bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of optimal timing and therapeutic efficacy of radium-223 therapy for metastatic castration-resistant prostate cancer: a multicenter collaborative study
Authors: Urabe Fumihiko , Kadena Soshi , Tashiro Kojiro , Tokuoka Kenichi , Taneda Yuki , Fujiwara Kensuke , Goto Yuma , Nakano Juria , Kawano Shota , Iwamoto Yuya , Fukuokaya Wataru , Imai Yu , Iwatani Kosuke , Atsuta Mahito , Ito Kagenori , Yanagisawa Takafumi , Murakami Masaya , Tsuzuki Shunsuke , Yamamoto Toshihiro , Shimomura Tatsuya , Miki Jun , Kimura Takahiro ,   JIKEI-YAYOI Collaborative Group
Published: January 2025

Background

Despite its demonstrated efficacy in prolonging overall survival (OS) and delaying skeletal-related events in the ALSYMPCA trial, the optimal timing of radium-223 initiation remains unclear. This study investigated factors influencing radium-223 treatment outcomes, including completion rates and survival.

Methods

This retrospective, multi-institutional study included 164 patients with metastatic castration-resistant prostate cancer (CRPC) who received radium-223 therapy. The primary endpoint was OS following radium-223 initiation. Secondary endpoints included factors associated with incomplete radium-223 treatment (< six cycles) and poor OS. Multivariate Cox regression and multivariate logistic regression analyses were conducted to identify prognostic factors.

Results

The median OS times after CRPC diagnosis and radium-223 initiation were 39 and 12.5 months, respectively. Kaplan–Meier analysis showed that the OS of patients who completed six cycles of radium-223 treatment was longer than that of those who did not (18 vs. 5 months; P < .001). Multivariate Cox analysis identified Eastern Cooperative Oncology Group performance status (ECOG-PS) ≥ 1 (hazard ratio [HR] = 1.74, P = .046), PSA > 17 ng/ml (HR = 2.93, P < .001), and radium-223 incompletion (HR = 3.23, P < .001) as independent predictors of poor OS. The radium-223 completion rate was 68.3%, and incompletion was significantly associated with prior docetaxel use (odds ratio [OR] = 5.97, P = .001), bone pain (OR = 2.64, P = .024), and PSA > 17 ng/ml at the start of radium-223 treatment (OR = 3.12, P = .013).

Conclusions

Completion of all six cycles of radium-223 treatment were associated with favorable survival outcomes in metastatic CRPC patients. Prior docetaxel use, bone pain, and elevated PSA levels were significant risk factors for radium-223 incompletion. These findings suggest the importance of initiating radium-223 earlier in the treatment course for patients with favorable clinical profiles to maximize the therapeutic benefits.
Clinical outcomes and treatment patterns of maintenance avelumab in locally advanced or metastatic urothelial carcinoma: a multicenter collaborative study
Authors: Taneda Yuki , Urabe Fumihiko , Uchida Naoki , Kadena Soshi , Shibata Ken , Hashimoto Masaki , Kawano Shota , Takiguchi Yuki , Ohtsuka Takashi , Nakazono Minoru , Imai Yu , Iwatani Kosuke , Kayano Sotaro , Atsuta Mahito , Tashiro Kojiro , Murakami Masaya , Tsuzuki Shunsuke , Yamamoto Toshihiro , Yamada Hiroki , Miki Jun , Kimura Takahiro ,   JIKEI-YAYOI Collaborative Group
Published: January 2025

Background

The JAVELIN Bladder 100 trial demonstrated improved overall survival (OS) with maintenance avelumab in patients with locally advanced or metastatic urothelial carcinoma UC (la/mUC) who achieved disease control following first-line platinum-based chemotherapy (1 L-PBC). However, real-world data on eligibility, utilization, and outcomes of maintenance avelumab therapy remain limited.

Methods

This retrospective study included patients with la/mUC who received 1 L-PBC. Eligibility for maintenance avelumab therapy was determined based on the best overall response to 1 L-PBC, with patients who achieved stable disease or a partial or complete response considered eligible. Survival outcomes were analyzed using the Kaplan–Meier method. Multivariate Cox regression analysis was used to identify prognostic factors among patients with la/mUC who received maintenance avelumab.

