based on the substantial similarities between IBD and ICI colitis (combo immune checkpoint inhibitors-induced colitis), this review proposes that targeting epithelial cells represents a crucial research direction for mitigating irAEs in the future.

Study protocol TransTAM: Transdiagnostic research into emotional disorders and cognitive-behavioral therapy of the adaptive mind

BackgroundEmotional disorders such as depression and anxiety disorders share substantial similarities in their etiology and treatment. In recent decades, these commonalities have been increasingly recognized in classification systems and treatment programs crossing diagnostic boundaries.MethodsTo examine the prospective effects of different transdiagnostic markers on relevant treatment outcomes, we plan to track a minimum of N = 200 patients with emotional disorders during their routine course of cognitive behavioral therapy at two German outpatient clinics. We will collect a wide range of transdiagnostic markers, ranging from basic perceptual processes and self-report measures to complex behavioral and neurobiological indicators, before entering therapy. Symptoms and psychopathological processes will be recorded before entering therapy, between the 20th and 24th therapy session, and at the end of therapy.DiscussionOur results could help to identify transdiagnostic markers with high predictive power, but also provide deeper insights into which patient groups with which symptom clusters are less likely to benefit from therapy, and for what reasons.Trial RegistrationThe trial was preregistered at the German Clinical Trial Register (DRKS-ID: DRKS00031206; 2023–05-09).

Bacterial hosts and horizontal transfer characteristics of clinically important tet(X)-variant genes in municipal wastewater treatment plants using epicPCR-directed cultivation strategy

Mobile tet(X)-variant genes confer resistance to a wide range of tetracyclines, including the antibiotic of last-resort, tigecycline, raising significant concerns regarding their potential spread cross-environmental dissemination. However, the bacterial hosts and environmental spread of these genes remain poorly understood. Herein, a retrospective study unveiled the prevalence of tet(X)-variant genes (ranging from tet(X3) to tet(X6)) in activated sludge samples from five municipal wastewater treatment plants (WWTPs) from 2013 to 2021. Among these variants, tet(X4) exhibited the highest detection frequency (100%) and abundance [(2.48 ± 3.07) × 107 copies/g dry weight] with an increasing trend. An epicPCR-directed cultivation strategy was proposed to facilitate the targeted isolation of tet(X4)-carrying bacterial hosts in activated sludge. This strategy involves the identification of bacterial host profiles using epicPCR and subsequent selective isolating target bacteria. Enterobacteriaceae emerged as the primary bacterial host for tet(X4), alongside previously unreported genera like Providencia, Advenella, and Moheibacter. Subsequent selective isolation of the most abundant Enterobacteriaceae based on the epicPCR-informed host spectrum yielded 39 tet(X4)-carrying Escherichia coli strains from the WWTP. Whole genome sequencing of tet(X4)-positive strains revealed that plasmid-mediated horizontal gene transfer is the primary mechanism driving tet(X4) dissemination. Plasmids including IncFIA(HI1)/IncHI1A/IncHI1B(R27) and IncX1, commonly reported in various clinical and animal settings, were identified as the predominant carriers of tet(X4). E. coli strains harbouring tet(X4) in the WWTP showed substantial genetic similarity to strains from hospital and animal sources, underscoring concerns about the potential risk of across diverse sectors. This study provided the first glimpse of the presence of mobile tet(X)-variants in WWTPs, and highlighted the promise of the epicPCR-directed cultivation strategy for exploring bacterial hosts of clinically important ARGs in different habitats from a One Health perspective.

