Discovery and In Situ Crystallization Studies of Cerium-Based Metal-Organic Frameworks with V-Shaped Linker Molecules.

We report the discovery and characterization of two porous Ce(III)-based metal-organic frameworks (MOFs) with the V-shaped linker molecules 4,4'-sulfonyldibenzoate (SDB2-) and 4,4'-(hexafluoroisopropylidene)bis(benzoate) (hfipbb2-). The compounds of framework composition [Ce2(H2O)(SDB)3] (1) and [Ce2(hfipbb)3] (2) were obtained by using a synthetic approach in acetonitrile that we recently established. Structure determination of 1 was accomplished from 3D electron diffraction (3D ED) data, while 2 could be refined against powder X-ray diffraction (PXRD) data using the crystal structure of an isostructural La-MOF as the starting model. Their framework structures consist of chain-like inorganic building units (IBUs) or hybrid-BUs that are interconnected by the V-shaped linker molecules to form framework structures with channel-type pores. The composition of both compounds was confirmed by PXRD, elemental analysis, as well as NMR and IR spectroscopy. Interestingly, despite the use of (NH4)2[CeIV(NO3)6] in the synthesis, cerium ions in both MOFs occur exclusively in the + III oxidation state as determined by X-ray absorption near edge structure (XANES) and X-ray photoelectron spectroscopy (XPS). Thermal analyses reveal remarkably high thermal stabilities of ≥400 °C for the MOFs. Initial N2 sorption measurements revealed the peculiar sorption behavior of 2 which prompted a deeper investigation by Ar and CO2 sorption experiments. The combination with nonlocal density functional theory (NL-DFT) calculations adds to the understanding of the nature of the different pore diameters in 2. An extensive quasi-simultaneous in situ XANES/XRD investigation was carried out to unveil the formation of Ce-MOFs during the solvothermal syntheses in acetonitrile. The crystallization of the two Ce(III)-MOFs presented herein as well as two previously reported Ce(IV)-MOFs, all obtained by a similar synthetic approach, were studied. While the XRD patterns show time-dependent MOF crystallization, the XANES data reveal the presence of Ce(III) intermediates and their subsequent conversion to the MOFs. The addition of acetic acid in combination with the V-shaped linker molecule was identified as the crucial factor for the formation of the crystalline Ce(III/IV)-MOFs.

The open toolbox for behavioral research.

In this work, we describe a new open-source MATLAB toolbox for the control of behavioral experiments. The toolbox caters to very different types of experiments in different species, and with different underlying hardware. Typical examples are operant chambers in animals, with or without neurophysiology, behavioral experiments in human subjects, and neurophysiological recordings in humans such as EEG and fMRI. In addition, the toolbox supports communication via Ethernet to either control and monitor one or several experimental setups remotely or to implement distributed paradigms across different computers. This flexibility is possible, since the toolbox supports a wide range of hardware, some of which is custom developments. An example is a fast network-based digital-IO device for the communication with experimental hardware such as feeders or triggers in neurophysiological setups. We also included functions for online video analysis allowing paradigms to be contingent on responses to a screen, the head movement of a bird in an operant chamber, or the physical location of an animal in an open arena. While the toolbox is well tested and many components of it have been in use for many years, we do not see it as a finished product but rather a continuing development with a focus on easy extendibility and customization.

Expression of Cyclin E1 in hepatic stellate cells is critical for the induction and progression of liver fibrosis and hepatocellular carcinoma in mice.