Results

Of 161 prospective patients, 67.1% were eligible for maintenance avelumab therapy, and 46.3% of eligible patients received the treatment. The median progression-free survival (PFS) following avelumab initiation was 10.2 months, whereas the median OS was not reached. Prognostic factors associated with PFS included the presence of liver metastases, elevated C-reactive protein (> 1.0 g/dL), and administration of more than five cycles of 1 L-PBC. Adverse events occurred in 60% of patients treated with avelumab, with 16% experiencing grade 3–4 adverse events.

Conclusion

We emphasize the real-world applicability of maintenance avelumab for Japanese patients with la/mUC. Maintenance avelumab demonstrated favorable survival outcomes, consistent with clinical trial data. Identifying prognostic factors and optimizing treatment sequencing are essential strategies for improving outcomes in this patient population.
Increasing photosynthetic benefit with decreasing irrigation frequency in an Australian temperate pasture exposed to elevated carbon dioxide
Authors: Missen Melika L , De Kauwe Martin G , Hovenden Mark J
Published: January 2025

Elevated atmospheric CO2 (e[CO2]) often enhances plant photosynthesis and improves water status. However, the effects of e[CO2] vary significantly and are believed to be influenced by water availability. With a future warmer climate expected to increase the frequency and severity of extreme rainfall, the response of plants to e[CO2] under changing precipitation patterns remains uncertain. We examined the effects of e[CO2] and different irrigation regimes on perennial ryegrass in a free-air CO2 enrichment (FACE) experiment. Immediately after irrigation, the mean net photosynthetic rate was 21.2% higher under e[CO2] compared with ambient conditions. This benefit increased over time, reaching a 31.3% higher rate as days since watering increased, indicating a substantial increase in photosynthetic benefit with longer intervals between watering. Mean stomatal conductance was 21% lower in ryegrass under e[CO2] immediately after irrigation compared with ambient plots. However, the reduction in stomatal conductance under e[CO2] decreased as the interval between irrigation events increased, showing no difference 7–10 d after an irrigation event. These results imply that plants benefit most from carbon fertilization, assimilating relatively more carbon and losing less water, during periods with less frequent rainfall. These findings have significant implications for understanding leaf-level responses to climate change.
Rising from the ashes: evidence of old stellar populations and rejuvenation events in the very early Universe
Authors: Witten Callum , McClymont William , Laporte Nicolas , Roberts-Borsani Guido , Sijacki Debora , Tacchella Sandro , Simmonds Charlotte , Katz Harley , Ellis Richard S , Witstok Joris , Maiolino Roberto , Ji Xihan , Hayes Billy R , Looser Tobias J , D’Eugenio Francesco
Published: January 2025

While JWST has observed galaxies assembling as early as $z\sim 14$, evidence of galaxies with significant old stellar populations in the Epoch of Reionization (EoR) – the descendants of these earliest galaxies – are few and far between. Bursty star-formation histories (SFHs) have been invoked to explain the detectability of the earliest UV-bright galaxies, but also to interpret galaxies showing Balmer breaks without nebular emission lines. We present the first spectroscopic evidence of a $z\sim 7.9$ galaxy, A2744-YD4, which shows a Balmer break and emission lines, indicating the presence of both a mature and young stellar population. The spectrum of A2744-YD4 shows peculiar emission line ratios suggesting a relatively low ionization parameter and high gas-phase metallicity. A median stack of galaxies with similar emission line ratios reveals a clear Balmer break in their stacked spectrum. This suggests that a mature stellar population (∼80 Myr old) has produced a chemically enriched, disrupted interstellar medium. Based on SED-fitting and comparison to simulations, we conclude that the observed young stellar population is in fact the result of a rejuvenation event following a lull in star formation lasting ∼20 Myr, making A2744-YD4 and our stack the first spectroscopic confirmation of galaxies that have rejuvenated following a mini-quenched phase. These rejuvenating galaxies appear to be in an exceptional evolutionary moment where they can be identified. Our analysis shows that a young stellar population of just ∼30 per cent of the total stellar mass would erase the Balmer break. Hence, ‘outshining’ through bursty SFHs in early galaxies is likely plaguing attempts to measure their stellar ages and masses accurately.
The ESO SupJup Survey V: exploring atmospheric variability and orbit of the super-Jupiter AB Pictoris b with CRIRES+
Authors: Gandhi Siddharth , de Regt Sam , Snellen Ignas , Palma-Bifani Paulina , Abdoulwahab Idriss , Chauvin Gaël , Picos Darío González , Zhang Yapeng , Landman Rico , Stolker Tomas , Kesseli Aurora , Mulder Willeke , Chomez Antoine , Lagrange Anne-Marie , Zurlo Alice
Published: January 2025

