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Malaria is one of the most widespread diseases worldwide. Besides a growing number of people potentially threatened by malaria, the consistent emergence of resistance against established antimalarial pharmaceuticals leads to an urge toward new antimalarial drugs. Hybridization of two chemically diverse compounds into a new bioactive product is a successful concept to improve the properties of a hybrid drug relative to the parent compounds and also to overcome multidrug resistance. 1,2,3-Triazoles are a significant pharmacophore system among nitrogen-containing heterocycles with various applications, such as antiviral, antimalarial, antibacterial, and anticancer agents. Several marketed drugs possess these versatile moieties, which are used in a wide range of medical indications. While the synthesis of hybrid compounds containing a 1,2,3-triazole unit was described using Cu- and Ru-catalyzed azide–alkyne cycloaddition, an alternative metal-free pathway has never been reported for the synthesis of antimalarial hybrids. However, a metal-free pathway is a green method that allows toxic and expensive metals to be replaced with an organocatalyst. Herein, we present the synthesis of new artemisinin–triazole antimalarial hybrids viaa facile Ramachary-Bressy-Wang organocatalyzed azide-carbonyl [3 + 2] cycloaddition (organo-click) reaction. The prepared new hybrid compounds are highly potent in vitroagainst chloroquine (CQ)-resistant and multi-drug-resistant Plasmodium falciparumstrains (IC50(Dd2) down to 2.1 nM; IC50(K1) down to 1.8 nM) compared to CQ (IC50(Dd2) = 165.3 nM; IC50(K1) = 302.8 nM). Moreover, the most potent hybrid drug was more efficacious in suppressing parasitemia and extending animal survival in Plasmodium berghei-infected mice (up to 100% animal survival and up to 40 days of survival time) than the reference drug artemisinin, illustrating the potential of the hybridization concept as an alternative and powerful drug-discovery approach.

Decreased insulin availability and high blood glucose levels, the hallmark features of poorly controlled diabetes, drive disease progression and are associated with decreased skeletal muscle mass. We have shown that mice with β‐cell dysfunction and normal insulin sensitivity have decreased skeletal muscle mass. This project asks how insulin deficiency impacts on the structure and function of the remaining skeletal muscle in these animals. Skeletal muscle function was determined by measuring exercise capacity and specific muscle strength prior to and after insulin supplementation for 28 days in 12‐week‐old mice with conditional β‐cell deletion of the ATP binding cassette transporters ABCA1 and ABCG1 (β‐DKO mice). Abca1and Abcg1floxed (fl/fl) mice were used as controls. RNAseq was used to quantify changes in transcripts in soleus and extensor digitorum longus muscles. Skeletal muscle and mitochondrial morphology were assessed by transmission electron microscopy. Myofibrillar Ca2+sensitivity and maximum isometric single muscle fibre force were assessed using MyoRobotbiomechatronics technology. RNA transcripts were significantly altered in β‐DKO mice compared with fl/fl controls (32 in extensor digitorum longus and 412 in soleus). Exercise capacity and muscle strength were significantly decreased in β‐DKO mice compared with fl/fl controls (P =0.012), and a loss of structural integrity was also observed in skeletal muscle from the β‐DKO mice. Supplementation of β‐DKO mice with insulin restored muscle integrity, strength and expression of 13 and 16 of the dysregulated transcripts in and extensor digitorum longus and soleus muscles, respectively. Insulin insufficiency due to β‐cell dysfunction perturbs the structure and function of skeletal muscle. These adverse effects are rectified by insulin supplementation.

ObjectiveMucosal T cells play a major role in inflammatory bowel disease (IBD). However, their immunometabolism during intestinal inflammation is poorly understood. Due to its impact on cellular metabolism and proinflammatory immune cell function, we here focus on the enzyme ATP citrate lyase (ACLY) in mucosal T cell immunometabolism and its relevance for IBD.DesignACLY expression and its immunometabolic impact on colitogenic T cell function were analysed in mucosal T cells from patients with IBD and in two experimental colitis models.ResultsACLY was markedly expressed in colon tissue under steady-state conditions but was significantly downregulated in lamina propria mononuclear cells in experimental dextran sodium sulfate-induced colitis and in CD4+and to a lesser extent in CD8+T cells infiltrating the inflamed gut in patients with IBD. ACLY-deficient CD4+T cells showed an impaired capacity to induce intestinal inflammation in a transfer colitis model as compared with wild-type T cells. Assessment of T cell immunometabolism revealed that ACLY deficiency dampened the production of IBD-relevant cytokines and impaired glycolytic ATP production but enriched metabolites involved in the biosynthesis of phospholipids and phosphatidylcholine. Interestingly, the short-chain fatty acid butyrate was identified as a potent suppressor of ACLY expression in T cells, while IL-36α and resolvin E1 induced ACLY levels. In a translational approach, in vivo administration of the butyrate prodrug tributyrin downregulated mucosal infiltration of ACLYhighCD4+T cells and ameliorated chronic colitis.ConclusionACLY controls mucosal T cell immunometabolism and experimental colitis. Therapeutic modulation of ACLY expression in T cells emerges as a novel strategy to promote the resolution of intestinal inflammation.

