Thrombogenicity of biodegradable metals.

Biodegradable metals offer a promising means to ameliorate many of the long-term risks associated with vascular devices made of conventional biostable stent metals. While numerous biodegradable metal alloys have been developed and characterized in animal models, knowledge of their blood reactivity and thrombogenicity remains unknown. Metal hemocompatibility is particularly valuable because current generation drug-eluting stents pose a significant long-term thrombosis risk. In this study, four pure metals, widely used as degradable base materials (Fe, Zn, Mg, and Mo), and three alloys commonly used in cardiovascular devices [NiTi, CoCr, and stainless steel (SS)] were evaluated. This work examined how each of these metals activate platelets, coagulation factors, and inflammation using in vitro hemocompatibility assays and a clinically relevant ex vivo non-human primate arteriovenous shunt model. Testing found that while all metals promoted a downstream activation of platelets and coagulation in flowing whole blood, platelet and fibrin attachment to Mg was markedly reduced. Additionally, Fe and Mo trended toward higher platelet attachment and contact pathway activation. Overall, the results suggest that Mg may delay clot initiation, but not eliminate clot formation, indicating the importance of understanding thrombosis in Mg alloys that are currently being developed for clinical use as biodegradable stents.

Proteomes of plasmodium knowlesi early and late ring-stage parasites and infected host erythrocytes.

The emerging malaria parasite Plasmodium knowlesi threatens the goal of worldwide malaria elimination due to its zoonotic spread in Southeast Asia. After brief ex-vivo culture we used 2D LC/MS/MS to examine the early and late ring stages of infected Macaca mulatta red blood cells harboring P. knowlesi. The M. mulatta clathrin heavy chain and T-cell and macrophage inhibitor ERMAP were overexpressed in the early ring stage; glutaredoxin 3 was overexpressed in the late ring stage; GO term differential enrichments included response to oxidative stress and the cortical cytoskeleton in the early ring stage. P. knowlesi clathrin heavy chain and 60S acidic ribosomal protein P2 were overexpressed in the late ring stage; GO term differential enrichments included vacuoles in the early ring stage, ribosomes and translation in the late ring stage, and Golgi- and COPI-coated vesicles, proteasomes, nucleosomes, vacuoles, ion-, peptide-, protein-, nucleocytoplasmic- and RNA-transport, antioxidant activity and glycolysis in both stages. SIGNIFICANCE: Due to its zoonotic spread, cases of the emerging human pathogen Plasmodium knowlesi in southeast Asia, and particularly in Malaysia, threaten regional and worldwide goals for malaria elimination. Infection by this parasite can be fatal to humans, and can be associated with significant morbidity. Due to zoonotic transmission from large macaque reservoirs that are untreatable by drugs, and outdoor biting mosquito vectors that negate use of preventive measures such as bed nets, its containment remains a challenge. Its biology remains incompletely understood. Thus we examine the expressed proteome of the early and late ex-vivo cultured ring stages, the first intraerythrocyte developmental stages after infection of host rhesus macaque erythrocytes. We used GO term enrichment strategies and differential protein expression to compare early and late ring stages. The early ring stage is characterized by the enrichment of P. knowlesi vacuoles, and overexpression of the M. mulatta clathrin heavy chain, important for clathrin-coated pits and vesicles, and clathrin-mediated endocytosis. The M. mulatta protein ERMAP was also overexpressed in the early ring stage, suggesting a potential role in early ring stage inhibition of T-cells and macrophages responding to P. knowlesi infection of reticulocytes. This could allow expansion of the host P. knowlesi cellular niche, allowing parasite adaptation to invasion of a wider age range of RBCs than the preferred young RBCs or reticulocytes, resulting in proliferation and increased pathogenesis in infected humans. Other GO terms differentially enriched in the early ring stage include the M. mulatta cortical cytoskeleton and response to oxidative stress. The late ring stage is characterized by overexpression of the P. knowlesi clathrin heavy chain. Combined with late ring stage GO term enrichment of Golgi-associated and coated vesicles, and enrichment of COPI-coated vesicles in both stages, this suggests the importance to P. knowlesi biology of clathrin-mediated endocytosis. P. knowlesi ribosomes and translation were also differentially enriched in the late ring stage. With expression of a variety of heat shock proteins, these results suggest production of folded parasite proteins is increasing by the late ring stage. M. mulatta endocytosis was differentially enriched in the late ring stage, as were clathrin-coated vesicles and endocytic vesicles. This suggests that M. mulatta clathrin-based endocytosis, perhaps in infected reticulocytes rather than mature RBC, may be an important process in the late ring stage. Additional ring stage biology from enriched GO terms includes M. mulatta proteasomes, protein folding and the chaperonin-containing T complex, actin and cortical actin cytoskeletons. P knowlesi biology also includes proteasomes, as well as nucleosomes, antioxidant activity, a variety of transport processes, glycolysis, vacuoles and protein folding. Mature RBCs have lost internal organelles, suggesting infection here may involve immature reticulocytes still retaining organelles. P. knowlesi parasite proteasomes and translational machinery may be ring stage drug targets for known selective inhibitors of these processes in other Plasmodium species. To our knowledge this is the first examination of more than one timepoint within the ring stage. Our results expand knowledge of both host and parasite proteins, pathways and organelles underlying P. knowlesi ring stage biology.