Hepatocellular carcinoma (HCC) is one of the most severe malignancies with increasing incidence and limited treatment options. Typically, HCC develops during a multistep process involving chronic liver inflammation and liver fibrosis. The latter is characterized by the accumulation of extracellular matrix produced by Hepatic Stellate Cells (HSCs). This process involves cell cycle re-entry and proliferation of normally quiescent HSCs in an ordered sequence that is highly regulated by cyclins and associated cyclin-dependent kinases (CDKs) such as the Cyclin E1 (CCNE1)/CDK2 kinase complex. In the present study, we examined the role of Cyclin E1 (Ccne1) and Cdk2 genes in HSCs for liver fibrogenesis and hepatocarcinogenesis. To this end, we generated conditional knockout mice lacking Ccne1 or Cdk2 specifically in HSCs (Ccne1∆HSC or Cdk2∆HSC). Ccne1∆HSC mice showed significantly reduced liver fibrosis formation and attenuated HSC activation in the carbon tetrachloride (CCl4) model. In a combined model of fibrosis-driven hepatocarcinogenesis, Ccne1∆HSC mice revealed decreased HSC activation even after long-term observation and substantially reduced tumor load in the liver when compared to wild-type controls. Importantly, the deletion of Cdk2 in HSCs also resulted in attenuated liver fibrosis after chronic CCl4 treatment. Single-cell RNA sequencing revealed that only a small fraction of HSCs expressed Ccne1/Cdk2 at a distinct time point after CCl4 treatment. In summary, we provide evidence that Ccne1 expression in a small population of HSCs is sufficient to trigger extensive liver fibrosis and hepatocarcinogenesis in a Cdk2-dependent manner. Thus, HSC-specific targeting of Ccne1 or Cdk2 in patients with liver fibrosis and high risk for HCC development could be therapeutically beneficial.

The impact of physical exercise on the consolidation of fear extinction memories.

Based on the mechanisms of fear extinction, exposure therapy is the most common treatment for anxiety disorders. However, extinguished fear responses can reemerge even after successful treatment. Novel interventions enhancing exposure therapy efficacy are therefore critically needed. Physical exercise improves learning and memory and was also shown to enhance extinction processes. This study tested whether physical exercise following fear extinction training improves the consolidation of extinction memories. Sixty healthy men underwent a differential fearconditioning paradigm with fear acquisition training on day 1 and fear extinction training followed by an exercise or resting control intervention on day 2. On day 3, retrieval and reinstatement were tested including two additional but perceptually similar stimuli to explore the generalization of exercise effects. Exercise significantly increased heart rate, salivary alpha amylase, and cortisol, indicating successful exercise manipulation. Contrary to our expectations, exercise did not enhance but rather impaired extinction memory retrieval on the next day, evidenced by significantly stronger differential skin conductance responses (SCRs) and pupil dilation (PD). Importantly, although conditioned fear responses were successfully acquired, they did not fully extinguish, explaining why exercise might have boosted the consolidation of the original fear memory trace instead. Additionally, stronger differential SCRs and PD toward the novel stimuli suggest that the memory enhancing effects of exercise also generalized to perceptually similar stimuli. Together, these findings indicate that physical exercise can facilitate both the long-term retrievability and generalization of extinction memories, but presumably only when extinction was successful in the first place.

Aqueous-phase photo-oxidation of selected green leaf volatiles initiated by OH radicals: Products and atmospheric implications.

C5- and C6- unsaturated oxygenated organic compounds emitted by plants under stress like cutting, freezing or drying, known as Green Leaf Volatiles (GLVs), may clear some of the existing uncertainties in secondary organic aerosol (SOA) budget. The transformations of GLVs are a potential source of SOA components through photo-oxidation processes occurring in the atmospheric aqueous phase. Here, we investigated the aqueous photo-oxidation products from three abundant GLVs (1-penten-3-ol, (Z)-2-hexen-1-ol, and (E)-2-hexen-1-al) induced by OH radicals, carried out in a photo-reactor under simulated solar conditions. The aqueous reaction samples were analyzed using advanced hyphenated mass spectrometry techniques: capillary gas chromatography mass spectrometry (c-GC-MS); and reversed-phase liquid chromatography high resolution mass spectrometry (LC-HRMS). Using carbonyl-targeted c-GC-MS analysis, we confirmed the presence of propionaldehyde, butyraldehyde, 1-penten-3-one, and 2-hexen-1-al in the reaction samples. The LC-HRMS analysis confirmed the presence of a new carbonyl product with the molecular formula C6H10O2, which probably bears the hydroxyhexenal or hydroxyhexenone structure. Density functional theory (DFT)-based quantum calculations were used to evaluate the experimental data and obtain insight into the formation mechanism and structures of the identified oxidation products via the addition and hydrogen-abstraction pathways. DFT calculations highlighted the importance of the hydrogen abstraction pathway leading to the new product C6H10O2. Atmospheric relevance of the identified products was evaluated using a set of physical property data like Henry's law constant (HLC) and vapor pressure (VP). The unknown product of molecular formula C6H10O2 has higher HLC and lower VP than the parent GLV and thus has potential to remain in the aqueous phase leading to possible aqueous SOA formation. Other observed carbonyl products are likely first stage oxidation products and precursors of aged SOA.

