ABSTRACT
Predicting the mechanical properties of powder mixtures without extensive experimentation is important for model driven design in solid dosage form manufacture. Here, a new binary interaction-based model is proposed for predicting the compressibility and compactability of directly compressed pharmaceutical powder mixtures based on the mixture composition. The model is validated using blends of MCC, lactose and paracetamol or ibuprofen. Both compressibility and compactability profiles are predicted well for a variety of blend compositions of ternary mixtures for the two formulations. The model performs well over a wide range of compositions for both blends and better than either an ideal mixing model or a ternary interaction model. A design of experiments which reduces the amount of API required for fitting the model parameters for a new formulation is proposed to reduce amount of API required. The design requires only three blends containing API. The model gives similar performance to the well-known Reynolds et al. model (2017) when trained using the same data sets. The binary interaction model approach is generalizable to other powder mixture properties. The model presented in this work is limited to curve-fitting of empirical compaction models for mixtures of common pharmaceutical powders and is not intended to provide guidance on the practical operating space (or design space) limits.
ABSTRACT
Community Based Natural Resource Management (CBNRM) is presented as an equitable approach, particularly relative to strict types of Area-based conservation. In Zambia, traditional and formal, contemporary institutions were combined to leverage CBNRM for natural resource management. We investigate whether and how this shift in conservation approach and interaction between institutions works in practice, and to what extent it produces more equitable governance processes. We identified 30 key informants from NGOs and government departments via snowball sampling. We conducted 20 focus group discussions involving local community participants in three Game Management Areas (GMAs) adjacent to North Luangwa National Park. Focus groups were divided by age and gender to minimize any potential influence of unequal power relations. Data collection included informal discussions with individual community members and participant observation. We found that the customary roles held by chiefs gave them relative power over the Community resources board and made them gatekeepers for NGOs and government institutions. Instead of fostering community participation and empowerment, new CBNRM institutions have had the unintended consequence of increasing the customary chiefs' power through commercialization and bureaucratization of their positions. Rather than reinforcing local and indigenous institutions CBNRM has become a vehicle through which governments and NGOs centralize power and manufacture consent while weakening traditional institutions and reproducing existing patterns of inequity. This research provides unique insights into the workings of a CBNRM institution that is a hybrid between traditional (socially embedded) and Government (bureaucratic) institutions. We recommend that rather than simply setting up idealized institutions as a means to devolve power and enhance equity, the realisation of effective local participation and representation in CBNRM projects requires careful assessment of cultural contexts, local institutions and power dynamics.
ABSTRACT
Drawing on 662 studies from 102 countries, we present a systematic review of published empirical studies about site-level biodiversity conservation initiated between 1970 and 2019. Within this sample, we find that knowledge production about the Global South is largely produced by researchers in the Global North, implying a neocolonial power dynamic. We also find evidence of bias in reported ecological outcomes linked to lack of independence in scientific studies, serving to uphold narratives about who should lead conservation. We explore relationships in the sample studies between conservation initiative types, the extent of Indigenous Peoples' and local communities' influence in governance, and reported social and ecological outcomes. Findings reveal positive ecological and social outcomes are strongly associated with higher levels of influence of Indigenous Peoples and local communities and their institutions, implying equity in conservation practice should be advanced not only for moral reasons, but because it can enhance conservation effectiveness.
ABSTRACT
Given the pathological role of Tau aggregation in Alzheimer's disease (AD), our laboratory previously developed the novel Tau aggregation inhibitor peptide, RI-AG03. As Tau aggregates accumulate intracellularly, it is essential that the peptide can traverse the cell membrane. Here we examine the cellular uptake and intracellular trafficking of RI-AG03, in both a free and liposome-conjugated form. We also characterize the impact of adding the cell-penetrating peptide (CPP) sequences, polyarginine (polyR) or transactivator of transcription (TAT), to RI-AG03. Our data show that liposome conjugation of CPP containing RI-AG03 peptides, with either the polyR or TAT sequence, increased cellular liposome association three-fold. Inhibition of macropinocytosis modestly reduced the uptake of unconjugated and RI-AG03-polyR-linked liposomes, while having no effect on RI-AG03-TAT-conjugated liposome uptake. Further supporting macropinocytosis-mediated internalization, a 'fair' co-localisation of the free and liposome-conjugated RI-AG03-polyR peptide with macropinosomes and lysosomes was observed. Interestingly, we also demonstrate that RI-AG03-polyR detaches from liposomes following cellular uptake, thereby largely evading organellar entrapment. Collectively, our data indicate that direct membrane penetration and macropinocytosis are key routes for the internalization of liposomes conjugated with CPP containing RI-AG03. Our study also demonstrates that peptide-liposomes are suitable nanocarriers for the cellular delivery of RI-AG03, furthering their potential use in targeting Tau pathology in AD.