Imaging associations enhance the understanding of ECG abnormalities in male Brazilian football players: findings from the B-Pro Foot ECG study.

OBJECTIVES: To evaluate the prevalence of abnormal ECG findings and their association with imaging results in male Brazilian football players. METHODS: The 'B-Pro Foot ECG' is a multicentre observational study conducted in 82 Brazilian professional clubs. It analysed 6125 players aged 15-35 years (2496 white, 2004 mixed-race and 1625 black individuals) who underwent cardiovascular screening from 2002 to 2023. All ECGs were reviewed by two experienced cardiologists in the athlete's care. Those with abnormal findings underwent further investigations, including a transthoracic echocardiogram (TTE). Cardiac magnetic resonance (CMR) was subsequently performed based on TTE findings or clinical suspicion. RESULTS: In total, 180 (3%) players had abnormal ECGs and 176 (98%) showed normal TTE results. Athletes aged 26-35 years had a higher prevalence of abnormal ECGs than younger athletes (15-25 years). Black players had a higher prevalence of T-wave inversion (TWI) in the inferior leads than white players (2.6% vs 1.4%; p=0.005), as well as in V5 (2.9%) and V6 (2.1%) compared with white (1.2% and 1.0%; p<0.001) and mixed-race (1.5% and 1.2%; p<0.05) players, respectively. TTE parameters were similar across ethnicities. However, four out of 75 players with inferolateral TWI showed abnormal TTEs and CMR findings consistent with cardiomyopathies. CMR also showed cardiomyopathies or myocarditis in four players with inferolateral TWI and normal TTEs. In total, nine (0.1%) athletes were diagnosed with cardiac diseases and were followed for 40±30 months, with no cardiac events documented. CONCLUSION: This study found a 3% prevalence of abnormal ECGs in male Brazilian football players. Inferolateral TWI was associated with cardiac pathologies confirmed by CMR, even in athletes with a normal TTE.

Protection from plague via single dose administration of antibody to neutralize the type I interferon response.

Yersinia pestis is a gram-negative bacterium and the causative agent for the plague. Yersinia spp . use effector proteins of the type III secretion system (T3SS) to skew the host immune response toward a bacterial advantage during infection. Previous work established that mice which lack the type I IFN receptor (IFNAR), exhibit resistance to pulmonary infection by Y. pestis . In this work, we addressed the efficacy of a single dose administration of neutralizing antibody to IFNAR (MAR1) as a preventive treatment for plague. We show that single dose administration of MAR1 provides protection from mortality due to secondary septicemic plague where it appears to reduce the production of serum TNFα during the disease phase. We further demonstrate that the T3SS effector protein YopJ is necessary for MAR1-induced protection, however IFNAR-dependent serum TNFα was observed independent of YopJ. We further define tissue-specific anti-bacterial roles of IFNAR that are blocked by YopJ activity indicating that YopJ and IFNAR work in parallel to promote disease. The combined data suggest that therapeutic targeting of IFNAR signaling may reduce the hyper-inflammatory response associated with plague.