Synthesis, Crystal Structure, and Photocatalytic Properties of Two Isoreticular Ce(IV)-MOFs with an Infinite Rod-Shaped Inorganic Building Unit.

The use of the V-shaped linker molecules 4,4'-oxydibenzoic acid (H2ODB) and 4,4'-carbonyldibenzoic acid (H2CDB) led to the discovery of two isoreticular Ce(IV)-based metal-organic frameworks (MOFs) of composition [CeO(H2O)(L)], L = ODB2-, CDB2-, denoted CAU-58 (CAU = Christian-Albrechts-University). The recently developed Ce-MOF synthesis approach in acetonitrile as the solvent proved effective in accessing Ce(IV)-MOF structures with infinite rod-shaped inorganic building units (IBUs) and circumventing the formation of the predominantly observed hexanuclear [Ce6O8] cluster. For the structure determination of the isoreticular MOFs, three-dimensional electron diffraction (3D ED) and powder X-ray diffraction (PXRD) data were used in combination with density functional theory (DFT) calculations. [CeO(H2O)(CDB)] shows reversible H2O adsorption by stirring in water and thermal treatment at 190 °C, which leads to a unit cell volume change of 11%. The MOFs feature high thermal stabilities (T > 290 °C), which exceed those of most Ce(IV)-MOFs and can be attributed to the infinite rod-shaped IBU. Surface and bulk oxidation states of the cerium ions were analyzed via X-ray photoelectron spectroscopy (XPS) and X-ray absorption near-edge spectroscopy (XANES). While Ce(III) ions are observed by the highly surface-sensitive XPS method, the bulk material contains predominantly Ce(IV) ions according to XANES. Application of the MOFs as catalysts for the catalytic degradation of methyl orange in aqueous solutions was also studied. While degradation activity for both MOFs was observed, only CAU-58-ODB revealed enhanced photocatalytic activity under ultraviolet (UV) light. The photocatalytic mechanism likely involves a ligand-to-metal charge transfer (LMCT) from the linkers to the Ce(IV) centers. Analyses by XANES and inductively coupled plasma-optical emission spectroscopy (ICP-OES) demonstrate that leaching of Cerium ions as well as partial reduction of Ce(IV) to Ce(III) takes place during catalysis. At the same time, PXRD data confirm the structural stability of the remaining MOF catalysts.

ACSL4-dependent ferroptosis does not represent a tumor-suppressive mechanism but ACSL4 rather promotes liver cancer progression.

