Literatura científica selecionada sobre o tema "Fic everett"

Background:The pathogenic role of B-cells in primary Sjögren’s Syndrome (pSS) is well established and B cell abnormalities. Because of the substantial role of B-cells, rituximab (RTX), a chimeric anti-CD20 monoclonal antibody, has been considered as a potential biologic disease modifying drug to reduce disease activity in pSS. To date, the TRial for Anti-B-Cell Therapy In patients with pSS (TRACTISS) is the largest multi-centre, placebo-controlled trial with RTX. Despite the unmet primary endpoints (30% reduction in fatigue or oral dryness, measured by visual analogue scale), RTX treated patients showed an improvement in unstimulated whole salivary flow (Bowman et al. Arthritis Rheumatol 2017;69:1440–1450).Objectives:To provide the first longitudinal transcriptomic and histological analysis at 3 time points over 48 weeks of labial SGs of pSS patients treated with RTX, in comparison to placebo, from the TRACTISS cohort.Methods:26 pSS patients randomised to RTX or placebo arm consented for labial SG biopsies at baseline, weeks 16 and 48. Patients received two 1000mg cycles of RTX or placebo at baseline and week 24. SG focus score, inflammatory aggregate area fraction, B-cells (CD20+), T-cells (CD3+), follicular dendritic cells (FDCs) (CD21+) and plasma cells (CD138+) density were assessed by H&E and immunofluorescence staining. The histological analysis was performed by digital imaging using QuPath software. RNA was extracted from matched labial SG lobules and sequenced with Illumina platform. A Principal Component Analysis (PCA) and features driving the PCA were investigated along with the most influential gene loadings. The limma-voom R pipeline was used to extract Differential Expressed Genes (DEGs) between placebo and RTX group at week 48, and gene ontology (GO) enrichment analysis performed through EnrichR to derive GO terms and pathways associated with DEGs.Results:Placebo-treated labial SGs showed a worsening of inflammation highlighted by the increment of B-cell density, development of new FDC networks, and a higher ectopic GC prevalence at week 48, compared to RTX-treated patients. No difference in total T-cells and plasma cell infiltration was observed. RTX downregulated genes involved in immune cell recruitment and inflammatory aggregate organisation (e.g. CCR7, CCL19, CD52, and PDCD1) and gene signature-based analysis of 64 immune cell types highlighted how RTX preferentially blocked class-switched- and memory-B-cells infiltration in SGs at week 48. Pathway analyses confirmed the downregulation of leukocyte migration, MHC class II antigen presentation, and T-cell co-stimulation immunological pathways, such as the CD40 receptor complex pathway. The analysis of placebo SGs transcriptomic at week 48 showed a higher expression of genes linked to ectopic GC organisation, such as CXCL13, CCL19, LTβ, in female compared to male subjects. Gender was confirmed as a key co-variate responsible for most of the variation in the PCA, together with the SG focus score and the foci area fraction.Conclusion:Treatment with RTX showed beneficial effects on labial SG inflammatory infiltration in pSS, by downregulating genes involved in immune cell recruitment, activation and organisation in ectopic GCs. Class-switched-B-cells, memory-B-cells and FDC network development were primarily affected appearing to be responsible for the lack of progression in SG B cell infiltration in the RTX compared to the placebo arm in which clear worsening of SG immunopathology over 48 weeks was detected in female patients. Although a clear association with the clinical improvement in unstimulated salivary flow observed at week 48 in RTX-treated patients could not be established given the low number of patients consenting to 3 longitudinal biopsies it is conceivable that RTX is responsible for preserving exocrine function.Acknowledgements:SJB receives a salary contribution from the NIHR Birmingham Biomedical Research Centre.Disclosure of Interests:Elena Pontarini: None declared, Farzana Chowdhury: None declared, Elisabetta Sciacca: None declared, Sofia Grigoriadou: None declared, Felice Rivellese: None declared, Davide Lucchesi: None declared, Katriona Goldmann: None declared, Liliane Fossati-Jimack: None declared, Paul Emery: None declared, Wan Fai Ng: None declared, Nurhan Sutcliffe: None declared, Colin Everett: None declared, Catherine Fernandez: None declared, Anwar Tappuni: None declared, Myles Lewis: None declared, Costantino Pitzalis: None declared, Simon J. Bowman Consultant of: SJB In 2020 I have received consultancy fees from Novartis, Abbvie and Galapagos., Michele Bombardieri: None declared