Subject(s)
Cell-Penetrating Peptides , Liposomes , Nanoparticles , Pinocytosis , tau Proteins , Cell-Penetrating Peptides/chemistry , Cell-Penetrating Peptides/pharmacology , Liposomes/chemistry , Humans , tau Proteins/metabolism , tau Proteins/chemistry , Nanoparticles/chemistry , Pinocytosis/drug effects , Peptides/chemistry , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Lysosomes/metabolism , Drug Delivery Systems/methodsABSTRACT
Wet granulation, a particle size enlargement process, can significantly enhance the critical quality attributes of powders and improve the ability to form tablets in pharmaceutical manufacturing. In this study, a mechanistic-based population balance model is applied to twin screw wet granulation. This model incorporated a recently developed breakage kernel specifically designed for twin screw granulation, along with nucleation, layering, and consolidation. Calibration and validation were performed on Hydrochlorothiazide and Acetaminophen formulations, which exhibit different particle size and wettability characteristics. Utilizing a compartmental experimental dataset, a comprehensive global sensitivity analysis identified critical inputs impacting quality attributes. The study revealed that the nucleation rate process model, effectively represented particle size distributions for both formulations. Adjustments to nucleation and breakage rate parameters, influenced by material properties and screw configuration, improved the model's accuracy. A model-driven workflow was proposed, offering step-by-step guidelines and facilitating PBM model usage, providing essential details for future active pharmaceutical ingredient (API) formulations.
Subject(s)
Acetaminophen , Drug Compounding , Hydrochlorothiazide , Particle Size , Acetaminophen/chemistry , Drug Compounding/methods , Calibration , Hydrochlorothiazide/chemistry , Workflow , Powders , Wettability , Chemistry, Pharmaceutical/methods , Tablets , Models, TheoreticalABSTRACT
Meta-analysis of genome-wide association study data has implicated PDE4B in the pathogenesis of Alzheimer's disease (AD), the leading cause of senile dementia. PDE4B encodes one of four subtypes of cyclic adenosine monophosphate (cAMP)-specific phosphodiesterase-4 (PDE4A-D). To interrogate the involvement of PDE4B in the manifestation of AD-related phenotypes, the effects of a hypomorphic mutation (Pde4bY358C) that decreases PDE4B's cAMP hydrolytic activity were evaluated in the AppNL-G-F knock-in mouse model of AD using the Barnes maze test of spatial memory, 14C-2-deoxyglucose autoradiography, thioflavin-S staining of ß-amyloid (Aß) plaques, and inflammatory marker assay and transcriptomic analysis (RNA sequencing) of cerebral cortical tissue. At 12 months of age, AppNL-G-F mice exhibited spatial memory and brain metabolism deficits, which were prevented by the hypomorphic PDE4B in AppNL-G-F/Pde4bY358C mice, without a decrease in Aß plaque burden. RNA sequencing revealed that, among the 531 transcripts differentially expressed in AppNL-G-F versus wild-type mice, only 13 transcripts from four genes - Ide, Btaf1, Padi2, and C1qb - were differentially expressed in AppNL-G-F/Pde4bY358C versus AppNL-G-F mice, identifying their potential involvement in the protective effect of hypomorphic PDE4B. Our data demonstrate that spatial memory and cerebral glucose metabolism deficits exhibited by 12-month-old AppNL-G-F mice are prevented by targeted inhibition of PDE4B. To our knowledge, this is the first demonstration of a protective effect of PDE4B subtype-specific inhibition in a preclinical model of AD. It thus identifies PDE4B as a key regulator of disease manifestation in the AppNL-G-F model and a promising therapeutic target for AD.