Duchenne muscular dystrophy (DMD) is a common inherited muscle disease showing chronic inflammation and progressive muscle weakness. Absent dystrophin renders sarcolemma more Ca.sub.2+-permeable, disturbs signalling and triggers inflammation. Sustained degeneration/regeneration cycles render muscle cytoarchitecture susceptible to remodelling. Quantitative morphometry was introduced in living cells using second-harmonic generation (SHG) microscopy of myosin. As the time course of cellular remodelling is not known, we used SHG microscopy in mdx muscle fibres over a wide age range for three-dimensional (3D) rendering and detection of verniers and cosine angle sums (CASs). Wild-type (wt) and transgenic mini-dystrophin mice (MinD) were also studied. Vernier densities (VDs) declined in wt and MinD fibres until adulthood, while in mdx fibres, VDs remained significantly elevated during the life span. CAS values were close to unity in adult wt and MinD fibres, in agreement with tight regular myofibril orientation, while always smaller in mdx fibres. Using SHG 3D morphometry, we identified two types of altered ultrastructure: branched fibres and a novel, previously undetected 'chaotic' fibre type, both of which can be classified by distinct CAS and VD combinations. We present a novel model of tissue remodelling in dystrophic progression with age that involves the transition from normal to chaotic to branched fibres. Our model predicts a a1/450% contribution of altered cytoarchitecture to progressive force loss with age. We also provide an improved automated image algorithm that is suitable for future ageing studies in human myopathies. Copyright A[c] 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

The development of suitable synthetic scaffolds for use as human tendon grafts to repair tendon ruptures remains a significant engineering challenge. Previous synthetic tendon grafts have demonstrated suboptimal tissue ingrowth and synovitis due to wear particles from fiber-to-fiber abrasion. In this study, we present a novel fiber-reinforced hydrogel (FRH) that mimics the hierarchical structure of the native human tendon for synthetic tendon graft material. Ultrahigh molecular weight polyethylene (UHMWPE) fibers were impregnated with either biosynthetic polyvinyl alcohol/gelatin hydrogel (FRH-PG) or with polyvinyl alcohol/gelatin + strontium-hardystonite (Sr-Ca2ZnSi2O7, Sr-HT) composite hydrogel (FRH-PGS). The scaffolds were fabricated and assessed to evaluate their suitability for tendon graft applications. The microstructure of both FRH-PG and FRH-PGS showed successful impregnation of the hydrogel component, and the tendon scaffolds exhibited equilibrium water content of ∼70 wt %, similar to the values reported for native human tendon, compared to ∼50 wt % water content retained in unmodified UHMWPE fibers. The tensile strength of FRH-PG and FRH-PGS (77.0–81.8 MPa) matched the range of human Achilles’ tendon tensile strengths reported in the literature. In vitro culture of rat tendon stem cells showed cell and tissue infiltration into both FRH-PG and FRH-PGS after 2 weeks, and the presence of Sr-HT ceramic particles influenced the expression of tenogenic markers. On the other hand, FRH-PG supported the proliferation of murine C2C12 myoblasts, whereas FRH-PGS seemingly did not support it under static culture conditions. In vivo implantation of FRH-PG and FRH-PGS scaffolds into full-thickness rat patellar tendon defects showed good collagenous tissue ingrowth into these scaffolds after 6 weeks. This study demonstrates the potential viability for our FRH-PG and FRH-PGS scaffolds to be used for off-the-shelf biosynthetic tendon graft material.

To contribute to a better understanding of Neogene climate evolution in Central Asia, we here present the first orbitally tuned time scale for a drillcore record from the Qaidam Basin (NE Tibetan Plateau) that consists of lacustrine sediments and spans the late Pliocene to early Pleistocene (~3.3 to 2.1 Ma). Our tuning of Core SG-1b is based on the ln(Rb/Sr) ratio derived from XRF core scanning and grain-size distribution data that trace wet-dry climate alternations predominantly paced by orbital obliquity. Based on our ln(Rb/Sr) record, obliquity-precession interferences persisted during the mid-Pliocene warm period, but disappeared during the early Pleistocene. This could indicate that over the course of the late Pliocene a low-latitude-derived climate modulator gained an increasingly prominent role in shaping the environment of the Qaidam paleolake. At the same time, the consistent presence of the precession signal during the early Pleistocene hampers a refinement of the entire tuning on precession time scales. The inferred changes in sedimentation rate from the late Pliocene to the early Pleistocene indicate a long-term decrease in sediment supply into the Qaidam paleolake. This finding is in line with the previously proposed notion of a long-term aridification trend across the Plio-Pleistocene transition in Central Asia.

Losing one's ability to speak, because of tissue deficiency at the vocal fold (VF), leads to serious impairment in the quality of life. Until now, there is no successful approach for regenerating the VF. The aim of this study was to show the advantage of magnetic nanoparticles in the generation of scaffold-free three-dimensional (3D) VF cell constructs by magnetic tissue engineering (MTE). Rabbit VF fibroblasts were used to establish MTE: after cellular uptake of superparamagnetic iron oxide nanoparticles (SPIONs), cells can be controlled with a magnetic field thereby forming solid 3D cell structures. To transfer this method into human cells, SPIONs were adapted accordingly and tested for their influence on human VF (hVF) cells and for their ability to perform MTE with hVF cells. Of interest, the cell number and the magnet's shape influence the form of the rabbit VF cell construct. After successful characterization of hVF cells, biocompatibility analyses revealed no significant influence of SPIONs on them, thus 3D hVF cell constructs could be successfully generated by MTE. These basic results are important to develop MTE as an innovative method to regenerate functional VFs. We expect that in vivostudies, including MTE as an elegant, far-field controlled and touchless technology, will translate MTE VF bioconstructs into reconstructive laryngeal medicine.Impact StatementThis study aims at nanotechnology for regenerative medicine by magnetic tissue engineering (MTE). New approaches for vocal fold (VF) reconstruction are desperately needed. Superparamagnetic iron oxide nanoparticles offer innovative, scaffold-free potentials for tissue engineering: MTE. By using MTE we could generate functional multilayered human VF cell constructs, which can consequently be used to regenerate the voice in patients with VF injuries.