A growing number of directly-imaged companions have been recently characterized, with robust constraints on carbon-to-oxygen ratios and even isotopic ratios. Many companions and isolated targets have also shown spectral variability. In this work, we observed the super-Jupiter AB Pictoris b across four consecutive nights using VLT/CRIRES+ as part of the ESO SupJup survey, exploring how the constraints on chemical composition and temperature profile change over time using spectral line shape variations between nights. We performed atmospheric retrievals of the high-resolution observations and found broadly consistent results across all four nights, but there were differences for some parameters. We clearly detect H$_2$O, $^{12}$CO, and $^{13}$CO in each night, but abundances varied by ${\sim} 2\sigma$, which was correlated to the deep atmosphere temperature profiles. We also found differences in the $^{12}$C$/^{13}$C ratios in each night by up to ${\sim} 3\sigma$, which seemed to be correlated with the cloud deck pressure. Our combined retrieval simultaneously analysing all nights together constrained broadly the average of each night individually, with the C/O$=0.59\pm 0.01$, consistent with solar composition, and $^{12}$C$/^{13}$C $= 102\pm 8$, slightly higher than the Interstellar Medium (ISM) and Solar System values. We also find a low projected rotational velocity, suggesting that AB Pictoris b is either intrinsically a slow rotator due to its young age or that the spin axis is observed pole-on with a ${\sim} 90^\circ$ misalignment with its orbit inclination. Future observations will be able to further explore the variability and orbit of AB Pictoris b as well as for other companions.
Cleaning WASP-33 b transits from the host star photometric variability: analysis of TESS data from two sectors
Authors: Baluev Roman V , Sokov Eugene N
Published: January 2025

Based on TESS observations of a $\delta$ Scuti variable WASP-33 obtained in 2019 and 2022, we thoroughly investigate the power spectrum of this target photometric flux and construct a statistically exhaustive model for its variability. This model contains 30 robustly justified harmonics detected in both the TESS sectors simultaneously, 13 less robust harmonics detected in a single TESS sector, a red noise, and a quasi-periodic noise term. This allowed us to greatly improve the accuracy of the exoplanet WASP-33 b transit timings, reducing the TTV residuals r.m.s. drastically, by a factor of 3.5, from 63 to 18 s. Finally, our analysis does not confirm existence of a detectable orbital phase variation claimed previously based on WASP-33 TESS photometry of 2019.
An analytic model of gravitational collapse induced by radiative cooling: instability scale, density profile, and mass infall rate
Authors: Gurian James , Liu Boyuan , Jeong Donghui , Hosokawa Takashi , Hirano Shingo , Yoshida Naoki
Published: January 2025

We present an analytic description of the spherically symmetric gravitational collapse of radiatively cooling gas clouds, which illustrates the mechanism by which radiative cooling induces gravitational instability at a characteristic mass scale determined by the microphysics of the gas. The approach is based on developing the density–temperature relationship of the gas into a full dynamical model. We convert the density–temperature relationship into a barotropic equation of state, based on which we develop a refined instability criterion and calculate the density and velocity profiles of the gas. From these quantities, we determine the time-dependent mass infall rate on to the centre of the cloud. This approach distinguishes the rapid, quasi-equilibrium contraction of a cooling gas core to high central densities from the legitimate instability this contraction establishes in the envelope. We explicate the model in the context of a primordial mini-halo cooled by molecular hydrogen, and then provide two further examples: a delayed collapse with hydrogen deuteride cooling and the collapse of an atomic-cooling halo. In all three cases, we show that our results agree well with full hydrodynamical treatments.
Direct Measurement of the Mutation Rate and Its Evolutionary Consequences in a Critically Endangered Mollusk
Authors: Wooldridge T Brock , Ford Sarah M , Conwell Holland C , Hyde John , Harris Kelley , Shapiro Beth
Published: January 2025

