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Background: The C22 mouse is a Charcot-Marie-Tooth 1A transgenic model with minimal axonal loss. Objective: To analyse early skeletal muscle changes resulting from this dysmyelinating neuropathy. Methods: Histology of tibialis anterior muscles of C22 mice and wild type litter mate controls for morphometric analysis and (immuno-)histochemistry for known denervation markers and candidate proteins identified by representational difference analysis (RDA) based on mRNA from the same muscles; quantitative PCR and Western blotting for confirmation of RDA findings. Results: At age 10 days, morphometry was not different between groups, while at 21 days, C22 showed significantly more small diameter fibres, indicating the onset of atrophy at an age when weakness becomes detectable. Neither (immuno-)histochemistry nor RDA detected extrajunctional expression of acetylcholine receptors by age 10 and 21 days, respectively. RDA identified some mRNA up-regulated in C22 muscles, among them at 10 days, prior to detectable weakness or atrophy, integral membrane protein 2a (Itm2a), eukaryotic initiation factor 2, subunit 2 (Eif2s2) and cytoplasmic phosphatidylinositol transfer protein 1 (Pitpnc1). However, qPCR failed to measure significant differences. In contrast, Itm2a and Eif2s2 mRNA were significantly down-regulated comparing 21 versus 10 days of age in both groups, C22 and controls. Western blotting confirmed significant down-regulation of ITM2A protein in C22 only. Conclusion: Denervation-like changes in this model develop slowly with onset of atrophy and weakness at about three weeks of age, before detection of extrajunctional acetylcholine receptors. Altered Itm2a expression seems to begin early as an increase, but becomes distinct as a decrease later.

Despite the increasing interest in targeting stromal elements of the tumor microenvironment, we still face tremendous challenges in developing adequate therapeutics to modify the tumor stromal landscape. A major obstacle to this is our poor understanding of the phenotypic and functional heterogeneity of stromal cells in tumors. Herein, we perform an unbiased interrogation of tumor mesenchymal cells, delineating the co-existence of distinct subsets of cancer-associated fibroblasts (CAFs) in the microenvironment of murine carcinomas, each endowed with unique phenotypic features and functions. Furthermore, our study shows that neutralization of TGFβ in vivo leads to remodeling of CAF dynamics, greatly reducing the frequency and activity of the myofibroblast subset, while promoting the formation of a fibroblast population characterized by strong response to interferon and heightened immunomodulatory properties. These changes correlate with the development of productive anti-tumor immunity and greater efficacy of PD1 immunotherapy. Along with providing the scientific rationale for the evaluation of TGFβ and PD1 co-blockade in the clinical setting, this study also supports the concept of plasticity of the stromal cell landscape in tumors, laying the foundation for future investigations aimed at defining pathways and molecules to program CAF composition for cancer therapy., Understanding the tumor microenviroment is important before it can be exploited therapeutically. Here, the authors use single cell sequencing to study stromal cells in mouse tumors and identify a subset of interferon-licensed cancer associated fibroblasts that appear after anti-TGFβ treatment.

Objectives Sabatolimab is a humanized monoclonal antibody (hIgG4, S228P) directed against human T-cell immunoglobulin domain and mucin domain-3 (TIM-3). Herein, we describe the development and characterization of sabatolimab. Methods Sabatolimab was tested for binding to its target TIM-3 and blocking properties. The functional effects of sabatolimab were tested in T-cell killing and myeloid cell cytokine assays. Antibody-mediated cell phagocytosis (ADCP) by sabatolimab was also assessed. Results Sabatolimab was shown to (i) enhance T-cell killing and inflammatory cytokine production by dendritic cells (DCs); (ii) facilitate the phagocytic uptake of TIM-3-expressing target cells; and (iii) block the interaction between TIM-3 and its ligands PtdSer/galectin-9. Conclusion Taken together, our results support both direct anti-leukemic effects and immune-mediated modulation by sabatolimab, reinforcing the notion that sabatolimab represents a novel immunotherapy with immuno-myeloid activity, holding promise for the treatment of myeloid cell neoplasms.