There is a converging body of evidence supporting a measurable slowdown of the Atlantic Meridional Overturning Circulation (AMOC) as climate warms and Northern Hemisphere ice sheets inexorably shrink. Within this context, we assess the variability of the AMOC during the Holocene based on a marine sediment core retrieved from the deep northwest Atlantic, which sensitively recorded large‐scale deglacial transitions in deep water circulation. While there is a diffuse notion of Holocene variability in Labrador and Nordic Seas overturning, we report a largely invariable deep water circulation for the last ~11,000 years, even during the meltwater pulse associated with the 8.2‐ka event. Sensitivity tests along with high‐resolution 231Pa/230Th data constrain the duration and the magnitude of possible Holocene AMOC variations. The generally constant baseline during the Holocene suggests attenuated natural variability of the large‐scale AMOC on submillennial timescales and calls for compensating effects involving the upstream components of North Atlantic Deep Water. High‐resolution 231Pa/230Th record from the Bermuda Rise for the past 11,000 years presentedLow variability of Holocene AMOC derived from 231Pa/230Th, εNd and δ13CDuration and magnitude of the 8.2‐ka event constrained by sensitivity tests

The North Atlantic Current (NAC) transports warm salty water to high northern latitudes, with important repercussions for ocean circulation and global climate. A southward displacement of the NAC and Subarctic Front, which separate subpolar and subtropical water masses, is widely suggested for the Last Glacial Maximum (LGM) and may have acted as a positive feedback in glacial expansion at this time. However, the role of the NAC during the intensification of Northern Hemisphere glaciation (iNHG) at ~3.5 to 2.5 Ma is less clear. Here we present new records from Integrated Ocean Drilling Program Site U1313 (41°N) spanning ~2.8–2.4 Ma to trace the influence of Subarctic Front waters above this mid‐latitude site. We reconstruct surface and permanent pycnocline temperatures and seawater δ18O using paired Mg/Ca‐δ18O measurements on the planktic foraminifers Globigerinoides ruberand Globorotalia crassaformisand determine abundances of the subpolar foraminifer Neogloboquadrina atlantica. We find that the first significant glacial incursions of Subarctic Front surface waters above Site U1313 did not occur until ~2.6 Ma. At no time during our study interval was (sub)surface reorganization in the midlatitude North Atlantic analogous to the LGM. Our findings suggest that LGM‐like processes sensu strictocannot be invoked to explain interglacial‐glacial cycle amplification during iNHG. They also imply that increased glacial productivity at Site U1313 during iNHG was not only driven by southward deflections of the Subarctic Front. We suggest that nutrient injection from cold‐core eddies and enhanced glacial dust delivery may have played additional roles in increasing export productivity in the midlatitude North Atlantic from 2.7 Ma. North Atlantic (sub)surface temperature and seawater δ18O reconstructions during the intensification of Northern Hemisphere glaciationSouthward shifts of Subarctic Front during the intensification of Northern Hemisphere glaciation not analogous to the Last Glacial MaximumDust and/or eddies are important drivers of glacial export productivity at 41°N from 2.7 Ma

The dynamics of Northern Hemisphere ice sheets during Late Quaternary glacials have yet been dominantly examined from a Laurentide Ice Sheet perspective, which helped shaping the idea of moisture‐starved glacials and small‐scale ice volume variability. However, the waxing and waning of the European Ice Sheet (EIS) casts doubt on this perception. Understanding EIS dynamics under glacial boundary conditions is crucial because its meltwater pulses influence global climate by weakening deepwater formation in the North Atlantic Ocean. Here we show that the advection of subtropical water toward the continental margin of western Europe lead to enhanced moisture availability on the continent and fueled the growth of EIS lobes during glacials. This warm‐water pooling was caused by monsoonally paced enhanced Mediterranean Outflow Water (MOW) entrainment that dragged subtropical surface waters toward the European margin. This mechanism presents a yet unrecognized marine‐terrestrial pathway that allows low‐latitude forcing to shape high‐latitude glaciations. The build‐up of glacial ice shields required large amounts of atmospheric precipitating as snow. However, under full glacial conditions, cold surface oceans reduce the amount of evaporation, which counteracts the growth of large continental ice shields. Our study aims to unravel the source and transport pathways of moisture that helped to rapidly form the European Ice Shield during the past two glacials. We propose the novel concept that the outflow of dense Mediterranean water into the North Atlantic played a decisive role as it helped to “drag” warm surface waters toward the European Margin by strengthening the Azores Current. This warm, subtropical water current supplied vast amounts of moisture, which then was transported northward into continental Europe and fueled ice sheet growth. The strength of Mediterranean Outflow Water discharge into the Atlantic strongly depends on monsoonal activity in its source region in the Eastern Mediterranean Sea. Thus, warm water advection toward western Europe and associated glacier growth of the European Ice Shield are intimately linked to low‐latitude climate changes, closely following the ~21 kyr beat of orbital precession. Mediterranean climate variability paced European Ice Sheet advancesGlacial warm‐water pooling along the continental margin of western Europe was caused by monsoonally paced enhanced Mediterranean Outflow Water entrainment into the midlatitude North AtlanticYet unrecognized marine‐terrestrial pathway that allows low‐latitude forcing to shape midlatitude glaciations