The rate at which mutations arise is a fundamental parameter of biology. Despite progress in measuring germline mutation rates across diverse taxa, such estimates are missing for much of Earth's biodiversity. Here, we present the first estimate of a germline mutation rate from the phylum Mollusca. We sequenced three pedigreed families of the white abalone Haliotis sorenseni, a long-lived, large-bodied, and critically endangered mollusk, and estimated a de novo mutation rate of 8.60 × 10−9 single nucleotide mutations per site per generation. This mutation rate is similar to rates measured in vertebrates with comparable generation times and longevity to abalone, and higher than mutation rates measured in faster-reproducing invertebrates. The spectrum of de novo mutations is also similar to that seen in vertebrate species, although an excess of rare C > A polymorphisms in wild individuals suggests that a modifier allele or environmental exposure may have once increased C > A mutation rates. We use our rate to infer baseline effective population sizes (Ne) across multiple Pacific abalone and find that abalone persisted over most of their evolutionary history as large and stable populations, in contrast to extreme fluctuations over recent history and small census sizes in the present day. We then use our mutation rate to infer the timing and pattern of evolution of the abalone genus Haliotis, which was previously unknown due to few fossil calibrations. Our findings are an important step toward understanding mutation rate evolution and they establish a key parameter for conservation and evolutionary genomics research in mollusks.
Protagoras
Authors: Lee Mi-Kyoung
Published: January 2025

Protagoras of Abdera was the most important and famous of the Greek Sophists of the fifth century bce. Though it is difficult to establish his dates with certainty, given the unreliable state of the doxographic tradition for pre-Platonic philosophers, it seems that Protagoras lived from c. 492 to 421 bce, making him about twenty years older than Socrates. Plato says in the Meno (91de = DK 80A8) that Protagoras was famous throughout Greece for forty years, and that he was seventy when he died. It is a tribute to Protagoras that Plato singled him out for repeated treatment and discussion in his dialogues—in particular, the Protagoras, the Theaetetus, and, to a lesser extent, the Sophist. Protagoras is known for his declaration of a human-centered philosophy (“man is the measure of all things”), for his skepticism or agnosticism about the gods, for his defense of democratic institutions, for his interest in language and logos, and for his formidable skill in argumentation, rivaling Socrates when it came to debate. Because so few fragments and ipsissima verba of Protagoras’s writings remain, we have to rely on testimony from a variety of sources, some more friendly than others. Plato is the most important of these, and as a consequence, much of the scholarly literature on Protagoras is literature on Plato as well; this entry will include many papers and books on Plato’s Protagoras and Theaetetus that are particularly relevant to the historical Protagoras. As to whether Plato is reliable, questions of source criticism unfortunately arise everywhere, not just with Plato, when it comes to Protagoras and the other Sophists, and those are dealt with in much of the scholarship on Protagoras and our sources for his thinking.
Rural Landscapes, Rural Communities, and Village Life in the Byzantine Empire
Authors: Armstrong Pamela
Published: January 2025

Villages were essentially the same all over the world in the medieval era: rural locations whose inhabitants’ survival was dependent on food production through cultivation and animal husbandry. Food production could be geared toward subsistence or for creating a surplus to feed people elsewhere. The basic elements of life would have been similar across cultures, varying according to different geographic and climactic locations. But what distinguishes life in a Byzantine village from the rest of the world? The status of the people who live there; the amount, if any, of tax they pay; the physical appearance of its structures; and their hierarchy within the great diversity of environment that the Byzantine Empire encompassed. Most of the population of the Byzantine Empire were peasants working as farmers and pastoralists. Despite their overwhelming presence and importance, peasants feature only in a secondary way in written texts and so details of rural societies remain obscure to modern historians. However archaeology, in particular the development of survey archaeology over the last fifty years, has greatly expanded understanding of rural and village life, especially in the practical aspects of size and materials. The concept of the ‘Byzantine village’ is broad both geographically and chronologically, extending throughout countries bordering the Black and Mediterranean Seas for over a thousand years. Obviously rural life varied across such a wide climatic zone; of lesser impact was the control exerted by political systems. The classical ancient Greek word kome (village) was replaced in the Byzantine system by three words: chorion, which could include rivers, forests, lakes, as well as the agricultural land in the vicinity of the built village; agridion (hamlet); and proasteion (estate). Metrokomia and komopoleis, colloquial terms not used in official documents, indicate that villages could be very large. Villages could encompass estates, both secular and ecclesiastical, as well as settlements of independent peasants. Although rural populations depended on animal husbandry and cultivation for their livelihoods, this was underpinned by engaging in crafts such as woodwork, basketry, weaving, or pottery making. Diversity was necessary to cushion unfavorable situations over which there was no control, such as drought or infestations, and created some level of economic stability. Rural communities could specialize in cash crops such as olive oil or wine, but this required an established infrastructure to connect with consumers, such as containers for exporting the produce which could be skins, wooden barrels, or ceramic amphoras, and political conditions that allowed uninterrupted transport of the goods. The disposal of surplus produce on a smaller scale was often carried out at rural fairs which were held regularly on appointed days.
Modernity and Neo-Tantra
Authors: Urban Hugh
Published: January 2025

