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DnaJ/Hsp40 (heat shock protein 40) proteins have been preserved throughout evolution and are important for protein translation, folding, unfolding, translocation, and degradation, primarily by stimulating the ATPase activity of chaperone proteins, Hsp70s. Because the ATP hydrolysis is essential for the activity of Hsp70s, DnaJ/Hsp40 proteins actually determine the activity of Hsp70s by stabilizing their interaction with substrate proteins. DnaJ/Hsp40 proteins all contain the J domain through which they bind to Hsp70s and can be categorized into three groups, depending on the presence of other domains. Six DnaJ homologs have been identified in Escherichia coli and 22 in Saccharomyces cerevisiae. Genome-wide analysis has revealed 41 DnaJ/Hsp40 family members (or putative members) in humans. While 34 contain the typical J domains, 7 bear partially conserved J-like domains, but are still suggested to function as DnaJ/ Hsp40 proteins. DnaJA2b, DnaJB1b, DnaJC2, DnaJC20, and DnaJC21 are named for the first time in this review; all other human DnaJ proteins were dubbed according to their gene names, e.g. DnaJA1 is the human protein named after its gene DNAJA1. This review highlights the progress in studying the domains in DnaJ/Hsp40 proteins, introduces the mechanisms by which they interact with Hsp70s, and stresses their functional diversity.

Background Accurate and robust pathological image analysis for colorectal cancer (CRC) diagnosis is time-consuming and knowledge-intensive, but is essential for CRC patients’ treatment. The current heavy workload of pathologists in clinics/hospitals may easily lead to unconscious misdiagnosis of CRC based on daily image analyses. Methods Based on a state-of-the-art transfer-learned deep convolutional neural network in artificial intelligence (AI), we proposed a novel patch aggregation strategy for clinic CRC diagnosis using weakly labeled pathological whole-slide image (WSI) patches. This approach was trained and validated using an unprecedented and enormously large number of 170,099 patches, > 14,680 WSIs, from > 9631 subjects that covered diverse and representative clinical cases from multi-independent-sources across China, the USA, and Germany. Results Our innovative AI tool consistently and nearly perfectly agreed with (average Kappa statistic 0.896) and even often better than most of the experienced expert pathologists when tested in diagnosing CRC WSIs from multicenters. The average area under the receiver operating characteristics curve (AUC) of AI was greater than that of the pathologists (0.988 vs 0.970) and achieved the best performance among the application of other AI methods to CRC diagnosis. Our AI-generated heatmap highlights the image regions of cancer tissue/cells. Conclusions This first-ever generalizable AI system can handle large amounts of WSIs consistently and robustly without potential bias due to fatigue commonly experienced by clinical pathologists. It will drastically alleviate the heavy clinical burden of daily pathology diagnosis and improve the treatment for CRC patients. This tool is generalizable to other cancer diagnosis based on image recognition.

This study focuses on mindfulness programs in the corporate world, which are receiving increasing attention from business practitioners and organizational scholars. The workplace mindfulness literature is rapidly evolving, but most studies are oriented toward demonstrating the positive impacts of mindfulness as a state of mind. This study adopts a critical perspective to evaluate workplace mindfulness practice as a developmental process, with a focus on its potential risks that have ethical implications and are currently neglected by both researchers and practitioners. We draw from a Buddhist perspective that understands mindfulness training as an ethics-based, longitudinal, and holistic path. To this end, we develop a four-stage model to illustrate a potential developmental process for participants in workplace mindfulness programs. This model comprises four stages of preliminary concentration, deep concentration, self-transcendence, and reengagement, each of which has its own underlying characteristics and impacts on individual participants and organizations.

