Miracle-dz/UniFAR-FTUs huggingface dataset:
Paleolakes and socioecological implications of last glacial “greening” of the South African interior

Significance Renowned for its rich evidence pertaining to early Homo sapiens, South Africa’s late Pleistocene archaeological record remains biased toward the continental margins. A profusion of coastal rockshelters, together with putative associations of glacial periods with intense aridity in the continental interior, has created historical impressions of an inland core hostile to human life during lengthy glacial phases. New geological data and large-scale hydrological modeling experiments reveal that a series of large, now-dry palaeolakes existed for protracted phases of marine isotope stages 3 and 2. Modern analog reconstructions of resulting vegetational and faunal communities suggest that glacial climates were capable of transforming South Africa’s central interior into a resource-rich landscape favorable to human populations.
Zika Virus Infection Induces Interleukin-1β-Mediated Inflammatory Responses by Macrophages in the Brain of an Adult Mouse Model

Zika virus (ZIKV) associated neurological impairments are an important global health problem. Our results suggest that ZIKV infection in the mouse brain can induce IL-1β-mediated inflammation and complement activation, thereby contributing to the development of neurological disorders. ABSTRACT During the 2015–2016 Zika virus (ZIKV) epidemic, ZIKV-associated neurological diseases were reported in adults, including microcephaly, Guillain-Barre syndrome, myelitis, meningoencephalitis, and fatal encephalitis. However, the mechanisms underlying the neuropathogenesis of ZIKV infection are not yet fully understood. In this study, we used an adult ZIKV infection mouse model (Ifnar1−/−) to investigate the mechanisms underlying neuroinflammation and neuropathogenesis. ZIKV infection induced the expression of proinflammatory cytokines, including interleukin-1β (IL-1β), IL-6, gamma interferon, and tumor necrosis factor alpha, in the brains of Ifnar1−/− mice. RNA-seq analysis of the infected mouse brain also revealed that genes involved in innate immune responses and cytokine-mediated signaling pathways were significantly upregulated at 6 days postinfection. Furthermore, ZIKV infection induced macrophage infiltration and activation and augmented IL-1β expression, whereas microgliosis was not observed in the brain. Using human monocyte THP-1 cells, we confirmed that ZIKV infection promotes inflammatory cell death and increases IL-1β secretion. In addition, expression of the complement component C3, which is associated with neurodegenerative diseases and known to be upregulated by proinflammatory cytokines, was induced by ZIKV infection through the IL-1β-mediated pathway. An increase in C5a produced by complement activation in the brains of ZIKV-infected mice was also verified. Taken together, our results suggest that ZIKV infection in the brain of this animal model augments IL-1β expression in infiltrating macrophages and elicits IL-1β-mediated inflammation, which can lead to the destructive consequences of neuroinflammation. IMPORTANCE Zika virus (ZIKV) associated neurological impairments are an important global health problem. Our results suggest that ZIKV infection in the mouse brain can induce IL-1β-mediated inflammation and complement activation, thereby contributing to the development of neurological disorders. Thus, our findings reveal a mechanism by which ZIKV induces neuroinflammation in the mouse brain. Although we used adult type I interferon receptor IFNAR knockout (Ifnar1−/−) mice owing to the limited mouse models of ZIKV pathogenesis, our conclusions contributed to the understanding ZIKV-associated neurological diseases to develop treatment strategies for patients with ZIKV infection based on these findings.
The neurovascular unit in healthy and injured spinal cord

The neurovascular unit (NVU) reflects the close temporal and spatial link between neurons and blood vessels. However, the understanding of the NVU in the spinal cord is far from clear and largely based on generalized knowledge obtained from the brain. Herein, we review the present knowledge of the NVU and highlight candidate approaches to investigate the NVU, particularly focusing on the spinal cord. Several unique features maintain the highly regulated microenvironment in the NVU. Autoregulation and neurovascular coupling ensure regional blood flow meets the metabolic demand according to the blood supply or local neural activation. The blood–central nervous system barrier partitions the circulating blood from neural parenchyma and facilitates the selective exchange of substances. Furthermore, we discuss spinal cord injury (SCI) as a common injury from the perspective of NVU dysfunction. Hopefully, this review will help expand the understanding of the NVU in the spinal cord and inspire new insights into SCI.
Local angiogenic interplay of Vegfc/d and Vegfa controls brain region-specific emergence of fenestrated capillaries

