Small molecule protein assembly modulators with pan-cancer therapeutic efficacy.

Two structurally unrelated small molecule chemotypes, represented by compounds PAV-617 and PAV-951, with antiviral activity in cell culture against Mpox virus (formerly known as monkeypox virus) and human immunodeficiency virus (HIV) respectively, were studied for anti-cancer efficacy. Each exhibited apparent pan-cancer cytotoxicity with reasonable pharmacokinetics. Non-toxicity is demonstrated in a non-cancer cell line and in mice at doses achieving drug exposure at active concentrations.

Impact of Cavity Length Non-uniformity on Reaction Rate Extraction in Strong Coupling Experiments.

Reports of altered chemical phenomena under vibrational strong coupling, including reaction rates, product distributions, intermolecular forces, and cavity-mediated vibrational energy transfer, have been met with a great deal of skepticism due to several irreproducible results and the lack of an accepted theoretical framework. In this work, we add some insight by identifying a UV-vis measurement artifact that distorts observed absorption peak positions, amplitudes, and consequently, chemical reaction rates extracted in optical microcavities. We predict and characterize the behavior of this artifact using the Transfer Matrix (TM) method and confirm its presence experimentally.

Changes in absolute coronary flow and microvascular resistance during exercise in patients with ANOCA.

Background: Whether saline-induced hyperaemia captures exercise-induced coronary flow regulation remains unknown.

Aims: Through this study, we aimed to describe absolute coronary flow (Q) and microvascular resistance (Rμ) adaptation during exercise in participants with angina with non-obstructive coronary artery disease (ANOCA) and to explore the correlations between saline- and exercise-derived coronary flow reserve (CFR) and microvascular resistance reserve (MRR).

Methods: Rμ, Q, CFR and MRR were assessed in the left anterior descending artery using continuous thermodilution with saline infusion at 10 mL/min (rest), 20 mL/min (hyperaemia) and finally at a 10 mL/min infusion rate during stress testing with a dedicated supine cycling ergometer.

Inhibition of OSBP blocks retrograde trafficking by inducing partial Golgi degradation.

Sterol-binding proteins are important regulators of lipid homeostasis and membrane integrity; however, the discovery of selective modulators can be challenging due to structural similarities in the sterol-binding domains. We report the discovery of potent and selective inhibitors of oxysterol-binding protein (OSBP), which we term oxybipins. Sterol-containing chemical chimeras aimed at identifying new sterol-binding proteins by targeted degradation, led to a significant reduction in levels of Golgi-associated proteins.

A multimodal interface for speech perception: the role of the left superior temporal sulcus in social cognition and autism.

Multimodal integration is crucial for human interaction, in particular for social communication, which relies on integrating information from various sensory modalities. Recently a third visual pathway specialized in social perception was proposed, which includes the right superior temporal sulcus (STS) playing a key role in processing socially relevant cues and high-level social perception. Importantly, it has also recently been proposed that the left STS contributes to audiovisual integration of speech processing.

A viral assembly inhibitor blocks SARS-CoV-2 replication in airway epithelial cells.

The ongoing evolution of SARS-CoV-2 to evade vaccines and therapeutics underlines the need for innovative therapies with high genetic barriers to resistance. Therefore, there is pronounced interest in identifying new pharmacological targets in the SARS-CoV-2 viral life cycle. The small molecule PAV-104, identified through a cell-free protein synthesis and assembly screen, was recently shown to target host protein assembly machinery in a manner specific to viral assembly.

Two-photon chemistry of tetrahydrofuran in clathrate hydrates.

High-lying electronic states hold the potential for new and unusual photochemical reactions. However, for conventional single-photon excitation in the condensed phase, reaching these states is often not possible because the vacuum-ultraviolet (VUV) light required is competitively absorbed by the surrounding matrix rather than the molecule of interest. Here, this hurdle is overcome by leveraging nonresonant two-photon absorption (2PA) at 265 nm to achieve preferential photolysis of tetrahydrofuran (THF) trapped within a clathrate hydrate network at 77 K.