Tantra is one of the most important but also most widely misunderstood and misrepresented currents within Asian religions. An incredibly diverse body of lineages, texts, and traditions, Tantra spread throughout the Hindu, Buddhist, and Jain traditions of South, Central, East, and Southeast Asia from roughly the sixth century ce onward. Historically, Tantra has had a significant influence not only on the religious practice but also on the art, architecture, literature, and political life of these regions. However, when European Orientalist scholars, Christian missionaries, and colonial administrators first encountered these traditions in the eighteenth and nineteenth centuries, they initially had an intensely negative view of Tantra. Denounced as black magic of the crudest and filthiest kind, Tantra was typically regarded as a perverse mixture of superstition, sorcery, and sexuality. These negative perceptions of Tantra were often internalized and repeated by many South Asian authors of the colonial era, particularly by Hindu reformers such as Rammohun Roy, Swami Vivekananda, and many others. Beginning in the twentieth century, however, a growing number of authors in the United States, England, and Europe began to embrace Tantra in a more positive form, now re-imagining this as a liberated path that celebrates the human body and sexuality. Throughout the twentieth century, Tantra was also combined with a variety of occult practices emerging from European esoteric traditions, such as techniques of sexual magic and modern forms of Satanism. By the 1960s, Tantra had become an important part of the counterculture and sexual revolution, now reimagined as “neo-Tantra” by global gurus such as Bhagwan Shree Rajneesh (also known as Osho). Finally, by the late twentieth and early twenty-first century, Tantra had also become a part of modern global consumer culture, often mass-marketed as a “cult of ecstasy” and “yoga of sex” through a wide array of best-selling paperbacks, videos, and Tantric sexual products.
History of Brazilian Foreign Policy (1808 to 1945)
Authors: Lessa Antônio Carlos , de Souza Farias Rogerio
Published: January 2025

Journalists, lawyers, and diplomats constituted the prime authors in the history of Brazilian foreign relations. They usually worked in a laudatory framework and had limited analytical and theoretical skills. This changed in the second half of the twentieth century. The rise of the professional study of history in universities and research institutes in Brazil and abroad brought new interpretations and methods. The field, however, has since struggled with three challenges. First, it still focuses on traditional actors, sources, and narratives. Few studies, therefore, promote genuine dialogue with other social sciences and emphasize issues like gender, migration, culture, and ideas. The second challenge is the limited use of primary sources from other countries to understand Brazilian foreign policy. The result is usually a self-centered approach that fails to consider broader geopolitical, economic, and social contexts. The third is the role of the Brazilian government in shaping the academic agenda. Several contributions are still biased, usually promoting the legitimacy of state actors and their goals and actions.
Gendering Forced Migration
Authors: Hall Lucy , Cleton Laura
Published: January 2025

This entry discusses gendered and feminist approaches to the study of forced migration. The distinction at its heart, that between “forced” and “voluntary” migration, is not a natural given. Instead, scholars argue that it stems from bureaucratic labeling and category-making practices that very rarely reflect the reality of people on the move. Studies consistently find that people leave their country of nationality for a variety of reasons that do not fit neatly within categories of “economic” (allegedly voluntary) or “political” (allegedly forced) migration, reflecting the distinction at the heart of the 1951 Refugee Convention. These binary bureaucratic labels and categories nevertheless have significant power, as they affect migration journeys, opportunities, and experiences. Studying forced migration from a gendered perspective thus has a twofold purpose. First, it functions as a lens through which world politics can be examined, as it shows how the world is shaped by gendered concepts, practices, and institutions. Next to revealing the particularities of women on the move, studies in this entry examine how a range of sites—such as the nation state, migration regimes and policies—are gendered and gendering. Doing so directs attention to dynamic processes involved in how inequality is performed and maintained through the patriarchy, and the intersections of gender, sexuality, racism, capitalism, heteronormativity, ableism, and age-ism. Second, a gendered analysis of forced migration, also critiques the aforementioned forced-voluntary migration binary. Feminist scholars do not simply accept discourses as handed to them. Instead, they actively deconstruct these discourses as well as recognize their own roles in their creation, maintenance, or disputation. This article, therefore, intentionally does not follow the voluntary/forced binary as propagated by migration bureaucracies and enshrined in the 1951 Refugee Convention. Instead, the article selects studies that actively challenge the voluntary/forced binary, by centering the way force is inflicted, experienced, and circumvented in various forms of migration, including environmental migration, labor migration, and transnational family relations. The entry limits itself to English-language scholarship with a focus on geographical sites in both the Global North and Global South. Broadening the scope of this entry allows us to not only to show that force is often inflicted and experienced along a continuum, shifting across time and space, but also that gender matters for all migration journeys, to all bureaucratic categories of migration and for the ways we envision people on the move within and across nation states.
Digital Nomads
Authors: Mancinelli Fabiola
Published: January 2025