Objective: To study fixed-dose combinations (FDC) of antibacterial and antiprotozoal products (ofloxacin and azoles), prescribed for the treatment of diarrhea. Methods: Rationality of these FDC products was verified by assessing parameters such as drug content and release by assay and dissolution tests, respectively mentioned in the Indian Pharmacopoeia (IP). Amount of drug solubilized and permeated as per the Biopharmaceutics Classification System (BCS) was determined. Ex vivo permeation study was performed on the gut of goat using the everted gut sac technique. Antimicrobial efficacy in terms of minimum inhibitory concentration (MIC) was assessed using agar well diffusion method against Shigella boydii, the causative agent for diarrhea. Comparative studies were performed on an individual as well as combination doses of antibacterial and antiprotozoal products for the synergistic effects to assess the rationale of these FDC. Results: The BCS solubility of ciprofloxacin (CPX), norfloxacin (NFX) and tinidazole (TNZ) was high in acidic medium (pH 1-5) and decreased at pH above 5. The assay studies showed that the individual drug contents of FDC were within the IP limits. In vitro dissolution results for both, individual drugs and their combination illustrated 99 % drug release within 30 min in 0.01N HCl. Ex vivo permeation of TNZ was higher than CPX and NFX in individual drugs. No significant change in the permeation rate was observed for individual drugs and their FDC. CPX and NFX exhibited more antimicrobial activity in terms of inhibitory zones than their FDC with antiprotozoal TNZ, above 2.5 µg/ml MIC. The pharmaceutical, biopharmaceutical and antimicrobial evaluation study showed the similarity of FDC with the individual drugs. Conclusion: The study showed no significant data to justify the therapeutic advantage of FDC over individual drugs.

IntroductionThe common origin of the adjective “corporeal” and the noun “corpse” in the Latin root corpus points to the value of mortuary practices for investigating how the human body is objectified. In post-mortem rituals, the body—formerly the manipulator of objects—becomes itself the object that is manipulated. Thus, these funerary rituals provide a type of double reflexivity, where the object and subject of manipulation can be used to reciprocally illuminate one another. To this extent, any consideration of corporeality can only benefit from a discussion of how the body is objectified through mortuary practices. This paper offers just such a discussion with respect to a selection of two contrasting mortuary practices, in the context of the prehistoric past and the Classical Era respectively. At the most general level, we are motivated by the same intellectual impulse that has stimulated expositions on corporeality, materiality, and incarnation in areas like phenomenology (Merleau-Ponty 77–234), Marxism (Adorno 112–119), gender studies (Grosz vii–xvi), history (Laqueur 193–244), and theology (Henry 33–53). That is to say, our goal is to show that the body, far from being a transparent frame through which we encounter the world, is in fact a locus where historical, social, cultural, and psychological forces intersect. On this view, “the body vanishes as a biological entity and becomes an infinitely malleable and highly unstable culturally constructed product” (Shilling 78). However, for all that the cited paradigms offer culturally situated appreciations of corporeality; our particular intellectual framework will be provided by cognitive science. Two reasons impel us towards this methodological choice.In the first instance, the study of ritual has, after several decades of stagnation, been rewarded—even revolutionised—by the application of insights from the new sciences of the mind (Whitehouse 1–12; McCauley and Lawson 1–37). Thus, there are good reasons to think that ritual treatments of the body will refract historical and social forces through empirically attested tendencies in human cognition. In the present connection, this means that knowledge of these tendencies will reward any attempt to theorise the objectification of the body in mortuary rituals.In the second instance, because beliefs concerning the afterlife can never be definitively judged to be true or false, they give free expression to tendencies in cognition that are otherwise constrained by the need to reflect external realities accurately. To this extent, they grant direct access to the intuitive ideas and biases that shape how we think about the world. Already, this idea has been exploited to good effect in areas like the cognitive anthropology of religion, which explores how counterfactual beings like ghosts, spirits, and gods conform to (and deviate from) pre-reflective cognitive patterns (Atran 83–112; Barrett and Keil 219–224; Barrett and Reed 252–255; Boyer 876–886). Necessarily, this implies that targeting post-mortem treatments of the body will offer unmediated access to some of the conceptual schemes that inform thinking about human corporeality.At a more detailed level, the specific methodology we propose to use will be provided by conceptual blending theory—a framework developed by Gilles Fauconnier, Mark Turner, and others to describe how structures from different areas of experience are creatively blended to form a new conceptual frame. In this system, a generic space provides the ground for coordinating two or more input spaces into a blended space that synthesises them into a single output. Here this would entail using natural or technological processes to structure mortuary practices in a way that satisfies various psychological needs.Take, for