The predictive validity of the DSM-5 alternative model for borderline personality disorder: Associations with coping strategies, general distress, rumination, and suicidal ideation across one year.

The DSM-5 Alternative Model for Personality Disorders (AMPD) characterizes borderline personality disorder (BPD) in part as a constellation of maladaptive personality trait facets including emotional lability, anxiousness, separation insecurity, depressivity, impulsivity, risk-taking, and hostility. Previous studies have supported the construct validity of AMPD-BPD; however, research examining its predictive validity in relation to theoretically and clinically relevant constructs remains needed. The present study investigates the longitudinal relationships between AMPD-BPD and general distress, rumination, and suicidal ideation, as well as adaptive and maladaptive coping targeted in Dialectical Behavior Therapy (DBT) in a sample of participants with elevated BPD symptomology. We also examined if dysfunctional coping skill use at 9-month follow-up explained the relationship between baseline BPD traits and outcomes at 1-year. There were significant correlations between baseline trait BPD with dysfunctional coping skill use at 9-month follow-up and psychological distress and rumination at 1-year follow-up. Dysfunctional skill use exhibited a significant indirect effect in the association between trait BPD and rumination after 1 year. The findings of this study support the construct validity of AMPD-BPD that can inform treatment and research.

Induced pluripotent stem cells display a distinct set of MHC I-associated peptides shared by human cancers.

Previous reports showed that mouse vaccination with pluripotent stem cells (PSCs) induces durable anti-tumor immune responses via T cell recognition of some elusive oncofetal epitopes. We characterize the MHC I-associated peptide (MAP) repertoire of human induced PSCs (iPSCs) using proteogenomics. Our analyses reveal a set of 46 pluripotency-associated MAPs (paMAPs) absent from the transcriptome of normal tissues and adult stem cells but expressed in PSCs and multiple adult cancers. These paMAPs derive from coding and allegedly non-coding (48%) transcripts involved in pluripotency maintenance, and their expression in The Cancer Genome Atlas samples correlates with source gene hypomethylation and genomic aberrations common across cancer types. We find that several of these paMAPs were immunogenic. However, paMAP expression in tumors coincides with activation of pathways instrumental in immune evasion (WNT, TGF-ß, and CDK4/6). We propose that currently available inhibitors of these pathways could synergize with immune targeting of paMAPs for the treatment of poorly differentiated cancers.

Phosphorylation state of the histone variant H2A.X controls human stem and progenitor cell fate decisions.

Histone variants (HVs) are a subfamily of epigenetic regulators implicated in embryonic development, but their role in human stem cell fate remains unclear. Here, we reveal that the phosphorylation state of the HV H2A.X (γH2A.X) regulates self-renewal and differentiation of human pluripotent stem cells (hPSCs) and leukemic progenitors. As demonstrated by CRISPR-Cas deletion, H2A.X is essential in maintaining normal hPSC behavior. However, reduced levels of γH2A.X enhances hPSC differentiation toward the hematopoietic lineage with concomitant inhibition of neural development. In contrast, activation and sustained levels of phosphorylated H2A.X enhance hPSC neural fate while suppressing hematopoiesis. This controlled lineage bias correlates to occupancy of γH2A.X at genomic loci associated with ectoderm versus mesoderm specification. Finally, drug modulation of H2A.X phosphorylation overcomes differentiation block of patient-derived leukemic progenitors. Our study demonstrates HVs may serve to regulate pluripotent cell fate and that this biology could be extended to somatic cancer stem cell control.

Rapamycin regulates autophagy and cell adhesion in induced pluripotent stem cells.

BACKGROUND: Cellular reprogramming is a stressful process, which requires cells to engulf somatic features and produce and maintain stemness machineries. Autophagy is a process to degrade unwanted proteins and is required for the derivation of induced pluripotent stem cells (iPSCs). However, the role of autophagy during iPSC maintenance remains undefined. METHODS: Human iPSCs were investigated by microscopy, immunofluorescence, and immunoblotting to detect autophagy machinery. Cells were treated with rapamycin to activate autophagy and with bafilomycin to block autophagy during iPSC maintenance. High concentrations of rapamycin treatment unexpectedly resulted in spontaneous formation of round floating spheres of uniform size, which were analyzed for differentiation into three germ layers. Mass spectrometry was deployed to reveal altered protein expression and pathways associated with rapamycin treatment. RESULTS: We demonstrate that human iPSCs express high basal levels of autophagy, including key components of APMKα, ULK1/2, BECLIN-1, ATG13, ATG101, ATG12, ATG3, ATG5, and LC3B. Block of autophagy by bafilomycin induces iPSC death and rapamycin attenuates the bafilomycin effect. Rapamycin treatment upregulates autophagy in iPSCs in a dose/time-dependent manner. High concentration of rapamycin reduces NANOG expression and induces spontaneous formation of round and uniformly sized embryoid bodies (EBs) with accelerated differentiation into three germ layers. Mass spectrometry analysis identifies actin cytoskeleton and adherens junctions as the major targets of rapamycin in mediating iPSC detachment and differentiation. CONCLUSIONS: High levels of basal autophagy activity are present during iPSC derivation and maintenance. Rapamycin alters expression of actin cytoskeleton and adherens junctions, induces uniform EB formation, and accelerates differentiation. IPSCs are sensitive to enzyme dissociation and require a lengthy differentiation time. The shape and size of EBs also play a role in the heterogeneity of end cell products. This research therefore highlights the potential of rapamycin in producing uniform EBs and in shortening iPSC differentiation duration.

Multiscale geometry and scaling of the turbulent-nonturbulent interface in high Reynolds number boundary layers.

The scaling and surface area properties of the wrinkled surface separating turbulent from nonturbulent regions in open shear flows are important to our understanding of entrainment mechanisms at the boundaries of turbulent flows. Particle image velocimetry data from high Reynolds number turbulent boundary layers covering three decades in scale are used to resolve the turbulent-nonturbulent interface experimentally and, for the first time, determine unambiguously whether such surfaces exhibit fractal scaling. Box counting of the interface intersection with the measurement plane exhibits power-law scaling, with an exponent between -1.3 and -1.4. A complementary analysis based on spatial filtering of the velocity fields also shows power-law behavior of the coarse-grained interface length as a function of filter width, with an exponent between -0.3 and -0.4. These results establish that the interface is fractal-like with a multiscale geometry and fractal dimension of Df≈2.3-2.4.

Approach to an asymptotic state for zero pressure gradient turbulent boundary layers.

Flat plate turbulent boundary layers under zero pressure gradient at high Reynolds numbers are studied to reveal appropriate scale relations and asymptotic behaviour. Careful examination of the skin-friction coefficient results confirms the necessity for direct and independent measurement of wall shear stress. We find that many of the previously proposed empirical relations accurately describe the local Cf behaviour when modified and underpinned by the same experimental data. The variation of the integral parameter, H, shows consistent agreement between the experimental data and the relation from classical theory. In accordance with the classical theory, the ratio of Delta and delta asymptotes to a constant. Then, the usefulness of the ratio of appropriately defined mean and turbulent time-scales to define and diagnose equilibrium flow is established. Next, the description of mean velocity profiles is revisited, and the validity of the logarithmic law is re-established using both the mean velocity profile and its diagnostic function. The wake parameter, Pi, is shown to reach an asymptotic value at the highest available experimental Reynolds numbers if correct values of logarithmic-law constants and an appropriate skin-friction estimate are used. The paper closes with a discussion of the Reynolds number trends of the outer velocity defect which are important to establish a consistent similarity theory and appropriate scaling.