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Pangolins have long been hunted for food and for their scales, but information on local hunting strategies in African range countries and the patterns of pangolin trafficking around sourcing areas is limited. Such knowledge is vital to inform monitoring approaches and conservation interventions. We administered questionnaires to 367 people from 20 villages around two national parks in Cameroon to gain insights into local hunting practices, and trading and trafficking patterns. We found that tracking was the preferred method of hunting pangolins. Trapping was also used, and setting traps on fallen logs and near burrows improved the likelihood of catching pangolins. The white-bellied pangolin Phataginus tricuspis was the most traded species, and the giant pangolin Smutsia gigantea was the most sought after. We found no evidence of trade in the black-bellied pangolin Phataginus tetradactyla. Most respondents stated that pangolin prices had increased over the last 5 years, and scarcity of pangolins was the primary reason given for this increase. We identified a pangolin scale trafficking network operating from rural communities to neighbouring cities. Although most respondents recognized that hunting pangolins is illegal, c. 30% indicated that they were engaged in pangolin hunting.

Achromobacterspecies are newly recognized opportunistic, pro-inflammatory Gram-negative pathogens in immunocompromised individuals, but how they interact with the innate immune system to drive inflammation is poorly understood. We createdsctV(Type 3 Secretion System baseplate) mutants in threeAchromobacterclinical isolates from two species and showed that all three required the T3SS to induce cell death in human macrophages. Mutating other critical T3SS components also abolished cell death, which was restored by genetic complementation. Cell death ofAchromobacter-infected macrophages was contact-dependent, enhanced by bacterial internalisation, and caused by inflammasome-dependent pyroptosis (typified by Gasdermin-D cleavage and IL-1β secretion). Macrophages deficient in the inflammasome sensors NLRC4 or NLRP3 underwent pyroptosis upon bacterial internalization but those deficient in both NLRC4 and NLRP3 did not, suggesting either sensor can mediate pyroptosis induction in a T3SS-dependent manner. Detailed analysis of the intracellular trafficking of one isolate indicated that the intracellular bacteria reside in an acidic LAMP-1/dextran-positive membrane compartment. Using an intranasal mouse infection model, we observed thatAchromobacterdamages lung structure and causes severe illness, contingent on a functional T3SS. Together, we demonstrate thatAchromobacterspecies can survive phagocytosis by macrophages and promote macrophage cell death and inflammation by redundant mechanisms of pyroptosis induction.

10D1F interacts with linear peptides from the HER3 domain II dimerization interface

10D1P demonstrates potent in vivo tumor growth inhibition in multiple xenograft tumor models

10D1F does not show rapid internalization in HER3 expressing cancer cell lines but activates ADCC

Supplementary Methods with References, Supplementary Figure Legends, and list of Supplementary Tables

Supplemental Table 2 - Summary of protein and gene expression data of HER family molecules, and their ligands, for the cancer cell lines used in this study

PDF file - 65K, Treatment with cisplatin and radiation therapy increases IAP gene expression in additional medulloblastoma cell lines

PDF file - 257K, Treatment with irradiation and LBW242 leads to apoptosis in medulloblastoma cell lines

PDF file - 47K, Supplementary Table 1 The combinatorial index of medulloblastoma cell lines treated with a combination of 1uM LBW-242 and 2 Gy (Daoy, D283) or 4Gy (UW228) irradiation in a colony formation assay. A CI of < 1 denotes a synergistic interaction, a CI of 1 +/-0.2 denotes an additive interaction, and a CI of > 1 indicates an antagonistic interaction. Supplementary Table 2: Clinical characteristics of patients from which short term primary tumor cultures were derived.Supplementary Table 3: The ID50 of medulloblastoma cell lines and primary cultures treated with LBW-242 and Cisplatin, calculated from synergy assay curves using interpolated x values (Graph Pad Prism 5). (IA = Inactive as single agent; N/A = not applicable.)