Earth’s climate during the Maastrichtian (latest Cretaceous) was punctuated by brief warming and cooling episodes, accompanied by perturbations of the global carbon cycle. Superimposed on a long-term cooling trend, the middle Maastrichtian is characterized by deep-sea warming and relatively high values of stable carbon-isotope ratios, followed by strong climatic variability towards the end of the Cretaceous. A lack of knowledge on the timing of climatic change inhibits our understanding of underlying causal mechanisms. We present an integrated stratigraphy from Integrated Ocean Drilling Program (IODP) Site U1403, providing an expanded deep ocean record from the North Atlantic (Expedition 342, Newfoundland Margin). Distinct sedimentary cyclicity suggests that orbital forcing played a major role in depositional processes, which is confirmed by statistical analyses of high resolution elemental data obtained by X-ray fluorescence (XRF) core scanning. Astronomical calibration reveals that the investigated interval encompasses seven 405-kyr cycles (Ma4051 to Ma4057) and spans the 2.8 Myr directly preceding the Cretaceous/Paleocene (K/Pg) boundary.

ABSTRACTIn yeast, Tom22, the central component of the TOMM (translocase of outer mitochondrial membrane) receptor complex, is responsible for the recognition and translocation of synthesized mitochondrial precursor proteins, and its protein kinase CK2-dependent phosphorylation is mandatory for TOMM complex biogenesis and proper mitochondrial protein import. In mammals, the biological function of protein kinase CSNK2/CK2 remains vastly elusive and it is unknown whether CSNK2-dependent phosphorylation of TOMM protein subunits has a similar role as that in yeast. To address this issue, we used a skeletal muscle-specific Csnk2b/Ck2β-conditional knockout (cKO) mouse model. Phenotypically, these skeletal muscle Csnk2bcKO mice showed reduced muscle strength and abnormal metabolic activity of mainly oxidative muscle fibers, which point towards mitochondrial dysfunction. Enzymatically, active muscle lysates from skeletal muscle Csnk2bcKO mice phosphorylate murine TOMM22, the mammalian ortholog of yeast Tom22, to a lower extent than lysates prepared from controls. Mechanistically, CSNK2-mediated phosphorylation of TOMM22 changes its binding affinity for mitochondrial precursor proteins. However, in contrast to yeast, mitochondrial protein import seems not to be affected in vitro using mitochondria isolated from muscles of skeletal muscle Csnk2bcKO mice. PINK1, a mitochondrial health sensor that undergoes constitutive import under physiological conditions, accumulates within skeletal muscle Csnk2bcKO fibers and labels abnormal mitochondria for removal by mitophagy as demonstrated by the appearance of mitochondria-containing autophagosomes through electron microscopy. Mitophagy can be normalized by either introduction of a phosphomimetic TOMM22 mutant in cultured myotubes, or by in vivo electroporation of phosphomimetic Tomm22into muscles of mice. Importantly, transfection of the phosphomimetic Tomm22mutant in muscle cells with ablated Csnk2brestored their oxygen consumption rate comparable to wild-type levels. In sum, our data show that mammalian CSNK2-dependent phosphorylation of TOMM22 is a critical switch for mitophagy and reveal CSNK2-dependent physiological implications on metabolism, muscle integrity and behavior.

Paleoclimate records from tropical South America typically show precession‐paced variability in rainfall, caused by insolation‐driven changes in the South American Monsoon System, however this mechanism may not be responsible for hydroclimate change outside of the core monsoon domain, such as in the coastal zone of tropical eastern Brazil. Our findings are based on a ∼850 kyr‐long multiproxy record from a marine sediment core collected from the eastern Brazilian margin that represents the longest continuous record of South American hydroclimate to date. Utilizing the ln (K/Al) chemical weathering proxy from the core, we determine that past hydroclimate change in the coastal zone was primarily modulated by obliquity forcing. We demonstrate that high obliquity is associated with an increase in the boreal summer interhemispheric insolation contrast which decreases the zonality of the southern trade winds and reduces moisture advection to the coastal zone. Based on the long‐term coherence between the ln (K/Al) record and benthic δ13C records from the Atlantic during Marine Isotope Stages 16–13, we infer that an increase in the strength of the overturning circulation, caused by Northern Hemisphere high‐latitude forcing, may have produced surface cooling in the western tropical South Atlantic which led to reduced moisture advection to the coastal zone. We suggest that this mechanism may have also caused the amplification in millennial‐scale variability in the coastal hydroclimate system, which began after the decoupling of the coastal hydroclimate system from obliquity forcing. Coastal precipitation in tropical eastern Brazil is dominated by obliquity forcing over most of the past ∼850 kyrMillennial‐scale hydroclimate variability increased during the most recent ∼200 kyr, as modulation by obliquity gradually weakenedNorthern Hemisphere high‐latitude climate fluctuations are linked to hydroclimate variations in the coastal zone of tropical eastern Brazil Coastal precipitation in tropical eastern Brazil is dominated by obliquity forcing over most of the past ∼850 kyr Millennial‐scale hydroclimate variability increased during the most recent ∼200 kyr, as modulation by obliquity gradually weakened Northern Hemisphere high‐latitude climate fluctuations are linked to hydroclimate variations in the coastal zone of tropical eastern Brazil