Increasing evidence suggests that both synaptic loss and neuroinflammation constitute early pathologic hallmarks of Alzheimer's disease. A downstream event during inflammatory activation of microglia and astrocytes is the induction of nitric oxide synthase type 2, resulting in an increased release of nitric oxide and the post-translational S-nitrosylation of protein cysteine residues. Both early events, inflammation and synaptic dysfunction, could be connected if this excess nitrosylation occurs on synaptic proteins. In the long term, such changes could provide new insight into patho-mechanisms as well as biomarker candidates from the early stages of disease progression. This study investigated S-nitrosylation in synaptosomal proteins isolated from APP/PS1 model mice in comparison to wild type and NOS2-/- mice, as well as human control, mild cognitive impairment and Alzheimer's disease brain tissues. Proteomics data were obtained using an established protocol utilizing an isobaric mass tag method, followed by nanocapillary high performance liquid chromatography tandem mass spectrometry. Statistical analysis identified the S-nitrosylation sites most likely derived from an increase in nitric oxide (NO) in dependence of presence of AD pathology, age and the key enzyme NOS2. The resulting list of candidate proteins is discussed considering function, previous findings in the context of neurodegeneration, and the potential for further validation studies.

Background Bacterial meningitis is a major cause of morbidity and mortality in sub-Saharan Africa. We analyzed data from the World Health Organization’s (WHO) Invasive Bacterial Vaccine-preventable Diseases Surveillance Network (2011–2016) to describe the epidemiology of laboratory-confirmed Streptococcus pneumoniae (Spn), Neisseria meningitidis, and Haemophilus influenzae meningitis within the WHO African Region. We also evaluated declines in vaccine-type pneumococcal meningitis following pneumococcal conjugate vaccine (PCV) introduction. Methods Reports of meningitis in children, We describe the epidemiology of meningitis cases due to Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae across 26 African countries participating in the World Health Organization’s Invasive Bacterial Vaccine-preventable Diseases Network, including trends in vaccine-type pneumococcal meningitis post–pneumococcal conjugate vaccine introduction.

This paper is part of a larger project investigating the relative roles of ideology and gender composition in determining organizational structure and behavior. The project’s genesis arose from a study by Meinhard and Foster (2003) that found that Canadian women’s voluntary organizations (WVOs) differed from gender-neutral and men’s organizations on many different measures. Women’s organizations were less likely to adopt a business orientation or pursue new revenue strategies, but were more likely to collaborate with other organizations and more likely to downsize. They also tended to be more pessimistic in their outlook and engaged in more advocacy and political action. Meinhard and Foster (2003) also found that among women’s organizations, those that were members of the Canadian National Action Committee on the Status of Women (NAC), an umbrella organization for feminist groups, were more extreme in their differences. In other words, although both NAC and non-NAC organizations differed significantly from gender-neutral organizations, NAC organizations differed the most. Keywords: CVSS, Centre for Voluntary Sector Studies, Working Paper Series,TRSM, Ted Rogers School of Management Citation

High-grade serous ovarian cancers (HGSOC) represent the most common subtype of ovarian malignancies. Due to the frequency of late-stage diagnosis and high rates of recurrence following standard of care treatments, novel therapies are needed to promote durable responses. We investigated the anti-tumor activity of CD3 T cell engaging bispecific antibodies (TCBs) directed against the PAX8 lineage-driven HGSOC tumor antigen LYPD1 and demonstrated that anti-LYPD1 TCBs induce T cell activation and promote in vivo tumor growth inhibition in LYPD1-expressing HGSOC. To selectively target LYPD1-expressing tumor cells with high expression while sparing cells with low expression, we coupled bivalent low-affinity anti-LYPD1 antigen-binding fragments (Fabs) with the anti-CD3 scFv. In contrast to the monovalent anti-LYPD1 high-affinity TCB (VHP354), the bivalent low-affinity anti-LYPD1 TCB (QZC131) demonstrated antigen density-dependent selectivity and showed tolerability in cynomolgus monkeys at the maximum dose tested of 3 mg/kg. Collectively, these data demonstrate that bivalent TCBs directed against LYPD1 have compelling efficacy and safety profiles to support its use as a treatment for high-grade serous ovarian cancers.

