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Purpose: To compare the clinical outcomes between conventional round tunnel and rectangular tunnel in anatomic anterior cruciate ligament (ACL) reconstruction.Methods: This was a retrospective comparative cohort study between March 2015 and September 2018. The primary ACL reconstructions using anteromedial portal technique with minimum of 2 years follow-up were enrolled for this study. The exclusion criteria were patients with revision ACL reconstruction, high tibial osteotomy, multiligament injuries, and associated fractures around the knee. Outcome measures included the subjective International Knee Documentation Committee score, Tegner activity score, knee laxity testing, and measurement of the centers of the femoral and tibial tunnels on postoperative computed tomography (CT) images.Results: Forty-seven patients with ACL reconstruction with rectangular tunnel (group 1) and 108 patients with ACL reconstructions with conventional rounded tunnel (group 2) were included consecutively. There were no significant differences between groups in terms of clinical scores or knee laxity, as well as femoral and tibial tunnel positions on CT. One patient in group 2 had ACL failure because of trauma and was treated with revision surgery. Two patients had incomplete tibial fracture, but they healed spontaneously and showed no residual laxity at final follow-up. The intraobserver and interobserver reliability for the radiological measurements ranged from 0.78 to 0.86.Conclusions: There were no differences in radiological and clinical results between rectangular tunnel group and conventional round tunnel group for arthroscopic ACL reconstruction. ACL reconstruction with a rectangular tunnel could be considered as a reliable technique, but care should be taken during tunnel establishment because of risk of fractures and malposition of rectangular tunnel. [ABSTRACT FROM AUTHOR]

A new approach of monitoring low-velocity impact events on composite structures was pre-sented and experimentally evaluated. In this approach, impact strain histories of a composite plate were measured with optical fiber sensors. The recorded signals were used to estimate locations and forces of low-velocity impact events. For experimental validation, four-sensor heads were surface mounted at the four corners of a composite panel. The optical sensors caught dynamic strain due to impacts on the panel, and the optical cables transmitted wave-length changes of the sensors. The multiplexed wavelength changes were measured using a high-speed fiber Bragg grating interrogator for the determination of impact location. The locations of impact events were estimated using a neural network program and measured signals. The estimated locations and converted strain signals were taken as the inputs to the process of reconstructing impact forces. Even though the current study is an initial investiga-tion on a simple impact problem, the result shows the possibility that the proposed technique can be applied to low-velocity impact monitoring of general composite structures. [ABSTRACT FROM AUTHOR]

The different molecular profiles of cerebrospinal fluid (CSF) between ventricular and lumbar compartments remain elusive, especially in the context of leptomeningeal metastasis (LM), which affects CSF flow. We evaluated CSF metabolomic and proteomic profiles based on the compartments and the diagnosis of spinal LM, proved by MRI from 20 paired ventricular and lumbar CSF samples of LM patients, including 12 spinal LM (+) samples. In metabolome analysis, 9512 low-mass ions (LMIs) were identified—7 LMIs were abundant in all lumbar versus paired ventricular CSF samples, and 3 LMIs were significantly abundant in all ventricular CSF. In comparisons between spinal LM (+) CSF and LM (−) CSF, 105 LMIs were discriminative for spinal LM (+) CSF. In proteome analysis, a total of 1536 proteins were measured. A total of 18 proteins, including complement C3, were more highly expressed in all lumbar CSF, compared with paired ventricular CSF, while 82 proteins, including coagulation factor V, were higher in the ventricular CSF. Of 37 discriminative proteins, including uteroglobin and complement component C8 gamma chain, 4 were higher in all spinal LM (+) CSF versus spinal LM (−) CSF. We further evaluated metabolic pathways associated with these discriminative proteins using the Gene Ontology database. We found that 16/17 spinal LM (+) pathways, including complement activation, were associated with lumbar discriminative proteins, whereas only 2 pathways were associated with ventricular-discriminative proteins. In conclusion, we determined that metabolite and protein profiles differed between paired lumbar and ventricular CSF samples. The protein profiles of spinal LM (+) CSF showed more similarity with the lumbar CSF than the ventricular CSF. Thus, we suggest that CSF LMIs and proteins could reflect LM disease activity and that LM-associated differences in CSF are more likely to be present in the lumbar compartment. [ABSTRACT FROM AUTHOR]