The pore size of biopolymer networks governs their mechanical properties and strongly impacts the behavior of embedded cells. Confocal reflection microscopy and second harmonic generation microscopy are widely used to image biopolymer networks; however, both techniques fail to resolve vertically oriented fibers. Here, we describe how such directionally biased data can be used to estimate the network pore size. We first determine the distribution of distances from random points in the fluid phase to the nearest fiber. This distribution follows a Rayleigh distribution, regardless of isotropy and data bias, and is fully described by a single parameter—the characteristic pore size of the network. The bias of the pore size estimate due to the missing fibers can be corrected by multiplication with the square root of the visible network fraction. We experimentally verify the validity of this approach by comparing our estimates with data obtained using confocal fluorescence microscopy, which represents the full structure of the network. As an important application, we investigate the pore size dependence of collagen and fibrin networks on protein concentration. We find that the pore size decreases with the square root of the concentration, consistent with a total fiber length that scales linearly with concentration.

The long-term climate cooling during Campanian – Maastrichtian times is not well understood to date, especially because of the uncertainty introduced by low temporal resolution of biostratigraphy and the pronounced provincialism between tropical and temperate taxa. Two new high-resolution carbon isotope records derived from the boreal shelf-sea section at Lägerdorf-Kronsmoor-Hemmoor, northern Germany and the tropical Pacific at Deep Sea Drilling Project Site 305, Shatsky Rise, reduce these uncertainties. The records can be correlated with an accuracy not achieved by biostratigraphic methods so far. Distinct carbon isotope events in the late Campanian and the early Maastrichtian can be identified at both localities suggesting to represent global carbon cycle perturbations. Especially, the negative carbon isotope excursion in the early Maastrichtian, a pronounced feature of open-ocean records from the Pacific and Southern oceans, is recognized for the first time at a shelf-sea locality related to the North Atlantic Ocean. Furthermore, two short-term positive excursions are identified as superimposed signals to this event. The improved stratigraphy provides the unique opportunity to recognize leads and lags between the carbon cycle and ocean circulation of different marine settings and ecosystems, leading to a better understanding of their causes and effects.

The second harmonic generation (SHG) signal intensity sourced from skeletal muscle myosin II strongly depends on the polarization of the incident laser beam relative to the muscle fiber axis. This dependence is related to the second-order susceptibility χ(2), which can be described by a single component ratio γunder generally assumed symmetries. We precisely extracted γfrom SHG polarization dependence curves with an extended focal field model. In murine myofibrillar preparations, we have found two distinct polarization dependencies: With the actomyosin system in the rigor state, γrighas a mean value of γrig = 0.52 (SD = 0.04, n= 55); in a relaxed state where myosin is not bound to actin, γrelhas a mean value of γrel= 0.24 (SD = 0.07, n = 70). We observed a similar value in an activated state where the myosin power stroke was pharmacologically inhibited using N-benzyl-p-toluene sulfonamide. In summary, different actomyosin states can be visualized noninvasively with SHG microscopy. Specifically, SHG even allows us to distinguish different actin-bound states of myosin II using γas a parameter.

The Mid‐Pleistocene Transition (MPT, 1,200–600 ka) marks the rapid expansion of Northern Hemisphere (NH) continental ice sheets and stronger precession pacing of glacial/interglacial cyclicity. Here, we investigate the relationship between thermocline depth in the central North Atlantic, subsurface northward heat transport and the initiation of the 100‐kyr cyclicity during the MPT. To reconstruct deep‐thermocline temperatures, we generated a Mg/Ca‐based temperature record of deep‐dwelling (∼800 m) planktonic foraminifera from mid‐latitude North Atlantic at Site U1313. This record shows phases of pronounced heat accumulation at subsurface levels during the mid‐MPT glacial driven by increased outflow of the Mediterranean Sea. Concurrent warming of the subtropical thermocline and subpolar surface waters indicates enhanced (subsurface) inter‐gyre transport of warm water to the subpolar North Atlantic, which provided moisture for ice‐sheet growth. Precession‐modulated variability in the northward transport of subtropical waters imprinted this orbital cyclicity into NH ice‐sheets after Marine Isotope Stage 24. Large continental ice‐sheets are a key component of the Earth's climate system, yet the factors controlling their build‐up and destabilization on geological time‐scales are far from understood. One of the remarkable aspects of Pleistocene (2.58 Ma to 11.65 ka) ice‐sheets is that they appear to be highly sensitive to low‐latitude forcing, a teleconnection that is yet not well‐understood. In this study, we investigate if changes in the subsurface transport of heat from the subtropics into the high latitude North Atlantic may have played an overlooked role in controlling ice‐sheet size. To address this issue, we obtained a new record of upper ocean temperature distribution in the North Atlantic during the Mid‐Pleistocene Transition (MPT, 1200–600 ka), a period when ice‐sheets expanded and our climate system shifted to longer glacial cycles. Our data reveal distinct pulses of low‐latitude heat that were transported northwards by the ocean, warming the surface of the high‐latitude North Atlantic during cold stages of prominent ice‐sheet build‐up. These anomalously warm surface waters may have provided excess moisture to the adjacent ice‐sheets. Thus, we suggest that subsurface transport of warm and salty waters northward imprinted low‐latitude variability into high‐latitude ice sheets starting during the MPT. Warming of the subtropical gyre at depth strengthens the subsurface heat transport from the subtropical gyre to the subpolar gyrePrecession‐paced northward heat transport may affect ice‐sheet mass balance by either contributing moisture or triggering destabilizationOnset of precession‐paced northward heat transport began around 930 ka, promoting the transition to 100‐kyr cyclicity Warming of the subtropical gyre at depth strengthens the subsurface heat transport from the subtropical gyre to the subpolar gyre Precession‐paced northward heat transport may affect ice‐sheet mass balance by either contributing moisture or triggering destabilization Onset of precession‐paced northward heat transport began around 930 ka, promoting the transition to 100‐kyr cyclicity

The current review focuses on recent studies, both clinical and from basic sciences, which approach possible pathomechanisms of critical illness myopathy in order to better derive potential clinical strategies for a preventive or curative clinical setting. Trends and concepts of clinical diagnosis and handling will be evaluated and their implications for muscle physiology and nutritional/metabolic intervention discussed.