Ferroptosis is a novel type of programmed cell death that differs from apoptosis in that it involves iron-dependent peroxidation of membrane phospholipids. Its role in a variety of human disorders, including cancer has been hypothesized in recent years. While it may function as an endogenous tumor suppressor in a variety of cancers, its role during initiation and progression of liver cancer, particularly hepatocellular carcinoma (HCC), is yet unknown. Because HCC is most commonly found in chronically injured livers, we utilized two well-established mouse models of chronic injury-dependent HCC formation: Treatment with streptozotocin and high-fat diet as metabolic injury model, as well as treatment with diethylnitrosamine and carbon tetrachloride as toxic injury model. We used mice with hepatocyte-specific deletion of Acsl4, a key mediator of ferroptosis, to explore the significance of ferroptotic cell death in hepatocytes, the cell type of origin for HCC. Surprisingly, preventing ferroptotic cell death in hepatocytes by deleting Acsl4 does not increase the formation of HCC. Furthermore, Acsl4-deficient livers display less fibrosis and proliferation, especially in the HCC model of toxic damage. Intriguingly, in this model, the absence of ACSL4-dependent processes such as ferroptosis significantly slow down the growth of HCC. These findings suggest that during HCC formation in a chronically injured liver, ferroptotic cell death is not an endogenous tumor-suppressive mechanism. Instead, we find that ACSL4-dependent processes have an unanticipated cancer-promoting effect during HCC formation, which is most likely due to aggravated liver damage as demonstrated by increased hepatic fibrosis. Previous studies suggested that ferroptosis might have beneficial effects for patients during HCC therapy. As a result, during HCC progression and therapy, ferroptosis may have both cancer-promoting and cancer-inhibitory effects, respectively.

NLRP6 Inflammasome Modulates Disease Progression in a Chronic-Plus-Binge Mouse Model of Alcoholic Liver Disease.

A considerable percentage of the population is affected by alcoholic liver disease (ALD). It is characterized by inflammatory signals from the liver and other organs, such as the intestine. The NLR family pyrin domain containing 6 (NLRP6) inflammasome complex is one of the most important inflammatory mediators. The aim of this study was to evaluate a novel mouse model for ALD characterized by 8-week chronic-plus-binge ethanol administration and to investigate the role of NLRP6 inflammasome for intestinal homeostasis and ALD progression using Nlrp6-/- mice. We showed that chronic-plus-binge ethanol administration triggers hepatic steatosis, injury, and neutrophil infiltration. Furthermore, we discovered significant changes of intestinal microbial communities, including increased relative abundances of bacteria within the phyla Bacteroidota and Campilobacterota, as well as reduced Firmicutes. In this ALD model, inhibiting NLRP6 signaling had no effect on liver steatosis or damage, but had a minor impact on intestinal homeostasis via affecting intestinal epithelium function and gut microbiota. Surprisingly, Nlrp6 loss resulted in significantly decreased hepatic immune cell infiltration. As a result, our novel mouse model encompasses several aspects of human ALD, such as intestinal dysbiosis. Interfering with NLRP6 inflammasome activity reduced hepatic immune cell recruitment, indicating a disease-aggravating role of NLRP6 during ALD.

Unihemispheric evidence accumulation in pigeons.

Perceptual decision making involves choices between alternatives based on sensory information. Studies in primates and rodents revealed a stochastic perceptual evidence accumulation process that, after reaching threshold, results in action execution. Birds represent a cognitively highly successful vertebrate class that has been evolving independent from mammals for more than 300 million years. The present study investigated whether perceptual decision making in pigeons shows behavioral and computational dynamics comparable to those in mammals and rodents. Using a novel "pigeon helmet" with liquid shutter displays that controls visual input to individual eyes/hemispheres with precise timing, we indeed revealed highly similar dynamics of perceptual decision making. Thus, both mammals and birds seem to share this core cognitive process that possibly represents a fundamental constituent of decision making throughout vertebrates. Interestingly, in our experiments we additionally discovered that both avian hemispheres start independent sensory accumulation processes without any major interhemispheric exchange. Because birds lack a corpus callosum and have only a small anterior commissure, they seem to be forced to decide on motor responses based on unihemispheric decisions under conditions of time pressure. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Reaction Kinetics of Green Leaf Volatiles with Sulfate, Hydroxyl, and Nitrate Radicals in Tropospheric Aqueous Phase.