Chronic neuroinflammation is a pathogenic component of Alzheimer’s disease (AD) that may limit the ability of the brain to clear amyloid deposits and cellular debris. Tight control of the immune system is therefore key to sustain the ability of the brain to repair itself during homeostasis and disease. The immune‐cell checkpoint receptor/ligand pair PD‐1/PD‐L1, known for their inhibitory immune function, is expressed also in the brain. Here, we report upregulated expression of PD‐L1 and PD‐1 in astrocytes and microglia, respectively, surrounding amyloid plaques in AD patients and in the APP/PS1 AD mouse model. We observed juxtamembrane shedding of PD‐L1 from astrocytes, which may mediate ectodomain signaling to PD‐1‐expressing microglia. Deletion of microglial PD‐1 evoked an inflammatory response and compromised amyloid‐β peptide (Aβ) uptake. APP/PS1 mice deficient for PD‐1 exhibited increased deposition of Aβ, reduced microglial Aβ uptake, and decreased expression of the Aβ receptor CD36 on microglia. Therefore, ineffective immune regulation by the PD‐1/PD‐L1 axis contributes to Aβ plaque deposition during chronic neuroinflammation in AD., The immune‐checkpoint receptor/ligand pair PD‐1/PD‐L1 sustains phagocytic function of microglia to prevent Aβ plaque deposition in APP/PS mouse models and patient tissues.

Neuroinflammation is a common feature of many neurodegenerative diseases. It fosters a dysfunctional neuron–microglia–astrocyte crosstalk that, in turn, maintains microglial cells in a perniciously reactive state that often enhances neuronal damage. The molecular components that mediate this critical communication are not fully explored. Here, we show that secreted frizzled-related protein 1 (SFRP1), a multifunctional regulator of cell-to-cell communication, is part of the cellular crosstalk underlying neuroinflammation. In mouse models of acute and chronic neuroinflammation, SFRP1, largely astrocyte-derived, promotes and sustains microglial activation, and thus a chronic inflammatory state. SFRP1 promotes the upregulation of components of the hypoxia-induced factor-dependent inflammatory pathway and, to a lower extent, of those downstream of the nuclear factor-kappa B. We thus propose that SFRP1 acts as an astrocyte-to-microglia amplifier of neuroinflammation, representing a potential valuable therapeutic target for counteracting the harmful effect of chronic inflammation in several neurodegenerative diseases., This work was supported by grants from the Spanish AEI (BFU2013-43213-P; BFU2016-75412-R with FEDER support and PID2019-104186RB-I00), Fundacion Tatiana Perez de Guzman el Bueno and CIBERER to PB. JRC (BES-2011-047189), GP (BES-2017- 080318) and MIM (BES-2014-068797) were supported by FPI fellowships from the AEI. We also acknowledge a CBM Institutional Grant from the Fundacion Ramon Areces.

Sepsis-associated encephalopathy (SAE) represents diverse cerebral dysfunctions in response to pathogen-induced systemic inflammation. Peripheral exposure to lipopolysaccharide (LPS), a component of the gram-negative bacterial cell wall, has been extensively used to model systemic inflammation. Our previous studies suggested that LPS led to hippocampal neuron death and synaptic destruction in vivo. However, the underlying roles of activated microglia in these neuronal changes remained unclear. Here, LPS from two different bacterial strains (Salmonella enterica or E. coli) were compared and injected in 14- to 16-month-old mice and evaluated for neuroinflammation and neuronal integrity in the hippocampus at 7 or 63 days post-injection (dpi). LPS injection resulted in persistent neuroinflammation lasting for seven days and a subsequent normalisation by 63 dpi. Of note, increases in proinflammatory cytokines, microglial morphology and microglial mean lysosome volume were more pronounced after E. coli LPS injection than Salmonella LPS at 7 dpi. While inhibitory synaptic puncta density remained normal, excitatory synaptic puncta were locally reduced in the CA3 region of the hippocampus at 63 dpi. Finally, we provide evidence that excitatory synapses coated with complement factor 3 (C3) decreased between 7 dpi and 63 dpi. Although we did not find an increase of synaptic pruning by microglia, it is plausible that microglia recognised and eliminated these C3-tagged synapses between the two time-points of investigation. Since a region-specific decline of CA3 synapses has previously been reported during normal ageing, we postulate that systemic inflammation may have accelerated or worsened the CA3 synaptic changes in the ageing brain.