10D1F demonstrates superior inhibition of cancer cell line proliferation by potently inhibiting downstream signaling through the PI3K pathway in additional cancer cell lines

10D1F parental antibody, 10D1P, binds with high affinity and specificity to a species-conserved epitope on HER3, and Class 1 and Class 2 HER3 antibodies show different HER3 binding profiles in presence and absence of NRG1

In recent years, HER3 has increasingly been implicated in the progression of a variety of tumor types and in acquired resistance to EGFR and HER2 therapies. Whereas EGFR and HER2 primarily signal through the MAPK pathway, HER3, as a heterodimer with EGFR or HER2, potently activates the PI3K pathway. Despite its critical role, previous attempts to target HER3 with neutralizing antibodies have shown disappointing efficacy in the clinic, most likely due to suboptimal and indirect mechanisms of action that fail to completely block heterodimerization; for example, tumors can escape inhibition of ligand binding by upregulating ligand-independent mechanisms of HER3 activation. We therefore developed 10D1F, a picomolar affinity, highly specific anti-HER3 neutralizing antibody that binds the HER3 heterodimerization interface, a region that was hitherto challenging to raise antibodies against. We demonstrate that 10D1F potently inhibits both EGFR:HER3 and HER2:HER3 heterodimerization to durably suppress activation of the PI3K pathway in a broad panel of tumor models. Even as a monotherapy, 10D1F shows superior inhibition of tumor growth in the same cell lines both in vitro and in mouse xenograft experiments, when compared with other classes of anti-HER3 antibodies. This includes models demonstrating ligand-independent activation of heterodimerization as well as constitutively activating mutations in the MAPK pathway. Possessing favorable pharmacokinetic and toxicologic profiles, 10D1F uniquely represents a new class of anti-HER3 neutralizing antibodies with a novel mechanism of action that offers significant potential for broad clinical benefit.10D1F is a novel anti-HER3 antibody that uniquely binds the receptor dimerization interface to block ligand-dependent and independent heterodimerization with EGFR/HER2 and thus more potently inhibits tumor growth than existing anti-HER3 antibodies.

Supplemental Table 3 - Toxicological data showing no adverse effects of 10D1F on the indicated hematological and biochemistry parameters in multiple rodent models

Supplemental Table 1 - Summary of the published functional mechanisms of action for anti-HER3 neutralizing antibodies in development

Acting in the environment results in both intended and unintended consequences. Action consequences provide feedback about the adequacy of actions while they are in progress and when they are completed and therefore contribute to monitoring actions, facilitate error detection, and are crucial for motor learning. In action imagery, no actual action takes place, and consequently, no actual action consequences are produced. However, imagined action consequences may replace actual action consequences, serving a similar function and facilitating performance improvements akin to that occurring with actual actions. In this paper, we conceptualize action imagery as a simulation based on internal models. During that simulation, forward models predict action consequences. A comparison of predicted and intended action consequences sometimes indicates the occurrence of action errors (or deviations from optimal performance) in action imagery. We review research indicating that action errors are indeed sometimes imagined in action imagery. These results are compatible with the view that action imagery is based on motor simulation but incompatible with the view that action imagery is solely based on abstract knowledge. The outlined framework seems suitable to cover a wide range of action imagery phenomena and can explain action imagery practice effects.

Li-M-Si ternary Zintl phases have gained attention recently due to their high structural stability, which can improve the cycling stability compared to a bulk Si electrode. Adding multivalent cation salts (such as Mg

Theories of motor imagery conflict in their account of what happens during an imagined movement, with some suggesting that movement is simulated while others suggest it involves creating and elaborating upon an internal representation of the movement. Here we report evidence that imagery involves the simulation of a movement and that it varies in accuracy. Two groups of participants performed a motor task focused on challenging movement execution either overtly or via motor imagery. Overt performance was used to model expected performance given required movement characteristics (i.e., speed, complexity, familiarity), which was then compared with self-reported accuracy during imagery. Movement characteristics had a large effect on self-reported accuracy compared with a small effect of imagery vividness. Self-reported accuracy improved across trials with familiar movements compared with novel movements in a similar manner for each group. The complexity of the imagined movement did not influence movement time during imagery or overt trials, further suggesting that imagined movements are simulated rather than abstractly represented. Our results therefore support models of motor imagery that involve the simulation of a movement and its viability, which may be the basis of imagery-based motor learning. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

