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An assembly algorithm that overlaps noisy long reads enables accurate and fast assembly of large genomes from single-molecule real-time sequences. Long-read, single-molecule real-time (SMRT) sequencing is routinely used to finish microbial genomes, but available assembly methods have not scaled well to larger genomes. We introduce the MinHash Alignment Process (MHAP) for overlapping noisy, long reads using probabilistic, locality-sensitive hashing. Integrating MHAP with the Celera Assembler enabled reference-grade de novo assemblies of Saccharomyces cerevisiae , Arabidopsis thaliana , Drosophila melanogaster and a human hydatidiform mole cell line (CHM1) from SMRT sequencing. The resulting assemblies are highly continuous, include fully resolved chromosome arms and close persistent gaps in these reference genomes. Our assembly of D. melanogaster revealed previously unknown heterochromatic and telomeric transition sequences, and we assembled low-complexity sequences from CHM1 that fill gaps in the human GRCh38 reference. Using MHAP and the Celera Assembler, single-molecule sequencing can produce de novo near-complete eukaryotic assemblies that are 99.99% accurate when compared with available reference genomes.

Unlike hybrid approaches that use multiple libraries for de novo assembly, the hierarchical genome-assembly process uses data from only a single long-read SMRT sequencing library to produce high-quality finished microbial genome or BAC assemblies in an automated workflow. We present a hierarchical genome-assembly process (HGAP) for high-quality de novo microbial genome assemblies using only a single, long-insert shotgun DNA library in conjunction with Single Molecule, Real-Time (SMRT) DNA sequencing. Our method uses the longest reads as seeds to recruit all other reads for construction of highly accurate preassembled reads through a directed acyclic graph–based consensus procedure, which we follow with assembly using off-the-shelf long-read assemblers. In contrast to hybrid approaches, HGAP does not require highly accurate raw reads for error correction. We demonstrate efficient genome assembly for several microorganisms using as few as three SMRT Cell zero-mode waveguide arrays of sequencing and for BACs using just one SMRT Cell. Long repeat regions can be successfully resolved with this workflow. We also describe a consensus algorithm that incorporates SMRT sequencing primary quality values to produce de novo genome sequence exceeding 99.999% accuracy.

Magnetic resonance-guided focused ultrasound (MRgFUS) has been demonstrated to be able to thermally ablate tendons with the aim to non-invasively disrupt tendon contractures in the clinical setting. However, the biomechanical changes of tendons permitting this disrupting is poorly understood. We aim to obtain a dose-dependent biomechanical response of tendons following magnetic resonance-guided focused ultrasound (MRgFUS) thermal ablation. Ex vivo porcine tendons (n = 72) were embedded in an agar phantom and randomly assigned to 12 groups based on MRgFUS treatment. The treatment time was 10, 20, or 30s, and the applied acoustic power was 25, 50, 75, or 100W. Following each MRgFUS treatment, tendons underwent biomechanical tensile testing on an Instron machine, which calculated stress-strain curves during tendon elongation. Rupture rate, maximum treatment temperature, Young's modulus and ultimate strength were analyzed for each treatment energy. The study revealed a dose-dependent response, with tendons rupturing in over 50% of cases when energy delivery exceeded 1000J and 100% disruption at energy levels beyond 2000J. The achieved temperatures during MRgFUS were directly proportional to energy delivery. The highest recorded temperature was 56.8°C ± 9.34 (3000J), while the lowest recorded temperate was 18.6°C ± 0.6 (control). The Young's modulus was highest in the control group (47.3 MPa ± 6.5) and lowest in the 3000J group (13.2 MPa ± 5.9). There was no statistically significant difference in ultimate strength between treatment groups. This study establishes crucial thresholds for reliable and repeatable disruption of tendons, laying the groundwork for future in vivo optimization. The findings prompt further exploration of MRgFUS as a non-invasive modality for tendon disruption, offering hope for improved outcomes in patients with musculotendinous contractures.

Nosocomial bacterial meningitis is most often related to either complicated head trauma or invasive procedures, such as craniotomy, placement of ventricular catheters, intrathecal infusion of medications, or spinal anesthesia. In addition, metastatic infection from hospital-acquired bacteremia occasionally leads to meningitis. The conditions are associated with different pathogenetic mechanisms and a different spectrum of microorganisms, and therefore the choice of empirical antimicrobial therapy will vary according to the condition. Nosocomial bacterial meningitis is associated with different pathogenetic mechanisms and a different spectrum of microorganisms. The choice of empirical antimicrobial therapy will vary according to the condition. Nosocomial bacterial meningitis may result from invasive procedures (e.g., craniotomy, placement of internal or external ventricular catheters, lumbar puncture, intrathecal infusions of medications, or spinal anesthesia), complicated head trauma, or in rare cases, metastatic infection in patients with hospital-acquired bacteremia. These cases of meningitis are caused by a different spectrum of microorganisms than cases acquired in the community setting, and illness is the result of diverse pathogenetic mechanisms (Figure 1). Epidemiology and Pathogenesis The central nervous system is protected against microbial entry from the bloodstream by the blood–brain barrier and by an external barrier that is formed by the skull . . .