Fenestrated and blood-brain barrier (BBB)-forming endothelial cells constitute major brain capillaries, and this vascular heterogeneity is crucial for region-specific neural function and brain homeostasis. How these capillary types emerge in a brain region-specific manner and subsequently establish intra-brain vascular heterogeneity remains unclear. Here, we performed a comparative analysis of vascularization across the zebrafish choroid plexuses (CPs), circumventricular organs (CVOs), and retinal choroid, and show common angiogenic mechanisms critical for fenestrated brain capillary formation. We found that zebrafish deficient for Gpr124, Reck, or Wnt7aa exhibit severely impaired BBB angiogenesis without any apparent defect in fenestrated capillary formation in the CPs, CVOs, and retinal choroid. Conversely, genetic loss of various Vegf combinations caused significant disruptions in Wnt7/Gpr124/Reck signaling-independent vascularization of these organs. The phenotypic variation and specificity revealed heterogeneous endothelial requirements for Vegfs-dependent angiogenesis during CP and CVO vascularization, identifying unexpected interplay of Vegfc/d and Vegfa in this process. Mechanistically, expression analysis and paracrine activity-deficient vegfc mutant characterization suggest that endothelial cells and non-neuronal specialized cell types present in the CPs and CVOs are major sources of Vegfs responsible for regionally restricted angiogenic interplay. Thus, brain region-specific presentations and interplay of Vegfc/d and Vegfa control emergence of fenestrated capillaries, providing insight into the mechanisms driving intra-brain vascular heterogeneity and fenestrated vessel formation in other organs.
Flexible nasal bronchoscopy vs. Airtraq® videolaryngoscopy for awake tracheal intubation: a randomised controlled non‐inferiority study

Videolaryngoscopy is a suitable alternative to flexible bronchoscopy to facilitate awake tracheal intubation. The relative effectiveness of these techniques in clinical practice is unknown. We compared flexible nasal bronchoscopy with Airtraq® videolaryngoscopy in patients with an anticipated difficult airway scheduled for awake tracheal intubation. Patients were allocated randomly to flexible nasal bronchoscopy or videolaryngoscopy. All procedures were performed with upper airway regional anaesthesia blockade and a target‐controlled intravenous infusion of remifentanil. The success rate with the allocated technique was the primary outcome. A non‐inferiority analysis with a predefined limit of 8% was planned. Seventy‐eight patients were recruited, allocated randomly and analysed. The rate of successful intubation was 97% and 82% in the flexible bronchoscopy and videolaryngoscopy groups, respectively, p = 0.032. The median (IQR [range]) time to tracheal intubation was shorter with the Airtraq, 163 (105–332 [40–1004]) vs. 217 (180–364 [120–780]) s, p = 0.030. There were no significant differences for complications found between the groups. The median visual analogue scale for ease of intubation was 8 (7–9 [0–10]) for Airtraq vs. 8 (7–9 [0–10]) for flexible bronchoscopy, p = 0.710. The median visual analogue scale for patient comfort for Airtraq was 8 (6–9 [2–10]) vs. 8 (7–9 [3–10]) for flexible bronchoscopy, p = 0.370. The Airtraq videolaryngoscope is not non‐inferior to flexible bronchoscopy for awake tracheal intubation in a clinical setting when awake tracheal intubation is indicted. It may be a suitable alternative when judged on a case‐by‐case basis.
Relative apical sparing in cardiac amyloidosis is not always explained by an amyloid gradient

Abstract Aims Myocardial longitudinal strain (LS) by two-dimensional (2D) speckle-tracking echocardiography has a diagnostic and prognostic role in cardiac amyloidosis (CA). Typically, the apical segments of the left ventricle (LV) are less affected by LS abnormalities, a finding called relative apical sparing (RELAPS). Whether a variable burden of CA might explain the RELAPS remains unknown. We aimed to evaluate the extent, distribution, and deposition pattern of amyloid in autopsy hearts of CA patients and to correlate the histopathology findings with 2D echocardiography. Methods and results This is a retrospective study of whole heart specimens of CA patients who died and underwent autopsy and 2D echocardiography. Amyloid burden quantification was assessed by histomorphometry in each segment at different LV levels. The LS analysis results were compared with the amyloid burden and the base-to-apex distribution. Histopathology investigation of 27 hearts with CA [immunoglobulin light chains (AL) 17 cases and transthyretin (ATTR) 10 cases] demonstrated an amyloid base-to-apex gradient. In 11 CA patients with 2D echocardiography, analysis of LS and histological amyloid burden allowed to identify different patterns: RELAPS (8 cases, 73%), with (2) or without (6) amyloid gradient, normal or mildly reduced LS with diffuse low amyloid (2, 18%), and severely reduced LS with diffuse high amyloid (1, 9%). Conclusion The typical RELAPS pattern at echocardiography is not always explained by a base-to-apex gradient of amyloid burden at histopathology, suggesting that RELAPS might be an epiphenomenon of complex interactions among amyloid infiltration, myocardial structure, and adaptation.
An in-vivo study of the combined therapeutic effects of pulsed non-thermal focused ultrasound and radiation for prostate cancer