Recreational Marijuana Laws and Teen Marijuana Use, 1993-2021.

This cross-sectional study uses data from the Youth Risk Behavior surveys to assess the association of state-level recreational marijuana laws and youth marijuana use.

Adaptation of sea turtles to climate warming: Will phenological responses be sufficient to counteract changes in reproductive output?

Sea turtles are vulnerable to climate change since their reproductive output is influenced by incubating temperatures, with warmer temperatures causing lower hatching success and increased feminization of embryos. Their ability to cope with projected increases in ambient temperatures will depend on their capacity to adapt to shifts in climatic regimes. Here, we assessed the extent to which phenological shifts could mitigate impacts from increases in ambient temperatures (from 1.5 to 3°C in air temperatures and from 1.4 to 2.3°C in sea surface temperatures by 2100 at our sites) on four species of sea turtles, under a "middle of the road" scenario (SSP2-4.5). Sand temperatures at sea turtle nesting sites are projected to increase from 0.58 to 4.17°C by 2100 and expected shifts in nesting of 26-43 days earlier will not be sufficient to maintain current incubation temperatures at 7 (29%) of our sites, hatching success rates at 10 (42%) of our sites, with current trends in hatchling sex ratio being able to be maintained at half of the sites. We also calculated the phenological shifts that would be required (both backward for an earlier shift in nesting and forward for a later shift) to keep up with present-day incubation temperatures, hatching success rates, and sex ratios. The required shifts backward in nesting for incubation temperatures ranged from -20 to -191 days, whereas the required shifts forward ranged from +54 to +180 days. However, for half of the sites, no matter the shift the median incubation temperature will always be warmer than the 75th percentile of current ranges. Given that phenological shifts will not be able to ameliorate predicted changes in temperature, hatching success and sex ratio at most sites, turtles may need to use other adaptive responses and/or there is the need to enhance sea turtle resilience to climate warming.

The relationship between depressive symptoms and physical performance in postmenopausal women: a cross-sectional investigation.

OBJECTIVE: The relationship between depressive symptoms and declining physical performance in postmenopausal women has been extensively examined. However, various confounding factors can influence this association. This study aimed to investigate the link between depressive symptoms and physical performance in postmenopausal women while considering potential interfering factors. METHODS: In this cross-sectional study, 137 postmenopausal women were categorized into two groups based on the presence of depressive symptoms (n = 58; mean ± SD age, 60.12 ± 8.45 y) and absence of depressive symptoms (n = 79; mean ± SD age, 60.72 ± 7.45) using the Geriatric Depression Scale (short version) (GDS-15). Thoracic kyphosis angle was measured using the flexicurve method. Physical performance was assessed through various tests, including Timed Up and Go, Five Times Stand and Sit Test, 6-minute Walking Speed, 10-meter Usual Walking Speed, 10-meter Fast Walking Speed, and dynamometry. The study compared variables between the two groups and used linear regression models adjusted for dynamometry, kyphosis angle, age, antidepressant usage, sitting time, and fall history to evaluate the relationship between GDS-15 scores and physical performance. RESULTS: Significant differences were observed in physical performance, body mass index, kyphosis angle, antidepressant usage, sitting time, and fall history between women with and without depressive symptoms. The GDS-15 showed a negative association with all walking speed tests (10-meter Usual Walking Speed, m/s; P < 0.001; B = -0.01; 10-meter Fast Walking Speed, m/s; P < 0.001; B = -0.02; 6-minute Walking Speed, m/s; P < 0.004; B = -0.01) and a positive association with the Five Times Stand and Sit Test ( P < 0.002; B = 0.21) and Timed Up and Go ( P < 0.001; B = 0.13) tests, regardless of grip strength, kyphosis angle, age, antidepressant use, sitting time, or fall history in postmenopausal women. CONCLUSIONS: This study underscores the independent and substantial impact of depressive symptoms on the physical performance of postmenopausal women. These findings emphasize the importance of addressing both mental health and physical well-being when providing care and support for this demographic.

