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BackgroundThe serine-threonine kinase mTORC1 (mechanistic target of rapamycin complex 1) is essential for normal cell function but is aberrantly activated in the brain in both genetic-developmental and sporadic diseases and is associated with a spectrum of neuropsychiatric symptoms. The underlying molecular mechanisms of cognitive and neuropsychiatric symptoms remain controversial.MethodsThe present study examines behaviors in transgenic models that express Rheb, the most proximal known activator of mTORC1, and profiles striatal phosphoproteomics in a model with persistently elevated mTORC1 signaling. Biochemistry, immunohistochemistry, electrophysiology, and behavior approaches are used to examine the impact of persistently elevated mTORC1 on D1 dopamine receptor (D1R) signaling. The effect of persistently elevated mTORC1 was confirmed using D1-Cre to elevate mTORC1 activity in D1R neurons.ResultsWe report that persistently elevated mTORC1 signaling blocks canonical D1R signaling that is dependent on DARPP-32 (dopamine- and cAMP-regulated neuronal phosphoprotein). The immediate downstream effector of mTORC1, ribosomal S6 kinase 1 (S6K1), phosphorylates and activates DARPP-32. Persistent elevation of mTORC1-S6K1 occludes dynamic D1R signaling downstream of DARPP-32 and blocks multiple D1R responses, including dynamic gene expression, D1R-dependent corticostriatal plasticity, and D1R behavioral responses including sociability. Candidate biomarkers of mTORC1-DARPP-32 occlusion are increased in the brain of human disease subjects in association with elevated mTORC1-S6K1, supporting a role for this mechanism in cognitive disease.ConclusionsThe mTORC1-S6K1 intersection with D1R signaling provides a molecular framework to understand the effects of pathological mTORC1 activation on behavioral symptoms in neuropsychiatric disease.

Background: Sepsis constitutes a condition that involves life-threatening organ dysfunction induced by severe infection. This nested case–control study investigated risk factors for severe sepsis and whether antipsychotic use is associated with severe sepsis risk in patients with schizophrenia, a topic that has not been comprehensively explored in previous studies. Methods: We selected 39,432 patients with schizophrenia aged between 15 and 65 years from Taiwan's Psychiatric Inpatient Medical Claims database for the period 2000–2012. The case group comprised patients with severe sepsis after their first psychiatric admission (n = 1382). The case and control groups were randomly matched (1:4) by age, sex and first psychiatric admission (year) and finally comprised 1382 and 5528 individuals, respectively. We employed multivariable conditional logistic regression to identify (1) risk factors (physical illnesses and nonpsychiatric medications) and (2) antipsychotic–severe sepsis associations. Results: Higher numbers of psychiatric admissions and physical illnesses such as delirium, cerebrovascular disease and cancer were significantly associated with a higher risk of severe sepsis. Furthermore, severe sepsis was associated with the use of antithrombotic agents, systemic corticosteroids and agents targeting the renin–angiotensin system. Clozapine (adjusted risk ratio = 1.65) and quetiapine (adjusted risk ratio = 1.59) use were associated with an increased risk of severe sepsis. The use of more than one antipsychotic drug could further increase this risk. Conclusion: Several physical illnesses and nonpsychiatric medications increase the risk of severe sepsis in patients with schizophrenia. Specifically, clozapine or quetiapine use significantly increased the risk of severe sepsis in these patients. [ABSTRACT FROM AUTHOR]

