The enhanced productive folding of translated polypeptides by heat shock protein 70 (HSP70) is often required for the survival of cancer cells. Although the folding activity of HSP70 is considered a significant determinant of the progression of cancer cells, it is still unknown how this activity could be regulated. Here, we report that the phosphorylation of HSP70 facilitates its folding activity, enhancing cell proliferation. Mass spectrometry identified the serine residues at positions 385 and 400 in the linker and substrate-binding domains of HSP70, respectively, as sites of phosphorylation mediated by EGF signaling, and this result was further confirmed by site-directed mutagenesis. ERK is known to be a specific kinase. The phosphorylation of the two sites induces the extended conformation of HSP70 via the regulation of the binding of the linker to the nucleotide- and substrate-binding domains, augmenting the binding affinity of HSP70 to substrates and enhancing its folding activity; this ultimately results in pro-proliferative effects. Cell lines harboring activated ERK showed increased phosphorylation of HSP70, and a positive correlation between the phosphorylation of HSP70 and the activity of ERK was observed. Thus, this study demonstrated that the ERK-dependent phosphorylation of HSP70 facilitated its folding activity and cellular proliferative function.

Aims

There are numerous risk or screening scores for the prediction of type-2 diabetes mellitus (DM). In contrast, few scores are available for preDM. In this paper, we compare the two screening scores from the American Diabetes Association (ADA) and Centers for Disease Control and Prevention (CDC) that can be used for DM as well as preDM.

Methods

Adult participants (N=9391) without known DM from the National Health and Nutrition Examination Surveys 2009-12 were included. We fitted the factors/items in the ADA and CDC scores in logistic regression with the outcomes of undiagnosed DM, preDM, and combination, and assessed the association and discrimination accuracy. We also evaluated the suggested cutpoints that define high risk individuals. We mimicked the original models/settings but also tested various deviations/modifications often encountered in practice.

Results

Both scores performed well and robustly, while the ADA score performed somewhat better (e.g., AUC=0.77 for ADA and 0.73-0.74 for CDC for DM; 0.72-0.74 and 0.70-0.71 for preDM). The same predictors and scoring rules seem to be reasonably justified with different cutpoints for DM and preDM, which can make usage easier and consistent. Some factors such as race and HDL/LDL cholesterols may be useful additions to health education.

Conclusions

Current DM education and screening focus on the prevention and management of DM. The ADA and CDC scores could further help when we identify individuals at high risk for preDM, and teach the importance of preDM during which lifestyle intervention can be effective and urgently needed.

A clinical prediction model can be applied to several challenging clinical scenarios: screening high-risk individuals for asymptomatic disease, predicting future events such as disease or death, and assisting medical decision-making and health education. Despite the impact of clinical prediction models on practice, prediction modeling is a complex process requiring careful statistical analyses and sound clinical judgement. Although there is no definite consensus on the best methodology for model development and validation, a few recommendations and checklists have been proposed. In this review, we summarize five steps for developing and validating a clinical prediction model: preparation for establishing clinical prediction models; dataset selection; handling variables; model generation; and model evaluation and validation. We also review several studies that detail methods for developing clinical prediction models with comparable examples from real practice. After model development and vigorous validation in relevant settings, possibly with evaluation of utility/usability and fine-tuning, good models can be ready for the use in practice. We anticipate that this framework will revitalize the use of predictive or prognostic research in endocrinology, leading to active applications in real clinical practice.

Single spectrometer-based complex conjugate artifact removal methods are evaluated for in vivo imaging with complementary metal-oxide semiconductor line scan camera based high-speed Fourier-domain optical coherence tomography (FD-OCT) at 100,000 axial scans per second. Performance of three different phase-shifting methods with the same OCT engine is evaluated using modified data acquisition schemes, depending on the requirements of each phase-shifting technique. The suppression ratio of complex conjugate artifact images using a paperboard is assessed for all tested methods. Several other characteristics, including a list of additional hardware requirements (beyond standard FD-OCT components) and data acquisition schemes for each of the methods is presented. In vivo full-range images of human fingerpad and nail are shown and compared with standard FD-OCT images. Additionally, a complex-conjugate-free human retinal volume acquired at the speed of 100,000 A-scans/s is presented.