Abstract Purpose The purpose of this study was to investigate the in vivo combined effects of pulsed focused ultrasound (pFUS) and radiation (RT) for prostate cancer treatment. Materials and Methods An animal prostate tumor model was developed by implanting human LNCaP tumor cells in the prostates of nude mice. Tumor-bearing mice were treated with pFUS, RT or both (pFUS + RT) and compared with a control group. Non-thermal pFUS treatment was delivered by keeping the body temperature below 42 °C as measured real-time by MR thermometry and using a pFUS protocol (1 MHz, 25 W focused ultrasound; 1 Hz pulse rate with a 10% duty cycle for 60 sec for each sonication). Each tumor was covered entirely using 4–8 sonication spots. RT treatment with a dose of 2 Gy was delivered using an external beam (6 MV photon energy with dose rate 300MU/min). Following the treatment, mice were scanned weekly with MRI for tumor volume measurement. Results The results showed that the tumor volume in the control group increased exponentially to 142 ± 6%, 205 ± 12%, 286 ± 22% and 410 ± 33% at 1, 2, 3 and 4 weeks after treatment, respectively. In contrast, the pFUS group was 29% (p < 0.05), 24% (p < 0.05), 8% and 9% smaller, the RT group was 7%, 10%, 12% and 18% smaller, and the pFUS + RT group was 32%, 39%, 41% and 44% (all with p < 0.05) smaller than the control group at 1, 2, 3, and 4 weeks post treatment, respectively. Tumors treated by pFUS showed an early response (i.e. the first 2 weeks), while the RT group showed a late response. The combined pFUS + RT treatment showed consistent response throughout the post-treatment weeks. Conclusions These results suggest that RT combined with non-thermal pFUS can significantly delay the tumor growth. The mechanism of tumor cell killing between pFUS and RT may be different. Pulsed FUS shows early tumor growth delay, while RT contributes to the late effect on tumor growth delay. The addition of pFUS to RT significantly enhanced the therapeutic effect for prostate cancer treatment.
Comparison of Oral and Intravenous Definitive Antibiotic Therapy for Beta-Hemolytic Streptococcus Species Bloodstream Infections from Soft Tissue Sources: a Propensity Score-Matched Analysis

Beta-hemolytic streptococci are common causes of bloodstream infection (BSI). There is emerging data regarding oral antibiotics for BSI but limited for beta-hemolytic streptococcal BSI. ABSTRACT Beta-hemolytic streptococci are common causes of bloodstream infection (BSI). There is emerging data regarding oral antibiotics for BSI but limited for beta-hemolytic streptococcal BSI. We conducted a retrospective study of adults with beta-hemolytic streptococcal BSI from a primary skin/soft tissue source from 2015 to 2020. Patients transitioned to oral antibiotics within 7 days of treatment initiation were compared to those who continued intravenous therapy, after propensity score matching. The primary outcome was 30-day treatment failure (composite of mortality, infection relapse, and hospital readmission). A prespecified 10% noninferiority margin was used for the primary outcome. We identified 66 matched pairs of patients treated with oral and intravenous antibiotics as definitive therapy. Based on an absolute difference in 30-day treatment failure of 13.6% (95% confidence interval 2.4 to 24.8%), the noninferiority of oral therapy was not confirmed (P = 0.741); on the contrary, the superiority of intravenous antibiotics is suggested by this difference. Acute kidney injury occurred in two patients who received intravenous treatment and zero who received oral therapy. No patients experienced deep vein thrombosis or other vascular complications related to treatment. In patients treated for beta-hemolytic streptococcal BSI, those who transitioned to oral antibiotics by day 7 showed higher rates of 30-day treatment failure than propensity-matched patients. This difference may have been driven by underdosing of oral therapy. Further investigation into optimal antibiotic choice, route, and dosing for definitive therapy of BSI is needed.
Efficacy and Imaging-Enabled Pharmacodynamic Profiling of KRAS G12C Inhibitors in Xenograft and Genetically Engineered Mouse Models of Cancer

