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1 H, 13 C and 15 N resonance assignments for human all-Ala α-lactalbumin in its molten globule and urea-denatured states
Get PDFMolten globules are compact, partially-folded proteins postulated to be general intermediates in protein folding. Human α-lactalbumin (α-LA) is a Ca2+-binding, four-disulphide protein whose native structure is divided into two lobes, one is largely helical, the α-domain, and the other has a significant β-sheet content, the β-domain. α-LA forms a “classical” molten globule at low pH which has been studied widely as a model system of a partially-folded protein. The α-LA molten globule is compact and has a native-like helical secondary structure content. All-Ala α-LA, which has all eight native cysteines mutated to alanine, also adopts a partially-folded molten globule conformation and gives a high-quality 1H-15N HSQC spectrum at pH 2 and 40 °C. The lack of cysteine residues makes all-Ala α-LA a suitable template for spin-labelling studies. In this report we present 1H, 13C and 15N assignments for human all-Ala α-LA in its molten globule and 8 M urea-denatured states. Analysis of the chemical shift data for the molten globule state shows they are consistent with high populations of conformations in the α region of φ,ψ space for residues in the α domain of the protein. In contrast, the data for the urea-denatured state are closely similar to those expected for a random coil
Therapeutic Hypothermia Alleviates Hydrocephalus and Neurological Dysfunction Post Intraventricular Hemorrhage by Enhancing Drainage of Glymphatic‐Meningeal Lymphatic‐Deep Cervical Lymphatic System
Get PDFAims: Intraventricular hemorrhage (IVH) has a high mortality and disability rate and poses significant clinical challenges, which often leads to hydrocephalus and neurological dysfunction. Emerging evidence implicates dysfunction of the glymphatic‐meningeal lymphatic‐deep cervical lymphatic system in the pathogenesis of post‐IVH hydrocephalus. Therapeutic hypothermia (TH) holds promise for mitigating these sequelae. This study investigates the potential of TH to ameliorate IVH‐induced hydrocephalus and neurological dysfunction, while elucidating its underlying mechanisms. Methods: Rat models of IVH are established by intraventricular injection of autologous blood. TH, deep cervical lymph nodes (dCLNs) ligation, and intraperitoneal injection of AMPK inhibitor are used to intervene. Results: In rat models of IVH, TH alleviates neurological dysfunction and attenuates hydrocephalus and pathology damage. TH protects physiological function and maintains normal structure of the glymphatic system. TH improves function and structure of the meningeal lymphatic system and promotes drainage of the deep cervical lymphatic system. TH upregulates RTN3, facilitates phosphorylation of AMPK, and suppresses ERS. All the above effects are reversed by ligation of dCLNs and AMPK inhibitor. Conclusion: TH alleviates hydrocephalus and neurological dysfunction post IVH by enhancing drainage of the glymphatic‐meningeal lymphatic‐deep cervical lymphatic system. The RTN3/AMPK/ERS pathway may be the proposed mechanism mediating this effect. TH is expected to become a novel therapeutic strategy for IVH
Exchangeable arrays and integrable systems for characteristic polynomials of random matrices
Get PDFThe joint moments of the derivatives of the characteristic polynomial of a random unitary matrix, and also a variant of the characteristic polynomial that is real on the unit circle, in the large matrix size limit, have been studied intensively in the past twenty five years, partly in relation to conjectural connections to the Riemann zeta-function and Hardy’s function. We completely settle the most general version of the problem of convergence of these joint moments, after they are suitably rescaled, for an arbitrary number of derivatives and with arbitrary positive real exponents. Our approach relies on a hidden, higher-order exchangeable structure, that of an exchangeable array, which, as far as we know, had never been used before in the study of characteristic polynomials of random matrices. We then develop a systematic method, based on a class of Hankel determinants shifted by partitions, that allows us for the first time to give an exact representation of all these joint moments, for finite matrix size, in terms of derivatives of σ- Painleve V transcendents. As an application, we can also represent all the joint moments of power sum linear statistics of a certain determinantal point process behind this problem in terms of derivatives of σ-Painleve III’ transcendents. This gives an efficient way to compute all these quantities explicitly. Our methods can be used to obtain analogous results for a number of other models sharing the same features
Modal syntactic predicates and their semantics: an analysis of semantic paradoxes by means of well- and ill-foundedness