Oxide electronics advance At surfaces or interfaces of materials, electronic states can form that have novel properties that are different from the bulk. Tailoring such properties in thin film oxide devices has led to a new field of research — known as oxide electronics — in which the material strontium titanate (SrTiO 3 ) takes a central role. In particular, an exotic two-dimensional electron gas (2DEG) forms at oxide interfaces based on SrTiO 3 , but the precise nature of the 2DEG has remained elusive. Santander-Syro et al . carry out a systematic study using angle-resolved photoemission spectroscopy (ARPES), and obtain new insights into the electronic bandstructure of the 2DEG. Their findings shed light on previous observations in SrTiO 3 -based heterostructures and suggest that different forms of electron confinement at the surface of SrTiO 3 lead to essentially the same 2DEG. An exotic two-dimensional electron gas (2DEG) forms at oxide interfaces based on SrTiO 3 , but the precise nature of the 2DEG has remained elusive. In a systematic study using angle-resolved photoemission spectroscopy (ARPES), new insights into the electronic structure of the 2DEG are obtained. The findings shed light on previous observations in SrTiO 3 -based heterostructures and suggest that different forms of electron confinement at the surface of SrTiO 3 lead to essentially the same 2DEG. As silicon is the basis of conventional electronics, so strontium titanate (SrTiO 3 ) is the foundation of the emerging field of oxide electronics 1 , 2 . SrTiO 3 is the preferred template for the creation of exotic, two-dimensional (2D) phases of electron matter at oxide interfaces 3 , 4 , 5 that have metal–insulator transitions 6 , 7 , superconductivity 8 , 9 or large negative magnetoresistance 10 . However, the physical nature of the electronic structure underlying these 2D electron gases (2DEGs), which is crucial to understanding their remarkable properties 11 , 12 , remains elusive. Here we show, using angle-resolved photoemission spectroscopy, that there is a highly metallic universal 2DEG at the vacuum-cleaved surface of SrTiO 3 (including the non-doped insulating material) independently of bulk carrier densities over more than seven decades. This 2DEG is confined within a region of about five unit cells and has a sheet carrier density of ∼ 0.33 electrons per square lattice parameter. The electronic structure consists of multiple subbands of heavy and light electrons. The similarity of this 2DEG to those reported in SrTiO 3 -based heterostructures 6 , 8 , 13 and field-effect transistors 9 , 14 suggests that different forms of electron confinement at the surface of SrTiO 3 lead to essentially the same 2DEG. Our discovery provides a model system for the study of the electronic structure of 2DEGs in SrTiO 3 -based devices and a novel means of generating 2DEGs at the surfaces of transition-metal oxides.

Strong coupling between discrete phonon and continuous electron–hole pair excitations can induce a pronounced asymmetry in the phonon line shape, known as the Fano resonance. This effect has been observed in various systems. Here we reveal explicit evidence for strong coupling between an infrared-active phonon and electronic transitions near the Weyl points through the observation of a Fano resonance in the Weyl semimetal TaAs. The resulting asymmetry in the phonon line shape, conspicuous at low temperatures, diminishes continuously with increasing temperature. This behaviour originates from the suppression of electronic transitions near the Weyl points due to the decreasing occupation of electronic states below the Fermi level ( E F ) with increasing temperature, as well as Pauli blocking caused by thermally excited electrons above E F . Our findings not only elucidate the mechanism governing the tunable Fano resonance but also open a route for exploring exotic physical phenomena through phonon properties in Weyl semimetals. The study of lattice vibrations coupled to electronic excitations may provide an avenue for exploring exotic physical phenomena. Here, Xu et al . observe a Fano resonance in the Weyl semimetal TaAs, revealing evidence for a strong coupling between phonons and Weyl fermions.

Aims/hypothesis Diabetes has been related to Alzheimer's disease with inconsistent findings. We aimed to clarify the association of diabetes with different dementing disorders taking into account glycaemic control, and to explore the link between glucose dysregulation and neurodegeneration. Methods A dementia-free cohort (n = 1,248) aged >=75 years was longitudinally examined to detect dementia, Alzheimer's disease and vascular dementia (VaD) cases (Diagnostic and Statistical Manual of Mental Disorders, revised third edition [DSM-III-R] criteria). The Alzheimer's disease diagnoses were subdivided into Alzheimer's disease with stroke and Alzheimer's disease without hypertension, heart disease and stroke. Diabetes was ascertained based on medical history, or hypoglycaemic medication use, or a random blood glucose level >=11.0 mmol/l, which included undiagnosed diabetes when neither a history of diabetes nor hypoglycaemic drugs use was present. Uncontrolled diabetes was classified as a random blood glucose level >=11.0 mmol/l in diabetic patients. Borderline diabetes was defined as a random blood glucose level of 7.8-11.0 mmol/l in diabetes-free individuals. Cox models were used to estimate HRs. Results During the 9 year follow-up, 420 individuals developed dementia, including 47 with VaD and 320 with Alzheimer's disease (of the 320 Alzheimer's disease cases, 78 had previous, temporally unrelated stroke, and 137 had no major vascular comorbidities). Overall diabetes was only related to VaD (HR 3.21, 95% CI 1.20-8.63). Undiagnosed diabetes led to an HR of 3.29 (95% CI 1.20-9.01) for Alzheimer's disease. Diabetic patients with random blood glucose levels <7.8 mmol/l showed no increased dementia risk. Uncontrolled and borderline diabetes were further associated with Alzheimer's disease without vascular comorbidities. Conclusions/interpretation Uncontrolled diabetes increases the risk of Alzheimer's disease and VaD. Our findings suggest a direct link between glucose dysregulation and neurodegeneration.