Digital nomads are individuals who combine remote work from anywhere that has Internet connection with ongoing international travel, leisure, and multi-local living. The term, coined in the early 1990s to indicate the irruption of portable technologies into leisure travel, gained substantial recognition post-pandemic when remote work became ubiquitous, drawing attention to a more widespread possibility of turning location-independence into a way of life for many. Although the experts in telecommunication and computing had already foreseen the potential of technology to free individuals from the constraints of geography, it was not until the mid-2010s that this emerging lifestyle started attracting academic attention, with initial research focusing on defining the phenomenon and its boundaries. The genesis of the digital nomads as a societal phenomenon can be traced back to a variety of sociocultural factors, including advancement in consumer technologies and Internet connectivity, evolving work arrangements, the growth of global tourism facilitated by the development of transport, the pervasive reach of the English language, and, last but not least, the social acceptance of mobile lifestyles. This trend signifies a blurring of traditional distinctions between work and vacation, challenging established binaries in social spheres like production/consumption, tourism/migration, and work/leisure, often experienced as distinct in time and space. The growing scholarship on digital nomadism fosters interdisciplinary dialogue, including anthropology, tourism, media and information technologies, organization studies, geography, sociology, business, and law. Within anthropology, it prompts reflection on the meanings of work, mobility, home, organization, and belonging while opening debates about the impacts of their relative privilege on locales. Beyond being a cultural phenomenon, digital nomads constitute a dynamic ecosystem of markets and services within the digital economy, where they simultaneously act as consumers and producers. As a societal trend, digital nomads epitomize individualization and increasing depoliticization, while their work practices challenge established values of labor and productivity within the life course, prompting scholars to ponder the future of work. Existing scholarship has prioritized the digital nomad’s perspective rather than the institutional or corporate management perspective. Likewise, studies on the impacts on local communities or the leveraging of local destinations are still scant. This selective bibliography reflects these gaps, while simultaneously attempting to identify different strands of research contributing to a comprehensive understanding of the phenomenon, maintaining a focus on critical and empirically informed approaches.
Mark Rutherford (William Hale White)
Authors: Brealey Michael , Crees Mark
Published: January 2025

Between 1881 and 1897 five novels were published under the name of Mark Rutherford: The Autobiography of Mark Rutherford (1881) and Mark Rutherford’s Deliverance (1885) were followed by The Revolution in Tanner’s Lane (1887), Miriam’s Schooling (1890), Catharine Furze (1893), and Clara Hopgood (1896). The identity of their writer, William Hale White (b.1831–d.1913), was concealed under this pseudonym (and the device of a fictional editor, “Reuben Shapcott”) for many years, only gradually becoming known in his old age. His readership was small, though some titles have been regularly reprinted. White’s interests and literary output ranged much more widely than his fiction, including journalism, literary criticism, and philosophical translation. He did not begin as a novelist, but had been supplying newspaper columns for many years before the publication of the Autobiography. He continued writing until his death, and important material was published posthumously. Born in Bedford, and growing up within the fellowship of Bunyan Meeting, White is celebrated as a chronicler of English Protestant Dissent. His personal struggle for faith leads him to be associated with the Victorian ‘crisis of faith,’ though he should not be simplistically characterized as a ‘doubter.’ Initially intended for the ministry, but excluded in still imperfectly understood circumstances from his training at New College, London, he went on to a working life spent chiefly as a civil servant, rising to a position of some responsibility at the Admiralty. The early forced change of direction, and the evidence of his long intellectual engagement with questions of belief and life-purpose, form a central theme in assessments of his life and writing, shape the presentation of the key monographs on White, and are reflected in analysis of the novels. Widowed in middle age, a late second marriage to the much younger Dorothy Smith was important for his legacy. She fostered his memory, in 1924 publishing selections from his correspondence (Letters to Three Friends) and her Groombridge Diary of their years together. Later she cooperated enthusiastically with researchers, sharing unpublished papers and her memories. Over time new approaches to the nature of writings with an autobiographical character have offered fresh ways to understand White through his novels. In this context his manuscript memoir posthumously published as The Early Life of Mark Rutherford (1913) has special significance. However, despite its apparent transparency its interpretation is not straightforward.
Franz Kafka
Authors: Liska Vivian , Balint Benjamin
Published: January 2025