instance, W.B. Yeats’s famous claim that “Too long a sacrifice / Can make a stone of the heart” (“Easter 1916” in Yeats 57-8). Here, the poet exploits a generic space—that of everyday objects and the effort involved in manipulating them—to coordinate an organic input from that taxonomy (the heart) with an inorganic input (a stone) to create the blended idea that too energetic a pursuit of an abstract ideal turns a person into an unfeeling object (the heart-as-stone). Although this particular example corresponds to a familiar rhetorical figure (the metaphor), the value of conceptual blending theory is that it cuts across distinctions of genre, media, language, and discourse level to provide a versatile framework for expressing how one area of human experience is related to another.As indicated, we will exploit this versatility to investigate two ways of objectifying the body through the examination of two contrasting mortuary practices—cremation and inhumation—against different cultural horizons. The first of these is the conceptualisation of the body as an object of a technical process, where the post-mortem cremation of the corpse is analogically correlated with the metallurgical refining of ore into base metal. Our area of focus here will be Bronze Age cremation practices. The second conceptual scheme we will investigate focuses on treatments of the body as a vegetable object; here, the relevant analogy likens the inhumation of the corpse to the planting of a seed in the soil from which future growth will come. This discussion will centre on the Classical Era. Burning: The Body as Manufactured ObjectThe Early and Middle Bronze Age in Western Europe (2500-1200 BCE) represented a period of change in funerary practices relative to the preceding Neolithic, exemplified by a move away from the use of Megalithic monuments, a proliferation of grave goods, and an increase in the use of cremation (Barrett 38-9; Cooney and Grogan 105-121; Brück, Material Metaphors 308; Waddell, Bronze Age 141-149). Moreover, the Western European Bronze Age is characterised by a shift away from communal burial towards single interment (Barrett 32; Bradley 158-168). Equally, the Bronze Age in Western Europe provides us with evidence of an increased use of cist and pit cremation burials concentrated in low-lying areas (Woodman 254; Waddell, Prehistoric 16; Cooney and Grogan 105-121; Bettencourt 103). This greater preference for lower-lying location appears to reflect a distinctive change in comparison to the distribution patterns of the Neolithic burials; these are often located on prominent, visible aspects of a landscape (Cooney and Grogan 53-61). These new Bronze Age burial practices appear to reflect a distancing in relation to the territories of the “old ancestors” typified by Megalithic monuments (Bettencourt 101-103). Crucially, the Bronze Age archaeological record provides us with evidence that indicates that cremation was becoming the dominant form of deposition of human remains throughout Central and Western Europe (Sørensen and Rebay 59-60).The activities associated with Bronze Age cremations such as the burning of the body and the fragmentation of the remains have often been considered as corporeal equivalents (or expressions) of the activities involved in metal (bronze) production (Brück, Death 84-86; Sørensen and Rebay 60–1; Rebay-Salisbury, Cremations 66-67). There are unequivocal similarities between the practices of cremation and contemporary bronze production technologies—particularly as both processes involve the transformation of material through the application of fire at temperatures between 700 ºC to 1000 ºC (Musgrove 272-276; Walker et al. 132; de Becdelievre et al. 222-223).We assert that the technologies that define the European Bronze Age—those involved in alloying copper and tin to produce bronze—offered a new conceptual frame that enabled the body to be objectified in new ways. The fundamental idea explored here is that the displacement of inhumation by cremation in the European Bronze Age was motivated by a cognitive shift, where new smelting technologies provided novel conceptual metaphors for thinking about age-old problems concerning human mortality and post-mortem survival. The increased use of cremation in the European Bronze Age contrasts with the archaeological record of the Near Eastern—where, despite the earlier emergence of metallurgy (3300–3000 BCE), we do not see a notable proliferation in the use of cremation in this region. Thus, mortuary practices (i.e. cremation) provide us with an insight into how Western European Bronze Age cultures mediated the body through changes in technological objects and processes.In the terminology of conceptual blending, the generic space in question centres on the technical manipulation of the material world. The first input space is associated with the anxiety attending mortality—specifically, the cessation of personal identity and the extinction of interpersonal relationships. The second input space represents the technical knowledge associated with bronze production; in particular, the extraction of ore from source material and its mixing with other metals