We use second harmonic generation (SHG) imaging to study and quantify a strong intrinsic SHG signal in skeletal muscle fiber preparations and single isolated myofibrils. The intrinsic signal follows the striation pattern of the muscle cells and is positioned at the sarcomeric location of the myosin filaments. Interestingly, the signal is enhanced at the region where the myosin heads are located on the myosin filaments. As the intrinsic signal reflects the subcellular structure in an accurate way, SHG can be used for noninvasive high resolution structural imaging without exogenous labels in living muscle cells. This may be very important for detecting changes in myofibrillar organization occurring under pathophysiological conditions, e.g., in cardiac and skeletal myopathies. Due to the strong dependency of SHG on orientation and symmetries of the tissue, it may allow the study of dynamic interactions between the contractile proteins actin and myosin during force production and muscle shortening. Furthermore, SHG imaging can be combined with other nonlinear microscopical techniques, such as laser scanning multiphoton fluorescence microscopy, to simultaneously measure other dynamic cellular processes, representing a complementary method and extending the range of nonlinear microscopical methods. © 2004 Society of Photo-Optical Instrumentation Engineers.

Calcium currents were recorded in contracting and actively shortening mammalian muscle fibers. In order to characterize the influence of extracellular calcium concentration changes in the small unstirred lumina of the transverse tubular system (TTS) on the time course of the slow L-type calcium current (ICa), we have combined experimental measurements of ICa with quantitative numerical simulations of Ca2+ depletion. ICa was recorded both in calcium-buffered and unbuffered external solutions using the two-microelectrode voltage clamp technique (2-MVC) on short murine toe muscle fibers. A simulation program based on a distributed TTS model was used to calculate the effect of ion depletion in the TTS. The experimental data obtained in a solution where ion depletion is suppressed by a high amount of a calcium buffering agent were used as input data for the simulation. The simulation output was then compared with experimental data from the same fiber obtained in unbuffered solution. Taking this approach, we could quantitatively show that the calculated Ca2+ depletion in the transverse tubular system of contracting mammalian muscle fibers significantly affects the time-dependent decline of Ca2+ currents. From our findings, we conclude that ion depletion in the tubular system may be one of the major effects for the ICa decline measured in isotonic physiological solution under voltage clamp conditions.

: Summary. Efficiency of high-order essentially non-oscillatory (ENO) approximations of conservation laws can be drastically improved if ideas of multiresolution analysis are taken into account. These methods of data compression not only reduce the necessary amount of discrete data but can also serve as tools in detecting local low-dimensional features in the numerical solution. We describe the mathematical background of the generalized multiresolution analysis as developed by Abgrall and Harten in [14], [15] and [3]. We were able to ultimately reduce the functional analytic background to matrix-vector operations of linear algebra. We consider the example of interpolation on the line as well as the important case of multiresolution analysis of cell average data which is used in finite volume approximations. In contrast to Abgrall and Harten, we develop a robust agglomeration procedure and recovery algorithms based on least-squeare polynomials. The efficiency of our algorithms is documented by means of several examples.

During the last deglaciation abrupt millennial‐scale perturbations of the Atlantic Meridional Overturning Circulation massively altered the interhemispheric heat distribution affecting, for example, continental ice volume and hydroclimate. If and how the related cross‐equatorial heat transport was controlled by the interplay between the southward‐flowing Brazil Current (BC) and northward‐flowing North Brazil Current (NBC) remains controversial. To assess the role of tropical heat transport during the last deglaciation, we obtained a high‐resolution foraminiferal Mg/Ca‐based sea surface temperature (SST) record from the BC domain at 21.5°S. The data reveal a yet undocumented warming of at least 4.6°C of the BC during Heinrich Stadial 1 at ∼16 ka indicating massive oceanic heat accumulation in the tropical South Atlantic. Simultaneously, a strongly diminished NBC prevented the release of this excess heat into the northern tropics. The observed magnitude of heat accumulation substantially exceeds numerical model simulations, stressing the need to further scrutinize atmospheric and oceanic heat transport during extreme climatic events. The Atlantic overturning circulation underwent abrupt millennial‐scale perturbations. Such phases of sluggish oceanic circulation resulted in a substantial reduction of northward heat transport. As a consequence, substantial cooling occurred in the Northern Hemisphere and warming occurred in the Southern Hemisphere with severe effects on tropical precipitation. The distribution of heat within the western tropical Atlantic is accomplished by the southward‐flowing BC and the northward‐flowing NBC. By reconstructing SSTs for the interval between 20,000 and 10,000 yr before present, we assess the role of both currents in the interhemispheric heat transport during weak Atlantic overturning. We found that a sluggish overturning circulation resulted in anomalous southward heat transport by the BC in concert with a weak NBC, which lead to a yet undocumented warming of at least 4.6°C in the western tropical South Atlantic. This warming significantly exceeds reconstructions based on numerical simulations. This points to the need to further improve our understanding of changes in the cross‐equatorial oceanic and atmospheric heat transport in response to rapid changes in ocean circulation, in particular as a significant weakening of the Atlantic overturning circulation is predicted in the wake of anthropogenic climate change. Brazil Current heat transport coupled to changes in strength of the Atlantic Meridional Overturning Circulation during the last deglacialAntiphased heat transport by the Brazil and North Brazil Currents during Heinrich Event 1Warming of western tropical South Atlantic sea surface based on foraminiferal Mg/Ca exceeds numerical model results for Heinrich Event 1 Brazil Current heat transport coupled to changes in strength of the Atlantic Meridional Overturning Circulation during the last deglacial Antiphased heat transport by the Brazil and North Brazil Currents during Heinrich Event 1 Warming of western tropical South Atlantic sea surface based on foraminiferal Mg/Ca exceeds numerical model results for Heinrich Event 1

