Sepsis Induces Physical and Mental Impairments in a Mouse Model of Post-Intensive Care Syndrome

Post-intensive care syndrome (PICS) is a physical, cognitive, and mental impairment observed in intensive care unit (ICU) survivors. Although this is an emerging problem in the ICU, how sepsis induces the characteristic symptoms of PICS remains unclear. To develop a model of PICS, we induced sepsis in male C57/B6 mice via sublethal cecum slurry injection and subsequently treated them using ICU-like interventions. At 1–2 weeks post-sepsis induction, we simultaneously evaluated the abilities of the surviving mice using the following behavioral tests: (1) a grip strength test (GST) and a treadmill test for physical assessment, (2) a novel object recognition test (NORT) for cognitive assessment, and (3) an open field test (OFT) and a marble burying test (MBT) for mental assessment. The surviving mice showed a range of deficits, including muscle weakness with significantly decreased grip strength in the GST; decreased total mileage during the treadmill test; anxiety and decreased activity, with significantly decreased time in the central area, and increased duration of immobility in the OFT; and an increased number of buried marbles in the MBT. Given these physical and mental impairments in the surviving mice, our model has the potential to elucidate mechanistic insights and to discover therapeutic targets and new interventions for PICS.

ABT-263 enhanced bacterial phagocytosis of macrophages in aged mouse through Beclin-1-dependent autophagy

Background Sepsis is a critical challenge for the older adults as the immune function is less responsive by aging. Although cell numbers seem preserved in the older adults, macrophages present age-related function decline, which including reduced chemokines, phagocytosis, and autophagy. ABT-263, an inhibitor of the anti-apoptotic protein Bcl-2, is reported had a senolytic effect which can selectively clear the senescent cells in vivo and rejuvenate the aged tissues. Methods We treated the aged (12–16 months) and young (4–6 months) C57BL/6 mouse with ABT-263, then gave the animals cecal slurry injection to induce sepsis to observe the effect of senolytic compound ABT-263 on the survival rate of sepsis. Additionally, we isolated peritoneal macrophages from the aged mouse to investigate the cell function and molecular mechanism. 3-methyladenine (3-MA), a phosphatidylinositol 3-kinases (PI3K) inhibitor, and rapamycin, an autophagy-enhancer, were used to block or mimic the autophagy, respectively. RT-PCR and Western Blot were used to detect autophagy related gene and protein changes in sepsis. EGFP-expressing E. coli was used as a marker to evaluate the phagocytic ability of macrophages. Results The results showed ABT-263 treatment improved the survival rate of sepsis in the aged mouse which related to autophagy, while blocking the autophagy can eliminate this effect. It is revealed that ABT-263 enhanced the phagocytic ability of the peritoneal macrophages by increasing the Trem-2 receptor. Additionally, ABT-263 blocked the binding of Bcl-2 to Beclin-1, thus induced Beclin-1-dependent autophagy. Conclusion ABT-263 enhanced the macrophage function in aged mouse by increasing the Trem-2 receptors and inducing a beclin-1-dependent autophagy, consequently, protected the aged mouse from sepsis.

A bigger splat: The catastrophic geology of a 1.2-b.y.-old terrestrial megaclast, northwest Scotland

Rockfalls are relatively little described from the ancient geological record, likely due to their poor preservation potential. At Clachtoll, northwest Scotland, a megaclast (100 m × 60 m × 15 m) of Neoarchean Lewisian gneiss with an estimated mass of 243 kt is associated with basal breccias of the Mesoproterozoic Stoer Group. Foliation in the megablock is misoriented by ~90° about a subvertical axis relative to that in the underlying basement gneisses, and it is cut by fracture networks filled with Stoer Group red sandstone. Bedded clastic fissure fills on top of the megablock preserve way-up criteria consistent with passive deposition during burial. Sediment-filled fractures on the lateral flanks and base show characteristics consistent with forceful injection. Using numerical calculations, we propose that rift-related seismic shaking caused the megablock to fall no more than 15 m onto unconsolidated wet sediment. On impact, overpressure and liquefaction of the water-laden sands below the basement block were sufficient to cause hydrofracturing and upward sediment slurry injection. In addition, asymmetrically distributed structures record internal deformation of the megablock as it slowed and came to rest. The megablock is unrelated to the younger Stac Fada impact event, and represents one of the oldest known terrestrial rockfall features on Earth.