Background TIM-3 is expressed on leukemic stem cells (LSCs) and blasts in AML,1 2 and TIM-3 expression on MDS blasts correlates with disease progression.3 Functional evidence for TIM-3 in AML was established with an anti-TIM-3 antibody which inhibited engraftment and development of human AML in immuno-deficient murine hosts.1 TIM-3 promotes an autocrine stimulatory loop via the TIM-3/Galectin-9 interaction, supporting LSC self-renewal.4 In addition to its cell-autonomous role on LSCs/blasts, TIM-3 also has a critical role in immune system regulation, in adaptive (CD4+ and CD8+ T effector cells, regulatory T cells) and innate (macrophages, dendritic cells, NK cells) immune responses.5 MBG453 is a high-affinity, humanized anti-TIM-3 IgG4 antibody (Ab) (stabilized hinge, S228P), which blocks the binding of TIM-3 to phosphatidylserine (PtdSer). Recent results from a multi-center, open label phase Ib dose-escalation study (NCT03066648) in patients with high-risk MDS and no prior hypomethylating agent therapy evaluating MBG453 in combination with decitabine demonstrated encouraging preliminary efficacy with an overall response rate of 58%,6 and MBG453 combined with azacitidine also showed encouraging response rates.7 Preclinical experiments were undertaken to define the mechanism of action of the hypomethylating agent and anti-TIM-3 combination. Methods THP-1 cells (a human monocytic AML cell line) were pre-treated with decitabine and co-cultured with anti-CD3 activated healthy human donor peripheral blood mononuclear cells (PBMCs) in an Incucyte-based assay to measure cell killing. The ability of MBG453 to mediate antibody-dependent cellular phagocytosis (ADCP) was measured by determining the phagocytic uptake of an engineered TIM-3-overexpressing Raji cell line in the presence of MBG453 by phorbol 12-myristate 13-acetate (PMA)-activated THP-1 cells. Patient-derived AML xenograft studies were undertaken in immune-deficient murine hosts to evaluate the combination of decitabine and MBG453. Results MBG453 was determined to partially block the TIM-3/Galectin-9 interaction in a plate-based MSD (Meso Scale Discovery) assay, supported by a crystal structure of human TIM-3.8 Pre-treatment of THP-1 cells with decitabine enhanced sensitivity to immune-mediated killing in the presence of MBG453. MBG453 was determined to mediate modest ADCP, relative to controls. MBG453 did not enhance the anti-leukemic activity of decitabine in patient-derived xenograft studies in immuno-deficient hosts. Conclusions Taken together, these results support both direct anti-leukemic effects and immune-mediated modulation by MBG453. Further studies are ongoing to determine: (1) whether MBG453 can mediate physiologically relevant ADCP of TIM-3-expressing leukemic cells; and (2) the potential of MBG453 to impact the autocrine feedback loop of TIM-3/Galectin-9. Ethics Approval The human tissue used in these studies was under the Novartis Institutes of BioMedical Research Ethics Board IRB, Approval Number 201252867. References Kikushige Y, Shima T, Takayanagi S, et al. TIM-3 is a promising target to selectively kill acute myeloid leukemia stem cells. Cell Stem Cell 2010;7(6):708–717. Jan M, Chao MP, Cha AC, et al. Prospective separation of normal and leukemic stem cells based on differential expression of TIM3, a human acute myeloid leukemia stem cell marker. Proc Natl Acad Sci USA 2011; 108(12): 5009–5014. Asayama T, Tamura H, Ishibashi M, et al. Functional expression of Tim-3 on blasts and clinical impact of its ligand galectin-9 in myelodysplastic syndromes. Oncotarget 2017;8(51): 88904–88917. Kikushige Y, Miyamoto T, Yuda J, et al. A TIM-3/Gal-9 autocrine stimulatory loop drives self-renewal of human myeloid leukemia stem cells and leukemic progression. Cell Stem Cell 2015; 17(3):341–352. Acharya N, Sabatos-Peyton C, Anderson AC. Tim-3 finds its place in the cancer immunotherapy landscape. J Immunother Cancer 2020; 8(1):e000911. Borate U, Esteve J, Porkka K, et al. Phase Ib Study of the Anti-TIM-3 Antibody MBG453 in combination with decitabine in patients with high-risk myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Blood 2019;134 (Supplement_1):570. Borate U, Esteve J, Porkka K, et al. Abstract S185: Anti-TIM-3 antibody MBG453 in combination with hypomethylating agents (HMAs) in patients (pts) with high-risk myelodysplastic syndrome (HR-MDS) and acute myeloid leukemia (AML): a Phase 1 study. EHA 2020. Sabatos-Peyton C. MBG453: A high affinity, ligand-blocking anti-TIM-3 monoclonal Ab. AACR 2016.