Diagnosing leptomeningeal metastasis (LM) in medulloblastoma is currently based on positive cerebrospinal fluid (CSF) cytology or magnetic resonance imaging (MRI) finding. However, the relevance of discordant results has not been established. We evaluated the diagnostic potential of CSF metabolomic profiles in the medulloblastoma LM assessment. A total of 83 CSF samples from medulloblastoma patients with documented MRI and CSF cytology results at the time of sampling for LM underwent low-mass ions (LMIs) analysis using liquid chromatography-mass spectrometry. Discriminating LMIs were selected by a summed sensitivity and specificity (>160%) and LMI discriminant equation (LOME) algorithms, evaluated by measuring diagnostic accuracy for verifying LM groups of different MRI/cytology results. Diagnostic accuracy of LM in medulloblastoma was 0.722 for cytology and 0.889 for MRI. Among 6572 LMIs identified in all sample, we identified 27 discriminative LMIs differentiating MRI (+)/cytology (+) from MRI (−)/cytology (−). Using LMI discriminant equation (LOME) analysis, we selected 9 LMIs with a sensitivity of 100% and a specificity of 93.6% for differentiating MRI (+)/cytology (+) from MRI (−)/cytology (−). Another LOME of 20 LMIs significantly differentiated sampling time relative to treatment (p = 0.007) and the presence or absence of LM-related symptoms (p = 0.03) in the MRI (+)/cytology (−) group. CSF metabolomics of medulloblastoma patients revealed significantly different profiles among LM diagnosed with different test results. We suggest that LM patients could be screened by appropriately selected LOME-generated LMIs to support LM diagnosis by either MRI or cytology alone. [ABSTRACT FROM AUTHOR]

Abstract: The regulation of poly(A) tail length is one important mechanism for controlling gene expression during early animal development. In Xenopus oocytes, the polyadenylation‐deadenylation of several essential dormant mRNAs, including cyclin B1 mRNA, are controlled by the cis‐acting cytoplasmic polyadenylation element (CPE) and the hexanucleotide AAUAAA through their associations with protein factors CPEB and CPSF, respectively. CPE‐containing, as well as CPE‐lacking, pre‐mRNAs acquire long poly(A) tails in the nucleus; after their export to the cytoplasm, there is subsequent deadenylation of CPE‐containing mRNAs that is controlled by the CPEB‐associated factor PARN, a poly(A)‐specific ribonuclease. In general, re‐adenylation after meiotic maturation of CPE‐containing mRNAs is mediated by Gld2, a poly(A) polymerase. Moreover, embryonic poly(A)‐binding protein, ePAB, is required for the subsequent elongation and stabilization of the poly(A) tail against PARN and other deadenylating enzymes. In this chapter, we present detailed information for measuring CPEB‐mediated cytoplasmic polyadenylation‐deadenylation in Xenopus laevis oocytes and egg extracts. [Copyright &y& Elsevier]

The p27Kip1 protein plays a critical role in the regulation of cell proliferation through the inhibition of cyclin-dependent kinase activity. Translation of p27Kipl is directed by an internal ribosomal entry site (IRES) in the 5' nontranslated region of p27Kipl mRNA. Here, we report that polypyrimidine tract-binding protein (PTB) specifically enhances the IRES activity of p27Kipl mRNA through an interaction with the IRES element. We found that addition of PTB to an in vitro translation system and overexpression of PTB in 293T cells augmented the IRES activity of p27Kipl mRNA but that knockdown of PTB by introduction of PTB-specific small interfering RNAs (siRNAs) diminished the IRES activity of p27Kipl mRNA. Moreover, the G1 phase in the cell cycle (which is maintained in part by p27Kipl was shortened in cells depleted of PTB by siRNA knockdown. 12-O-Tetradecanoylphorbol-13oacetate (TPA)-induced differentiation in HL60 cells was used to examine PTB-induced modulation of p27Kipl protein synthesis during differentiation. The IRES activity of p27Kipl mRNA in HL60 cells was increased by TPA treatment (with a concomitant increase in PTB protein levels), but the levels of p27Kipl mRNA remained unchanged. Together, these data suggest that PTB modulates cell cycle and differentiation, at least in part, by enhancing the IRES activity of p27Kipl mRNA. [ABSTRACT FROM AUTHOR]

In this paper, an RF curve-fitting predistorter is proposed to extend the linearized dynamic range of a power amplifier. AM-AM and AM-PM distortion of the power amplifier can be compensated by accurately adjusting the gain and phase gradients of the three-reflection-type diode predistorter. The proposed predistorter extends the linearized dynamic range by more than six times that of a conventional predistorter. © 2004 Wiley Periodicals, Inc. Microwave Opt Technol Lett 40: 83–87, 2004; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/mop.11292 [ABSTRACT FROM AUTHOR]

New dual-mode microstrip ring bandpass filters with an interdigital side-coupling structure are proposed for the lower insertion and return losses and narrow passband characteristics. The dual-mode microstrip ring bandpass filters with one or two local resonant sectors (LRSs) show 3 dB bandwidths of 70 and 75 MHz with insertion losses of 2.75 and 2.12 dB, respectively. © 2001 John Wiley & Sons, Inc. Microwave Opt Technol Lett 28: 131–135, 2001. [ABSTRACT FROM AUTHOR]