Enhancing Wound Healing Potential through the Development of a Herbosomal Transdermal Patch Containing Terminalia bellerica Ethanolic Extract

The process of wound recovery is a complex challenge, wherein the skin and the underlying tissue undergo self-repair following an injury. Wound healing comprises four fundamental stages: haemostasis, inflammation, proliferation, and maturation. The leaves of Terminalia bellerica are widely employed in traditional Indian medicine for the treatment of wounds. Terminalia bellerica contains a variety of chemical constituents, including alkaloids, flavonoids, terpenoids, phenols, tannins, saponins, glycosides, sterols, amino acids, and reducing sugars such as ribose, glucose, lactose, maltose, and sucrose. This study specifically addresses the composition of Terminalia bellerica, focusing particularly on its Herbosomal formulation with potential in wound healing, along with a method for preparing a transdermal patch. Over a 16-day period, a transdermal patch (incorporating F5 composition) demonstrated a reduction in the wound area across different animal groups. Consequently, the formulation (containing F5 composition) expeditiously promotes wound healing (epithelialization time 15.52–16.21 days) and exhibits substantial similarity to the group treated with 5% povidone–iodine ointment. In comparison to existing technology, the transdermal patch (F5 composition with only 50mg of the drug) achieved complete healing in 16.86±3.22 days with 96.10±2.88% wound contraction. The results highlight a significant enhancement in bioavailability and specific wound healing activity for the prepared formulation.

Evaluating the effectiveness of safety countermeasures at highway–railway grade crossing based on a machine learning framework

Objective This research aims to cluster similar highway–railway grade crossings (HRGCs) to examine the safety countermeasures at HRGCs. Methods The methodology integrates inventory and collision data from Federal Railroad Association (FRA) data set during years 2010 to 2022 . The XGBoost and random forest (RF) algorithms are employed to identify influential collision severity factors. Then, the deep latent class analysis (DLCA) method is utilized on selected inventory factors as important features to cluster similar HRGCs. Afterward, collision modification factor (CMF) and standard error (SE) measures are computed for each countermeasure through collisions within each HRGC cluster. Results XGBoost successfully identified 20 important collision and inventory factors with importance levels exceeding 94%, such as the number of daily trains and the surface material. Then, the DCLA method achieved 4 distinct clusters optimized by high similarity within each cluster and significant independence among clusters. The effectiveness of countermeasures was computed in terms of CMF and SE. The CMF results demonstrated that bells achieved superior safety compared to other countermeasures in clusters with sharper track angles and high maximum train speeds. Implementing bells decreased collisions across Clusters 1 and 4, with reductions of 53% (CMF = 0.47) and 46% (CMF = 0.54), respectively. Conclusions The results highlight XGBoost’s capability to identify important collision and inventory factors, successfully uncovering 20 of the most important factors. The DCLA clustering method forms 4 distinct groups marked by substantial internal similarity within each cluster. This approach contributes to a clearer understanding of how each countermeasure impacts collision frequency. The findings highlight the varying effectiveness of different countermeasures across clusters, improving decision making for safety at HRGCs. The study highlights the efficacy of crossbucks in addressing safety concerns during moderate traffic conditions, particularly evident in environments with a highway speed limit between 100 and 125 mph. Additionally, bells demonstrate notable effectiveness in areas with sharper track angles.

The vacuolar sulfate transporter PsSULTR4 is a key determinant of seed yield and protein composition in pea.

Pea is a grain legume crop with a high potential to accelerate the food transition due to its high seed protein content and relatively well-balanced amino acid composition. The critical role of external sulfur (S) supply in determining seed yield and seed quality in pea makes it essential to understand the impact of whole plant S management on the trade-off between these two traits. Here, we investigated the physiological relevance of vacuolar sulfate remobilization by targeting PsSULTR4, the only pea sulfate transporter showing substantial similarity to the vacuolar sulfate exporter AtSULTR4;1. Five mutations in PsSULTR4 were identified by TILLING (Targeting Induced Local Lesions IN Genomes), two of which, a loss of function (W78*) and a missense (E568K), significantly decreased seed yield under S deprivation. We demonstrate that PsSULTR4 triggers S distribution from source tissues, especially lower leaves, to reproductive organs to maintain seed yield under S deficiency. Under sufficient S supply, sultr4 seeds display lower levels of the S-rich storage protein PA1 at maturity. They also overaccumulate sulfate in the endosperm at the onset of seed filling. These findings uncover a role of PsSULTR4 in the remobilization of vacuolar sulfate during embryo development, allowing the efficient synthesis of S-rich proteins. Our study uncovers that PsSULTR4 functions (i) in source tissues to remobilize stored vacuolar sulfate for seed production under low S availability and (ii) in developing seeds well supplied with S to fine-tune sulfate remobilization from the endosperm as a critical control point for storage activities in the embryo.