Electroactive hydrogels can be used to influence cell response and maturation by electrical stimulation. However, hydrogel formulations which are 3D printable, electroactive, cytocompatible, and allow cell adhesion, remain a challenge in the design of such stimuli‐responsive biomaterials for tissue engineering. Here, a combination of pyrrole with a high gelatin‐content oxidized alginate‐gelatin (ADA‐GEL) hydrogel is reported, offering 3D‐printability of hydrogel precursors to prepare cytocompatible and electrically conductive hydrogel scaffolds. By oxidation of pyrrole, electroactive polypyrrole:polystyrenesulfonate (PPy:PSS) is synthesized inside the ADA‐GEL matrix. The hydrogels are assessed regarding their electrical/mechanical properties, 3D‐printability, and cytocompatibility. It is possible to prepare open‐porous scaffolds via bioplotting which are electrically conductive and have a higher cell seeding efficiency in scaffold depth in comparison to flat 2D hydrogels, which is confirmed via multiphoton fluorescence microscopy. The formation of an interpenetrating polypyrrole matrix in the hydrogel matrix increases the conductivity and stiffness of the hydrogels, maintaining the capacity of the gels to promote cell adhesion and proliferation. The results demonstrate that a 3D‐printable ADA‐GEL can be rendered conductive (ADA‐GEL‐PPy:PSS), and that such hydrogel formulations have promise for cell therapies, in vitro cell culture, and electrical‐stimulation assisted tissue engineering. Extrusion‐printed hydrogels are presented, which show enhanced electrical conductivity. Oxidized alginate‐gelatin hydrogel in combination with conductive polypyrrole polymer allows for the fabrication of 3D‐printed cell adhesive and electrically functional biomaterial scaffolds. Enzymatic and ionic crosslinking achieve material stability of 30 days in vitro. Together, this material can be used as a platform to study electrical stimulation assisted tissue engineering.

Upwelling within the Eastern Equatorial Pacific (EEP) Ocean is a key factor for the Earth's climate because it supports >10% of the present‐day biological production. The dynamics of upwelling in the EEP across the Plio‐Pleistocene transition—an interval particularly relevant for understanding near‐future warming due to Anthropocene‐like atmospheric carbon‐dioxide levels—have been intensively studied for the region east of the East Pacific Rise. In contrast, changes of the equatorial upwelling regime in the open Pacific Ocean west of this oceanographic barrier have received markedly less attention. We therefore provide new proxy records from Ocean Drilling Program Site 849 located within the EEP open‐ocean upwelling regime. Our target interval (∼3.35–2.0 Ma) covers the Plio‐Pleistocene transition characterized by the intensification of Northern Hemisphere Glaciation (iNHG). We use benthic δ18O values to generate a new, high‐resolution age model for Site 849, and sand‐accumulation rates together with benthic δ13C values to evaluate net export production. Although showing temporary substantial glacial‐interglacial variations, our records indicate stability in net export production on secular timescales across the iNHG. We suggest the following processes to have controlled the long‐term evolution of primary productivity at Site 849. First, nutrient export from the high latitudes to the EEP; second, a successive shoaling of the Pacific nutricline during the studied interval; and third, a simultaneous reduction in dust‐borne iron input. Glacial‐interglacial change in net export production at East Pacific Site 849 from ∼3.35 to 2.0 MaNo secular change in net export production in the East Pacific across the Plio‐Pleistocene transitionNet export production on secular timescales regulated by nutrient content of upwelled waters, nutricline dynamics, and iron fertilization Glacial‐interglacial change in net export production at East Pacific Site 849 from ∼3.35 to 2.0 Ma No secular change in net export production in the East Pacific across the Plio‐Pleistocene transition Net export production on secular timescales regulated by nutrient content of upwelled waters, nutricline dynamics, and iron fertilization

The mechanical properties of hydrogels, as well as native and engineered tissues are key parameters frequently assessed in biomaterial science and tissue engineering research. However, a lack of standardized methods and user-independent data analysis has impacted the research community for many decades and contributes to poor reproducibility and comparability of datasets, representing a significant issue often neglected in publications. Here, we provide a software package, MechAnalyze, facilitating the standardized and automated analysis of force-displacement data generated in unconfined compression tests. Using comparative studies of datasets analyzed manually and with MechAnalyze, we demonstrate that the software reliably determines the compressive moduli, failure stress and failure strain of hydrogels, as well as engineered and native tissues, while providing an intuitive user interface that requires minimal user input. MechAnalyze provides a fast and user-independent data analysis method and advances process standardization, reproducibility, and comparability of data for the mechanical characterization of biomaterials as well as native and engineered tissues.

