Distinct molecular profiles of skull bone marrow in health and neurological disorders.

The bone marrow in the skull is important for shaping immune responses in the brain and meninges, but its molecular makeup among bones and relevance in human diseases remain unclear. Here, we show that the mouse skull has the most distinct transcriptomic profile compared with other bones in states of health and injury, characterized by a late-stage neutrophil phenotype. In humans, proteome analysis reveals that the skull marrow is the most distinct, with differentially expressed neutrophil-related pathways and a unique synaptic protein signature. 3D imaging demonstrates the structural and cellular details of human skull-meninges connections (SMCs) compared with veins. Last, using translocator protein positron emission tomography (TSPO-PET) imaging, we show that the skull bone marrow reflects inflammatory brain responses with a disease-specific spatial distribution in patients with various neurological disorders. The unique molecular profile and anatomical and functional connections of the skull show its potential as a site for diagnosing, monitoring, and treating brain diseases.

Structural basis for the extended CAP-Gly domains of p150(glued) binding to microtubules and the implication for tubulin dynamics.

p150(glued) belongs to a group of proteins accumulating at microtubule plus ends (+TIPs). It plays a key role in initiating retrograde transport by recruiting and tethering endosomes and dynein to microtubules. p150(glued) contains an N-terminal microtubule-binding cytoskeleton-associated protein glycine-rich (CAP-Gly) domain that accelerates tubulin polymerization. Although this copolymerization is well-studied using light microscopic techniques, structural consequences of this interaction are elusive. Here, using electron-microscopic and spectroscopic approaches, we provide a detailed structural view of p150(glued) CAP-Gly binding to microtubules and tubulin. Cryo-EM 3D reconstructions of p150(glued)-CAP-Gly complexed with microtubules revealed the recognition of the microtubule surface, including tubulin C-terminal tails by CAP-Gly. These binding surfaces differ from other retrograde initiation proteins like EB1 or dynein, which could facilitate the simultaneous attachment of all accessory components. Furthermore, the CAP-Gly domain, with its basic extensions, facilitates lateral and longitudinal interactions of tubulin molecules by covering the tubulin acidic tails. This shielding effect of CAP-Gly and its basic extensions may provide a molecular basis of the roles of p150(glued) in microtubule dynamics.

Negative symptoms in depressed and schizophrenic patients: how do they differ?

BACKGROUND: The present study evaluated differences in negative symptoms between schizophrenic and depressive patients and investigated whether a consideration of the nature of negative symptoms (enduring vs. nonenduring) can help to improve their specificity for schizophrenia. METHOD: Patients enrolled in the study were consecutively hospitalized with an acute exacerbation of schizophrenia (N = 33) or major depressive disorder (N = 43) (DSM-IV). Negative and depressive symptoms were assessed with the Scale for the Assessment of Negative Symptoms (SANS) and the Montgomery-Asberg Depression Rating Scale, respectively. Duration of negative symptoms was assessed through a semistructured interview with the patients and their closest relatives. On the basis of the assessed duration of symptoms, negative symptoms were categorized as enduring or nonenduring. RESULTS: Analyses revealed high SANS ratings for both diagnostic groups. Negative symptoms in depressive patients (p =.01), but not in schizophrenic patients, were significantly associated with the presence or the emergence of depressive symptoms. The prevalence of enduring negative symptoms was significantly higher in schizophrenic patients than in depressive patients (p <.01). A consideration of enduring negative symptoms significantly increased the discriminative power of negative symptoms for schizophrenia (p =.02). CONCLUSION: The present findings suggest that negative symptoms in most depressive patients are just an epiphenomenon of depressive symptoms and can be distinguished from schizophrenic negative symptoms.