12 p.-7 fig.-1 schem.-1 graph. abst., Modern adjuvants for vaccine formulations are immunostimulating agents whose action is based on the activation of pattern recognition receptors (PRRs) by well-defined ligands to boost innate and adaptive immune responses. Monophosphoryl lipid A (MPLA), a detoxified analogue of lipid A, is a clinically approved adjuvant that stimulates toll-like receptor 4 (TLR4). The synthesis of MPLA poses manufacturing and quality assessment challenges. Bridging this gap, we report here the development and preclinical testing of chemically simplified TLR4 agonists that could sustainably be produced in high purity and on a large scale. Underpinned by computational and biological experiments, we show that synthetic monosaccharide-based molecules (FP compounds) bind to the TLR4/MD-2 dimer with submicromolar affinities stabilizing the active receptor conformation. This results in the activation of MyD88- and TRIF-dependent TLR4 signaling and the NLRP3 inflammasome. FP compounds lack in vivo toxicity and exhibit adjuvant activity by stimulating antibody responses with a potency comparable to MPLA., The support from European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No. 860325 (www.BactiVax.eu), Italian Ministry grant PRIN 2017, no. 2017E44A9P (BacHounds:Supramolecular nanostructures for bacteria detection), and the Spanish Ministry for Science and Innovation (grants CTQ2017-88353-R and PRE2018-086249) is acknowledged.

Emotions provoke change, yet are often discredited at best and demonized at worst in modernity and positivism. We currently face a global climate crisis – one so dangerous that biocultural diversit...

Secretory leucoprotease inhibitor (SLPI) has multifaceted functions, including inhibition of protease activity, antimicrobial functions, and anti-inflammatory properties. In this study, we show that SLPI plays a role in controlling pulmonary P. aeruginosa infection. Mice lacking SLPI were highly susceptible to P. aeruginosa infection, however had no difference in bacterial burden. Utilising a model of P. aeruginosa LPS-induced lung inflammation, human recombinant SLPI (hrSLPI) administered intraperitoneally suppressed the recruitment of inflammatory cells in the bronchoalveolar lavage fluid (BALF) and resulted in reduced BALF and serum levels of inflammatory cytokines and chemokines. This anti-inflammatory effect of hrSLPI was similarly demonstrated in a systemic inflammation model induced by intraperitoneal injection of LPS from various bacteria or lipoteichoic acid, highlighting the broad anti-inflammatory properties of hrSLPI. Moreover, in bone-marrow-derived macrophages, hrSLPI reduced LPS-induced phosphorylation of p-IkB-α, p-IKK-α/β, p-P38, demonstrating that the anti-inflammatory effect of hrSLPI was due to the inhibition of the NFB and MAPK pathways. In conclusion, administration of hrSLPI attenuates excessive inflammatory responses and is therefore, a promising strategy to target inflammatory diseases such as acute respiratory distress syndrome or sepsis and could potentially be used to augment antibiotic treatment.

Secretory leucoprotease inhibitor (SLPI) has multifaceted functions, including inhibition of protease activity, antimicrobial functions, and anti-inflammatory properties. In this study, we show that SLPI plays a role in controlling pulmonary

Reversible electrochemical magnesium plating/stripping processes are important for the development of high-energy-density Mg batteries based on Mg anodes. Ether glyme solutions such as monoglyme (G1), diglyme (G2), and triglyme (G3) with the MgTFSI2 salt are one of the conventional and commonly used electrolytes that can obtain the reversible behavior of Mg electrodes. However, the electrolyte cathodic efficiency is argued to be limited due to the enormous parasitic reductive decomposition and passivation, which is governed by impurities. In this work, a systematic identification of the impurities in these systems and their effect on the Mg deposition–dissolution processes is reported. The mitigation methods generally used for eliminating impurities are evaluated, and their beneficial effects on the improved reactivity are also discussed. By comparing the performances, we proposed a necessary conditioning protocol that can be easy to handle and much safer toward the practical application of MgTFSI2/glyme electrolytes containing impurities.

A sense of school belonging has been associated with a number of positive outcomes for young people Two core aspects are feeling part of the school, and feeling safe. This paper examines qualitative data from a mixed methods questionnaire designed to inform schools on the barriers and supports to participation in school life and the relationship with students’ feelings of belonging. It contributes to the limited existing qualitative data and can be set alongside students’ quantitative measures to provide new insights. We explore responses from 595 students, to the open questions of a survey. Students frequently mentioned relationships with teachers and peers, often in the context of feeling safe to be themselves, suggesting that feeling part of the school and feeling safe are intertwined. The comments reveal the importance of being recognised and accepted and not having their identity purely defined in relation to attainment on a narrowly defined curriculum.

The Mg battery is an energy storage technology which has garnered significant interest in recent years. Mg batteries incorporating a metal oxide cathode (MOC) are potential candidates to supersede ...