Abstract KRAS is one of the most commonly mutated oncogenes in lung, colorectal, and pancreatic cancers. Recent clinical trials directly targeting KRAS G12C presented encouraging results for a large population of non–small cell lung cancer (NSCLC), but resistance to treatment is a concern. Continued exploration of new inhibitors and preclinical models is needed to address resistance mechanisms and improve duration of patient responses. To further enable the development of KRAS G12C inhibitors, we present a preclinical framework involving translational, non-invasive imaging modalities (CT and PET) and histopathology in a conventional xenograft model and a novel KRAS G12C knock-in mouse model of NSCLC. We utilized an in-house developed KRAS G12C inhibitor (Compound A) as a tool to demonstrate the value of this framework in studying in vivo pharmacokinetic/pharmacodynamic (PK/PD) relationship and anti-tumor efficacy. We characterized the Kras G12C-driven genetically engineered mouse model (GEMM) and identify tumor growth and signaling differences compared to its Kras G12D-driven counterpart. We also find that Compound A has comparable efficacy to sotorasib in the Kras G12C-driven lung tumors arising in the GEMM, but like observations in the clinic, some tumors inevitably progress on treatment. These findings establish a foundation for evaluating future KRAS G12C inhibitors that is not limited to xenograft studies and can be applied in a translationally relevant mouse model that mirrors human disease progression and resistance.
Distinct subunit architecture and assembly pattern of DNA gyrase from mycobacteria

DNA gyrase, the sole negative supercoiling type II topoisomerase, is composed of two subunits, GyrA and GyrB, encoded by the gyrA and gyrB genes, respectively, that form a quaternary complex of A2B2. In this study, we have investigated the assembly of mycobacterial DNA gyrase from its individual subunits, a step prerequisite for its activity. Using analytical size‐exclusion chromatography, we show that GyrA from Mycobacterium tuberculosis and Mycobacterium smegmatis forms tetramers (A4) in solution unlike in Escherichia coli and other bacteria where GyrA exists as a dimer. GyrB, however, persists as a monomer, resembling the pattern found in E. coli. GyrB in both mycobacterial species interacts with GyrA and triggers the dissociation of the GyrA tetramer to facilitate the formation of catalytically active A2B2. Despite oligomerisation, the GyrA tetramer retained its DNA binding ability, and DNA binding had no effect on GyrA's oligomeric state in both species. Moreover, the presence of DNA facilitated the assembly of holoenzyme in the case of M. smegmatis by stabilising the GyrA2B2 tetramer but with little effect in M. tuberculosis. Thus, in addition to the distinct organisation and regulation of the gyr locus in mycobacteria, the enzyme assembly also follows a different pattern.
Contrasting sensitivity of soil bacterial and fungal community composition to one year of water limitation in Scots pine mesocosms

Abstract The soil microbiome is crucial for regulating biogeochemical processes and can, thus, strongly influence tree health, especially under stress conditions. However, little is known about the effect of prolonged water deficit on soil microbial communities during the development of saplings. We assessed the response of prokaryotic and fungal communities to different levels of experimental water limitation in mesocosms with Scots pine saplings. We combined analyses of physicochemical soil properties and tree growth with DNA metabarcoding of soil microbial communities throughout four seasons. Seasonal changes in soil temperature and soil water content and a decreasing soil pH strongly influenced the composition of microbial communities but not their total abundance. Contrasting levels of soil water contents gradually altered the soil microbial community structure over the four seasons. Results indicated that prokaryotic communities were less resistant to water limitation than fungal communities. Water limitation promoted the proliferation of desiccation tolerant, oligotrophic taxa. Moreover, water limitation and an associated increase in soil C/N ratio induced a shift in the potential lifestyle of taxa from symbiotic to saprotrophic. Overall, water limitation appeared to alter soil microbial communities involved in nutrient cycling, pointing to potential consequences for forest health affected by prolonged episodes of drought.
An asymptotic study of instability to Langmuir circulation in shallow layers