Subject(s)
Alzheimer Disease , Amyloid beta-Protein Precursor , Cyclic Nucleotide Phosphodiesterases, Type 4 , Disease Models, Animal , Gene Knock-In Techniques , Mice, Transgenic , Phosphodiesterase 4 Inhibitors , Animals , Cyclic Nucleotide Phosphodiesterases, Type 4/metabolism , Cyclic Nucleotide Phosphodiesterases, Type 4/genetics , Alzheimer Disease/genetics , Alzheimer Disease/metabolism , Phosphodiesterase 4 Inhibitors/pharmacology , Mice , Amyloid beta-Protein Precursor/genetics , Male , Plaque, Amyloid/pathology , Plaque, Amyloid/metabolism , Spatial Memory/physiology , Mice, Inbred C57BL , Amyloid beta-Peptides/metabolism , Maze Learning/physiologyABSTRACT
This work presents a granule size prediction approach applicable to diverse formulations containing new active pharmaceutical ingredients (APIs) in continuous twin-screw wet granulation. The approach consists of a surrogate selection method to identify similar materials with new APIs and a T-shaped partial least squares (T-PLS) model for granule size prediction across varying formulations and process conditions. We devised a surrogate material selection method, employing a combination of linear pre-processing and nonlinear classification algorithms, which effectively identified suitable surrogates for new materials. Using only material properties obtained through four characterization methods, our approach demonstrated its predictive prowess. The selected surrogate methods were seamlessly integrated with our developed T-PLS model, which was meticulously validated for high-dose formulations involving three new APIs. When surrogating new APIs based on Gaussian process classification, we achieved the lowest prediction errors, signifying the method's robustness. The predicted d-values were within the range of uncertainty bounds for all cases, except for d90 of API C. Notably, the approach offers a direct and efficient solution for early-phase formulation and process development, considerably reducing the need for extensive experimental work. By relying on just four material characterization methods, it streamlines the research process while maintaining a high degree of accuracy.
Subject(s)
Bone Screws , Technology, Pharmaceutical , Least-Squares Analysis , Particle Size , Pharmaceutical Preparations , Drug Compounding , TabletsABSTRACT
Autism spectrum disorders are more common in males, and have a substantial genetic component. Chromosomal 16p11.2 deletions in particular carry strong genetic risk for autism, yet their neurobiological impact is poorly characterised, particularly at the integrated systems level. Here we show that mice reproducing this deletion (16p11.2 DEL mice) have reduced GABAergic interneuron gene expression (decreased parvalbumin mRNA in orbitofrontal cortex, and male-specific decreases in Gad67 mRNA in parietal and insular cortex and medial septum). Metabolic activity was increased in medial septum, and in its efferent targets: mammillary body and (males only) subiculum. Functional connectivity was altered between orbitofrontal, insular and auditory cortex, and between septum and hippocampus/subiculum. Consistent with this circuit dysfunction, 16p11.2 DEL mice showed reduced prepulse inhibition, but enhanced performance in the continuous performance test of attentional ability. Level 1 autistic individuals show similarly heightened performance in the equivalent human test, also associated with parietal, insular-orbitofrontal and septo-subicular dysfunction. The data implicate cortical and septal GABAergic dysfunction, and resulting connectivity changes, as the cause of pre-attentional and attentional changes in autism.
Subject(s)
Auditory Cortex , Autism Spectrum Disorder , Humans , Animals , Male , Mice , Chromosome Structures , Chromosome Deletion , Autism Spectrum Disorder/genetics , RNA, MessengerABSTRACT
We argue that solutions-based research must avoid treating climate change as a merely technical problem, recognizing instead that it is symptomatic of the history of European and North American colonialism. It must therefore be addressed by decolonizing the research process and transforming relations between scientific expertise and the knowledge systems of Indigenous Peoples and of local communities. Partnership across diverse knowledge systems can be a path to transformative change only if those systems are respected in their entirety, as indivisible cultural wholes of knowledge, practices, values, and worldviews. This argument grounds our specific recommendations for governance at the local, national, and international scales. As concrete mechanisms to guide collaboration across knowledge systems, we propose a set of instruments based on the principles of consent, intellectual and cultural autonomy, and justice. We recommend these instruments as tools to ensure that collaborations across knowledge systems embody just partnerships in support of a decolonial transformation of relations between human communities and between humanity and the more-than-human world.
Subject(s)
Colonialism , Knowledge , Humans , Climate Change , Indigenous PeoplesABSTRACT
The solvent-mediated crystal morphologies of the α and ß polymorphic forms of l-glutamic acid are presented. This work applies a digital mechanistically based workflow that encompasses calculation of the crystal lattice energy and its constituent intermolecular synthons, their interaction energies, and their key role in understanding and predicting crystal morphology as well as assessing the surface chemistry, topology, and solvent binding on crystal habit growth surfaces. Through a comparison between the contrasting morphologies of the conformational polymorphs of l-glutamic acid, this approach highlights how the interfacial chemistry of organic crystalline materials and their inherent anisotropic interactions with their solvation environments direct their crystal habit with potential impact on their further downstream processing behavior.