Given the failure of the world's governments to improve the status of biodiversity by 2020, a new strategic plan for 2030 is being developed. In order to be successful, a step-change is needed to not just simply halt biodiversity loss, but to bend the curve of biodiversity loss to stable or increasing species' populations. Here, we propose a framework that quantifies species' responses across gradients of threat intensity to implement more efficient and better targeted conservation actions. Our framework acknowledges the variation in threat intensities as well as the differences among species in their capacity to respond, and is implemented at a relevant scale for national and international policy-making.

Ion transport in solid-state cathode materials prescribes a fundamental limit to the rates batteries can operate; therefore, an accurate understanding of ion transport is a critical missing piece to enable new battery technologies, such as magnesium batteries. Based on our conventional understanding of lithium-ion materials, MgCr

Patients with epilepsy develop reproductive endocrine comorbidities at a rate higher than that of the general population. Clinical studies have identified disrupted luteinizing hormone (LH) release patterns in patients of both sexes, suggesting potential epilepsy-associated changes in hypothalamic gonadotropin-releasing hormone (GnRH) neuron function. In previous work, we found that GnRH neuron firing is increased in diestrous females and males in the intrahippocampal kainic acid (IHKA) mouse model of temporal lobe epilepsy. Notably, GABAA receptor activation is depolarizing in adult GnRH neurons. Therefore, here we tested the hypothesis that increased GnRH neuron firing in IHKA mice is associated with increased GABAergic drive to GnRH neurons. When ionotropic glutamate receptors (iGluRs) were blocked to isolate GABAergic postsynaptic currents (PSCs), no differences in PSC frequency were seen between GnRH neurons from control and IHKA diestrous females. In the absence of iGluR blockade, however, GABA PSC frequency was increased in GnRH neurons from IHKA females with disrupted estrous cycles, but not saline-injected controls nor IHKA females without estrous cycle disruption. GABA PSC amplitude was also increased in IHKA females with disrupted estrous cycles. These findings suggest the presence of an iGluR-dependent increase in feed-forward GABAergic transmission to GnRH neurons specific to IHKA females with comorbid cycle disruption. In males, GABA PSC frequency and amplitude were unchanged but PSC duration was reduced. Together, these findings suggest that increased GABA transmission helps drive elevated firing in IHKA females on diestrus and indicate the presence of a sex-specific hypothalamic mechanism underlying reproductive endocrine dysfunction in IHKA mice.HIGHLIGHTSIncreased GABA transmission to GnRH neurons in IHKA mouse model of epilepsyIncreased GABA transmission is dependent on upstream glutamate signalingIncreased GABA transmission only seen in females with disrupted estrous cyclesPotential sex-specific mechanism for reproductive endocrine dysfunction in epilepsy

Pupils with special educational needs and disabilities (SEND) are disproportionately over-represented in official statistics on exclusion suggesting that mainstream schools are failing to meet their needs. We argue for the importance of looking at the cultures of schooling. School belonging (or connectedness) has been widely associated with a raft of positive outcomes although there is relatively little research that has focused on pupils with SEND. This paper contributes to that gap presenting questionnaire data collected on the barriers and supports to inclusion and girls’ feelings of belonging in school. The needs of girls who identify as having SEND can be more difficult to discern, their strategies for coping effectively masking their difficulties. Our data reveal that the girls in the study with SEND feel less connected to school than other girls. Their scores for their sense of belonging were significantly associated with the barriers and supports they encounter across a range of school contexts. It was the relational aspects of schooling that were most important for girls with SEND. Feeling you belong means that you feel safe to be yourself, that you don’t need to hide your “quirky bits,” with the attendant demands on mental health.

α-V2O5 has been extensively explored as a Mg2+ intercalation host with potential as a battery cathode, offering high theoretical capacities and potentials vs. Mg2+/Mg. However, large voltage hysteresis is observed with Mg insertion and extraction, introducing significant and unacceptable round-trip energy losses with cycling. Conventional interpretations suggest that bulk ion transport of Mg2+ within the cathode particles is the major source of this hysteresis. Herein, we demonstrate that nanosizing α-V2O5 gives a measurable reduction to voltage hysteresis on the first cycle that substantially raises energy efficiency, indicating that mechanical formatting of the α-V2O5 particles contributes to hysteresis. However, no measurable improvement in hysteresis is found in the nanosized α-V2O5 in latter cycles despite the much shorter diffusion lengths, suggesting that other factors aside from Mg transport, such as Mg transfer between the electrolyte and electrode, contribute to this hysteresis. This observation is in sharp contrast to the conventional interpretation of Mg electrochemistry. Therefore, this study uncovers critical fundamental underpinning limiting factors in Mg battery electrochemistry, and constitutes a pivotal step towards a high-voltage, high-capacity electrode material suitable for Mg batteries with high energy density.