Franz Kafka (born 1883, Prague, Austria-Hungary [now in Czech Republic]—died 1924, Kierling, near Vienna, Austria) was a German-language writer whose works—most famously The Trial (Der Prozess, 1925) and Metamorphosis (Die Verwandlung, 1915)—gave us the twentieth century’s most imperishable fables about disorientation, guilt, and absurdity and, more generally, about the human condition in modernity. His writings, particularly his diaries and letters, also point to the complex ways “Western” Jews have negotiated between assimilation and tradition. The son of Julie Löwy and Hermann Kafka, Franz Kafka was born into a prosperous middle-class Jewish family. In his “Letter to the Father” (“Brief an den Vater,” 1919), Kafka blames his father for his alienation from his own Jewish heritage. “It was conceivable that we might have found each other in Judaism.” But the flimsy vestiges of Judaism passed on to him, Kafka writes, were “an insufficient scrap . . . a mere nothing, a joke—not even a joke. . . . It all dribbled away while you were passing it on” (Letter to his Father. New York: Schocken, 1966, p. 182). Kafka’s conflict with his father gets its fictional expression in his breakthrough story The Judgment (Das Urteil, 1913). Kafka did associate with German-Jewish intellectuals in Prague, including Max Brod, who would become Kafka’s promoter, literary executor, and first biographer. Kafka proved no less sensitive than Brod and his Zionist friends to the roiling anti-Semitism that would reach its horrific climax only after Kafka’s death. (Kafka’s three sisters were murdered in Nazi concentration camps.) Kafka witnessed firsthand the rising racism that accompanied the disintegration of the Habsburg Empire, including a three-day riot in Prague in December 1897. Yet Kafka did not take refuge in the embrace of Jewish belonging. “What have I in common with Jews?” he later remarked. “I have hardly anything in common with myself” (The Diaries of Franz Kafka. Translated by Ross Benjamin. New York: Schocken, 2023, p. 330). At age twenty-five, after earning a law degree at the University of Prague, Kafka was hired at the Workers’ Accident Insurance Institute. One of only two Jews among the 260 employees, he earned a reputation for diligence but found the office drudgery unbearable. He remained there until 1917, when he was diagnosed with tuberculosis. With considerable reluctance, Kafka published some fiction during his lifetime, including The Judgment, Metamorphosis, In the Penal Colony (In der Strafkolonie, 1919), and A Country Doctor (Ein Landarzt, 1919). A Hunger Artist (Ein Hungerkünstler, 1924) appeared shortly after his death. For the rest, we owe the survival of Kafka’s works to Brod’s disregard of Kafka’s instruction that his unpublished manuscripts be destroyed. After the Second World War, Brod edited a collected edition of Kafka’s works and letters (published in seven volumes by S. Fischer Verlag in 1976).
Improving future agricultural sustainability by optimizing crop distributions in China
Authors: Guan Qi , Tang Jing , Davis Kyle Frankel , Kong Mengxiang , Feng Lian , Shi Kun , Schurgers Guy
Published: January 2025