Green plants exposed to abiotic or biotic stress release C-5 and C-6 unsaturated oxygenated hydrocarbons called Green Leaf Volatiles (GLVs). GLVs partition into tropospheric waters and react to form secondary organic aerosol (SOA). We explored the kinetics of aqueous-phase reactions of 1-penten-3-ol (PENTOL), (Z)-2-hexen-1-ol (HEXOL), and (E)-2-hexen-1-al (HEXAL) with SO4•-, •OH, and NO3•. At 298 K, the rate constants for reactions of PENTOL, HEXOL, and HEXAL with SO4•- were, respectively, (9.4 ± 1.0) × 108 L mol-1 s-1, (2.5 ± 0.3) × 109 L mol-1 s-1, and (4.8 ± 0.2) × 108 L mol-1 s-1; with •OH - (6.3 ± 0.1) × 109 L mol-1 s-1, (6.7 ± 0.3) × 109 L mol-1 s-1, and (4.8 ± 0.3) × 109 L mol-1 s-1; and with NO3• - (1.5 ± 0.15) × 108 L mol-1 s-1, (8.4 ± 2.3) × 108 L mol-1 s-1, and (3.0 ± 0.7) × 107 L mol-1 s-1. The rate constants increased weakly with temperatures ranging from 278 to 318 K. The diffusional limitations of the rate constants appeared significant only for the GLV-•OH reactions. The aqueous-phase reactions appeared negligible in deliquescent aerosol and haze water but not in clouds and rains. The atmospheric lifetimes of GLVs decreased from many days to hours with increasing liquid water content and radicals' concentration.

The DA-antagonist Tiapride affects context-related extinction learning in a predictive learning task, but not initial forming of associations, or renewal.

Renewal describes the recovery of an extinguished response if the contexts of extinction and recall differ, highlighting the context dependency of extinction. Studies demonstrated dopaminergic (DA) signalling to be important for context-related extinction learning with and without a fear component. In a previous study in humans, administration of the dopamine D2/D3 antagonist tiapride prior to extinction impaired extinction learning in a novel, but not a familiar context, without affecting renewal. In a further study, context processing during initial acquisition of associations was shown to be related to renewal. In this human fMRI study we investigated the potential role of DA signalling during this initial conditioning for the learning process and for renewal. While tiapride, administered prior to the start of learning, did not affect initial acquisition and renewal, extinction learning in a novel context was impaired, associated with reduced BOLD activation in vmPFC, left iFG and ACC - regions mediating response inhibition and selection from competing options using contextual information. Thus, different timepoints of administration of tiapride (before initial conditioning or extinction) had largely similar effects upon extinction and renewal. In addition, retrieval of previously acquired associations was impaired, pointing towards weaker association forming during acquisition. Conceivably, effects of the DA blockade are associated with the challenge present in the respective task rather than the administration timepoint: the cognitive flexibility required for forming a new inhibitory association that includes a novel element clearly requires DA processing, while initial forming of associations, or of inhibitory associations without a new element, apparently rely less on the proper function of the DA system.

Pigeons show how meta-control enables decision-making in an ambiguous world.

In situations where the left and right brain sides receive conflicting information that leads to incompatible response options, the brain requires efficient problem-solving mechanisms. This problem is particularly significant in lateralized brains, in which the hemispheres differ in encoding strategies or attention focus and hence, consider different information for decision-making. Meta-control, in which one hemisphere dominates ambiguous decisions, can be a mechanism that ensures fast behavioral reactions. We therefore confronted pigeons with a task in which two stimulus classes were brought into conflict. To this end, we trained pigeons simultaneously on two categories (cats or dogs) whereby each hemisphere learnt only one of the categories respectively. After learning, the birds were confronted with stimulus pairs that combined a picture with a cat (positive for one hemisphere) and a picture with a dog (positive for the other hemisphere). Pecking responses indicated the hemisphere dominating response selection. Pigeons displayed individual meta-control despite equal categorization performances of both brain hemispheres. This means that hemispheric dominance only emerged in interhemispheric conflict situations. The analysis of response latencies indicate that conflict decisions relied on intrahemispheric processes. Interhemispheric components played a role for more complex decisions. This flexibility could be a crucial building block for the evolutionary success of a lateralized brain.

Targeting Aberrant FGFR Signaling to Overcome CDK4/6 Inhibitor Resistance in Breast Cancer.