Calcium-ion batteries (CIBs) are under investigation as next-generation energy storage devices due to their theoretically high operating potentials and lower costs tied to the high natural abundanc...

Nonaqueous Mg batteries can theoretically reach high energy density with cost-effective materials, yet no such device to date has performance competitive with Li-ion technologies. A major barrier i...

Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) affect the home-ostasis of chloride flux by epithelial cells. This has deleterious consequences, especially in respira-tory epithelia, where the defect results in mucus accumulation distinctive of cystic fibrosis. CFTRis, however, also expressed in phagocytic cells, like macrophages. Immune cells are highly sensitiveto conditioning by their environment; thus, CFTR dysfunction in epithelia influences macrophagesby affecting the lung milieu, but the mutations also appear to be directly consequential for intrin-sic macrophage functions. Particular mutations can alter CFTR’s folding, traffic of the proteinto the membrane and function. As such, understanding the intrinsic effects of CFTR mutationrequires distinguishing the secondary effects of misfolded CFTR on cell stress pathways from theprimary defect of CFTR dysfunction/absence. Investigations into CFTR’s role in macrophages haveexploited various models, each with their own advantages and limitations. This review summarizesthese methodologic approaches, discussing their physiological correspondence and highlightingkey findings. The controversy surrounding CFTR-dependent acidification is used as a case studyto highlight difficulties in commensurability across model systems. Recent work in macrophagebiology, including polarization and host–pathogen interaction studies, brought into the context ofCFTR research, offers potential explanations for observed discrepancies between studies. More-over, the rapid advancement of novel gene editing technologies and new macrophage model sys-tems makes this assessment of the field’s models and methodologies timely.Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) affect the home-ostasis of chloride flux by epithelial cells. This has deleterious consequences, especially in respira-tory epithelia, where the defect results in mucus accumulation distinctive of cystic fibrosis. CFTRis, however, also expressed in phagocytic cells, like macrophages. Immune cells are highly sensitiveto conditioning by their environment; thus, CFTR dysfunction in epithelia influences macrophagesby affecting the lung milieu, but the mutations also appear to be directly consequential for intrin-sic macrophage functions. Particular mutations can alter CFTR’s folding, traffic of the proteinto the membrane and function. As such, understanding the intrinsic effects of CFTR mutationrequires distinguishing the secondary effects of misfolded CFTR on cell stress pathways from theprimary defect of CFTR dysfunction/absence. Investigations into CFTR’s role in macrophages haveexploited various models, each with their own advantages and limitations. This review summarizesthese methodologic approaches, discussing their physiological correspondence and highlightingkey findings. The controversy surrounding CFTR-dependent acidification is used as a case studyto highlight difficulties in commensurability across model systems. Recent work in macrophagebiology, including polarization and host–pathogen interaction studies, brought into the context ofCFTR research, offers potential explanations for observed discrepancies between studies. More-over, the rapid advancement of novel gene editing technologies and new macrophage model sys-tems makes this assessment of the field’s models and methodologies timely.

Commercial Li-ion batteries typically incorporate a small amount of high-capacity silicon (Si)-based materials in the composite graphite-based anode to increase the energy density of the battery. However, very little is known about the effects of Si on the fast-charging behavior of composite anodes. Herein, we examine the effects of the Si/graphite ratio in the composite anode on the fast-charging behavior of full cells. We show that addition of Si increases the rate capability from 1C to 8C and improves the capacity retention in early cycles at 6C due to reduced overpotential in constant current charging cycles. The impacts of Si content on fast-charging aging were identified by Post-Test characterization. Despite realizing benefits of available capacity and reduced Li plating at 6C, silicon–electrolyte interactions lead the time-dependent cell performance to fade quickly in the long term. The Post-Test analysis also revealed the thickening of the electrode and nonuniform distribution of electrolyte decomposition products on the Si-containing anodes, as well as the organic-rich solid electrolyte interphase (SEI), which are the factors behind cell degradation. Our study sheds insight on the advantages and disadvantages of Si/graphite composite anodes when they are used in fast-charging applications and guides further research in the area by designing an optimized composition of Si incorporated in a mature graphite matrix.