In the present study we introduce a sensitive video-based test for the evaluation of subtle mindreading difficulties: the Movie for the Assessment of Social Cognition (MASC). This new mindreading tool involves watching a short film and answering questions referring to the actors' mental states. A group of adults with Asperger syndrome (n = 19) and well-matched control subjects (n = 20) were administered the MASC and three other mindreading tools as part of a broader neuropsychological testing session. Compared to control subjects, Asperger individuals exhibited marked and selective difficulties in social cognition. A Receiver Operating Characteristic (ROC) analysis for the mindreading tests identified the MASC as discriminating the diagnostic groups most accurately. Issues pertaining to the multidimensionality of the social cognition construct are discussed.

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Highlights d Development of a CDK6-selective small-molecule degrader d Mechanistically understood selectivity via differential ternary complex formation d Profiling of consequences of CDK6 degradation on signaling and gene regulation d Precise exploitation of genetic dependencies through homolog-selective degradation Authors

Objective: To study awareness of cognitive dysfunction in patients with very mild Alzheimer’s disease (AD) and subjects with mild cognitive impairment (MCI). Methods: A complaint interview covering 13 cognitive domains was administered to 82 AD and 79 MCI patients and their caregivers. The patient groups were comparable according to age and education, and Mini Mental State Examination (MMSE) scores were ≧24 in all cases. The discrepancy between the patients’ and caregivers’ estimations of impairments was taken as a measure of anosognosia. Results: Self-reports of cognitive difficulties were comparable for AD and MCI patients. However, while in comparison to caregivers MCI patients reported significantly more cognitive impairment (p < 0.05), AD patients complained significantly less cognitive dysfunctions (p < 0.001). Conclusions: While most MCI patients tend to overestimate cognitive deficits when compared to their caregiver’s assessment, AD patients in early stages of disease underestimate cognitive dysfunctions. Anosognosia can thus be regarded as a characteristic symptom at a stage of very mild AD (MMSE ≧24) but not MCI. Accordingly, medical history even in mildly affected patients should always include information from both patient and caregiver.

Protein degradation is an emerging therapeutic strategy with a unique molecular pharmacology that enables the disruption of all functions associated with a target. This is particularly relevant for proteins depending on molecular scaffolding, such as transcription factors or receptor tyrosine kinases (RTKs). To address tractability of multiple RTKs for chemical degradation by the E3 ligase CUL4-RBX1-DDB1-CRBN (CRL4), we synthesized a series of phthalimide degraders based on the promiscuous kinase inhibitors sunitinib and PHA665752. While both series failed to induce degradation of their consensus targets, individual molecules displayed pronounced efficacy in leukemia cell lines. Orthogonal target identification supported by molecular docking led us to identify the translation termination factor G1 to S phase transition 1 (GSPT1) as a converging off-target, resulting from inadvertent E3 ligase modulation. This research highlights the importance of monitoring degradation events that are independent of the respective targeting ligand as a unique feature of small-molecule degraders.

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Highlights d Unbiased survey reveals global and specific effectors for target degradation d CRL dependency on CAND1/CSN is ligase and context specific d Perturbing CAND1/CSN abrogates CRL plasticity and prompts ligase auto-degradation d CSN inactivation blocks substrate-driven CRL assembly

The adherence of 58 nontypeable Haemophilus influenzae isolates obtained from patients with otitis media or chronic obstructive pulmonary disease (COPD) and obtained from the throats of healthy individuals to Chang and NCI-H292 epithelial cells was compared. Otitis media isolates, but not COPD isolates, adhered significantly more to both cell lines than did throat isolates. Since high-molecular-weight (HMW) proteins are major adhesins of nontypeable H. influenzae, the isolates were screened for HMW protein expression by Western blotting with two polyclonal sera and PCR with hmw-specific primers. Twenty-three of the 32 adhering isolates (72%) and only 1 of the 26 nonadherent strains were HMW protein or hmw gene positive. Among the 32 isolates adhering to either cell line, 5 different adherence patterns were distinguished based on the inhibiting effect of dextran sulfate. Using H. influenzae strain 12 expressing two well-defined HMW proteins (HMW1 and HMW2) and its isogenic mutants as a reference, we observed HMW1-like adherence to both cell lines for 16 of the 32 adherent isolates. Four others showed HMW2-like adherence to NCI-H292. Of the three other patterns of adherence, one probably also involved HMW protein. Screening of the isolates with six HMW-specific monoclonal antibodies in a whole-cell enzyme-linked immunosorbent assay showed that the HMW proteins of COPD isolates and carrier isolates were more distinct from the HMW proteins from H. influenzae strain 12 than those from otitis media isolates. Characterization of the HMW protein of a COPD isolate by adherence and DNA sequence analysis showed that despite large sequence diversity in the hmwA gene, probably resulting in the antigenic differences, the HMW protein mediated the HMW2-like adherence of this strain.The gram-negative bacterium Haemophilus influenzae is a commensal of the human upper respiratory tract. Encapsulated strains, in particular those with a serotype b polysaccharide, are important pathogens causing systemic disease, such as meningitis, epiglottitis, cellulitis, arthritis, sepsis, and pneumonia. Nonencapsulated (nontypeable) H. influenzae is a frequent cause of respiratory tract infections, including otitis media, sinusitis, and lower respiratory tract infections in patients with chronic obstructive pulmonary disease (COPD) (20,34,35).Adherence of H. influenzae to the respiratory epithelial cells is considered an important step in the colonization of the respiratory mucosa. Several adhesins of H. influenzae have been determined, each with different adherence specificities (23, 30, 39). Adherence of H. influenzae by a fimbriamediated as well as a fimbria-independent mechanism has been described. Fimbria-mediated adherence seems to be especially relevant for the adherence of encapsulated H. influenzae isolates to different cells (8,17,24,29), since this type of adherence is not hampered by capsule expression (28, 30). Only a minority of nontypeable H. influenzae isolates from different sources contained a fimbria gene cluster (9, 10, 15). ...