Field, petrographical and geochemical characterization of a layered anorthosite sequence in the Upper Main Zone of the Bushveld Complex

A sequence of eight poikilitic anorthosite layers (labeled 1 to 8), within the Upper Main Zone in the eastern lobe of the Bushveld Complex, are exposed along a road-cut, 5.3 km northeast of the town of Apel, Limpopo Province. The anorthosite layers are meter-scale in thickness (0.4 to 10 m), have sharp contacts and are defined on the size and shape of pyroxene oikocrysts they contain. The anorthosite sequence is bounded by typical Main Zone gabbronorites. Euhedral, zoned primocrystic laths of plagioclase (An62.5-80.6; 0.2 to 4 mm long) are morphologically identical throughout the anorthosite sequence and define a moderate to strong foliation that is typically aligned parallel to the plane of layering. Interstitial clinopyroxene and orthopyroxene typically occur as large (0.8 to 80 cm) oikocrysts enclosing numerous partly rounded plagioclase chadacrysts. Rarely, orthopyroxene appears as subophitic crystals enclosing few and significantly smaller (0.08 to 0.4 mm), equant plagioclase inclusions. Detailed plagioclase and pyroxene mineral compositions for layers 2 to 5 show minimal variations within layers (0.1 to 2.3 mol% An and 0.7 mol% Mg#), whereas compositional breaks occur between layers (0.5 to 3.8 mol% An and 1.3 mol% Mg#). In layers 2 to 5, the An-content of plagioclase cores and the Mg# of both clinopyroxene and orthopyroxene crystals decrease by 2.5 mol%, 8.6 mol% and 13.0 mol% upwards, respectively. Bulk-rock incompatible trace element concentrations and patterns are similar for all analyzed anorthosite layers indicating that they are related to the same parental magma. However, bulk-rock major element oxides (e.g. Al2O3, TiO2, K2O) and atomic Mg# become more evolved upwards, consistent with magmatic differentiation. Based on the consistent plagioclase crystal morphologies and relatively constant chemistries within each anorthosite layer, we propose that each layer was formed by the intrusion of a plagioclase slurry. The upwards-evolving mineral chemistries, bulk-rock major element oxides and atomic Mg# suggests that each plagioclase slurry injection, that yielded an anorthosite layer, was derived from a slightly more fractionated parental magma prior to emplacement.

ABT-263 enhanced bacterial phagocytosis of macrophages in aged mouse through Beclin-1-dependent autophagy

Background: Sepsis is a critical challenge for the elderly population as the immune function is less responsive by aging. Although cell numbers seem preserved in the elderly, macrophages present age-related function decline, which including reduced chemokines, phagocytosis, and autophagy. ABT-263, an inhibitor of the anti-apoptotic protein Bcl-2, is reported had a senolytic effect which can selectively clear the senescent cells in vivo and rejuvenate the aged tissues.Methods: We treated the aged (12-16 months) and young (4-6 months) C57BL/6 mouse with ABT-263, then gave the animals cecal slurry injection to induce sepsis to observe the effect of senolytic compound ABT-263 on the survival rate of sepsis. Additionally, we isolated peritoneal macrophages from the aged mouse to investigate the cell function and molecular mechanism. 3-methyladenine (3-MA), a phosphatidylinositol 3-kinases (PI3K) inhibitor, and rapamycin, an autophagy-enhancer, were used to block or mimic the autophagy, respectively. RT-PCR and Western Blot were used to detect autophagy related gene and protein changes in sepsis. EGFP-expressing E. Coli was used as a marker to evaluate the phagocytic ability of macrophages. Results: The results showed ABT-263 treatment improved the survival rate of sepsis in the aged mouse which related to autophagy, while blocking the autophagy can eliminate this effect. It is revealed that ABT-263 enhanced the phagocytic ability of the peritoneal macrophages by increasing the Trem-2 receptor. Additionally, ABT-263 blocked the binding of Bcl-2 to Beclin-1, thus induced Beclin-1-dependent autophagy. Conclusion: ABT-263 enhanced the macrophage function in aged mouse by increasing the Trem-2 receptors and inducing a beclin-1-dependent autophagy, consequently, protected the aged mouse from sepsis.