The diagnosis of leptomeningeal metastasis (LM) is often difficult due to the paucity of cancer cells in cerebrospinal fluid (CSF) and nonspecific findings on neuroimaging. Investigations of extracellular microRNAs (miRNAs) in CSF could be used for both the diagnosis and study of LM pathogenesis because they reflect the activity of disseminating cancer cells. We isolated CSF extracellular miRNAs from patients (n = 65) of different central nervous system tumor statuses, including cancer control, healthy control, LM, brain metastasis (BM), and primary brain tumor (BT) groups, and performed miRNA microarrays. In unsupervised clustering analyses, all LM and two BM samples showed unique profiles. Among 30 miRNAs identified for LM-specific biomarkers via a Prediction Analysis of Microarrays, miR-335-5p and miR-34b-3p were confirmed in both the discovery and validation samples (n = 23). Next, we performed a significance analysis of the microarray (SAM) to extract discriminative miRNA profiles of two selected CSF groups, with LM samples revealing a greater number of discriminative miRNAs than BM and BT samples compared to controls. Using SAM comparisons between LM and BM samples, we identified 30 upregulated and 6 downregulated LM miRNAs. To reduce bias from different primary cancers, we performed a subset analysis with primary non-small cell lung cancer, and 12 of 13 upregulated miRNAs in LM vs. BM belonged to the upregulated miRNAs in LM. We identified possible target genes and their biological processes that could be affected by LM discriminative miRNAs in NSCLC using the gene ontology database. In conclusion, we identified a unique extracellular miRNA profile in LM CSF that was different from BM, suggesting the use of miRNAs as LM biomarkers in studies of LM pathogenesis. [ABSTRACT FROM AUTHOR]

Sodium-ion batteries (SIBs) have been increasingly studied due to sodium (Na) being an inexpensive ionic resource (Na) and their battery chemistry being similar to that of current lithium-ion batteries (LIBs). However, SIBs have faced substantial challenges in developing high-performance anode materials that can reversibly store Na+ in the host structure. To address these challenges, molybdenum sulfide (MoS2)-based active materials have been considered as promising anodes, owing to the two-dimensional layered structure of MoS2 for stably (de)inserting Na+. Nevertheless, intrinsic issues of MoS2—such as low electronic conductivity and the loss of active S elements after a conversion reaction—have limited the viability of MoS2 in practical SIBs. Here, we report MoS2 embedded in carbon nanofibers encapsulated with a reduced graphene oxide (MoS2@CNFs@rGO) composite for SIB anodes. The MoS2@CNFs@rGO delivered a high capacity of 345.8 mAh g−1 at a current density of 100 mA g−1 for 90 cycles. The CNFs and rGO were synergistically taken into account for providing rapid pathways for electrons and preventing the dissolution of S sources during repetitive conversion reactions. This work offers a new point of view to realize MoS2-based anode materials in practical SIBs. [ABSTRACT FROM AUTHOR]

Spinal muscular atrophy (SMA) is caused by homozygous survival of motor neurons 1 (SMN1) gene deletion, leaving a duplicate gene, SMN2, as the sole source of SMN protein. However, a defect in SMN2 splicing, involving exon 7 skipping, results in a low level of functional SMN protein. Therefore, the upregulation of SMN protein expression from the SMN2 gene is generally considered to be one of the best therapeutic strategies to treat SMA. Most of the SMA drug discovery is based on synthetic compounds, and very few natural compounds have been explored thus far. Here, we performed an unbiased mechanism-independent and image-based screen of a library of microbial metabolites in SMA fibroblasts using an SMN-specific immunoassay. In doing so, we identified brefeldin A (BFA), a well-known inhibitor of ER-Golgi protein trafficking, as a strong inducer of SMN protein. The profound increase in SMN protein was attributed to, in part, the rescue of the SMN2 pre-mRNA splicing defect. Intriguingly, BFA increased the intracellular calcium concentration, and the BFA-induced exon 7 inclusion of SMN2 splicing, was abrogated by the depletion of intracellular calcium and by the pharmacological inhibition of calcium/calmodulin-dependent kinases (CaMKs). Moreover, BFA considerably reduced the expression of Tra2-β and SRSF9 proteins in SMA fibroblasts and enhanced the binding of PSF and hnRNP M to an exonic splicing enhancer (ESE) of exon 7. Together, our results demonstrate a significant role for calcium and its signaling on the regulation of SMN splicing, probably through modulating the expression/activity of splicing factors. [ABSTRACT FROM AUTHOR]

