Nerve growth factor (NGF) binds to TrkA and forms a NGF/TrkA complex at the cell surface, which is then internalized into signaling endosomes and promotes neuronal survival and neurite outgrowth. The ...small GTPase Rab5 is reported to localize on the plasma membrane and early endosomes, regulating endosome fusion. It was reported that endogenous Rab5 function may need to be suppressed during NGF-induced neurite outgrowth and cell differentiation. Two Rab5 homologs (MoRab5A: MGG_06241 and MoRab5B:MGG_01185) were characterized from the rice blast fungus Magnaporthe oryzae, and MoRab5B was identified as the Rab5 ortholog promoting early endosomal fusion, while MoRab5A specialized to perform a non-redundant function in endosomal sorting. In this study, we examined whether MoRab5A and MoRab5B play different roles in NGF-induced neurite outgrowth and cell differentiation in PC12 cells (a rat pheochromocytoma cell line). Our data showed that MoRab5B is a negative regulator of NGF signaling and neurite outgrowth in PC12 cells, similar to human Rab5 (hRab5). MoRab5B:WT inhibits NGF signaling-dependent neurite outgrowth while the dominant-negative MoRab5B mutant (MoRab5B:DN) enhances NGF signaling and neurite outgrowth. In contrast, MoRab5A:WT and MoRab5A:DN both significantly promote NGF-induced neurite outgrowth, indicating that MoRab5B is more similar to hRab5 than MoRab5A in the regulation of NGF signal transduction.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Nitroreductase (NTR), a common enzymatic biomarker of hypoxia, is widely used to evaluate tumor microenvironments. To date, numerous optical probes have been reported for NTRs detection. Approaches ...capable of concisely guiding the probe design of NTRs suitable for deep‐tissue imaging, however, are still lacking. As such, direct optical imaging of endogenous NTR activities from tumors derived from cancer patients is thus far not possible. Herein, aided by computational calculations, the authors have successfully developed a series of two‐photon (TP) small‐molecule fluorogenic probes capable of sensitively detecting general NTR activities from various biological samples; by optimizing the distance between the recognition moiety and the reactive site of NTRs from different sources, the authors have discovered and experimentally proven that X4 displays the best performance in both sensitivity and selectivity. Furthermore, X4 shows excellent TP excited fluorescence properties capable of directly monitoring/imaging endogenous NTR activities from live mammalian cells, growing zebrafish, and tumor‐bearing mice. Finally, with an outstanding TP tissue‐penetrating imaging property, X4 is used, for the first time, to successfully detect endogenous NTR activities from the liver lysates and cardia tissues of a cancer patient. The work may provide a universal strategy to design novel TP small‐molecule enzymatic probes in future clinical applications.
By using computational calculations, a series of two‐photon small‐molecule fluorogenic probes is developed capable of successfully detecting endogenous NTR activities from the liver lysates and cardia tissues of a cancer patient.
Full text
Available for:
FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
We have identified 14 families with ataxia-telangiectasia (A-T) in which mutation of the ATM gene is associated with a less severe clinical and cellular phenotype (approximately 10%-15% of A-T ...families identified in the United Kingdom). In 10 of these families, all the homozygotes have a 137-bp insertion in their cDNA caused by a point mutation in a sequence resembling a splice-donor site. The second A-T allele has a different mutation in each patient. We show that the less severe phenotype in these patients is caused by some degree of normal splicing, which occurs as an alternative product from the insertion-containing allele. The level of the 137-bp PCR product containing the insertion was lowest in two patients who showed a later onset of cerebellar ataxia. A further four families who do not have this insertion have been identified. Mutations detected in two of four of these are missense mutations, normally rare in A-T patients. The demonstration of mutations giving rise to a slightly milder phenotype in A-T raises the interesting question of what range of phenotypes might occur in individuals in whom both mutations are milder. One possibility might be that individuals who are compound heterozygotes for ATM mutations are more common than we realize.
Objective:
This case study of 4 patients followed for at least 2 years was conducted to evaluate a cartilage repair procedure that involves transplanting particulated juvenile allograft cartilage.
...Design:
A multicenter, prospective, single-arm, 25-subject case study was designed to evaluate clinical outcomes such as IKDC and KOOS scores as well as the extent and quality of repair with MRI. In addition, there is an option for the transplants to be biopsied at various time points after implantation (up to 5 years). Currently, 25 patients with 1 or 2 chondral lesions on the femoral condyles and trochlea have been enrolled and treated in the prospective study.
Results:
The first 4 patients have completed an evaluation at 24 months postoperative follow-up. Improvements in clinical outcomes over the preoperative baseline data have been observed.
Conclusions:
The present report describes, for the first time, clinical intermediate-term results of a novel cartilage repair procedure that involves transplanting particulated juvenile cartilage tissue allograft into prepared cartilage lesions of the femoral condyles and/or trochlea. Clinical outcome data of 4 patients who have reached the 24-month postimplantation milestone indicate early positive outcomes and suggest that this technique is capable of improving clinical symptoms. MRI data suggest that defect filling is possible and persists to at least 2 years. Continued clinical evaluation of this technique is needed with extended follow-up of all 25 patients in the series.