to form an alloy. The blended space coordinates these inputs to objectify the human body as an object that is ritually transformed into a new but more durable substance via the cremation process. In this contention we use the archaeological record to draw a conceptual parallel between the emergence of bronze production technology—centring on transition of naturally occurring material to a new subsistence (bronze)—and the transitional nature of the cremation process.In this theoretical framework, treating the body as a mixture of substances that can be reduced to its constituents and transformed through technologies of cremation enabled Western European Bronze Age society to intervene in the natural process of putrefaction and transform the organic matter into something more permanent. This transformative aspect of the cremation is seen in the evidence we have for secondary burial practices involving the curation and circulation of cremated bones of deceased members of a group (Brück, Death 87-93). This evidence allows us to assert that cremated human remains and objects were considered products of the same transformation into a more permanent state via burning, fragmentation, dispersal, and curation. Sofaer (62-69) states that the living body is regarded as a person, but as soon as the transition to death is made, the body becomes an object; this is an “ontological shift in the perception of the body that assumes a sudden change in its qualities” (62).Moreover, some authors have proposed that the exchange of fragmented human remains was central to mortuary practices and was central in establishing and maintaining social relations (Brück, Death 76-88). It is suggested that in the Early Bronze Age the perceptions of the human body mirrored the perceptions of objects associated with the arrival of the new bronze technology (Brück, Death 88-92). This idea is more pronounced if we consider the emergence of bronze technology as the beginning of a period of capital intensification of natural resources. Through this connection, the Bronze Age can be regarded as the point at which a particular natural resource—in this case, copper—went through myriad intensive manufacturing stages, which are still present today (intensive extraction, production/manufacturing, and distribution). Unlike stone tool production, bronze production had the addition of fire as the explicit method of transformation (Brück, Death 88-92). Thus, such views maintain that the transition achieved by cremation—i.e. reducing the human remains to objects or tokens that could be exchanged and curated relatively soon after the death of the individual—is equivalent to the framework of commodification connected with bronze production.A sample of cremated remains from Castlehyde in County Cork, Ireland, provides us with an example of a Bronze Age cremation burial in a Western European context (McCarthy). This is chosen because it is a typical example of a Bronze Age cremation burial in the context of Western Europe; also, one of the authors (MG) has first-hand experience in the analysis of its associated remains. The Castlehyde cremation burial consisted of a rectangular, stone-lined cist (McCarthy). The cist contained cremated, calcined human remains, with the fragments generally ranging from a greyish white to white in colour; this indicates that the bones were subject to a temperature range of 700-900ºC. The organic content of bone was destroyed during the cremation process, leaving only the inorganic matrix (brittle bone which is, often, described as metallic in consistency—e.g. Gejvall 470-475). There is evidence that remains may have been circulated in a manner akin to valuable metal objects. First of all, the absence of long bones indicates that there may have been a practice of removing salient remains as curatable records of ancestral ties. Secondly, remains show traces of metal staining from objects that are no longer extant, which suggests that graves were subject to secondary burial practices involving the removal of metal objects and/or human bone. To this extent, we can discern that human remains were being processed, curated, and circulated in a similar manner to metal objects.Thus, there are remarkable similarities between the treatment of the human body in cremation and bronze metal production technologies in the European Bronze Age. On the one hand, the parallel between smelting and cremation allowed death to be understood as a process of transformation in which the individual was removed from processes of organic decay. On the other hand, the circulation of the transformed remains conferred a type of post-mortem survival on the deceased. In this way, cremation practices may have enabled Bronze Age society to symbolically overcome the existential anxiety concerning the loss of personhood and the breaking of human relationships through death. In relation to the former point, the resurgence of cremation in nineteenth century Europe provides us with an example of how the disposal of a human body can be contextualised in relation to socio-technological advancements. The (re)emergence of cremation in this period reflects the post-Enlightenment