ABSTRACT
2p16.3 deletion, involving NEUREXIN1 (NRXN1) heterozygous deletion, substantially increases the risk of developing autism and other neurodevelopmental disorders. We have a poor understanding of how NRXN1 heterozygosity impacts on brain function and cognition to increase the risk of developing the disorder. Here we characterize the impact of Nrxn1α heterozygosity on cerebral metabolism, in mice, using 14 C-2-deoxyglucose imaging. We also assess performance in an olfactory-based discrimination and reversal learning (OB-DaRL) task and locomotor activity. We use decision tree classifiers to test the predictive relationship between cerebral metabolism and Nrxn1α genotype. Our data show that Nrxn1α heterozygosity induces prefrontal cortex (medial prelimbic cortex, mPrL) hypometabolism and a contrasting dorsal raphé nucleus (DRN) hypermetabolism. Metabolism in these regions allows for the predictive classification of Nrxn1α genotype. Consistent with reduced mPrL glucose utilization, prefrontal cortex insulin receptor signaling is decreased in Nrxn1α+/- mice. Behaviorally, Nrxn1α+/- mice show enhanced learning of a novel discrimination, impaired reversal learning and an increased latency to make correct choices. In addition, male Nrxn1α+/- mice show hyperlocomotor activity. Correlative analysis suggests that mPrL hypometabolism contributes to the enhanced novel odor discrimination seen in Nrxn1α+/- mice, while DRN hypermetabolism contributes to their increased latency in making correct choices. The data show that Nrxn1α heterozygosity impacts on prefrontal cortex and serotonin system function, which contribute to the cognitive alterations seen in these animals. The data suggest that Nrxn1α+/- mice provide a translational model for the cognitive and behavioral alterations seen in autism and other neurodevelopmental disorders associated with 2p16.3 deletion. LAY SUMMARY: Deletion of the chromosomal region 2p16.3, involving reduced NEUREXIN1 gene expression, dramatically increases the risk of developing autism. Here, we show that reduced Neurexin1α expression, in mice, impacts on the prefrontal cortex and impairs cognitive flexibility. The data suggest that 2p16.3 deletion increases the risk of developing autism by impacting on the prefrontal cortex. Mice with the deletion are a useful model for testing new drugs to treat the cognitive flexibility problems experienced by people with autism.
Subject(s)
Autism Spectrum Disorder , Autistic Disorder , Animals , Autism Spectrum Disorder/genetics , Disease Models, Animal , Dorsal Raphe Nucleus , Genotype , Humans , Male , Mice , Prefrontal Cortex/diagnostic imaging , Reversal LearningABSTRACT
BACKGROUND: The Alzheimer's disease (AD)-associated amyloid-beta protein precursor (AßPP) can be cleaved by ß-site AßPP cleaving enzyme 1 (BACE1) and the γ-secretase complex to yield neurotoxic amyloid-ß (Aß) peptides. However, AßPP can also be cleaved in a 'non-amyloidogenic' manner either by α-secretase to produce soluble AßPP alpha (sAßPPα) (a fragment with neuroprotective/neurogenic functions) or through alternative BACE1-mediated 'beta prime' activity yielding soluble AßPP beta prime (sAßPPß'). OBJECTIVE: To determine whether sAßPPα depletion, as opposed to Aß peptide accumulation, contributes to cytotoxicity in AD-relevant SH-SY5Y neuroblastoma cell models. METHODS: AßPP proteolysis was characterized by immunoblotting in mock-, wild-type AßPP (wtAßPP)-, BACE1-, and Swedish mutant AßPP (SweAßPP)-transfected cells. AßPP beta prime cleavage was confirmed through secretase inhibitor studies and C-terminal fragment analysis. The roles of sAßPPα and sAßPPß' in cell viability were confirmed by overexpression studies. RESULTS: Despite producing enhanced Aß peptide levels, wtAßPP- and SweAßPP-transfected cells did not exhibit reduced viability whereas BACE1-transfected cells did. sAßPPα generation in SH-SY5Y-BACE1 cells was virtually ablated in lieu of BACE1-mediated sAßPPß' production. sAßPPα overexpression in SH-SY5Y-BACE1 cells restored viability whereas sAßPPß' overexpression decreased viability further. The anti-AßPP 6E10 antibody was shown to cross-react with sAßPPß'. CONCLUSION: sAßPPα depletion and/or sAßPPß' accumulation, but not elevated Aß peptide levels, represent the cytotoxic mechanism following BACE1 overexpression in SH-SY5Y cells. These data support the novel concept that competitive sAßPPα depletion by BACE1 beta prime activity might contribute to AD. The cross-reactivity of 6E10 with AßPPß'also questions whether previous studies assessing sAßPPα as a biomarker using this antibody should be revisited.