Pre-hospital ECPR in an Australian metropolitan setting: a single-arm feasibility assessment-The CPR, pre-hospital ECPR and early reperfusion (CHEER3) study.

INTRODUCTION: Survival from refractory out of hospital cardiac arrest (OHCA) without timely return of spontaneous circulation (ROSC) utilising conventional advanced cardiac life support (ACLS) therapies is dismal. CHEER3 was a safety and feasibility study of pre-hospital deployed extracorporeal membrane oxygenation (ECMO) during cardiopulmonary resuscitation (ECPR) for refractory OHCA in metropolitan Australia. METHODS: This was a single jurisdiction, single-arm feasibility study. Physicians, with pre-existing ECMO expertise, responded to witnessed OHCA, age < 65 yrs, within 30 min driving-time, using an ECMO equipped rapid response vehicle. If pre-hospital ECPR was undertaken, patients were transported to hospital for investigations and therapies including emergent coronary catheterisation, and standard intensive care (ICU) therapy until either cardiac and neurological recovery or palliation occurred. Analyses were descriptive. RESULTS: From February 2020 to May 2023, over 117 days, the team responded to 709 "potential cardiac arrest" emergency calls. 358 were confirmed OHCA. Time from emergency call to scene arrival was 27 min (15-37 min). 10 patients fulfilled the pre-defined inclusion criteria and all were successfully cannulated on scene. Time from emergency call to ECMO initiation was 50 min (35-62 min). Time from decision to ECMO support was 16 min (11-26 min). CPR duration was 46 min (32-62 min). All 10 patients were transferred to hospital for investigations and therapy. 4 patients (40%) survived to hospital discharge neurologically intact (CPC 1/2). CONCLUSION: Pre-hospital ECPR was feasible, using an experienced ECMO team from a single-centre. Overall survival was promising in this highly selected group. Further prospective studies are now warranted.

Hyperon Polarization along the Beam Direction Relative to the Second and Third Harmonic Event Planes in Isobar Collisions at sqrt[s_{NN}]=200 GeV.

The polarization of Λ and Λ[over ¯] hyperons along the beam direction has been measured relative to the second and third harmonic event planes in isobar Ru+Ru and Zr+Zr collisions at sqrt[s_{NN}]=200 GeV. This is the first experimental evidence of the hyperon polarization by the triangular flow originating from the initial density fluctuations. The amplitudes of the sine modulation for the second and third harmonic results are comparable in magnitude, increase from central to peripheral collisions, and show a mild p_{T} dependence. The azimuthal angle dependence of the polarization follows the vorticity pattern expected due to elliptic and triangular anisotropic flow, and qualitatively disagrees with most hydrodynamic model calculations based on thermal vorticity and shear induced contributions. The model results based on one of existing implementations of the shear contribution lead to a correct azimuthal angle dependence, but predict centrality and p_{T} dependence that still disagree with experimental measurements. Thus, our results provide stringent constraints on the thermal vorticity and shear-induced contributions to hyperon polarization. Comparison to previous measurements at RHIC and the LHC for the second-order harmonic results shows little dependence on the collision system size and collision energy.

A resonant sextuplet of sub-Neptunes transiting the bright star HD 110067.

Planets with radii between that of the Earth and Neptune (hereafter referred to as 'sub-Neptunes') are found in close-in orbits around more than half of all Sun-like stars1,2. However, their composition, formation and evolution remain poorly understood3. The study of multiplanetary systems offers an opportunity to investigate the outcomes of planet formation and evolution while controlling for initial conditions and environment. Those in resonance (with their orbital periods related by a ratio of small integers) are particularly valuable because they imply a system architecture practically unchanged since its birth. Here we present the observations of six transiting planets around the bright nearby star HD 110067. We find that the planets follow a chain of resonant orbits. A dynamical study of the innermost planet triplet allowed the prediction and later confirmation of the orbits of the rest of the planets in the system. The six planets are found to be sub-Neptunes with radii ranging from 1.94R⊕ to 2.85R⊕. Three of the planets have measured masses, yielding low bulk densities that suggest the presence of large hydrogen-dominated atmospheres.