We investigated the patterns and processes of storm deposition in coastal lakes by conducting sediment-coring, coupled with hydrodynamic measurements, before and after Hurricanes Gustav and Ike in ...Bay Champagne, Lafourche Parish, in Louisiana. Bay Champagne is a brackish-water backbarrier lake separated from the Gulf of Mexico by a low sand barrier < 1 m above mean sea level, thus this lake is vulnerable to overwash processes caused by hurricanes. Two bottom-mounted CTDs (Conductivity, Temperature and Depth sensors) deployed on August 29, 2008, three days before Hurricane Gustav’s landfall, recorded a maximum storm surge of ∼ 2.7 m. A sharp drop of salinity was recorded at the peak of the surge, suggesting an impact of heavy rain and possibly freshwater coming from the surrounding wetlands. A core taken along a transect in Bay Champagne after Hurricanes Gustav and Ike indicates that a sand layer up to 17 cm in thickness was deposited in the lake. A segment of loose sediment occurring in the middle of this storm deposit was probably formed by the reworking of the upper part of the Gustav storm deposit by Hurricane Ike, when the latter storm struck 12 days later. This interpretation is also supported by pollen data, which show that the presumed Gustav and Ike storm deposits have different palynological contents. This pilot study in process-oriented paleotempestology allows us to examine the relationship between the sedimentary process and the sedimentary pattern in a coastal lake resulting from a hurricane strike.
Full text
Available for:
BFBNIB, DOBA, IZUM, KILJ, NMLJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Super-resolution imaging provides a powerful approach to image dynamic biomolecule events at nanoscale resolution. An ingenious method involving tuning intramolecular spirocyclization in rhodamine ...offers an appealing strategy to design cell-permeable fluorogenic probes for super-resolution imaging. Nevertheless, precise control of rhodamine spirocyclization presents a significant challenge. Through detailed study of the structure–activity relationship, we identified that multiple key factors control rhodamime spirocyclization. The findings provide opportunities to create fluorogenic probes with tailored properties. On the basis of our findings, we constructed self-assembling rhodamine probes for no-wash live-cell confocal and super-resolution imaging. The designed self-assembling probe Rho-2CF3 specifically labeled its target proteins and displayed high ring-opening ability, fast labeling kinetics (<1 min), and large turn-on fold (>80 folds), which is very difficult to be realized by the existing methods. Using the probe, we achieved high-contrast super-resolution imaging of nuclei and mitochondria with a spatial resolution of up to 42 nm. The probe also showed excellent photostability and proved ideal for real-time and long-term tracking of mitochondrial fission and fusion events with high spatiotemporal resolution. Furthermore, Rho-2CF3 could resolve the ultrastructure of mitochondrial cristae and quantify their morphological changes under drug treatment at nanoscale. Our strategy thus demonstrates its usefulness in designing self-assembling probes for super-resolution imaging.
Full text
Available for:
IJS, KILJ, NUK, PNG, UL, UM
Herein, as a proof of concept, we developed the first enzymatic VIE fluorogenic probe for protein tyrosine phosphatase 1B (PTP1B). The detection and imaging of PTP1B using VIE in living cells were ...both realized. Particularly importantly, the designed probe herein provides a guideline and platform for the development of new VIE-based enzymatic probes.
Herein, as a proof of concept, we developed the first enzymatic VIE fluorogenic probe for protein tyrosine phosphatase 1B (PTP1B).
Background
While the majority of COVID‐19 patients fully recover from the infection and become asymptomatic, a significant proportion of COVID‐19 survivors experience a broad spectrum of symptoms ...lasting weeks to months post‐infection, a phenomenon termed “post‐acute sequelae of COVID‐19 (PASC).” The aim of this study is to determine whether inflammatory proteins are dysregulated and can serve as potential biomarkers for systemic inflammation in COVID‐19 survivors.
Methods
We determined the levels of inflammatory proteins in plasma from 22 coronavirus disease 2019 (COVID‐19) long haulers (COV‐LH), 22 COVID‐19 asymptomatic survivors (COV‐AS), and 22 healthy subjects (HS) using an Olink proteomics assay and assessed the results by a beads‐based multiplex immunoassay.
Results
Compared to HS, we found that COVID‐19 survivors still exhibited systemic inflammation, as evidenced by significant changes in the levels of multiple inflammatory proteins in plasma from both COV‐LH and COV‐AS. CXCL10 was the only protein that significantly upregulated in COV‐LH compared with COV‐AS and HS.
Conclusions
Our results indicate that several inflammatory proteins remain aberrantly dysregulated in COVID‐19 survivors and CXCL10 might serve as a potential biomarker to typify COV‐LH. Further characterization of these signature inflammatory molecules might improve the understanding of the long‐term impacts of COVID‐19 and provide new targets for the diagnosis and treatment of COVID‐19 survivors with PASC.
Full text
Available for:
FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
PDF