Neuroinflammation is a common feature of many neurodegenerative diseases, which fosters a dysfunctional neuron-microglia-astrocyte crosstalk that, in turn, maintains microglial cells into a perniciously reactive state that often enhance neuronal damage. The molecular components that mediate this critical communication are however not fully explored. Here, we have asked whether Secreted-Frizzled-Related-Protein-1 (SFRP1), a multifunctional regulator of cell-to-cell communication, is part of the cellular crosstalk underlying neuroinflammation. We show that in mouse models of acute and chronic neuroinflammation, astrocyte-derived SFRP1 is sufficient to promote and sustain microglial activation, and thus a chronic inflammatory state. SFRP1 allows the upregulation of components of Hypoxia Induced Factors-dependent inflammatory pathway and, to a lower extent, of those downstream of the Nuclear Factor-kappaB. We thus propose that SFRP1 acts as a critical astrocyte to microglia amplifier of neuroinflammation, representing a potential valuable therapeutic target for counteracting the harmful effect of chronic inflammation present in several neurodegenerative diseases.

International audience; Microglia are the CNS resident immune cells that react to misfolded proteins through pattern recognition receptor ligation and activation of inflammatory pathways. Here, we studied how microglia handle and cope with $\alpha$-synuclein ($\alpha$-syn) fibrils and their clearance. We found that microglia exposed to $\alpha$-syn establish a cellular network through the formation of F-actin-dependent intercellular connections, which transfer $\alpha$-syn from overloaded microglia to neighboring naive microglia where the $\alpha$-syn cargo got rapidly and effectively degraded. Lowering the $\alpha$-syn burden attenuated the inflammatory profile of microglia and improved their survival. This degradation strategy was compromised in cells carrying the LRRK2 G2019S mutation. We confirmed the intercellular transfer of $\alpha$-syn assemblies in microglia using organotypic slice cultures, 2-photon microscopy, and neuropathology of patients. Together, these data identify a mechanism by which microglia create an ''on-demand'' functional network in order to improve pathogenic $\alpha$-syn clearance.

Anxiety disorders impact a significant number of youth with a 6.5% worldwide prevalence of anxiety disorders among children and adolescents. Anxious children and adolescents are at risk for significant negative outcomes, both in the short and long term. The cognitive behavioral therapies including rational emotive and cognitive behavioral therapy (RE-CBT) have been shown to be the most efficacious form of psychotherapy for the treatment of anxiety disorders, fears, and phobias among youth. This chapter is intended to provide a comprehensive overview of the clinical characteristics and maintenance factors of child and adolescent anxiety, an overview of current assessment methods, and discuss effective implementation of RE-CBT treatment strategies in children and adolescents.