Breast cancer (BC) is the most common cause of cancer-related death in women worldwide. Therapies targeting molecular pathways altered in BC had significantly enhanced treatment options for BC over the last decades, which ultimately improved the lives of millions of women worldwide. Among various molecular pathways accruing substantial interest for the development of targeted therapies are cyclin-dependent kinases (CDKs)-in particular, the two closely related members CDK4 and CDK6. CDK4/6 inhibitors indirectly trigger the dephosphorylation of retinoblastoma tumor suppressor protein by blocking CDK4/6, thereby blocking the cell cycle transition from the G1 to S phase. Although the CDK4/6 inhibitors abemaciclib, palbociclib, and ribociclib gained FDA approval for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative BC as they significantly improved progression-free survival (PFS) in randomized clinical trials, regrettably, some patients showed resistance to these therapies. Though multiple molecular pathways could be mechanistically responsible for CDK4/6 inhibitor therapy resistance, one of the most predominant ones seems to be the fibroblast growth factor receptor (FGFR) pathway. FGFRs are involved in many aspects of cancer formation, such as cell proliferation, differentiation, and growth. Importantly, FGFRs are frequently mutated in BC, and their overexpression and/or hyperactivation correlates with CDK4/6 inhibitor resistance and shortened PFS in BC. Intriguingly, the inhibition of aberrant FGFR activity is capable of reversing the resistance to CDK4/6 inhibitors. This review summarizes the molecular background of FGFR signaling and discusses the role of aberrant FGFR signaling during cancer development in general and during the development of CDK4/6 inhibitor resistance in BC in particular, together with other possible mechanisms for resistance to CDK4/6 inhibitors. Subsequently, future directions on novel therapeutic strategies targeting FGFR signaling to overcome such resistance during BC treatment will be further debated.

Hepatocyte-specific NRF2 activation controls fibrogenesis and carcinogenesis in steatohepatitis.

BACKGROUND & AIMS: In chronic liver diseases, inflammation induces oxidative stress and thus may contribute to the progression of liver injury, fibrosis, and carcinogenesis. The KEAP1/NRF2 axis is a major regulator of cellular redox balance. In the present study, we investigated whether the KEAP1/NRF2 system is involved in liver disease progression in humans and mice. METHODS: The clinical relevance of oxidative stress was investigated by liver RNA sequencing in a well-characterized cohort of patients with non-alcoholic fatty liver disease (n = 63) and correlated with histological and clinical parameters. For functional analysis, hepatocyte-specific Nemo knockout (NEMOΔhepa) mice were crossed with hepatocyte-specific Keap1 knockout (KEAP1Δhepa) mice. RESULTS: Immunohistochemical analysis of human liver sections showed increased oxidative stress and high NRF2 expression in patients with chronic liver disease. RNA sequencing of liver samples in a human pediatric NAFLD cohort revealed a significant increase of NRF2 activation correlating with the grade of inflammation, but not with the grade of steatosis, which could be confirmed in a second adult NASH cohort. In mice, microarray analysis revealed that Keap1 deletion induces NRF2 target genes involved in glutathione metabolism and xenobiotic stress (e.g., Nqo1). Furthermore, deficiency of one of the most important antioxidants, glutathione (GSH), in NEMOΔhepa livers was rescued after deleting Keap1. As a consequence, NEMOΔhepa/KEAP1Δhepa livers showed reduced apoptosis compared to NEMOΔhepa livers as well as a dramatic downregulation of genes involved in cell cycle regulation and DNA replication. Consequently, NEMOΔhepa/KEAP1Δhepa compared to NEMOΔhepa livers displayed decreased fibrogenesis, lower tumor incidence, reduced tumor number, and decreased tumor size. CONCLUSIONS: NRF2 activation in patients with non-alcoholic steatohepatitis correlates with the grade of inflammation, but not steatosis. Functional analysis in mice demonstrated that NRF2 activation in chronic liver disease is protective by ameliorating fibrogenesis, initiation and progression of hepatocellular carcinogenesis. LAY SUMMARY: The KEAP1 (Kelch-like ECH-associated protein-1)/NRF2 (erythroid 2-related factor 2) axis has a major role in regulating cellular redox balance. Herein, we show that NRF2 activity correlates with the grade of inflammation in patients with non-alcoholic steatohepatitis. Functional studies in mice actually show that NRF2 activation, resulting from KEAP1 deletion, protects against fibrosis and cancer.