A Novel Viral Assembly Inhibitor Blocks SARS-CoV-2 Replication in Airway Epithelial Cells.

The ongoing evolution of SARS-CoV-2 to evade vaccines and therapeutics underlines the need for novel therapies with high genetic barriers to resistance. The small molecule PAV-104, identified through a cell-free protein synthesis and assembly screen, was recently shown to target host protein assembly machinery in a manner specific to viral assembly. Here, we investigated the capacity of PAV-104 to inhibit SARS-CoV-2 replication in human airway epithelial cells (AECs).

Multimodal imitative learning and synchrony in cetaceans: A model for speech and singing evolution.

Multimodal imitation of actions, gestures and vocal production is a hallmark of the evolution of human communication, as both, vocal learning and visual-gestural imitation, were crucial factors that facilitated the evolution of speech and singing. Comparative evidence has revealed that humans are an odd case in this respect, as the case for multimodal imitation is barely documented in non-human animals. While there is evidence of vocal learning in birds and in mammals like bats, elephants and marine mammals, evidence in both domains, vocal and gestural, exists for two Psittacine birds (budgerigars and grey parrots) and cetaceans only.

In Vitro Biological Effects of E-Cigarette on the Cardiovascular System-Pro-Inflammatory Response Enhanced by the Presence of the Cinnamon Flavor.

The potential cardiovascular effects of e-cigarettes remain largely unidentified and poorly understood. E-liquids contain numerous chemical compounds and can induce exposure to potentially toxic ingredients (e.g.

Peroxide-Selective Reduction of O at Redox-Inactive Rare-Earth(III) Triflates Generates an Ambiphilic Peroxide.

Metal peroxides are key species involved in a range of critical biological and synthetic processes. Rare-earth (group III and the lanthanides; Sc, Y, La-Lu) peroxides have been implicated as reactive intermediates in catalysis; however, reactivity studies of isolated, structurally characterized rare-earth peroxides have been limited. Herein, we report the peroxide-selective (93-99% O) reduction of dioxygen (O) at redox-inactive rare-earth triflates in methanol using a mild metallocene reductant, decamethylferrocene (Fc*).

Faces and Voices Processing in Human and Primate Brains: Rhythmic and Multimodal Mechanisms Underlying the Evolution and Development of Speech.

While influential works since the 1970s have widely assumed that imitation is an innate skill in both human and non-human primate neonates, recent empirical studies and meta-analyses have challenged this view, indicating other forms of reward-based learning as relevant factors in the development of social behavior. The visual input translation into matching motor output that underlies imitation abilities instead seems to develop along with social interactions and sensorimotor experience during infancy and childhood. Recently, a new visual stream has been identified in both human and non-human primate brains, updating the dual visual stream model.

A Pan-Respiratory Antiviral Chemotype Targeting a Host Multi-Protein Complex.

We present a novel small molecule antiviral chemotype that was identified by an unconventional cell-free protein synthesis and assembly-based phenotypic screen for modulation of viral capsid assembly. Activity of PAV-431, a representative compound from the series, has been validated against infectious virus in multiple cell culture models for all six families of viruses causing most respiratory disease in humans. In animals this chemotype has been demonstrated efficacious for Porcine Epidemic Diarrhea Virus (a coronavirus) and Respiratory Syncytial Virus (a paramyxovirus).

Electrophysiological Dynamics of Visual Speech Processing and the Role of Orofacial Effectors for Cross-Modal Predictions.

The human brain generates predictions about future events. During face-to-face conversations, visemic information is used to predict upcoming auditory input. Recent studies suggest that the speech motor system plays a role in these cross-modal predictions, however, usually only audio-visual paradigms are employed.

Origin and evolution of human speech: Emergence from a trimodal auditory, visual and vocal network.

In recent years, there have been important additions to the classical model of speech processing as originally depicted by the Broca-Wernicke model consisting of an anterior, productive region and a posterior, perceptive region, both connected via the arcuate fasciculus. The modern view implies a separation into a dorsal and a ventral pathway conveying different kinds of linguistic information, which parallels the organization of the visual system. Furthermore, this organization is highly conserved in evolution and can be seen as the neural scaffolding from which the speech networks originated.