The energy crisis of the 1970s sparked growing concern over minimizing fuel consumption in water, land, and air transportation. Researchers fascinated by sharks' effortless swimming abilities investigated shark skin denticles and uncovered functions beyond drag reduction, such as antifouling, protection, and bioluminescence. Over the past five decades, significant progress has been made in comprehending drag reduction and antifouling functions of denticle structures; however, the investigation of other functions remains limited. Recent discoveries of diverse denticle morphologies have ignited a keen interest in obtaining morphogroups that can aid other functional studies. This work integrates advances in antifouling, hydrodynamics, aerodynamics, bioluminescence, and protective functions to provide a holistic understanding of their diverse roles. Additionally, this work also dictates multi‐functional adaptations of denticles and contributes to the relatively less‐explored but essential aspects, such as protective functions and denticle morphogroups. By examining these functions together, this work aims to uncover potential synergies and interactions, facilitating the development of multifunctional materials inspired by shark skin denticles. [ABSTRACT FROM AUTHOR]

Freeze casting is an effective way to fabricate the porous ceramics with anisotropic and interconnected porous structures and can be used in various applications, such as filtration, adsorption, and insulation. However, the ceramic‐based scaffolds fabricated by freeze casting have the upper limit of porosity since excessively low solid content in the slurry will lead to structural instability and cracks formation in scaffolds. This study aims at combining the freeze casting and sol–gel method and developing a hybrid process to overcome the limitation of freeze casting. Besides, the effects of solid content and cooling rates on the microstructure of ultralightweight alumina scaffolds (ULASs) and their mechanical and thermal properties were investigated. Aluminum isopropoxide was selected as the precursor to conduct the hydrolysis reaction in acid environment and condensation process by heat treatment. The successfully synthesized alumina scaffolds have ultrahigh porosity (>90%), low bulk density (0.1240–0.2429 g/cm3), and low relative density (0.0314–0.0615). The anisotropic porous lamellar structure was evaluated by scanning electron microscope, µ‐CT, and mercury porosimeter. A lot of nanoscale pores are observed on the lamellae surfaces, forming the dual‐scale porous structure inside the scaffolds and contributing to higher specific surface area. The unique anisotropic structure, high porosity, and stable mechanical properties enable ULASs to deliver a low thermal conductivity of 0.2 W/m/K and large anisotropy in thermal properties, possessing great potential for thermal insulative materials. This sol–gel/freeze‐casting hybrid approach is believed to be extended to different material systems and provide promising potentials in fabricating the porous materials with various functionalities. [ABSTRACT FROM AUTHOR]

Key Clinical Message: Invasive cribriform carcinoma (ICC) is a rare form of invasive breast carcinoma with good prognosis. To date, case reports considering skin manifestations of ICC are scarce. We herein report a case of pure ICC presenting as an erythematous papule on the nipple with mammary Paget's disease in the epidermis. We aim to bring awareness to skin manifestation of ICC. [ABSTRACT FROM AUTHOR]

Recent studies have shown that dexmedetomidine may improve microcirculation and prevent organ failure. However, most evidence was obtained from experimental animals and patients receiving cardiac surgery with cardiopulmonary bypass. This study aimed to investigate the effect of dexmedetomidine on microcirculation and organ injuries in critically ill general surgical patients.In this prospective randomized trial, patients admitted to the surgical intensive care unit after general surgery were enrolled and randomly allocated to the dexmedetomidine or propofol groups. Patients received continuous dexmedetomidine or propofol infusions to meet their requirement of sedation according to their grouping. At each time point, sublingual microcirculation images were obtained using the incident dark field video microscope.Overall, 60 patients finished the trial and were analyzed. Microcirculation parameters did not differ significantly between two groups. Heart rate at 4 h after ICU admission and mean arterial pressures at 12 h and 24 h after ICU admission were lower in the dexmedetomidine group than in the propofol group. At 24 h, serum aspartate aminotransferase (41 (25–118) vs 86 (34–129) U/L, p = 0.035) and alanine aminotransferase (50 (26–160) vs 68 (35–172) U/L, p = 0.019) levels were significantly lower in the dexmedetomidine group than in the propofol group.Microcirculation parameters did not differ significantly between the dexmedetomidine and propofol groups. At 24 h after ICU admission, serum liver enzyme levels were lower in patients receiving dexmedetomidine as compared to propofol. [ABSTRACT FROM AUTHOR]