shift from an understanding of the world through religious beliefs to the use of rational, scientific approaches to examine the natural world, including the human body (and death). The controlled use of fire in the cremation process, as well as the architecture of crematories, reflected the industrial context of the period (Rebay-Salisbury, Inhumation 16).With respect to the circulation of cremated remains, Smith suggests that Early Medieval Christian relics of individual bones or bone fragments reflect a reconceptualised continuation of pre-Christian practices (beginning in Christian areas of the Roman Empire). In this context, it is claimed, firstly, that the curation of bone relics and the use of mobile bone relics of important, saintly individuals provided an embodied connection between the sacred sphere and the earthly world; and secondly, that the use of individual bones or fragments of bone made the Christian message something portable, which could be used to reinforce individual or collective adherence to Christianity (Smith 143-167). Using the example of the Christian bone relics, we can thus propose that the curation and circulation of Bronze Age cremated material may have served a role similar to tools for focusing religiously oriented cognition. Burying: The Body as a Vegetable ObjectGiven that the designation “the Classical Era” nominates the entirety of the Graeco-Roman world (including the Near East and North Africa) from about 800 BCE to 600 CE, there were obviously no mortuary practices common to all cultures. Nevertheless, in both classical Greece and Rome, we have examples of periods when either cremation or inhumation was the principal funerary custom (Rebay-Salisbury, Inhumation 19-21).For instance, the ancient Homeric texts inform us that the ancient Greeks believed that “the spirit of the departed was sentient and still in the world of the living as long as the flesh was in existence […] and would rather have the body devoured by purifying fire than by dogs or worms” (Mylonas 484). However, the primary sources and archaeological record indicate that cremation practices declined in Athens circa 400 BCE (Rebay-Salisbury, Inhumation 20). With respect to the Roman Empire, scholarly opinion argues that inhumation was the dominant funerary rite in the eastern part of the Empire (Rebay-Salisbury, Inhumation 17-21; Morris 52). Complementing this, the archaeological and historical record indicates that inhumation became the primary rite throughout the Roman Empire in the first century CE. Inhumation was considered to be an essential rite in the context of an emerging belief that a peaceful afterlife was reflected by a peaceful burial in which bodily integrity was maintained (Rebay-Salisbury, Inhumation 19-21; Morris 52; Toynbee 41). The question that this poses is how these beliefs were framed in the broader discourses of Classical culture.In this regard, our claim is that the growth in inhumation was driven (at least in part) by the spread of a conceptual scheme, implicit in Greek fertility myths that objectify the body as a seed. The conceptual logic here is that the post-mortem continuation of personal identity is (symbolically) achieved by objectifying the body as a vegetable object that will re-grow from its own physical remains. Although the dominant metaphor here is vegetable, there is no doubt that the motivating concern of this mythological fabulation is human mortality. As Jon Davies notes, “the myths of Hades, Persephone and Demeter, of Orpheus and Eurydice, of Adonis and Aphrodite, of Selene and Endymion, of Herakles and Dionysus, are myths of death and rebirth, of journeys into and out of the underworld, of transactions and transformations between gods and humans” (128). Thus, such myths reveal important patterns in how the post-mortem fate of the body was conceptualised.In the terminology of mental mapping, the generic space relevant to inhumation contains knowledge pertaining to folk biology—specifically, pre-theoretical ideas concerning regeneration, survival, and mortality. The first input space attaches to human mortality; it departs from the anxiety associated with the seeming cessation of personal identity and dissolution of kin relationships subsequent to death. The second input space is the subset of knowledge concerning vegetable life, and how the immersion of seeds in the soil produces a new generation of plants with the passage of time. The blended space combines the two input spaces by way of the funerary script, which involves depositing the body in the soil with a view to securing its eventual rebirth by analogy with the sprouting of a planted seed.As indicated, the most important illustration of this conceptual pattern can be found in the fertility myths of ancient Greece. The Homeric Hymns, in particular, provide a number of narratives that trace out correspondences between vegetation cycles, human mortality, and inhumation, which inform ritual practice (Frazer 223–404; Carney 355–65; Sowa 121–44). The Homeric Hymn to Demeter, for instance, charts how Persephone is abducted by Hades, god of the dead, and taken to his underground kingdom. While searching