Parkinson’s disease (PD) is the second most common age-related neurodegenerative disorder characterized by the formation of cellular inclusions inside neurons that are rich in an abnormal form of the protein α-synuclein (α-syn). Microglia are the CNS resident immune cells that react to misfolded proteins through pattern recognition receptor ligation and activation of signaling transduction pathways. Here, we studied microglial activation by distinct α-syn forms and their clearance. Internalization of α-syn monomers and oligomers efficiently activated the NLRP3 inflammasome via Toll-like receptor-2 and -5 ligation, thereby acting on different signaling checkpoints. We found that primary microglia effectively engulf α-syn, but hesitate in its degradation. NLRP3 inhibition by the selective inhibitor CRID3 and NLRP3 deficiency improved the overall clearance of α-syn oligomers. Together, these data show that distinct α-syn forms exert different microglial NLRP3 inflammasome activation properties, thereby compromising its degradation which can be prevented by NLRP3 inhibition.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder causing memory loss, language problems and behavioural disturbances. AD is associated with the accumulation of fibrillar amyloid-β (Aβ) and the formation of neurofibrillary tau tangles. Fibrillar Aβ itself represents a danger-associated molecular pattern, which is recognized by specific microglial receptors. One of the key players is formation of the NOD-, LRR- and pyrin domain-containing 3 (NLRP3) inflammasome, whose activation has been demonstrated in AD patient brains and transgenic animal models of AD. Here, we investigated whether Aβ oligomers or protofibrils that represent lower molecular aggregates prior to Aβ deposition are able to activate the NLRP3 inflammasome and subsequent interleukin-1 beta (IL-1β) release by microglia. In our study, we used Aβ preparations of different sizes: small oligomers and protofibrils of which the structure was confirmed by atomic force microscopy. Primary microglial cells from C57BL/6 mice were treated with the respective Aβ preparations and NLRP3 inflammasome activation, represented by caspase-1 cleavage, IL-1β production, and apoptosis-associated speck-like protein containing a CARD speck formation was analysed. Both protofibrils and low molecular weight Aβ aggregates induced a significant increase in IL-1β release. Inflammasome activation was confirmed by apoptosis-associated speck-like protein containing a CARD speck formation and detection of active caspase-1. The NLRP3 inflammasome inhibitor MCC950 completely inhibited the Aβ-induced immune response. Our results show that the NLRP3 inflammasome is activated not only by fibrillar Aβ aggregates as reported before, but also by lower molecular weight Aβ oligomers and protofibrils, highlighting the possibility that microglial activation by these Aβ species may initiate innate immune responses in the central nervous system prior to the onset of Aβ deposition. Cover Image for this issue: https://doi.org/10.1111/jnc.14773.

International audience; Alzheimer's disease is characterized by the accumulation of amyloid-beta in plaques, aggregation of hyperphosphorylated tau in neurofibrillary tangles and neuroinflammation, together resulting in neurodegeneration and cognitive decline1. The NLRP3 inflammasome assembles inside of microglia on activation, leading to increased cleavage and activity of caspase-1 and downstream interleukin-1β release2. Although the NLRP3 inflammasome has been shown to be essential for the development and progression of amyloid-beta pathology in mice3, the precise effect on tau pathology remains unknown. Here we show that loss of NLRP3 inflammasome function reduced tau hyperphosphorylation and aggregation by regulating tau kinases and phosphatases. Tau activated the NLRP3 inflammasome and intracerebral injection of fibrillar amyloid-beta-containing brain homogenates induced tau pathology in an NLRP3-dependent manner. These data identify an important role of microglia and NLRP3 inflammasome activation in the pathogenesis of tauopathies and support the amyloid-cascade hypothesis in Alzheimer's disease, demonstrating that neurofibrillary tangles develop downstream of amyloid-beta-induced microglial activation.

In 1988, the Cuban collective ABTV engaged in its first of several acts of art-historical homage. ABTV (Tanya Angulo, Juan Pablo Ballester, José Ángel Toirac, and Illeana Villazón) photocopied reproductions of Sherrie Levine's After Series, the now canonical work of postmodernism in which Levine rephotographed reproductions of selection of photographs by America's white male modernist masters. This essay takes ABTV's homage as the starting point for an inquiry into the relationship between postmodernism and postcolonialism. How, it asks, has an obsession with “ends” shaped our histories of photography and revolution?