Inflammation unites diverse acute and chronic diseases.

Inflammation and immunity contribute pivotally to diverse acute and chronic diseases. Inflammatory pathways have become increasingly targets for therapy. Yet, despite substantial similarity in mechanisms and pathways, the scientific, medical, pharma and biotechnology sectors have generally focused programs finely on a single disease entity or organ system. This insularity may impede progress in innovation and the harnessing of powerful new insights into inflammation biology ripe for clinical translation. A multidisciplinary thinktank reviewed highlights how inflammation contributes to diverse diseases, disturbed homeostasis, ageing and impaired healthspan. We explored how common inflammatory and immune mechanisms that operate in key conditions in their respective domains. This consensus review highlights the high degree of commonality of inflammatory mechanisms in a diverse array of conditions that together contribute a major part of the global burden of morbidity and mortality and present an enormous challenge to public health and drain on resources. We demonstrate how that shared inflammatory mechanisms unite many seemingly disparate diseases, both acute and chronic. The examples of infection, cardiovascular conditions, pulmonary diseases, rheumatological disorders, dementia, cancer and ageing illustrate the overlapping pathogenesis. We outline opportunities to synergize, reduce duplication and consolidate efforts of the clinical, research and pharmaceutical communities. Enhanced recognition of these commonalties should promote cross-fertilization and hasten progress in this rapidly moving domain. Greater appreciation of the shared mechanisms should simplify understanding seemingly disparate diseases for clinicians and help them to recognize inflammation as a therapeutic target which the development of novel therapies is rendering actionable.

Inductive thematic analysis of healthcare qualitative interviews using open-source large language models: How does it compare to traditional methods?

BackgroundLarge language models (LLMs) are generative artificial intelligence that have ignited much interest and discussion about their utility in clinical and research settings. Despite this interest there is sparse analysis of their use in qualitative thematic analysis comparing their current ability to that of human coding and analysis. In addition, there has been no published analysis of their use in real-world, protected health information. ObjectiveHere we fill that gap in the literature by comparing an LLM to standard human thematic analysis in real-world, semi-structured interviews of both patients and clinicians within a psychiatric setting. MethodsUsing a 70 billion parameter open-source LLM running on local hardware and advanced prompt engineering techniques, we produced themes that summarized a full corpus of interviews in minutes. Subsequently we used three different evaluation methods for quantifying similarity between themes produced by the LLM and those produced by humans. ResultsThese revealed similarities ranging from moderate to substantial (Jaccard similarity coefficients 0.44–0.69), which are promising preliminary results. ConclusionOur study demonstrates that open-source LLMs can effectively generate robust themes from qualitative data, achieving substantial similarity to human-generated themes. The validation of LLMs in thematic analysis, coupled with evaluation methodologies, highlights their potential to enhance and democratize qualitative research across diverse fields.

Legal Protection of Registered Marks given Law Number 20 of 2016 concerning Brands and Geographical Indications

This research examines the legal protection of registered trademarks based on Law Number 20 of 2016 and handles registered trademark disputes in legal protection initiatives. Even though this research is descriptive and analytical, the author uses normative legal techniques. Article 35 of Law Number 20 of 2016 states that brand protection only applies to registered marks. Ten (10) years are allowed to protect a registered trademark upon receipt, and this period may be extended. The purpose of protecting a registered trademark is to give the owner of the trademark exclusive (special) rights and specific legal remedies that he can take. If there is substantial similarity or malicious intent behind the trademark issue,

Tarda and Tagish Lake: Samples from the same outer Solar System asteroid and implications for D- and P-type asteroids