Nucleolin binds to and regulates transcription of hepatitis B virus covalently closed circular DNA minichromosome.

Hepatitis B virus (HBV) remains a major public health threat with nearly 300 million people chronically infected worldwide who are at a high risk of developing hepatocellular carcinoma. Current therapies are effective in suppressing HBV replication but rarely lead to cure. Current therapies do not affect the HBV covalently closed circular DNA (cccDNA), which serves as the template for viral transcription and replication and is highly stable in infected cells to ensure viral persistence. In this study, we aim to identify and elucidate the functional role of cccDNA-associated host factors using affinity purification and protein mass spectrometry in HBV-infected cells. Nucleolin was identified as a key cccDNA-binding protein and shown to play an important role in HBV cccDNA transcription, likely via epigenetic regulation. Targeting nucleolin to silence cccDNA transcription in infected hepatocytes may be a promising therapeutic strategy for a functional cure of HBV.

A theory of pitch for the hydrodynamic properties of molecules, helices, and achiral swimmers at low Reynolds number.

We present a theory for pitch, a matrix property that is linked to the coupling of rotational and translational motion of rigid bodies at low Reynolds numbers. The pitch matrix is a geometric property of objects in contact with a surrounding fluid, and it can be decomposed into three principal axes of pitch and their associated moments of pitch. The moments of pitch predict the translational motion in a direction parallel to each pitch axis when the object is rotated around that axis and can be used to explain translational drift, particularly for rotating helices. We also provide a symmetrized boundary element model for blocks of the resistance tensor, allowing calculation of the pitch matrix for arbitrary rigid bodies. We analyze a range of chiral objects, including chiral molecules and helices. Chiral objects with a Cn symmetry axis with n > 2 show additional symmetries in their pitch matrices. We also show that some achiral objects have non-vanishing pitch matrices, and we use this result to explain recent observations of achiral microswimmers. We also discuss the small but non-zero pitch of Lord Kelvin's isotropic helicoid.

PI3K-AKT activation resculpts integrin signaling to drive filamentous tau-induced proinflammatory astrogliosis.

Background Microtubule-binding protein tau is a misfolding-prone protein associated with tauopathies. As tau undergoes cell-to-cell transmission, extracellular tau aggregates convert astrocytes into a pro-inflammatory state via integrin activation, causing them to release unknown neurotoxic factors. Results Here, we combine transcriptomics with isotope labeling-based quantitative mass spectrometry analysis of mouse primary astrocyte secretome to establish PI3K-AKT as a critical differentiator between pathogenic and physiological integrin activation; simultaneous activation of PI3K-AKT and focal adhesion kinase (FAK) in tau fibril-treated astrocytes changes the output of integrin signaling, causing pro-inflammatory gene upregulation, trans-Golgi network restructuring, and altered secretory flow. Furthermore, NCAM1, as a proximal signaling component in tau-stimulated integrin and PI3K-AKT activation, facilitates the secretion of complement C3 as a main neurotoxic factor. Significantly, tau fibrils-associated astrogliosis and C3 secretion can be mitigated by FAK or PI3K inhibitors. Conclusions These findings reveal an unexpected function for PI3K-AKT in tauopathy-associated reactive astrogliosis, which may be a promising target for anti-inflammation-based Alzheimer's therapy.

Erratum: Global Polarization of Ξ and Ω Hyperons in Au+Au Collisions at sqrt[s_{NN}]=200 GeV [Phys. Rev. Lett. 126, 162301 (2021)].

This corrects the article DOI: 10.1103/PhysRevLett.126.162301.

PI3K-AKT activation resculpts integrin signaling to drive filamentous tau-induced proinflammatory astrogliosis.