Get PDFIn contemporary philosophical discourse modality plays a central theoretical role. One approach to formalising modalities is what this thesis calls the mention predicate approach, where a modality is formalised as a first-order predicate that predicates on names of sentences / formulae, or names of propositions. There is a relative lack of philosophical interest in the mention predicate approach because it is prone to paradox, most notably Montague’s Paradox. This thesis argues why this is unwarranted; and critically assesses and contributes to topics relating to the mention predicate approach. Chapter 3 of this thesis critically assesses how Stern 2014c; Stern 2015 resolves the paradoxes of the mention predicate approach. Chapter 4 of this thesis contributes to the categorisation of the paradoxes that the mention predicate approach is prone to. Moreover, this chapter contributes to the understanding of the extent and limitations of the semantics of the mention predicate approach. In particular, chapter 4 provides a limitative result which functions as a categorisation theorem indicating when paradox arises. Chapter 5 of this thesis provides an example of a modality in the philosophical literature that is most appropriately formalised using the mention predicate approach. In particular, chapter 5 critically assesses the account of modal potentialism in the philosophy of mathematics developed by Linnebo 2018. In doing so, chapter 5 shows that, as it stands, Linnebo 2018 provides an account of modal potentialism that is incoherent
Incidence of first and subsequent fractures in multiple myeloma patients: a parallel cohort study using UK CPRD dataset
Get PDFPurpose: Whilst multiple myeloma (MM) is known to increase fracture risk, the incidence of subsequent fractures is poorly described. Here, we describe the incidence of index and subsequent fractures in a real-world cohort of MM patients, compared to non-MM controls.Methods: Using the UK Clinical Practice Research Datalink GOLD, we identified a MM cohort with age-, sex-, and GP-practice-matched controls from 1995-2017. The primary outcome was the incidence of fracture at major osteoporotic sites (i.e. hip, vertebral, wrist or humerus) within two years before and after MM diagnosis. The cumulative incidence of subsequent fractures up to two years post-index fracture was estimated using Cox proportional hazards models.Results: 1,974 patients (59.6% male, median age 70 years) with MM were matched to 6,429 non-MM controls. The index fracture rate was significantly greater in the MM cohort compared to non-MM cohort from one year prior to MM diagnosis onwards. Post-index fracture, the overall 2-year subsequent major fracture rate was 16.4% (95% CI:11.1-21.5) and 12.0% (95% CI:7.50-16.30) in the MM and non-MM cohorts, respectively. Within two years post-index fracture, the risk of subsequent vertebral fracture was significantly greater in MM patients (aHR: 11.6 (95% CI:1.47-91.8), p=0.02)).Conclusions: MM patients are at higher risk of having an index fracture from one year pre-diagnosis and a subsequent vertebral fractures in the two years post-index fracture, compared to non-MM controls. These findings highlight the potential for earlier MM diagnosis in adults presenting with a major fracture, and the need to reduce subsequent fracture risk
The Conceptualization, Experience, and Recognition of Emotion in Autism: Differences in the Psychological Mechanisms Involved in Autistic and Non‐Autistic Emotion Recognition
Get PDFSummary: This study investigated how autistic and non‐autistic adults experience and understand emotions, and how these abilities relate to recognizing emotions in others. We found that autistic and non‐autistic adults did not differ in (1) how consistently they experienced emotions, (2) their understanding of emotion terms, and (3) their ability to distinguish between different emotional experiences or emotion terms. For non‐autistic individuals, recognizing emotions was linked to how well they could tell apart emotion terms and their own feelings. For autistic individuals, a clear understanding of emotion terms was associated with better emotion recognition. These insights could support the development of tools to enhance emotion recognition for both groups
Core components of teaching at the right level
Get PDFThis working paper synthesises evidence and implementer insights to distil the core components of Teaching at the Right Level (TaRL), an evidence-backed foundational literacy and numeracy approach used in South Asia and Sub-Saharan Africa. By combining impact evaluations, related academic evidence (cognitive science, educational psychology), and interviews with implementers, the authors identify nine critical elements across classroom instruction, pedagogical support, and system-level authorising environments that are essential for effective design, adaptation, and large-scale implementation of TaRL programmes
Expanding the life framework of values