We report a comprehensive study of the ungrouped type 2 carbonaceous chondrite, Tarda, which fell in Morocco in 2020. This meteorite exhibits substantial similarities to Tagish Lake, Wisconsin Range 91600, and Meteorite Hills 00432, which are generally considered to have originated from a D-type asteroid(s). We constrain the compositions and petrologies of the materials present in a potential sample of a D-type asteroid by reporting the petrography, bulk chemical compositions, bulk H, C, N, Cr, and Ti isotopic compositions, reflectance spectra, and in situ chemical compositions of metals, sulfides, carbonates, and FeO-poor and FeO-rich chondrule silicates of Tarda. We also present new data for Tagish Lake. We then compare Tarda with the other Tagish Lake-like meteorites.Tarda and Tagish Lake appear to be from the same parent body, as demonstrated by their similar petrologies (modal abundances, chondrule sizes), mineral compositions, bulk chemical and isotopic compositions, and reflectance spectra. While the two other Tagish Lake-like meteorites, Wisconsin Range 91600 and Meteorite Hills 00432, show some affinities to Tagish Lake and Tarda, they also share similar characteristics to the Mighei-like carbonaceous (CM) chondrites, warranting further study. Similarities in reflectance spectra suggest that P-type asteroids 65 Cybele and 76 Freia are potential parent bodies of Tarda and the Tagish Lake-like meteorites, or at least have similar surface materials. Since upcoming spacecraft missions will spectrally survey D-type, P-type, and C-type Trojan asteroids (NASA's Lucy) and spectrally study and return samples from Mars' moon Phobos (JAXA's Martian Moons eXploration mission), which is spectrally similar to D-type asteroids, these meteorites are of substantial scientific interest. Furthermore, since Tarda closely spectrally matches P-type asteroids (but compositionally matches the D-type asteroid like Tagish Lake meteorite), P-type and D-type asteroids may represent fragments of the same or similar parent bodies.

Variations in characteristics of bamboo vascular bundles between Dendrocalamus and Bambusa

Unraveling the characteristics of bamboo vascular bundles is critical for understanding their physiology and mechanical properties. However, different bamboo species have different vascular bundles, leading to significant variations in their industrial applications. In this paper, the You Only Look Once algorithm was applied to examine the vascular bundles of several species representatives within Dendrocalamus (Dendrocalamus farinosus, Dendrocalamus asper, and Dendrocalamus latiflorus) and Bambusa (Bambusa pervariabilis, Bambusa textilis, and Bambusa arundinacea), considering their economic and ecological importance. The analysis included the classifications of vascular bundles, their dimensions, and the areas of fiber sheaths. The results showed that the vascular bundles of Dendrocalamus and Bambusa were mainly broken-waist type. Along the radial direction, both Dendrocalamus and Bambusa exhibited gradient variability in vascular bundles, suggesting a similar underlying structural pattern. Quadratic functions could be employed to represent the radial distributions of vascular bundle size and fiber sheath area. Statistically, the fiber sheath area was positively correlated with vascular bundle size (P<0.05). In addition, significant differences in vascular bundles were detected among different bamboo species, which may lead to substantial variations in their mechanical properties. In particular, Bambusa arundinacea had the highest vascular bundle length (724.57 μm) and length/width ratio (1.69), while Dendrocalamus asper had the highest vascular bundle width (552.20 μm) and fiber sheath area (0.22 mm2). Nevertheless, principal component analysis indicated substantial similarity in the vascular bundles of Dendrocalamus and Bambusa. Moreover, the interspecific variations in vascular bundles were notably more pronounced within Dendrocalamus compared to those observed within Bambusa. Overall, our study examined the variations in vascular bundles between Dendrocalamus and Bambusa, offering insights that hold significant potential for bamboo taxonomy and the design of bio-inspired materials.

Aptamer Proteomics for Biomarker Discovery in Heart Failure With Preserved Ejection Fraction: The PARAGON-HF Proteomic Substudy.