Particles are accelerated to very high, non-thermal energies during explosive energy-release phenomena in space, solar, and astrophysical plasma environments. While it has been established that magnetic reconnection plays an important role in the dynamics of Earth’s magnetosphere, it remains unclear how magnetic reconnection can further explain particle acceleration to non-thermal energies. Here we review recent progress in our understanding of particle acceleration by magnetic reconnection in Earth’s magnetosphere. With improved resolutions, recent spacecraft missions have enabled detailed studies of particle acceleration at various structures such as the diffusion region, separatrix, jets, magnetic islands (flux ropes), and dipolarization front. With the guiding-center approximation of particle motion, many studies have discussed the relative importance of the parallel electric field as well as the Fermi and betatron effects. However, in order to fully understand the particle acceleration mechanism and further compare with particle acceleration in solar and astrophysical plasma environments, there is a need for further investigation of, for example, energy partition and the precise role of turbulence.

Macrophages (MØs) are sentinels of the immune system that use pattern recognition receptors such as Toll-like receptors (TLR) to detect invading pathogens and immune receptors such as FcγR to sense the host's immune state. Crosstalk between these two signaling pathways allows the MØ to tailor the cell's overall response to prevailing conditions. However, the molecular mechanisms underlying TLR-FcγR crosstalk are only partially understood. Therefore, we employed an immunologically-relevant MØ stimulus, an inactivated gram-negative bacterium that bears TLR2 agonists but no TLR4 agonist (iBTLR2) opsonized with a monoclonal antibody (mAb-iBTLR2), as a tool to study FcγR regulation of TLR2-driven production of IL-6, a key inflammatory cytokine. We chose this particular agonist as an investigational tool because MØ production of any detectable IL-6 in response to mAb-iBTLR2 requires both TLR2 and FcγR signaling, making it an excellent system for the study of receptor synergy. Using genetic, pharmacological and immunological approaches, we demonstrate that the murine MØ IL-6 response to mAb-iBTLR2 requires activation of both the TLR/NF-κB and FcγR/ITAM signaling pathways. mAb-iBTLR2 engagement of TLR2 drives NF-κB activation and up-regulation of IL-6 mRNA but fails to result in IL-6 cytokine production/release. Here, Src family kinase-driven FcγR ITAM signaling is necessary to enable IL-6 mRNA incorporation into polysomes and translation. These results reveal a novel mechanism by which FcγR ITAM signaling synergizes with TLR signaling, by \"licensing\" cytokine mRNA ribosome binding/translation to drive a strong murine MØ cytokine response.

Objectives The objectives of this manuscript were to review the literature concerning 3D printing of brain and cranial vault pathology and use these data to define the gaps in global utilization of 3D printing technology for neurosurgical education. Methods Using specified criteria, literature searching was conducted to identify publications describing engineered neurosurgical simulators. Included in the study were manuscripts highlighting designs validated for neurosurgical skill transfer. Purely anatomical designs, lacking aspects of surgical simulation, were excluded. Eligible manuscripts were analyzed. Data on the types of simulators, representing the various modelled neurosurgical pathologies, were recorded. Authors’ countries of affiliation were also recorded. Results A total of thirty-six articles, representing ten countries in five continents were identified. Geographically, Africa as a continent was not represented in any of the publications. The simulation-modelling encompassed a variety of neurosurgical subspecialties including: vascular, skull base, ventriculoscopy / ventriculostomy, craniosynostosis, skull lesions / skull defects, intrinsic brain tumor and other. Finally, the vascular and skull base categories together accounted for over half (52.8 %) of the 3D printed simulated neurosurgical pathology. Conclusions Despite the growing body of literature supporting 3D printing in neurosurgical education, its full potential has not been maximized. Unexplored areas of 3D printing for neurosurgical simulation include models simulating the resection of intrinsic brain tumors or of epilepsy surgery lesions, as these require complex models to accurately simulate fine dissection techniques. 3D printed surgical phantoms offer an avenue for the advancement of global-surgery education initiatives.