In this paper the weighted ENO (essentially non-oscillatory) scheme developed for the one-dimensional case by Liu, Osher, and Chan is applied to the case of unstructured triangular grids in two space dimensions. Ideas from Jiang and Shu, especially their new way of smoothness measuring, are considered. As a starting point for the unstructured case we use an ENO scheme like the one introduced by Abgrall. Beside the application of the weighted ENO ideas the whole reconstruction algorithm is analyzed and described in detail. Here we also concentrate on technical problems and their solution. Finally, some applications are given to demonstrate the accuracy and robustness of the resulting new method. The whole reconstruction algorithm described here can be applied to any kind of data on triangular unstructured grids, although it is used in the framework of compressible flow computation in this paper only.

Precipitation extremes with devastating socioeconomic consequences within the South American Monsoon System (SAMS) are expected to become more frequent in the near future. The complexity in SAMS behavior, however, poses severe challenges for reliable future projections. Thus, robust paleomonsoon records are needed to constrain the high spatiotemporal variability in the response of SAMS rainfall to different climatic drivers. This study uses Ti/Ca ratios from X‐ray fluorescence scanning of a sediment core retrieved off eastern Brazilian to trace precipitation changes over the past 322 Kyr. The results indicate that despite the spatiotemporal complexity of the SAMS, insolation forcing is the primary pacemaker of variations in the monsoonal system. Additional modulation by atmospheric pCO2suggests that SAMS intensity over eastern Brazil will be suppressed by rising CO2emissions in the future. Lastly, our record reveals an unprecedented strong and persistent wet period during Marine Isotope Stage 6 driven by anomalously strong trade winds. Insolation is the main driver of orbital‐scale South American Monsoon System rainfall variability in eastern Brazil over the past 322 kyrMonsoonal rainfall intensity is indirectly modulated by greenhouse gas forcing through changes to the latitudinal temperature gradientsDuring MIS 6, precipitation in eastern Brazil remained anomalously strong and deviated from the regular orbitally paced insolation forcing

The intensification of Northern Hemisphere glaciation (iNHG) and uplift of the Tibetan Plateau have been argued to be among the main drivers of climate change in midlatitude Central Asia during the Pliocene/Pleistocene. While most proxy records that support this hypothesis are from regions outside the Tibetan Plateau (such as from the Chinese Loess Plateau), detailed paleoclimatic information for the plateau itself during that time has yet remained elusive. Here we present a temporally highly resolved (~500 years) sedimentological record from the Qaidam Basin situated on the northeastern Tibetan Plateau that shows pronounced glacial‐interglacial climate variability during the interval from 2.7 to 2.1 Ma. Glacial (interglacial) intervals are generally characterized by coarser (finer) grain size, minima (maxima) in organic matter content, and maxima (minima) in carbonate content. Comparison of our results with Earth's orbital parameters and proxy records from the Chinese Loess Plateau suggests that the observed climate fluctuations were mainly driven by changes in the Siberian High/East Asian winter monsoon system as a response to the iNHG. They are further proposed to be enhanced by the topography of the Tibetan Plateau and its impact on the position and intensity of the westerlies. Pronounced glacial‐interglacial climate fluctuations on the NE Tibetan Plateau during the latest Pliocene and early PleistoceneChanges in East Asian Winter Monsoon and the position of the westerlies influenced sediment transport on the NE Tibetan PlateauIntensification of Northern Hemisphere glaciation amplified climate fluctuations on the NE Tibetan Plateau

In article number 1801298, Hala Zreiqat and co‐workers showcase a Sr‐HT‐Gahnite bone substitute implanted in a sheep tibial segmental defect for one year. Focused ion beam scanning electron microscopy (FIB‐SEM) cross‐section of the implant‐bone interface shows nanoscale detail of the scaffold (top) and loose connective tissue (bottom), between which is a disrupted zone of ceramic degradation and tissue infiltration.

Extensive bone loss due to trauma or disease leads to impaired healing. Current bone grafts and substitutes have major drawbacks that limit their effectiveness for treating large bone defects. A number of bone substitutes in development are undergoing preclinical testing, but few studies specifically investigate the in vivo material–tissue interactions that provide an important indicator to long‐term implant safety and efficacy. This study is the first of its kind to specifically investigate in vivo material–tissue interactions at the bone–implant interface. Baghdadite scaffolds implanted in critical‐sized segmental defects in sheep tibia for 26 weeks are analyzed by focused ion beam scanning electron microscopy, multiphoton microscopy, and histology. The scaffolds are seen to induce extensive bone formation that directly abut the implant surfaces with no evidence of chronic inflammation or fibrous capsule formation. Bone remodeling is influenced by slow in vivo degradation around and within the implant, causing portions of the implant to be incorporated into the newly formed bone. These findings have important implications for predicting the long‐term effects of baghdadite ceramics in promoting defect healing, and support the translation of baghdadite scaffolds as a new generation of bone graft substitutes with improved properties for the repair of large bone defects. Material–tissue interactionscontrol the long‐term outcomes of bone repair using synthetic bone substitutes. For the first time, specific material–tissue interactions at the bone–implant interface are investigated following implantation of a synthetic scaffold for critical‐sized defect repair in sheep tibia. Focused ion beam scanning electron microscopy, multiphoton microscopy, and histology provide important information that enables predictions of long‐term implant performance.