Prognostic markers and biological pathways linked to detrimental clinical outcomes in heart failure with preserved ejection fraction (HFpEF) remain incompletely defined. We measured serum levels of 4123 unique proteins in 1117 patients with HFpEF enrolled in the PARAGON-HF (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction) trial using a modified aptamer proteomic assay. Baseline circulating protein concentrations significantly associated with the primary end point and the timing and occurrence of total heart failure hospitalization and cardiovascular death were identified by recurrent events regression, accounting for multiple testing, adjusted for age, sex, treatment, and anticoagulant use, and compared with published analyses in 2515 patients with heart failure with reduced ejection fraction from the PARADIGM-HF (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) and ATMOSPHERE (Efficacy and Safety of Aliskiren and Aliskiren/Enalapril Combination on Morbidity-Mortality in Patients With Chronic Heart Failure) clinical trials. We identified 288 proteins that were robustly associated with the risk of heart failure hospitalization and cardiovascular death in patients with HFpEF. The baseline proteins most strongly related to outcomes included B2M (β-2 microglobulin), TIMP1 (tissue inhibitor of matrix metalloproteinase 1), SERPINA4 (serpin family A member 4), and SVEP1 (sushi, von Willebrand factor type A, EGF, and pentraxin domain containing 1). Overall, the protein-outcome associations in patients with HFpEF did not markedly differ as compared with patients with heart failure with reduced ejection fraction. A proteomic risk score derived in patients with HFpEF was not superior to a previous proteomic score derived in heart failure with reduced ejection fraction nor to clinical risk factors, NT-proBNP (N-terminal pro-B-type natriuretic peptide), or high-sensitivity cardiac troponin. Numerous serum proteins linked to metabolic, coagulation, and extracellular matrix regulatory pathways were associated with worse HFpEF prognosis in the PARAGON-HF proteomic substudy. Our results demonstrate substantial similarities among serum proteomic risk markers for heart failure hospitalization and cardiovascular death when comparing clinical trial participants with heart failure across the ejection fraction spectrum. URL: https://www.clinicaltrials.gov; Unique Identifiers: NCT01920711, NCT01035255, NCT00853658.

Constrained hidden Markov models reveal further Hsp90 protein states

Time series of conformational dynamics in proteins are usually evaluated with hidden Markov models (HMMs). This approach works well if the number of states and their connectivity is known. However, for the multi-domain protein Hsp90, a standard HMM analysis with optimization of the BIC (Bayesian information criterion) cannot explain long-lived states well. Therefore, here we employ constrained HMMs, which neglect transitions between states by including assumptions. Gradually tuning a model with justified and focused changes allows us to improve its effectiveness and the score of the BIC. This became possible by analyzing time traces with several thousand observable transitions and, therefore, superb statistics. In this scheme, we also monitor the residences in the states reconstructed by the model, aiming to find exponentially distributed dwell times. We show how introducing new states can achieve these statistics but also point out limitations, e.g. for substantial similarity of two states connected to a common neighbor. One of the states displays the lowest free energy and could be the idle open ‘waiting state’, in which Hsp90 waits for the binding of nucleotides, cochaperones, or clients.

Epigenomic differences between osteoarthritis grades in primary cartilage

ObjectiveOsteoarthritis is a common and complex joint disorder that shows higher prevalence and greater disease severity in women. Here, we investigate genome-wide methylation profiles of primary chondrocytes from osteoarthritis patients. DesignWe compare genome-wide methylation profiles of macroscopically intact (low-grade) and degraded (high-grade) osteoarthritis cartilage samples matched from osteoarthritis patients undergoing knee replacement surgery. We perform an epigenome-wide association study (EWAS) for cartilage degeneration across 170 patients and separately in 96 women and 74 men. ResultsWe reveal widespread epigenetic differences with enrichments of nervous system and apoptosis-related processes. We further identify substantial similarities between sexes, but also sex-specific markers and pathways. ConclusionsTogether, we provide the largest genome-wide methylation profiles of primary cartilage to date with enhanced and sex-specific insights into epigenetic processes underlying osteoarthritis progression.