BACKGROUND: Microtubule-binding protein tau is a misfolding-prone protein associated with tauopathies. As tau undergoes cell-to-cell transmission, extracellular tau aggregates convert astrocytes into a pro-inflammatory state via integrin activation, causing them to release unknown neurotoxic factors. RESULTS: Here, we combine transcriptomics with isotope labeling-based quantitative mass spectrometry analysis of mouse primary astrocyte secretome to establish PI3K-AKT as a critical differentiator between pathogenic and physiological integrin activation; simultaneous activation of PI3K-AKT and focal adhesion kinase (FAK) in tau fibril-treated astrocytes changes the output of integrin signaling, causing pro-inflammatory gene upregulation, trans-Golgi network restructuring, and altered secretory flow. Furthermore, NCAM1, as a proximal signaling component in tau-stimulated integrin and PI3K-AKT activation, facilitates the secretion of complement C3 as a main neurotoxic factor. Significantly, tau fibrils-associated astrogliosis and C3 secretion can be mitigated by FAK or PI3K inhibitors. CONCLUSIONS: These findings reveal an unexpected function for PI3K-AKT in tauopathy-associated reactive astrogliosis, which may be a promising target for anti-inflammation-based Alzheimer's therapy.

In vivo Polycystin-1 interactome using a novel Pkd1 knock-in mouse model.

PKD1 is the most commonly mutated gene causing autosomal dominant polycystic kidney disease (ADPKD). It encodes Polycystin-1 (PC1), a putative membrane protein that undergoes a set of incompletely characterized post-transcriptional cleavage steps and has been reported to localize in multiple subcellular locations, including the primary cilium and mitochondria. However, direct visualization of PC1 and detailed characterization of its binding partners remain challenging. We now report a new mouse model with HA epitopes and eGFP knocked-in frame into the endogenous mouse Pkd1 gene by CRISPR/Cas9. Using this model, we sought to visualize endogenous PC1-eGFP and performed affinity-purification mass spectrometry (AP-MS) and network analyses. We show that the modified Pkd1 allele is fully functional but the eGFP-tagged protein cannot be detected without signal amplification by secondary antibodies. Using nanobody-coupled beads and large quantities of tissue, AP-MS identified an in vivo PC1 interactome, which is enriched for mitochondrial proteins and components of metabolic pathways. These studies suggest this mouse model and interactome data will be useful to understand PC1 function, but that new methods and brighter tags will be required to track endogenous PC1.

The effects of becoming a physician on prescription drug use and mental health treatment.

There is evidence that physicians disproportionately suffer from substance use disorder and mental health problems. It is not clear, however, whether these phenomena are causal. We use data on Dutch medical school applicants to examine the effects of becoming a physician on prescription drug use and the receipt of treatment from a mental health facility. Leveraging variation from lottery outcomes that determine admission into medical schools, we find that becoming a physician increases the use of antidepressants, anxiolytics, opioids, and sedatives. Increases in the use of antidepressants, anxiolytics, and sedatives are larger among female physicians than among their male counterparts.

Measurements of the Elliptic and Triangular Azimuthal Anisotropies in Central

The elliptic (v_{2}) and triangular (v_{3}) azimuthal anisotropy coefficients in central ^{3}He+Au, d+Au, and p+Au collisions at sqrt[s_{NN}]=200 GeV are measured as a function of transverse momentum (p_{T}) at midrapidity (|η|<0.9), via the azimuthal angular correlation between two particles both at |η|<0.9. While the v_{2}(p_{T}) values depend on the colliding systems, the v_{3}(p_{T}) values are system independent within the uncertainties, suggesting an influence on eccentricity from subnucleonic fluctuations in these small-sized systems. These results also provide stringent constraints for the hydrodynamic modeling of these systems.

Observation of Directed Flow of Hypernuclei _{Λ}

We report here the first observation of directed flow (v_{1}) of the hypernuclei _{Λ}^{3}H and _{Λ}^{4}H in mid-central Au+Au collisions at sqrt[s_{NN}]=3 GeV at RHIC. These data are taken as part of the beam energy scan program carried out by the STAR experiment. From 165×10^{6} events in 5%-40% centrality, about 8400 _{Λ}^{3}H and 5200 _{Λ}^{4}H candidates are reconstructed through two- and three-body decay channels. We observe that these hypernuclei exhibit significant directed flow. Comparing to that of light nuclei, it is found that the midrapidity v_{1} slopes of _{Λ}^{3}H and _{Λ}^{4}H follow baryon number scaling, implying that the coalescence is the dominant mechanism for these hypernuclei production in the 3 GeV Au+Au collisions.