for her missing daughter, Demeter, goddess of fertility, neglects the earth, causing widespread devastation. Matters are resolved when Zeus intervenes to restore Persephone to Demeter. However, having ingested part of Hades’s kingdom (a pomegranate seed), Persephone is obliged to spend half the year below ground with her captor and the other half above ground with her mother.The objectification of Persephone as both a seed and a corpse in this narrative is clearly signalled by her seasonal inhumation in Hades’ chthonic realm, which is at once both the soil and the grave. And, just as the planting of seeds in autumn ensures rebirth in spring, Persephone’s seasonal passage from the Kingdom of the Dead nominates the individual human life as just one season in an endless cycle of death and rebirth. A further signifying element is added by the ingestion of the pomegranate seed. This is evocative of her being inseminated by Hades; thus, the coordination of vegetation cycles with life and death is correlated with secondary transition—that from childhood to adulthood (Kerényi 119–183).In the examples given, we can see how the Homeric Hymn objectifies both the mortal and sexual destiny of the body in terms of thresholds derived from the vegetable world. Moreover, this mapping is not merely an intellectual exercise. Its emotional and social appeal is visible in the fact that the Eleusinian mysteries—which offered the ritual homologue to the Homeric Hymn to Demeter—persisted from the Mycenaean period to 396 CE, one of the longest recorded durations for any ritual (Ferguson 254–9; Cosmopoulos 1–24). In sum, then, classical myth provided a precedent for treating the body as a vegetable object—most often, a seed—that would, in turn, have driven the move towards inhumation as an important mortuary practice. The result is to create a ritual form that makes key aspects of human experience intelligible by connecting them with cyclical processes like the seasons of the year, the harvesting of crops, and the intergenerational oscillation between the roles of parent and child. Indeed, this pattern remains visible in the germination metaphors and burial practices of contemporary religions such as Christianity, which draw heavily on the symbolism associated with mystery cults like that at Eleusis (Nock 177–213).ConclusionWe acknowledge that our examples offer a limited reflection of the ethnographic and archaeological data, and that they need to be expanded to a much greater degree if they are to be more than merely suggestive. Nevertheless, suggestiveness has its value, too, and we submit that the speculations explored here may well offer a useful starting point for a larger survey. In particular, they showcase how a recurring existential anxiety concerning death—involving the fear of loss of personal identity and kinship relations—is addressed by different ways of objectifying the body. Given that the body is not reducible to the objects with which it is identified, these objectifications can never be entirely successful in negotiating the boundary between life and death. In the words of Jon Davies, “there is simply no let-up in the efforts by human beings to transcend this boundary, no matter how poignantly each failure seemed to reinforce it” (128). For this reason, we can expect that the record will be replete with conceptual and cognitive schemes that mediate the experience of death.At a more general level, it should also be clear that our understanding of human corporeality is rewarded by the study of mortuary practices. No less than having a body is coextensive with being human, so too is dying, with the consequence that investigating the intersection of both areas is likely to reveal insights into issues of universal cultural concern. For this reason, we advocate the study of mortuary practices as an evolving record of how various cultures understand human corporeality by way of external objects.ReferencesAdorno, Theodor W. Metaphysics: Concept and Problems. Trans. Rolf Tiedemann. Stanford: Stanford UP, 2002.Atran, Scott. In Gods We Trust: The Evolutionary Landscape of Religion. Oxford: Oxford UP, 2002.Barrett, John C. “The Living, the Dead and the Ancestors: Neolithic and Bronze Age Mortuary Practices.” The Archaeology of Context in the Neolithic and Bronze Age: Recent Trends. Eds. John. C. Barrett and Ian. A. Kinnes. 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Everett’s Relative State Formulation is one of the most famous and debated interpretations of Quantum Theory. Further deepening of the debates has been made possible by the discovery of his unpublished notes and manuscripts. My purpose is to examine Everett’s ideas about physical theories, and show that his understanding of actual experience can be put into correspondence with the latest forms of constructive empiricism and empirical adequacy: the problem of ‘extra structure’, which is the reason for metaphysical interpretations, can be solved by using a pragmatic criterion to choose in which way the theory should correspond to empirical evidence. A quantitative justification for probabilities in Everettian context is given in terms of typicality.