Event-related functional MRI of awake behaving pigeons at 7T.

Animal-fMRI is a powerful method to understand neural mechanisms of cognition, but it remains a major challenge to scan actively participating small animals under low-stress conditions. Here, we present an event-related functional MRI platform in awake pigeons using single-shot RARE fMRI to investigate the neural fundaments for visually-guided decision making. We established a head-fixated Go/NoGo paradigm, which the animals quickly learned under low-stress conditions. The animals were motivated by water reward and behavior was assessed by logging mandibulations during the fMRI experiment with close to zero motion artifacts over hundreds of repeats. To achieve optimal results, we characterized the species-specific hemodynamic response function. As a proof-of-principle, we run a color discrimination task and discovered differential neural networks for Go-, NoGo-, and response execution-phases. Our findings open the door to visualize the neural fundaments of perceptual and cognitive functions in birds-a vertebrate class of which some clades are cognitively on par with primates.

Increased lysosomal biomass is responsible for the resistance of triple-negative breast cancers to CDK4/6 inhibition.

Inhibitors of cyclin-dependent kinases CDK4 and CDK6 have been approved for treatment of hormone receptor-positive breast cancers. In contrast, triple-negative breast cancers (TNBCs) are resistant to CDK4/6 inhibition. Here, we demonstrate that a subset of TNBC critically requires CDK4/6 for proliferation, and yet, these TNBC are resistant to CDK4/6 inhibition due to sequestration of CDK4/6 inhibitors into tumor cell lysosomes. This sequestration is caused by enhanced lysosomal biogenesis and increased lysosomal numbers in TNBC cells. We developed new CDK4/6 inhibitor compounds that evade the lysosomal sequestration and are efficacious against resistant TNBC. We also show that coadministration of lysosomotropic or lysosome-destabilizing compounds (an antibiotic azithromycin, an antidepressant siramesine, an antimalaria compound chloroquine) renders resistant tumor cells sensitive to currently used CDK4/6 inhibitors. Lastly, coinhibition of CDK2 arrested proliferation of CDK4/6 inhibitor-resistant cells. These observations may extend the use of CDK4/6 inhibitors to TNBCs that are refractory to current anti-CDK4/6 therapies.

Acute stress improves the effectivity of cognitive emotion regulation in men.

Emotion regulation is crucial for coping with stressors but in turn can also be influenced by stress. Initial studies provided mixed evidence showing either beneficial or impairing stress effects on cognitive emotion regulation depending on stress timing, sex or the regulatory strategy. Here, we investigated the impact of acute stress on different emotion regulation strategies in men and women. N = 118 healthy participants were subjected to the Trier Social Stress Test or a control condition after which they completed an emotion regulation paradigm, requiring them to regulate their emotions in response to negative pictures using reappraisal or distraction. Cortisol levels were repeatedly measured to quantify changes in HPA axis activity. Affective ratings and pupil dilation served to measure emotion regulation success and the cognitive effort to regulate emotions. Stress reduced arousal and increased valence and success ratings for reappraisal in men, whereas no significant stress effects were found in women. Moreover, stressed men displayed a significant expansion of pupil diameter during reappraisal suggesting enhanced cognitive regulatory engagement, which ultimately may have led to better emotion regulation outcomes. Cortisol secretion positively correlated with subjective reappraisal success in men, suggesting a glucocorticoid-driven mechanism that may promote emotion regulatory performance in the aftermath of stress.

Cdk1 Controls Global Epigenetic Landscape in Embryonic Stem Cells.