We acquired in vivo images of the human optic nerve head (ONH) using an adaptive optics-optical coherence tomography (AO-OCT) system. In order to improve imaging of the lamina cribrosa in the ONH with high lateral resolution and sensitivity, we implemented a complex conjugate artifact-free Fourier domain OCT (Fd-OCT) acquisition scheme with a reference arm-based phase shifting method. This allowed positioning of the lamina cribrosa structures near the zero path length difference where AO-OCT imaging achieves highest sensitivity. Implementation of our complex conjugate artifact removal (CCR) method required constant phase shifts between consecutive axial scans (A-scans), generated by continuous beam path-length changes from offsetting the pivot point of the scanning mirror placed in the reference arm. Fourier transform along the transverse axis and a filtering algorithm allowed reconstruction of CCR AO-OCT images. The suppression ratio of the mirror artifact was approximately 22 dB (at 18,000 A-scans per second acquisition speed) with a paperboard test target and an optimum phase-shift value. Finally, we reconstructed the three-dimensional structure of human ONH with enhanced depth range and sensitivity using CCR AO-OCT.

ARS-interacting multifunctional proteins 2 (AIMP2) is known to be a powerful tumour suppressor. However, the target AIMP2-DX2, AIMP2-lacking exon 2, is often detected in many cancer patients and cells. The predominant approach for targeting AIMP-DX2 has been attempted via small molecule mediated inhibition, but due to the lack of satisfactory activity against AIMP2-DX2, new therapeutic strategies are needed to develop a novel drug for AIMP2-DX2. Here, we report the use of the PROTAC strategy that combines small-molecule AIMP2-DX2 inhibitors with selective E3-ligase ligands with optimised linkers. Consequently, candidate compound 45 was found to be a degrader of AIMP2-DX2. Together, these findings demonstrate that our PROTAC technology targeting AIMP2-DX2 would be a potential new strategy for future lung cancer treatment.

We present a noninvasive phase-variance (pv)–based motion contrast method for depth-resolved imaging of the human chorioretinal complex microcirculation with a newly developed phase-stabilized high speed (100-kHz A-scans/s) 1-μm swept- ource optical coherence tomography (SSOCT) system. Compared to our previous spectral-domain (spectrometer based) pv-spectral domain OCT (SDOCT) system, this system has the advantages of higher sensitivity, reduced fringe wash-out for high blood flow speeds and deeper penetration in choroid. High phase stability SSOCT imaging was achieved by using a computationally efficient phase stabilization approach. This process does not require additional calibration hardware and complex numerical procedures. Our phase stabilization method is simple and can be employed in a variety of SSOCT systems. Examples of vasculature in the chorioretinal complex imaged by pv-SSOCT from normal as well as diseased eyes are presented and compared to retinal images of the same subjects acquired with fluorescein angiography and indocyanine green angiography. Observations of morphology of vascular perfusion in chorioretinal complex visualized by our method are listed.

Hybridization between conduction electrons and the strongly interacting f-electrons in rare earth or actinide compounds may result in new states of matter. Depending on the exact location of the concomitant hybridization gap with respect to the Fermi energy, a heavy fermion or an insulating ground state ensues. To study this entanglement locally, we conducted scanning tunneling microscopy and spectroscopy (STS) measurements on the "Kondo insulator" SmB6. The vast majority of surface areas investigated were reconstructed, but infrequently, patches of varying sizes of nonreconstructed Sm- or B-terminated surfaces also were found. On the smallest patches, clear indications for the hybridization gap with logarithmic temperature dependence (as expected for a Kondo system) and for intermultiplet transitions were observed. On nonreconstructed surface areas large enough for coherent cotunneling, we were able to observe clear-cut Fano resonances. Our locally resolved STS indicated considerable finite conductance on all surfaces independent of their structure, not proving but leaving open the possibility of the existence of a topologically protected surface state.

Samarium hexaboride (SmB6), a well-known Kondo insulator in which the insulating bulk arises from strong electron correlations, has recently attracted great attention owing to increasing evidence for its topological nature, thereby harboring protected surface states. However, corroborative spectroscopic evidence is still lacking, unlike in the weakly correlated counterparts, including Bi2Se3 Here, we report results from planar tunneling that unveil the detailed spectroscopic properties of SmB6 The tunneling conductance obtained on the (001) and (011) single crystal surfaces reveals linear density of states as expected for two and one Dirac cone(s), respectively. Quite remarkably, it is found that these topological states are not protected completely within the bulk hybridization gap. A phenomenological model of the tunneling process invoking interaction of the surface states with bulk excitations (spin excitons), as predicted by a recent theory, provides a consistent explanation for all of the observed features. Our spectroscopic study supports and explains the proposed picture of the incompletely protected surface states in this topological Kondo insulator SmB6.