Outcomes of Prolonged Treatment With Intravenous Immunoglobulin Infusions for Acute Antibody-mediated Rejection in Kidney Transplant Recipients.

Background: Treatment of antibody-mediated rejection (AMR) is one of the main problems after kidney transplantation (KTx). The results of intensive AMR treatment with plasmapheresis (PF) and repeated infusions of intravenous immunoglobulin (IVIg) are presented.

Methods: Diagnosis of AMR was based on graft biopsy and the presence of donor-specific antibodies (DSAs).

Word reading and translation in bilinguals: the impact of formal and informal translation expertise.

Studies on bilingual word reading and translation have examined the effects of lexical variables (e.g., concreteness, cognate status) by comparing groups of non-translators with varying levels of L2 proficiency.

How embodied is action language? Neurological evidence from motor diseases.

Although motor-language coupling is now being extensively studied, its underlying mechanisms are not fully understood. In this sense, a crucial opposition has emerged between the non-representational and the representational views of embodiment. The former posits that action language is grounded on the non-brain motor system directly engaged by musculoskeletal activity - i.

Vasculitis neuropathy mimicking lower limb mono-radiculopathy: a study and follow-up of 8 cases.

The aim of this study was to describe misleading lower limb mono radiculopathy revealing peripheral nerve vasculitis. Retrospective review of eight patients with biopsy confirmed vasculitis presenting as mono-radicululopathy in a tertiary referral centre dedicated to patients with rare peripheral neuropathies. Patients presented with chronic (6/8) or acute (n = 2) radiculopathy in L4, L5 or S1 territories associated with subtle systemic signs.

Assessment and determinants of aesthetic discomfort in hand osteoarthritis.

Background: Dissatisfaction with hand appearance is frequently the presenting complaint of patients with hand osteoarthritis (HOA), yet no tool exists for its measurement and few studies have examined aesthetic discomfort.

Objectives: The aims of this study were to measure the extent and to explore the associations of aesthetic concerns in HOA.

Methods: 172 patients with HOA were assessed with tender joint and node count, global and pain scores, Functional Index for Hand Osteoarthritis, Short Form-12, Hospital Anxiety and Depression Scale and posterior-anterior hand radiographs.

Assessing health-related quality of life in hand osteoarthritis: a literature review.

Background: Hand osteoarthritis (HOA) is a common disease that affects up to 40% of adults and may severely impair their health-related quality of life (HRQL).

Objectives: To assess how HRQL has been evaluated in HOA, focusing on a comparison of HRQL impairment in HOA and rheumatoid arthritis (RA), differences between erosive and non-erosive HOA and differences between OA of the thumb base (TB) and interphalangeal (IP) OA.

Methods: A systematic review of the literature.

Second-trimester ductus venosus measurement and adverse perinatal outcome in fetuses with congenital heart disease.

Objective: The purpose of this study was to determine whether Doppler velocimetry of the ductus venosus (DV) predicts adverse perinatal outcome in congenital heart disease (CHD).

Methods: We conducted a retrospective cohort study of all pregnant women undergoing fetal echocardiography for CHD in a single perinatal center during a 2-year period. We compared outcomes for fetuses having a diagnosis of CHD in the second trimester and abnormal DV Doppler velocimetric findings with those having CHD and normal DV Doppler findings.

[Shoulder arthritis due to Haemophilus aphrophilus].

We report a case of shoulder arthritis due to Haemophilus aphrophilus. The patient, a 56 year-old woman, was immunocompetent. She presented with a septic arthritis of the left shoulder without portal of entry.

Amiodarone therapy for drug-refractory fetal tachycardia.

Background: Fetal tachycardia complicated by ventricular dysfunction and hydrops fetalis carries a significant risk of morbidity and mortality. Transplacental digoxin is effective therapy in a small percentage, but there is no consensus with regard to antiarrhythmic treatment if digoxin fails. This study evaluates the safety, efficacy, and outcome of amiodarone therapy for digoxin-refractory fetal tachycardia with heart failure.