Efforts directed at mitigating neurological disability in preterm infants with intraventricular hemorrhage (IVH) and post hemorrhagic hydrocephalus (PHH) are limited by a dearth of quantifiable metrics capable of predicting long-term outcome. The objective of this study was to examine the relationships between candidate cerebrospinal fluid (CSF) biomarkers of PHH and neurodevelopmental outcomes in infants undergoing neurosurgical treatment for PHH. Preterm infants with PHH were enrolled across the Hydrocephalus Clinical Research Network. CSF samples were collected at the time of temporizing neurosurgical procedure (n = 98). Amyloid precursor protein (APP), L1CAM, NCAM-1, and total protein (TP) were compared in PHH versus control CSF. Fifty-four of these PHH subjects underwent Bayley Scales of Infant Development-III (Bayley-III) testing at 15-30 months corrected age. Controlling for false discovery rate (FDR) and adjusting for post-menstrual age (PMA) and IVH grade, Pearson's partial correlation coefficients were used to examine relationships between CSF proteins and Bayley-III composite cognitive, language, and motor scores. CSF APP, L1CAM, NCAM-1, and TP were elevated in PHH over control at temporizing surgery. CSF NCAM-1 was associated with Bayley-III motor score (R = -0.422, p = 0.007, FDR Q = 0.089), with modest relationships noted with cognition (R = -0.335, p = 0.030, FDR Q = 0.182) and language (R = -0.314, p = 0.048, FDR Q = 0.194) scores. No relationships were observed between CSF APP, L1CAM, or TP and Bayley-III scores. FOHR at the time of temporization did not correlate with Bayley-III scores, though trends were observed with Bayley-III motor (p = 0.0647 and R = -0.2912) and cognitive scores (p = 0.0506 and R = -0.2966). CSF NCAM-1 was associated with neurodevelopment in this multi-institutional PHH cohort. This is the first report relating a specific CSF protein, NCAM-1, to neurodevelopment in PHH. Future work will further investigate a possible role for NCAM-1 as a biomarker of PHH-associated neurological disability.

Diffusion magnetic resonance imaging and tractography has an important role in the visualization of brain white matter and assessment of tissue microstructure. There is a lack of correspondence between diffusion metrics of live tissue, ex vivo tissue, and histological findings. The objective of this study is to elucidate this connection by determining the specific diffusion alterations between live and ex vivo brain tissue. This may have an important role in the incorporation of diffusion imaging in ex vivo studies as a complement to histological sectioning as well as investigations of novel neurosurgical techniques. This study presents a method of high angular resolution diffusion imaging and tractography of intact and non-fixed ex vivo piglet brains. Most studies involving ex vivo brain specimens have been formalin-fixed or excised from their original biological environment, processes both of which are known to affect diffusion parameters. Thus, non-fixed ex vivo tissue is used. A region-of-interest based analysis of diffusion tensor metrics are compared to in vivo subjects in a selection of major white matter bundles in order to assess the translatability of ex vivo diffusion measurements. Tractography was successfully achieved in both in vivo and ex vivo groups. No significant differences were found in tract connectivity, average streamline length, or apparent fiber density. Significantly decreased diffusivity (mean, axial, and radial; p<0.0005) in the non-fixed ex vivo group and unaltered fractional anisotropy (p>0.059) between groups were observed. This study validates the extrapolation of non-fixed fractional anisotropy measurements to live tissue and the potential use of ex vivo tissue for methodological development.

Following antigen recognition, B cell receptor (BCR)-mediated endocytosis is the first step of antigen processing and presentation to CD4+ T cells, a crucial component of the initiation and control of the humoral immune response. Despite this, the molecular mechanism of BCR internalization is poorly understood. Recently, studies of activated B cell-like diffuse large B cell lymphoma (ABC DLBCL) have shown that mutations within the BCR subunit CD79b leads to increased BCR surface expression, suggesting that CD79b may control BCR internalization. Adaptor protein 2 (AP2) is the major mediator of receptor endocytosis via clathrin-coated pits. The BCR contains five putative AP2-binding YxxØ motifs, including four that are present within two immunoreceptor tyrosine-based activation motifs (ITAMs). Using a combination of in vitro and in situ approaches, we establish that the sole mediator of AP2-dependent BCR internalization is the membrane proximal ITAM YxxØ motif in CD79b, which is a major target of mutation in ABC DLBCL. In addition, we establish that BCR internalization can be regulated at a minimum of two different levels: regulation of YxxØ AP2 binding in cis by downstream ITAM-embedded DCSM and QTAT regulatory elements and regulation in trans by the partner cytoplasmic domain of the CD79 heterodimer. Beyond establishing the basic rules governing BCR internalization, these results illustrate an underappreciated role for ITAM residues in controlling clathrin-dependent endocytosis and highlight the complex mechanisms that control the activity of AP2 binding motifs in this receptor system.