Despite its wide application in studies on memory and disease-related cognitive impairment, the use of the novel object recognition (NOR) test in research on aging has been limited and produced conflicting results. The purpose of this study was to characterize NOR across the lifespan of male C57BL/6 mice (3, 6, 9, 12, 15, and 24 months), the most popular rodent model of aging. NOR, measured after a delay of 24 hours, was analyzed with respect to variability, its dependence on locomotor and exploratory activity, and with an emphasis on its temporal dynamics. The latter has been recognized in rats, but never been investigated in mice. We find that although locomotor activity decreases monotonically above 3 months of age, exploratory activity in our setup remains constant and sufficient for NOR testing up to 12 months. As a major finding, we show that NOR depends on exploration time in the test phase in an age-dependent manner. Whereas NOR in our paradigm remains significant up to at least 20 seconds total exploration time in 3 and 6 months old mice, novel object preference at 9 and 12 months of age is detectable after 10 seconds exploration, but decreases rapidly and is missed when the first 20 seconds are analyzed. Analysis of the first 2 minutes of the test phase does not detect NOR except for 3 months old mice. We conclude that temporal aspects of NOR have been neglected and must be considered when making comparisons between or within mice at different ages.

The spreading of pathology within and between brain areas is a hallmark of neurodegenerative disorders. In patients with Alzheimer's disease, deposition of amyloid-beta is accompanied by activation of the innate immune system and involves inflammasome-dependent formation of ASC specks in microglia. ASC specks released by microglia bind rapidly to amyloid-beta and increase the formation of amyloid-beta oligomers and aggregates, acting as an inflammation-driven cross-seed for amyloid-beta pathology. Here we show that intrahippocampal injection of ASC specks resulted in spreading of amyloid-beta pathology in transgenic double-mutant APP(Swe)PSEN1(dE9) mice. By contrast, homogenates from brains of APP(Swe)PSEN1(dE9) mice failed to induce seeding and spreading of amyloid-beta pathology in ASC-deficient APP(Swe)PSEN1(dE9) mice. Moreover, co-application of an anti-ASC antibody blocked the increase in amyloid-beta pathology in APP(Swe)PSEN1(dE9) mice. These findings support the concept that inflammasome activation is connected to seeding and spreading of amyloid-beta pathology in patients with Alzheimer's disease.

Prompted by the publication of David Campany's study of the magazine work produced by the American photographer Walker Evans, Stephanie Schwartz talks with the author about the questions it raises for our understanding of photographic history, of the relation between the illustrated press and museums, and between journalism, documentary, and art.

In 1932, Paul Strand travelled to Mexico. The work he completed during his two-year stay has framed our histories of Strand's practice in the 1930s and 1940s as a history of his turning away from his commitment to formalism in the 1920s. Paul Strand's Living Labor challenges this history through an examination of The Wave, a documentary film Strand shot in 1934. A study of labor struggles in post-revolutionary Mexico, The Wave, this essay argues, reanimates Strand's investigation of the relationship between man and machine evident in his first film, Manhatta (1921). Focusing on Strand's obsession with the close-up and the portrait, Paul Strand's Living Labor organizes a history of Strand's work that rejects the binaries framing our studies of Strand: between New York and Mexico, film and photography, modernism and documentary.

Summary Background To combat Neisseria meningitidis serogroup A epidemics in the meningitis belt of sub-Saharan Africa, a meningococcal serogroup A conjugate vaccine (MACV) has been progressively rolled out since 2010. We report the first meningitis epidemic in Niger since the nationwide introduction of MACV. Methods We compiled and analysed nationwide case-based meningitis surveillance data in Niger. Cases were confirmed by culture or direct real-time PCR, or both, of cerebrospinal fluid specimens, and whole-genome sequencing was used to characterise isolates. Information on vaccination campaigns was collected by the Niger Ministry of Health and WHO. Findings From Jan 1 to June 30, 2015, 9367 suspected meningitis cases and 549 deaths were reported in Niger. Among 4301 cerebrospinal fluid specimens tested, 1603 (37·3%) were positive for a bacterial pathogen, including 1147 (71·5%) that were positive for N meningitidis serogroup C (NmC). Whole-genome sequencing of 77 NmC isolates revealed the strain to be ST-10217. Although vaccination campaigns were limited in scope because of a global vaccine shortage, 1·4 million people were vaccinated from March to June, 2015. Interpretation This epidemic represents the largest global NmC outbreak so far and shows the continued threat of N meningitidis in sub-Saharan Africa. The risk of further regional expansion of this novel clone highlights the need for continued strengthening of case-based surveillance. The availability of an affordable, multivalent conjugate vaccine may be important in future epidemic response. Funding MenAfriNet consortium, a partnership between the US Centers for Disease Control and Prevention, WHO, and Agence de Medecine Preventive, through a grant from the Bill & Melinda Gates Foundation.