Trekking to Everest from the Sola Khumbu in Nepal is most definitely one of life’s great treats. When Nepal first opened up to foreigners in 1950 there was only one road from India to Kathmandu via the border town of Raxaul. Early expeditions to Everest had to trek from the plains of India either from Jogbani or Jaynagar in south-eastern Nepal. For the purist, the trail nowadays starts in the Kathmandu Valley, whilst the road head at the village of Jiri is the normal starting point for overlanders. The first week’s walking goes from west to east towards the village of Junbesi, against the grain of the land, crossing three passes and several rivers draining south from the Rolwaling and Khumbu Himalaya. Once across the Dudh Kosi River and up the hill to Lukla, the trail heads north up into the high country. Many trekkers nowadays fly directly into Lukla, where the plane lands at the impressive and frighteningly tilted airstrip built by Edmund Hillary and his Sherpa friends high on the side of the Dudh Kosi. From Lukla, the trail winds through forests of blue pine, fir, silver birch, and the ubiquitous rhododendron. In spring the hills are a mass of red, pink, and white rhododendrons. Meadows are carpeted in wild flowers—gentians, primrose, edelweiss, and the magical Himalayan blue poppy. Small Sherpa villages with their sturdy homes built from slabs of schist and gneiss have expanded with new trekking lodges springing up annually. The terraced rice paddies of the lowlands are soon left behind and apple orchards are a mass of blooms in the spring. Clouds well up and float quietly down into the valleys. The forests with their hanging mosses become eerily quiet. The senses dwell on the serene beauty of the forests and streams, all green and full of life and sound. Suddenly one’s eye is caught by something higher up, way above the clouds. With amazement, one realizes that is no cloud up there: it is a mountain, five miles high, far above the peaceful green of the valley.

‘Quantum theory’ is not a single physical theory but a framework in which many different concrete theories fit. As such, a solution to the quantum measurement problem ought to provide a recipe to interpret each such concrete theory, in a mutually consistent way. But with the exception of the Everett interpretation, the main extant solutions either try to make sense of the abstract framework as if it were concrete, or else interpret one particular quantum theory under the fiction that it is fundamental and exact. In either case, these approaches are unable to help themselves to the very theory-laden, level-relative ways in which quantum theory makes contact with experiment in mainstream physics, and so are committed to major revisionary projects which have not been carried out even in outline. As such, only the Everett interpretation is currently suited to make sense of quantum physics as it is found.

Abstract Pirahã tense is interesting because non-transparent temporal interpretations require more information than the syntax (or the pragmatics) provides. Moreover, not only are temporal interpretations in Pirahã underdetermined by Pirahã syntax, but this underdetermination provides yet more evidence against what one might label ‘naive compositionality’—the idea that meanings are provided Montague-style by mappings from syntax to semantics. However, if we reinterpret compositionality as a subtype of inference in the Peircean sense, we are able not only to understand better some peculiarities in the relationship between Pirahã language and cognition but also to predict (as per Everett 2017 and Barham and Everett 2020) ‘degrees of fit’ between morphosyntactic structures, meanings, and cultures across languages, leading to an informal typology of language types that includes languages without sentential recursion (e.g., but not limited to, Pirahã). Finally, Pirahã temporal semantics is interesting because it forces an adjustment of Reichenbach’s theory of tense

Abstract ‘These are times for historians to write who seek to avoid all calm narrations as a dead water, to fill their volumes with cruell wars and seditions. I desire not employment at these times’. So wrote Sir Henry Slingsby at the beginning of the Bishops’ Wars. As James Bond put the point in the inimitably different idiom of the late twentieth century, ‘it reads better than it lives’. Interesting times are often more interesting to those who do not suffer the misfortune of living in them. In these days of social history, it is no longer clear that historians, as a profession, deserve Sir Henry Slingsby’s reproaches, but we have certainly spilt enough ink on the causes of the English Civil War. Contemplating the umpteenth assault on this subject, I feel bound to echo Eric Shipton on Mount Everest: ‘for God’s sake let’s climb the bloody thing, and then get back to real mountaineering’. The hunt for the causes of the Civil War has not, on the whole, had a beneficial effect on seventeenth-century historiography: not all the most important developments in the early seventeenth century can be assumed to be causes of the English Civil War. There is a risk that important themes may be either ignored, or strait-jacketed in order to turn them into causes of the Civil War when they are not. To take a couple of examples, the fact that England reached the top of the demographic curve sometime around 1640 is clearly of the highest long-term importance. The coincidence of dates makes it tempting to see whether this can be turned into a cause of the Civil War, but though it is possible to make a connection by way of resistance to taxation, such a connection is highly tangential, and it is hard to make it of the first importance. In the long term, the slow growth of cultural diversity is also of the highest importance. This at first sight looks a little more promising, but in fact it turns out that only those manifestations of diversity which can be directly related to religion, such as maypoles or the sabbath, will fit at all accurately into the jigsaw.