Subject(s)
Alzheimer Disease , Amyloid Precursor Protein Secretases , Amyloid beta-Peptides , Alzheimer Disease/metabolism , Amyloid Precursor Protein Secretases/metabolism , Amyloid beta-Peptides/metabolism , Amyloid beta-Protein Precursor/metabolism , Aspartic Acid Endopeptidases/metabolism , Cell Survival , HumansABSTRACT
Attempts to link human development and biodiversity conservation goals remain a constant feature of policy and practice related to protected areas (PAs). Underlying these approaches are narratives that simplify assumptions, shaping how interventions are designed and implemented. We examine evidence for five key narratives: 1) conservation is pro-poor; 2) poverty reduction benefits conservation; 3) compensation neutralises costs of conservation; 4) local participation is good for conservation; 5) secure tenure rights for local communities support effective conservation. Through a mixed-method synthesis combining a review of 100 peer-reviewed papers and 25 expert interviews, we examined if and how each narrative is supported or countered by the evidence. The first three narratives are particularly problematic. PAs can reduce material poverty, but exclusion brings substantial local costs to wellbeing, often felt by the poorest. Poverty reduction will not inevitably deliver on conservation goals and trade-offs are common. Compensation (for damage due to human wildlife conflict, or for opportunity costs), is rarely sufficient or commensurate with costs to wellbeing and experienced injustices. There is more support for narratives 4 and 5 on participation and secure tenure rights, highlighting the importance of redistributing power towards Indigenous Peoples and Local Communities in successful conservation. In light of the proposed expansion of PAs under the post-2020 Global Biodiversity Framework, we outline implications of our review for the enhancement and implementation of global targets in order to proactively integrate social equity into conservation and the accountability of conservation actors.
ABSTRACT
BACKGROUND: Cognitive deficits profoundly impact on the quality of life of patients with schizophrenia. Alterations in brain derived neurotrophic factor (BDNF) signalling, which regulates synaptic function through the activation of full-length tropomyosin-related kinase B receptors (TrkB-FL), are implicated in the aetiology of schizophrenia, as is N-methyl-D-aspartate receptor (NMDA-R) hypofunction. However, whether NMDA-R hypofunction contributes to the disrupted BDNF signalling seen in patients remains unknown. AIMS: The purpose of this study was to characterise BDNF signalling and function in a preclinical rodent model relevant to schizophrenia induced by prolonged NMDA-R hypofunction. METHODS: Using the subchronic phencyclidine (PCP) model, we performed electrophysiology approaches, molecular characterisation and behavioural analysis. RESULTS: The data showed that prolonged NMDA-R antagonism, induced by subchronic PCP treatment, impairs long-term potentiation (LTP) and the facilitatory effect of BDNF upon LTP in the medial prefrontal cortex (PFC) of adult mice. Additionally, TrkB-FL receptor expression is decreased in the PFC of these animals. By contrast, these changes were not present in the hippocampus of PCP-treated mice. Moreover, BDNF levels were not altered in the hippocampus or PFC of PCP-treated mice. Interestingly, these observations are paralleled by impaired performance in PFC-dependent cognitive tests in mice treated with PCP. CONCLUSIONS: Overall, these data suggest that NMDA-R hypofunction induces dysfunctional BDNF signalling in the PFC, but not in the hippocampus, which may contribute to the PFC-dependent cognitive deficits seen in the subchronic PCP model. Additionally, these data suggest that targeting BDNF signalling may be a mechanism to improve PFC-dependent cognitive dysfunction in schizophrenia.