Background: Defects in the ataxin-2 (ATXN-2) protein and CAG trinucleotide repeat expansion in its coding gene, Atxn-2, cause the neurodegenerative disorder spinocerebellar ataxia type 2 (SCA2). While clinical studies suggest potential benefits of human-derived mesenchymal stem cells (hMSCs) for treating various ataxias, the exact mechanisms underlying their therapeutic effects and interaction with host tissue to stimulate neurotrophin expression remain unclear specifically in the context of SCA2. Methods: Human bone marrow-derived MSCs (hMSCs) were injected into the cisterna magna of 26-week-old wild-type and SCA2 mice. Mice were assessed for impaired motor coordination using the accelerating rotarod, open field test, and composite phenotype scoring. At 50 weeks, the cerebellum vermis was harvested for protein assessment and immunohistochemical analysis. Results: Significant loss of NeuN and calbindin was observed in 25-week-old SCA2 mice. However, after receiving multiple injections of hMSCs starting at 26 weeks of age, these mice exhibited a significant improvement in abnormal motor performance and a protective effect on Purkinje cells. This beneficial effect persisted until the mice reached 50 weeks of age, at which point they were sacrificed to study further mechanistic events triggered by the administration of hMSCs. Calbindin-positive cells in the Purkinje cell layer expressed bone-derived neurotrophic factor after hMSC administration, contributing to the protection of cerebellar neurons from cell death. Conclusion: In conclusion, repeated administration of hMSCs shows promise in alleviating SCA2 symptoms by preserving Purkinje cells, improving neurotrophic support, and reducing inflammation, ultimately leading to the preservation of locomotor function in SCA2 mice. [ABSTRACT FROM AUTHOR]

Multiple studies have shown that astrocytes in the medullary dorsal horn (MDH) play an important role in the development of pathologic pain. However, little is known about the structural reorganization of the peripheral astrocytic processes (PAP), the main functional part of the astrocyte, in MDH in neuropathic state. For this, we investigated the structural relationship between PAP and their adjacent presynaptic axon terminals and postsynaptic dendrites in the superficial laminae of the MDH using electron microscopical immunohistochemistry for ezrin, a marker for PAP, and quantitative analysis in a rat model of neuropathic pain following chronic constriction injury of the infraorbital nerve (CCI-ION). We found that, compared to controls, in rats with CCI-ION, (1) the number, % area, surface density, and volume fraction of ezrin-positive (+) PAP, as well as the fraction of synaptic edge apposed by ezrin + PAP and the degree of its coverage of presynaptic axon terminals and postsynaptic dendrites increased significantly, (2) these effects were abolished by administration of the mGluR5 antagonist 2-methyl-6-(phenylethynyl) pyridine (MPEP). These findings indicate that PAP undergoes structural reorganization around the central synapses of sensory afferents following nerve injury, suggest that it may be mediated by mGluR5, and may represent the structural basis for enhancing astrocyte-neuron interaction in neuropathic pain. [ABSTRACT FROM AUTHOR]

Immunodepression, whether due to HIV infection or organ transplantation, has increased human vulnerability to fungal infections. These conditions have created an optimal environment for the emergence of opportunistic infections, which is concomitant to the increase in antifungal resistance. The use of conventional antifungal drugs as azoles and polyenes can lead to clinical failure, particularly in immunocompromised individuals. Difficulties related to treating fungal infections combined with the time required to develop new drugs, require urgent consideration of other therapeutic alternatives. Drug repurposing is one of the most promising and rapid solutions that the scientific and medical community can turn to, with low costs and safety advantages. To treat life-threatening resistant fungal infections, drug repurposing has led to the consideration of well-known and potential molecules as a last-line therapy. The aim of this review is to provide a summary of current antifungal compounds and their main resistance mechanisms, following by an overview of the antifungal activity of non-traditional antimicrobial drugs. We provide their eventual mechanisms of action and the synergistic combinations that improve the activity of current antifungal treatments. Finally, we discuss drug repurposing for the main emerging multidrug resistant (MDR) fungus, including the Candida auris, Aspergillus or Cryptococcus species. [ABSTRACT FROM AUTHOR]

Candidiasis, caused by yeasts of the genus Candida, is the second cause of superficial and mucosal infections and the fourth cause of bloodstream infections. Although some antifungal drugs to treat candidiasis are available, resistant strains to current therapies are emerging. Therefore, the search for new candicidal compounds is certainly a priority. In this regard, a series of indazole and pyrazole derivatives were designed in this work, employing bioisosteric replacement, homologation, and molecular simplification as new anticandidal agents. Compounds were synthesized and evaluated against C. albicans, C. glabrata, and C. tropicalis strains. The series of 3-phenyl-1H-indazole moiety (10a–i) demonstrated to have the best broad anticandidal activity. Particularly, compound 10g, with N,N-diethylcarboxamide substituent, was the most active against C. albicans and both miconazole susceptible and resistant C. glabrata species. Therefore, the 3-phenyl-1H-indazole scaffold represents an opportunity for the development of new anticandidal agents with a new chemotype. [ABSTRACT FROM AUTHOR]