Unveiling the Complexities of ESG and CSR Disclosures Determinants: A Systematic Literature Review

The intensifying focus on environmental, social, and governance (ESG) and corporate social responsibility (CSR) in recent years has attracted substantial scholarly interest in investigating the determinants of these disclosure practices. While notable similarities between ESG and CSR were found, the somewhat murky relationship between the two has introduced significant ambiguities into the academic discourse. To address this issue, this study performed a systematic review of 164 articles sourced from the Web of Science and Scopus databases, indicating post-2018 articles to constitute 70% and 81% concentrating on the extent of disclosures. The literature revealed substantial similarities in the theoretical frameworks and discovered determinants, but exposed considerable confusion concerning the definitions and proxies used for CSR disclosures which future research can address. The study offers insightful clarity to the burgeoning knowledge of ESG and CSR, benefiting both academicians and practitioners.

Exploiting and Enhancing the Heat Transport Rate of MoS2-Ag/EO Hybrid Nanofluid Flow via a Stretching Cylinder using Extended Yamada-Ota and Xue Models.

The current model offers valuable insights for materials science, heat exchangers, renewable energy production, nanotechnology, manufacturing, medicinal treatments, and environmental engineering. The findings of this study have the potential to improve material design, increase heat transfer efficiency across various systems, enhance energy conversion processes, and drive advancements in nanotechnology, medicinal treatments, and engineering design. The goal of the current research is to analyze the effects of thermal radiation and the volume fraction of nanoparticles in MoS2-Ag/engine oil-based hybrid nanofluid flow passing through a cylinder. After performing a substantial similarity transformation, the nonlinear dimensionless framework is recast as ODEs. The Yamada-Ota and Xue models are then applied to the dimensionless equation setup, which is numerically solved using the BVP4C approach. The resulting velocity and temperature fields, corresponding to various parameters, are examined and compared across both models. This investigation demonstrates a significant variation in heat transfer rates between the Yamada-Ota and Xue models, with the former having a larger impact. The velocity and temperature fields decrease as the magnetic field parameter increases in both nanofluids. However, as the magnetic field parameter values grow, the velocity fields in the two nanofluids behave differently. The Yamada-Ota and Xue models are used to determine the behavior of the hybrid nanofluid flow over a nonlinear extended cylinder. In all situations, the velocity and temperature fields exhibit superior decay characteristics.

Design, Synthesis, and Structure-Activity Relationships of Novel Peptide Derivatives of the Severe Acute Respiratory Syndrome-Coronavirus-2 Spike-Protein that Potently Inhibit Nicotinic Acetylcholine Receptors.

The spike-protein of SARS-CoV-2 has a distinctive amino-acid sequence (682RRARS686) that forms a cleavage site for the enzyme furin. Strikingly, the structure of the spike-protein loop containing the furin cleavage site bears substantial similarity to neurotoxin peptides found in the venoms of certain snakes and marine cone snails. Leveraging this relationship, we designed and synthesized disulfide-constrained peptides with amino-acid sequences corresponding to the furin cleavage-sites of wild-type (B.1 variant) SARS-CoV-2 or the Alpha, Delta, and Omicron variants. Remarkably, some of these peptides potently inhibited α7 and α9α10 nicotinic acetylcholine receptors (nAChR) with nM affinity and showed SARS-CoV-2 variant and nAChR subtype-dependent potencies. Nuclear magnetic resonance spectroscopy and molecular dynamics were used to rationalize structure-activity relationships between peptides and their cognate receptors. These findings delineate nAChR subtypes that can serve as high-affinity spike-protein targets in tissues central to COVID-19 pathophysiology and identify ligands and target receptors to inform the development of novel SARS-CoV-2 therapeutics.

How Generative AI Turns Copyright Law Upside Down

While courts are litigating many copyright issues involving generative AI, from who owns AI-generated works to the fair use of training to infringement by AI outputs, the most fundamental changes generative AI will bring to copyright law don’t fit in any of those categories. The new model of creativity, generative AI puts considerable strain on copyright’s two most fundamental legal doctrines: the idea-expression dichotomy and the substantial similarity test for infringement. Increasingly, creativity will be lodged in asking the right questions, not in creating the answers. Asking questions may sometimes be creative, but the AI does the bulk of the work that copyright traditionally exists to reward, and that work will not be protected. That inverts what copyright law now prizes. And because asking the questions will be the basis for copyrightability, similarity of expression in the answers will no longer be of much use in proving the copying of the questions. That means we may need to throw out our test for infringement, or at least apply it in fundamentally different ways.