Subject(s)
Brain-Derived Neurotrophic Factor/metabolism , Cognition Disorders/physiopathology , Receptors, N-Methyl-D-Aspartate/metabolism , Schizophrenia/physiopathology , Animals , Cognition/physiology , Disease Models, Animal , Hippocampus/pathology , Male , Mice , Mice, Inbred C57BL , Neuropsychological Tests , Phencyclidine , Prefrontal Cortex/pathology , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Signal Transduction/physiologyABSTRACT
Alzheimer's disease (AD) is the leading form of dementia but lacks curative treatments. Current understanding of AD aetiology attributes the development of the disease to the misfolding of two proteins; amyloid-ß (Aß) and hyperphosphorylated tau, with their pathological accumulation leading to concomitant oxidative stress, neuroinflammation, and neuronal death. These processes are regulated at multiple levels to maintain homeostasis and avert disease. However, many of the relevant regulatory proteins appear to be downregulated in the AD-afflicted brain. Enhancement/restoration of these 'protective' proteins, therefore, represents an attractive therapeutic avenue. Gene therapy is a desirable means of achieving this because it is not associated with the side-effects linked to systemic protein administration, and sustained protein expression virtually eliminates compliance issues. The current article represents a focused and succinct review of the better established 'protective' protein targets for gene therapy enhancement/restoration rather than being designed as an exhaustive review incorporating less validated protein subjects. In addition, we will discuss how the risks associated with uncontrolled or irreversible gene expression might be mitigated through combining neuronal-specific promoters, inducible expression systems and localised injections. Whilst many of the gene therapy targets reviewed herein are yet to enter clinical trials, preclinical testing has thus far demonstrated encouraging potential for the gene therapy-based treatment of AD.
Subject(s)
Alzheimer Disease/therapy , Genetic Therapy , Neurons/metabolism , Protein Processing, Post-Translational/physiology , Alzheimer Disease/metabolism , Genetic Therapy/methods , Humans , Neuroinflammatory Diseases/genetics , Neuroinflammatory Diseases/therapy , Oxidative StressABSTRACT
The attrition of drug particles during the process of dry granulation, which may (or may not) be incorporated into granules, could be an important factor in determining the subsequent performance of that granulation, including key factors such as sticking to punches and bio-performance of the dosage form. It has previously been demonstrated that such attrition occurs in one common dry granulation process train; however, the fate of these comminuted particles in granules was not determined. An understanding of the phenomena of attrition and incorporation into granule will improve our ability to understand the performance of granulated systems, ultimately leading to an improvement in our ability to optimize and model the process. Unique feeding mechanisms, geometry, and milling systems of roller compaction equipment mean that attrition could be more or less substantial for any given equipment train. In this work, we examined attrition of API particles and their incorporation into granule in an equipment train from Gerteis, a commonly used equipment train for dry granulation. The results demonstrate that comminuted drug particles can exist free in post-milling blends of roller compaction equipment trains. This information can help better understand the performance of the granulations, and be incorporated into mechanistic models to optimize such processes.
Subject(s)
Drug Compounding/methods , Technology, Pharmaceutical/methods , Particle Size , Powders , TabletsABSTRACT
There are no current treatments for autism, despite its high prevalence. Deletions of chromosome 16p11.2 dramatically increase risk for autism, suggesting that mice with an equivalent genetic rearrangement may offer a valuable model for the testing of novel classes of therapeutic drug. 16p11.2 deletion (16p11.2 DEL) mice and wild-type controls were assessed using an ethological approach, with 24 h monitoring of activity and social interaction of groups of mice in a home-cage environment. The ability of the excitation/inhibition modulator N-acetyl cysteine (NAC) and the 5-HT1B/1D/1F receptor agonist eletriptan to normalise the behavioural deficits observed was tested. 16p11.2 DEL mice exhibited largely normal behaviours, but, following the stress of an injection, showed hyperlocomotion, reduced sociability, and a strong anxiolytic phenotype. The hyperactivity and reduced sociability, but not the suppressed anxiety, were effectively attenuated by both NAC and eletriptan. The data suggest that 16p11.2 DEL mice show an autism-relevant phenotype that becomes overt after an acute stressor, emphasising the importance of gene-environmental interactions in phenotypic analysis. Further, they add to an emerging view that NAC, or 5-HT1B/1D/1F receptor agonist treatment, may be a promising strategy for further investigation as a future treatment.