Get PDFConceptualising and organising the range of value orientations and worldviews underpinning human–nature relationships is useful for understanding different, and sometimes conflicting, perspectives on how nature should be managed and working towards just and equitable policies. We test the applicability and current scope of the Life Framework of Values (living from‐, living in‐, living with‐ and living as‐nature) by aligning it with pre‐existing literature, drawn heavily from the context of wildlife management and conservation, but with wider relevance. Pre‐existing value categorisations align with the Life Framework of Values in accounting for instrumental, relational and intrinsic values of nature. However, the framework does not account for the multiple ways in which people may be considered as living against‐, living separated from‐ and living disconnected from‐/living indifferently to‐nature. By first considering these additional worldviews, we then propose the introduction of a complimentary overarching living apart from nature value frame. We identify three pathways by which people may fall within the living apart from nature frame: (1) loving nature so deeply that you choose to separate yourself from it (living separated from nature), (2) disregarding nature to the extent that you are willing to destroy it (living against nature) and (3) becoming indifferent or disconnected, a state that can emerge from modern urban lifestyles (living disconnected from‐/living indifferently to‐nature). Synthesis and applications. Including the living apart from nature frame to the Life Framework of Values allows for a more realistic and complete view of the diversity of human–nature interactions thus helping it contribute to addressing the global biodiversity crisis and transforming societies towards more sustainable pathways. Future research should focus on empirically testing the extent to which people fit discretely and consistently into Life Frames or worldviews as opposed to simultaneously holding diverse positions on different specific issues. Read the free Plain Language Summary for this article on the Journal blo
What it means to be a zero: the meaning of legal status, restrictions and freedom among stateless people in northern Thailand
No full textThis research explores the everyday lived experiences of de jure statelessness in northern Thailand. The region is home to approximately 200,000 registered stateless people—including ethnically non-Thai groups in the borderlands, undocumented migrants, and their children. Despite ties to Thailand—by birth, long-term residence, documentation, and even ancestry—they remain without Thai citizenship for varied reasons, such as ethnicized politics of identity amid changing geopolitics and complex regulations and bureaucracy. Due to their lack of citizen status, stateless people face restricted access to domestic and international mobility, education and occupation, political participation, as well as stigma and discrimination. Central to this research is its analytical standpoint to look beyond the state in debates on statelessness by: 1) acknowledging that the state, as a series of contradictory and complementary actors and practices, is ever-present in the everyday lives of stateless people; 2) yet, attending to what other factors condition stateless people’s access to rights, opportunities, and citizenship; 3) unpacking the normative presumptions about citizenship and the state; 4) destabilizing the presumed dichotomy between statelessness and citizenship. For this approach, this dissertation proposes a novel analytical framework consisting of three concepts: liminality, precarity, and intersectionality. Drawing on this framework, this research shows that statelessness is one form of legal non-citizenship which can be shaped and navigated by individuals’ differentiated negotiations of their inclusion, exclusion, and belonging across multiple times, spaces, and scales and along intersecting identities. I engage in three discussions which correspond to my empirical chapters. The first chapter demonstrates that stateless people attribute different meanings to legal citizenship, as their lives are shaped not only by state regulations but also by everyday flows of power, such as social relations and gendered ethnic norms. The second chapter illustrates that stateless people’s experiences of applying for Thai citizenship are governed not only by the state-mandated regulations but also by imaginations and speculations, as well as multiple standards of (il)legality and (il)legitimacy. The final empirical chapter demonstrates that stateless people’s individual and collective exercise of agency, although seemingly fragmented and obscure in the potential to incur structural change, is politically profound. Based on the discussions, this research puts forward two interrelated arguments. First, it argues that statelessness must be understood as a status and experience shaped from multiple directions and across scales, and not by lack of legal citizenship alone. Second, it argues that future efforts to address statelessness can benefit by re-orienting the aim to mitigate specific vulnerabilities experienced by stateless people and by taking into account the significance of actors and practices which are often presumed to be apolitical—instead of narrowly focusing on citizenship conferral. This research is built upon a 10-month ethnographic fieldwork in the provinces of Chiang Mai and Chiang Rai in northern Thailand