Evaluation of comparative chemical profiling and bioactivities of medicinal and non-medicinal parts of Ampelopsis delavayana

Ampelopsis delavayana, a distinctive Yi medicine, utilized the roots as an essential medicinal substance for trauma treatment of the “Yunnan Hong Yao”. A. delavayana, however, cannot be cultivated artificially presently, and it has been described with a phenomenon of mixed utilization of roots and stems, impeding pharmaceutical quality control. In response to resource scarcity and standardization issues, the research comprehensively compares the material basis and efficacy of medicinal (roots) and non-medicinal (stems) parts by using chemical profiling and pharmacological methodologies. Chemical disparity between two parts was compared by TLC and HPLC. Analgesia and anti-inflammatory capabilities of both parts were comprehensively evaluated through acetic acid writhing test, hot plate test, and xylene-induced mouse ear swelling test. Additionally, all the extracts were evaluated for anti-inflammatory activities by monitoring regulation of the levels of TNF-α, IL-1β, IL-6, and IgE in ear tissue. Consequently, the findings of TLC and HPLC revealed substantial similarity in the material basis of the medicinal and non-medicinal parts of A. delavayana, and pharmacological activities of anti-inflammatory and analgesic between two parts were consistent. Different extracts remarkably reduced the levels of TNF-α, IL-1β, IL-6, and IgE, demonstrating no discernible differences. Collectively, the comprehensive exploitation indicated that the medicinal and non-medicinal parts of A. delavayana exhibited identical chemical profiling and bioactivities, providing a theoretical rationale and scientific evidence for using stems as a therapeutic part, thereby holding considerable potential for ameliorating the current status of its medicinal reserves.

Acromegaly in humans and cats: Pathophysiological, clinical and management resemblances and differences

ObjectiveAcromegaly is a disorder associated with excessive levels of growth hormone (GH) and insulin-like growth factor-1 (IGF-1). In general, GH/IGF-1 excess leads to morphologic craniofacial and acral changes as well as cardiometabolic complications, but the phenotypic changes and clinical presentation of acromegaly differ across species. Here, we review the pathophysiology, clinical presentation and management of acromegaly in humans and cats, and we provide a systematic comparison between this disease across these different species. DesignA comprehensive literature review of pathophysiology, clinical features, diagnosis and management of acromegaly in humans and in cats was performed. ResultsAcromegaly is associated with prominent craniofacial changes in both species: frontal bossing, enlarged nose, ears and lips, and protuberant cheekbones are typically encountered in humans, whereas increased width of the head and skull enlargement are commonly found in cats. Malocclusion, prognathism, dental diastema and upper airway obstruction by soft tissue enlargement are reported in both species, as well as continuous growth and widening of extremities resulting in osteoarticular compromise. Increase of articular joint cartilage thickness, vertebral fractures and spine malalignment is more evident in humans, while arthropathy and spondylosis deformans may also occur in cats. Generalized organomegaly is equally observed in both species. Other similarities between humans and cats with acromegaly include heart failure, ventricular hypertrophy, diabetes mellitus, and an overall increased cardiometabolic risk. In GH-secreting pituitary tumours, local compressive effects and behavioral changes are mostly observed in humans, but also present in cats. Cutis verticis gyrata and skin tags are exclusively found in humans, while palmigrade/plantigrade stance may occur in some acromegalic cats.Serum IGF-1 is used for acromegaly diagnosis in both species, but an oral glucose tolerance test with GH measurement is only useful in humans, as glucose load does not inhibit GH secretion in cats. Imaging studies are regularly performed in both species after biochemical diagnosis of acromegaly. Hypophysectomy is the first line treatment for humans and cats, although not always available in veterinary medicine. ConclusionAcromegaly in humans and cats has substantial similarities, as a result of common pathophysiological mechanisms, however species-specific features may be found.