Hec1 (highly expressed in cancer 1) or Nek2 (NIMA-related kinase 2) is often overexpressed in cancers with poor prognosis. Both are critical mitotic regulators, and phosphorylation of Hec1 S165 by Nek2 is required for proper chromosome segregation. Therefore, inactivation of Hec1 and Nek2 by targeting their interaction with small molecules represents an ideal strategy for tackling these types of cancers. Here we showed that new derivatives of INH (inhibitor for Nek2 and Hec1 binding) bind to Hec1 at amino acids 394–408 on W395, L399 and K400 residues, effectively blocking Hec1 phosphorylation on S165 by Nek2, and killing cancer cells at the nanomolar range. Mechanistically, the D-box (destruction-box) region of Nek2 specifically binds to Hec1 at amino acids 408–422, immediately adjacent to the INH binding motif. Subsequent binding of Nek2 to INH-bound Hec1 triggered proteasome-mediated Nek2 degradation, whereas the Hec1 binding defective Nek2 mutant, Nek2 R361L, resisted INH-induced Nek2 degradation. This finding unveils a novel drug-action mechanism where the binding of INHs to Hec1 forms a virtual death-trap to trigger Nek2 degradation and eventually cell death. Furthermore, analysis of the gene expression profiles of breast cancer patient samples revealed that co-elevated expressions of Hec1 and Nek2 correlated with the shortest survival. Treatment of mice with this kind of tumor with INHs significantly suppressed tumor growth without obvious toxicity. Taken together, the new INH derivatives are suitable for translation into clinical application.

SIRT4 is well-known for its deacetylase activity in energy metabolism, but little is known about its roles in carcinogenesis. We demonstrated that SIRT4 was decreased in 70 out of 133 non-small cell lung cancer (NSCLC) cases by immunohistochemical staining and localized in the mitochondria using confocal microscopy. Low levels of SIRT4 expression was correlated with tumor node metastasis (TNM) stage, histological type of tumor (adenocarcinoma), lymph nodal status, Ki-67 (proliferation index) and poor overall survival. We also studied the biological role of SIRT4 in lung cancer cell lines transfected with SIRT4 plasmid or SIRT4-siRNA. SIRT4 inhibited lung cancer cell proliferation, blocked the cell cycle and repressed cell invasion and migration. Mitochondrial dynamics has been implicated in malignant properties of cells, particularly metastasis that is the major cause of death in patients diagnosed with cancer including lung cancer. This is the first study to identify an association between SIRT4 expression and decreased mitochondrial fission, which was driven by Drp1. SIRT4 inhibited Drp1 phosphorylation and weakened Drp1 recruitment to the mitochondrial membrane via an interaction with Fis-1. SIRT4 expression was lower in nodal metastatic tumor samples than their corresponding primary tumors, and cases with low expression of SIRT4 tended to have high p-Drp1 labeling. Also, MEK/ERK activity appeared to be hampered by SIRT4 expression, which may have implications for cells’ invasive capacities. In conclusion, our findings suggest that SIRT4 functions as an important antitumor protein in NSCLC, and should be investigated further with respect to future anticancer strategies.

Artificial nanostructures, each composed of a copper(II) phthalocyanine (CuPc) molecule bonded to two gold atomic chains with a controlled gap, were assembled on a NiAl(110) surface by manipulation of individual gold atoms and CuPc molecules with a scanning tunneling microscope. The electronic densities of states of these hybrid structures were measured by spatially resolved electronic spectroscopy and systematically tuned by varying the number of gold atoms in the chains one by one. The present approach provides structural images and electronic characterization of the metal-molecule-metal junction, thereby elucidating the nature of the contacts between the molecule and metal in this junction.

The time-resolved magneto-optical (MO) Voigt effect can be utilized to study the Néel order dynamics in antiferromagnetic (AFM) materials, but it has been limited for collinear AFM spin configuration. Here, we have demonstrated that in Mn 3 Sn with an inverse triangular spin structure, the quench of AFM order by ultrafast laser pulses can result in a large Voigt effect modulation. The modulated Voigt angle is significantly larger than the polarization rotation due to the crystal-structure related linear dichroism effect and the modulated MO Kerr angle arising from the ferroic ordering of cluster magnetic octupole. The AFM order quench time shows negligible change with increasing temperature approaching the Néel temperature ( T N ), in markedly contrast with the pronounced slowing-down demagnetization typically observed in conventional magnetic materials. This atypical behavior can be explained by the influence of weakened Dzyaloshinskii–Moriya interaction rather than the smaller exchange splitting on the diminished AFM order near T N . The temperature-insensitive ultrafast spin manipulation can pave the way for high-speed spintronic devices either working at a wide range of temperature or demanding spin switching near T N . Mn3Sn is an anti-ferromagnetic material which displays a large magneto-optical Kerr effect, despite lacking a ferromagnetic moment. Here, the authors show that likewise, Mn3Sn, also presents a particularly large magneto-optical Voigt signal, with a negligible change in the quench time over a wide temperature range.