The rôle of boundary conditions applied to perturbation equations describing the instability of wavy shear flows to counter-rotating vortical structures aligned with the flow in shallow water layers is considered. In the ocean context the structures are described by the Craik-Leibovich equations and are known as Langmuir circulation (LC); they arise via an instability mechanism known as CL2, which requires the presence of shear and differential drift of the same sense and that a threshold Rayleigh number be exceeded. While Neumann or stress-free boundary conditions applied at the free surface in deep water act to yield a physically plausible spanwise wavenumber l at onset, that is not the case in shallow layers, where non-zero l at onset is ensured only when mixed boundary conditions are applied. This paper questions why that is so and goes on to determine how onset is affected by distributions of and . In order to proceed analytically, results are computed by a small-l asymptotic approximation for which an algorithm is generated enabling computation to, essentially, any order. It is found that the extra stress induced by the perturbed motion, which is reflected in mixed but not Neumann boundary conditions, acts to suppress the growth rate of the instability over all wavenumbers, thereby restricting instability to non-zero l; further details are seen to depend on the distributions of and . Specifically, while the critical wavenumber is not overly sensitive to precise distributions of and , the critical Rayleigh number is sensitive. Minor variations in and can also lead to multiple rather than single layers of LC and even contrive to ensure non-zero l at onset with Neumann boundary conditions. Finally, although crafted as an asymptotic approximation for , the results concur closely with numerical calculations at much larger l.
Particle motion and diffusion at weak bed load: accounting for unsteadiness effects of entrainment and disentrainment

ABSTRACT A study of weak bed load over a plane bed is presented with a particular focus on the motion and diffusion of individual particles that were tracked along their movements. Grain position, velocity and acceleration were measured with particle-scale resolution; ensemble statistics over a significant sample of particle trajectories were then computed, enabling unsteady phases of particle motion (corresponding to entrainment and disentrainment) to be identified. Based on the experimental findings, a physically-based conceptual model for particle kinematics consisting of an initial (entrainment) unsteady phase, a quasi-steady phase, and a final (disentrainment) unsteady phase is explored. The unsteadiness effects in particle dispersion due to entrainment and disentrainment, typically overlooked in previous studies, are explicitly quantified by analysing the time evolution of the particle position variance. Starting with a previously published model of particle diffusion, a refined model is proposed which explicitly accounts for the unsteadiness effects in particle motion.
In Vitro Metabolism of 2-Methoxy-N-[3-[4-[3-methyl-4-[(6-methyl- 3-pyridinyl)oxy]anilino]-6-quinazolinyl]prop-2-enyl]acetamide (CP-724,714) by Aldehyde Oxidase and Predicting Its Percent Contribution Relative to CYP-Mediated Metabolism

2-methoxy-N-[3-[4-[3-methyl-4-[(6-methyl-3-pyridinyl)oxy]anilino]-6-quinazolinyl]prop-2-enyl]acetamide (CP-724,714) is an anticancer drug that was discontinued due to hepatotoxicity found in clinical studies. Metabolite analysis of CP-724,714 was conducted using human hepatocytes, in which twelve oxidative metabolites and one hydrolyzed metabolite were formed. Among the three mono-oxidative metabolites, the formation of two was inhibited by adding 1-aminobenzotriazole, a pan-CYP inhibitor. In contrast, the remaining one was not affected by this inhibitor but partially inhibited by hydralazine, indicating that aldehyde oxidase (AO) was involved in metabolizing CP-724,714, which contains a quinazoline substructure, a heterocyclic aromatic quinazoline ring, known to be preferably metabolized by AO. One of the oxidative metabolites of CP-724,714 observed in human hepatocytes was also generated in recombinant human AO. Although CP-724,714 is metabolized by both CYPs and AO in human hepatocytes, the contribution level of AO could not be evaluated using its specific inhibitors because of low AO activity in in vitro human materials. Here, we present a metabolic pathway for CP-724,714 in human hepatocytes and the involvement of AO in CP-724,714 metabolism. We showed here a plausible workflow for predicting AO contribution to the metabolism of CP-724,714 based on DMPK screening data. SIGNIFICANCE STATEMENT 2-methoxy-N-[3-[4-[3-methyl-4-[(6-methyl-3-pyridinyl)oxy]anilino]-6-quinazolinyl]prop-2-enyl]acetamide (CP-724,714) was identified as a substrate of aldehyde oxidase (AO) rather than xanthine oxidase. Since CP-724,714 is also metabolized by cytochrome P450s (CYPs), the contribution levels of AO and CYPs in the metabolism of CP-724,714 were estimated simultaneously based on in vitro drug metabolism screening data.