The cyclin-dependent kinase 1 (Cdk1) drives cell division. To uncover additional functions of Cdk1, we generated knockin mice expressing an analog-sensitive version of Cdk1 in place of wild-type Cdk1. In our study, we focused on embryonic stem cells (ESCs), because this cell type displays particularly high Cdk1 activity. We found that in ESCs, a large fraction of Cdk1 substrates is localized on chromatin. Cdk1 phosphorylates many proteins involved in epigenetic regulation, including writers and erasers of all major histone marks. Consistent with these findings, inhibition of Cdk1 altered histone-modification status of ESCs. High levels of Cdk1 in ESCs phosphorylate and partially inactivate Dot1l, the H3K79 methyltransferase responsible for placing activating marks on gene bodies. Decrease of Cdk1 activity during ESC differentiation de-represses Dot1l, thereby allowing coordinated expression of differentiation genes. These analyses indicate that Cdk1 functions to maintain the epigenetic identity of ESCs.

Organosulfates in Ambient Aerosol: State of Knowledge and Future Research Directions on Formation, Abundance, Fate, and Importance.

Organosulfates (OSs), also referred to as organic sulfate esters, are well-known and ubiquitous constituents of atmospheric aerosol particles. Commonly, they are assumed to form upon mixing of air masses of biogenic and anthropogenic origin, that is, through multiphase reactions between organic compounds and acidic sulfate particles. However, in contrast to this simplified picture, recent studies suggest that OSs may also originate from purely anthropogenic precursors or even directly from biomass and fossil fuel burning. Moreover, besides classical OS formation pathways, several alternative routes have been discovered, suggesting that OS formation possibly occurs through a wider variety of formation mechanisms in the atmosphere than initially expected. During the past decade, OSs have reached a constantly growing attention within the atmospheric science community with evermore studies reporting on large numbers of OS species in ambient aerosol. Nonetheless, estimates on OS concentrations and implications on atmospheric physicochemical processes are still connected to large uncertainties, calling for combined field, laboratory, and modeling studies. In this Critical Review, we summarize the current state of knowledge in atmospheric OS research, discuss unresolved questions, and outline future research needs, also in view of reductions of anthropogenic sulfur dioxide (SO2) emissions. Particularly, we focus on (1) field measurements of OSs and measurement techniques, (2) formation pathways of OSs and their atmospheric relevance, (3) transformation, reactivity, and fate of OSs in atmospheric particles, and (4) modeling efforts of OS formation and their global abundance.

MyD88-dependent signaling in non-parenchymal cells promotes liver carcinogenesis.

In Western countries, a rising incidence of obesity and type 2 diabetes correlates with an increase of non-alcoholic steatohepatitis (NASH)-a major risk factor for liver cirrhosis and hepatocellular carcinoma (HCC). NASH is associated with chronic liver injury, triggering hepatocyte death and enhanced translocation of intestinal bacteria, leading to persistent liver inflammation through activation of Toll-like receptors and their adapter protein myeloid differentiation factor 88 (MyD88). Therefore, we investigated the role of MyD88 during progression from NASH to HCC using a mouse model of chronic liver injury (hepatocyte-specific deletion of nuclear factor κB essential modulator, Nemo; NemoΔhepa). NemoΔhepa; NemoΔhepa/MyD88-/- and NemoΔhepa/MyD88Δhepa were generated and the impact on liver disease progression was investigated. Ubiquitous MyD88 ablation (NemoΔhepa/MyD88-/-) aggravated the degree of liver damage, accompanied by an overall decrease in inflammation, whereas infiltrating macrophages and natural killer cells were elevated. At a later stage, MyD88 deficiency impaired HCC formation. In contrast, hepatocyte-specific MyD88 deletion (NemoΔhepa/MyD88Δhepa) did not affect disease progression. These results suggest that signaling of Toll-like receptors through MyD88 in non-parenchymal liver cells is required for carcinogenesis during chronic liver injury. Hence, blocking MyD88 signaling may offer a therapeutic option to prevent HCC formation in patients with NASH.