Subject(s)
Autistic Disorder/drug therapy , Autistic Disorder/genetics , Chromosome Deletion , Chromosomes, Mammalian/genetics , Gene-Environment Interaction , Acetylcysteine/pharmacology , Acetylcysteine/therapeutic use , Animals , Anxiety/genetics , Autistic Disorder/physiopathology , Disease Models, Animal , Humans , Male , Mice, Inbred C57BL , Motor Activity , Phenotype , Social Behavior , Social InteractionABSTRACT
Chromosome 16p11.2 duplications dramatically increase risk for schizophrenia, but the mechanisms remain largely unknown. Here, we show that mice with an equivalent genetic mutation (16p11.2 duplication mice) exhibit impaired hippocampal-orbitofrontal and hippocampal-amygdala functional connectivity. Expression of schizophrenia-relevant GABAergic cell markers (parvalbumin and calbindin) is selectively decreased in orbitofrontal cortex, while somatostatin expression is decreased in lateral amygdala. When 16p11.2 duplication mice are tested in cognitive tasks dependent on hippocampal-orbitofrontal connectivity, performance is impaired in an 8-arm maze "N-back" working memory task and in a touchscreen continuous performance task. Consistent with hippocampal-amygdala dysconnectivity, deficits in ethologically relevant social behaviors are also observed. Overall, the cellular/molecular, brain network, and behavioral alterations markedly mirror those observed in schizophrenia patients. Moreover, the data suggest that 16p11.2 duplications selectively impact hippocampal-amygdaloid-orbitofrontal circuitry, supporting emerging ideas that dysfunction in this network is a core element of schizophrenia and defining a neural circuit endophenotype for the disease.
Subject(s)
Amygdala/physiopathology , Autistic Disorder/genetics , Chromosome Disorders/genetics , Endophenotypes/metabolism , Hippocampus/physiopathology , Intellectual Disability/genetics , Prefrontal Cortex/physiopathology , Schizophrenia/genetics , Animals , Chromosome Deletion , Chromosomes, Human, Pair 16/genetics , Female , Humans , Male , MiceABSTRACT
Punch sticking during tablet manufacturing is a common problem facing the pharmaceutical industry. Using several model compounds, effects of crystal size and shape of active pharmaceutical ingredients (API) on punch sticking propensity were systematically investigated in this work to provide molecular insights into the punch-sticking phenomenon. In contrast to the common belief that smaller API particles aggravate punch sticking, results show that particle size reduction can either reduce or enhance API punch sticking, depending on the complex interplay among the particle surface area, plasticity, cohesive strength, and specific surface functional groups. Therefore, other factors, such as crystal mechanical properties, surface chemistry of crystal facets exposed to the punch face, and choice of excipients in a formulation, should be considered for a more reliable prediction of the initiation and progression of punch sticking. The exposure of strong electronegative groups to the punch face facilitates the onset of sticking, while higher plasticity and cohesive strength aggravate sticking.
Subject(s)
Pharmaceutical Preparations/chemistry , Powders/chemistry , Tablets/chemistry , Adhesiveness , Chemistry, Pharmaceutical/methods , Excipients/chemistry , Particle Size , Pressure , Surface PropertiesABSTRACT
Mitogen-activated protein kinases (MAPKs) regulate normal brain functioning, and their dysfunction is implicated in a number of brain disorders. Thus, there is great interest in understanding the signalling systems that control MAPK functioning. One family of proteins that contribute to this process, the mitogen-activated protein kinase phosphatases (MKPs), directly inactivate MAPKs through dephosphorylation. Recent studies have identified novel functions of MKPs in foetal development, the immune system, cancer and synaptic plasticity and memory. In the present study, we performed an unbiased investigation using MKP-2-/- mice to assess whether MKP-2 plays a global role in modulating brain function. Local cerebral glucose utilization is significantly increased in the ventral tegmental area (VTA) of MKP-2-/- mice, with connectivity analysis revealing alterations in VTA functional connectivity, including a significant reduction in connectivity to the nucleus accumbens and hippocampus. In addition, spontaneous excitatory postsynaptic current frequency, but not amplitude, onto putative dopamine neurons in the VTA is increased in MKP-2-/- mice, which indicates that increased excitatory drive may account for the increased VTA glucose utilization. Consistent with modified VTA function and connectivity, in behavioural tests MKP-2-/- mice exhibited increased sucrose preference and impaired amphetamine-induced hyperlocomotion. Overall, these data reveal that MKP-2 plays a role in modulating VTA function and that its dysfunction may contribute to brain disorders in which altered reward processing is present.