In 1969, S. G. Brush and C. W. F. Everitt published a historical review, that was reprinted as subchapter 5.5 Maxwell, Osborne Reynolds, and the radiometer, in Stephen G. Brush’s famous book The Kind of Motion We Call Heat. This review covers the history of the explanation of the forces acting on the vanes of Crookes radiometer up to the end of the 19th century. The forces moving the vanes in Crookes radiometer (which are not due to radiation pressure, as initially believed by Crookes and Maxwell) have been recognized as thermal effects of the remaining gas by Reynolds — from his experimental and theoretical work on Thermal Transpiration and Impulsion, in 1879 — and by the development of the differential equations describing Thermal Creeping Flow, induced by tangential stresses due to a temperature gradient on a solid surface by Maxwell, earlier in the same year, 1879. These fundamental physical laws have not yet made their way into the majority of textbooks of heat transfer and fluid mechanics so far. A literature research about the terms of Thermal Transpiration and Thermal Creeping Flow, in connection with the radiometer forces, resulted in a large number of interesting papers; not only the original ones as mentioned in subchapter 5.5 of Brush’s book, but many more in the earlier twentieth century, by Martin Knudsen, Wilhelm Westphal, Albert Einstein, Theodor Sexl, Paul Epstein and others. The forces as calculated from free molecular flow (by Knudsen), increase linearly with pressure, while the forces from Maxwell’s Thermal Creeping Flow decrease with pressure. In an intermediate range of pressures, depending on the characteristic geometrical dimensions of flow channels or radiometer vanes, an appropriate interpolation between these two kinds of forces, as suggested by Wilhelm Westphal and later by G. Hettner, goes through a maximum. Albert Einstein’s approximate solution of the problem happens to give the order of magnitude of the forces in the maximum range. A comprehensive formula and a graph of the these forces versus pressure combines all the relevant theories by Knudsen (1910), Einstein (1924), Maxwell (1879) (and Hettner (1926), Sexl (1928), and Epstein (1929) who found mathematical solutions for Maxwells creeping flow equations for non-isothermal spheres and circular discs, which are important for thermophoresis and for the radiometer). The mechanism of Thermal Creeping Flow will become of increasing interest in micro- and submicro-channels in various new applications, so it ought to be known to every graduate student of heat transfer in the future. That’s one of the reasons why some authors have recently questioned the validity of the classical Navier-Stokes, Fourier, and Fick equations: Dieter Straub (1996) published a book on an Alternative Mathematical Theory of Non-equilibrium Phenomena. Howard Brenner (since 2005) wrote a number of papers, like Navier-Stokes, revisited, and Bi-velocity hydrodynamics, explicitly pointing to the forces acting on the vanes of the lightmill, to thermophoresis and related phenomena. Franz Durst (since 2006) also developed modifications of the classical Navier-Stokes equations. So, Reynolds, Maxwell, and the radiometer may finally have initiated a revision of the fundamental equations of thermofluiddynamics and heat- and mass transfer.