Recorded in Havana in June 2009, this conversation addresses a series of works by the Cuban artist Manuel Pina. Moving between Pina's recent video work, his earlier photographic practices and the tradition of photojournalism in Cuba, we investigate the continued and dynamic intersection between documentary work and revolutionary politics. This conversation reminds us that debates about the ‘end of Communism’ and the rise of the global art market must also contend with art production still confronting the realities of a socialist revolution.

This study examined gender differences in 79 high‐school students’ attitudes towards their science classes, their perceptions of science and scientists, and their views about majoring in science. The study identified some of the subtleties underlying females’ low participation in, and interest in, science documented in previous research. Four themes emerged from responses on the rating scales and questionnaire. First, even when females planned to major in science, they were more interested than males in the people‐oriented aspects of their planned majors. Second, biology was the one exception to females’ low interest in science. Third, females often planned a science major mainly because they needed a science background in order to enter a health profession such as medicine or physical therapy. Fourth, females generally found science uninteresting and the scientific lifestyle (as perceived by them) unattractive. Implications for teaching science were discussed.

Alzheimer's disease (AD) is a neurodegenerative condition that leads to neuronal death and memory dysfunction. In the past, specific peroxisome proliferator-activated receptor (PPAR)γ-agonists, such as pioglitazone, have been tested with limited success to improve AD pathology. Here, we investigated the therapeutic efficacy of GFT1803, a novel potent PPAR agonist that activates all the three PPAR isoforms (α/δ/γ) in the APP/PS1 mouse model in comparison to the selective PPARγ-agonist pioglitazone. Both compounds showed similar brain/plasma partitioning ratios, although whole body and brain exposure to GFT1803 was significantly lower as compared to pioglitazone, at doses used in this study. Oral treatment of APP/PS1 mice with GFT1803 decreased microglial activation, amyloid β (Aβ) plaque area, Aβ levels in sodium dodecyl sulfate- and formic acid-soluble fractions in a concentration-dependent manner. With a single exception of Aβ38 and Aβ40 levels, measured by ELISA, these effects were not observed in mice treated with pioglitazone. Both ligands decreased glial fibrillary acidic protein (GFAP) expression to similar extent and did not affect ApoE expression. Finally, GFT1803 increased insulin-degrading enzyme expression. Analysis of spatial memory formation in the Morris water maze demonstrated that both compounds were able to partially revert the phenotype of APP/PS1 mice in comparison to wild-type mice with GFT1803 being most effective. As compared to pioglitazone, GFT1803 (pan-PPAR agonist) produced both quantitatively superior and qualitatively different therapeutic effects with respect to amyloid plaque burden, insoluble Aβ content, and neuroinflammation at significantly lower whole body and brain exposure rates.

To assess the consequences of locus ceruleus (LC) degeneration and subsequent noradrenaline (NA) deficiency in early Alzheimer’sdisease (AD), mice overexpressing mutant amyloid precursor protein and presenilin-1 (APP/PS1) were crossed with Ear2( / ) micethat have a severe loss of LC neurons projecting to the hippocampus and neocortex. Testing spatial memory and hippocampal long-termpotentiation revealed an impairment in APP/PS1 Ear2( / ) mice, whereas APP/PS1 or Ear2( / ) mice showed only minor changes.These deficits were associated with distinct synaptic changes including reduced expression of theNMDA2A subunit and increased levelsof NMDA receptor 2B in APP/PS1 Ear2( / ) mice. Acute pharmacological replacement of NA by L -threo-DOPS partially restoredphosphorylation of -CaMKII and spatial memory performance in APP/PS1 Ear2( / ) mice. These changes were not accompanied byaltered APP processing or amyloid peptide (A ) deposition. Thus, early LC degeneration and subsequentNAreduction may contributeto cognitive deficits via CaMKII and NMDA receptor dysfunction independent of A and suggests that NA supplementation could bebeneficial in treating AD.