Improving agricultural sustainability is a global challenge, particularly for China's high-input and low-efficiency cropping systems with environmental tradeoffs. Although national strategies have been implemented to achieve Sustainable Development Goals in agriculture, the potential contributions of crop switching as a promising solution under varying future climate change are still under-explored. Here, we optimize cropping patterns spatially with the targets of enhancing agriculture production, reducing environmental burdens, and achieving sustainable fertilization across different climate scenarios. Compared with current cropping patterns, the optimal crop distributions under different climate scenarios consistently suggest allocating the planting areas of maize and rapeseed to the other crops (rice, wheat, soybean, peanut, and potato). Such crop switching can consequently increase crop production by 14.1%, with accompanying reductions in environmental impacts (8.2% for leached nitrogen and 24.0% for irrigation water use) across three representative Shared Socio-economic Pathways from 2020 to 2100. The sustainable fertilization rates vary from 148–173 kg N ha−1 in 2030 to 213–253 kg N ha−1 in 2070, significantly smaller than the current rate (305 kg N ha−1). These outcomes highlight large potential benefits of crop switching and fertilizer management for improving China's future agricultural sustainability.
An orally available P1′-5-fluorinated Mpro inhibitor blocks SARS-CoV-2 replication without booster and exhibits high genetic barrier
Authors: Higashi-Kuwata Nobuyo , Bulut Haydar , Hayashi Hironori , Tsuji Kohei , Ogata-Aoki Hiromi , Kiso Maki , Takamune Nobutoki , Kishimoto Naoki , Hattori Shin-ichiro , Ishii Takahiro , Kobayakawa Takuya , Nakano Kenta , Shimizu Yukiko , Das Debananda , Saruwatari Junji , Hasegawa Kazuya , Murayama Kazutaka , Sukenaga Yoshikazu , Takamatsu Yuki , Yoshimura Kazuhisa , Aoki Manabu , Furusawa Yuri , Okamura Tadashi , Yamayoshi Seiya , Kawaoka Yoshihiro , Misumi Shogo , Tamamura Hirokazu , Mitsuya Hiroaki
Published: January 2025

We identified a 5-fluoro-benzothiazole-containing small molecule, TKB272, through fluorine-scanning of the benzothiazole moiety, which more potently inhibits the enzymatic activity of SARS-CoV-2's main protease (Mpro) and more effectively blocks the infectivity and replication of all SARS-CoV-2 strains examined including Omicron variants such as SARS-CoV-2XBB1.5 and SARS-CoV-2EG.5.1 than two Mpro inhibitors: nirmatrelvir and ensitrelvir. Notably, the administration of ritonavir-boosted nirmatrelvir and ensitrelvir causes drug–drug interactions warranting cautions due to their CYP3A4 inhibition, thereby limiting their clinical utility. When orally administered, TKB272 blocked SARS-CoV-2XBB1.5 replication without ritonavir in B6.Cg-Tg(K18-hACE2)2-Prlmn/J-transgenic mice, comparably as did ritonavir-boosted nirmatrelvir. When the ancestral SARS-CoV-2 was propagated with nirmatrelvir in vitro, a highly nirmatrelvir-resistant E166V-carrying variant (SARS-CoV-2E166V−P14) readily emerged by passage 14; however, when propagated with TKB272, no variants emerged by passage 25. SARS-CoV-2E166V showed some cross-resistance to TKB272 but was substantially sensitive to the compound. X-ray structural analyses and mass-spectrometric data showed that the E166V substitution disrupts the critical dimerization-initiating Ser1′-E166 interactions, thereby limiting nirmatrelvir's Mpro inhibition but that TKB272 nevertheless forms a tight binding with Mpro's catalytic active sight even in the presence of the E166V substitution. TKB272 shows no apparent genotoxicity as tested in the micro-Ames test. Highly potent TKB272 may serve as a COVID-19 therapeutic, overcome resistance to existing Mpro inhibitors.
Is blameworthiness terminable?
Authors: Clarke Randolph
Published: January 2025

Benjamin Matheson has recently argued that blameworthiness is terminable: in at least some cases, one's blameworthiness for a given offense can be diminished or even eliminated. Although Matheson presents a forceful challenge to those who deny this view—interminability theorists, he calls them—he misconstrues their position and fails to come to grips with several considerations that favor it. This paper aims to clarify key aspects of the debate and defend the claim that blameworthiness is interminable.
An exploratory analysis of the operational restrictions of virtual peer review panels
Authors: Derrick G E
Published: January 2025

In the early months of the COVID-19 pandemic, many research funding organizations were faced with the choice of suspending their peer review panels, or else continuing their decision-making processes virtually. Although seen part of a longer drive to make peer review more cost and time efficient as well as to combat climate and sustainability goals by reducing academic travel, it is still not fully understood how the adoption of the virtual peer review panels influences the decision-making process. Using an initial exploratory approach and using a series of observations of four peer review panels conducted virtually during 2020 at the Research Council of Norway (Forskningsrådet), this research explores how panellists behaved, and deliberations operated within virtual environments. The initial, exploratory findings show that despite arguments that virtual panels are more efficient, by saving time and money by allowing panellists to participate from their home settings, behaviours around the role of Panel Chair, and the ability of panellists to move in and out of deliberations, suggests alterations in how panels reached and then confirmed a consensus in the virtual environment. Deliberate mechanisms to confirm consensus were required during virtual panels, suggesting a more onerous workload mid- and post-panel for Panel Chairs and Call managers. Whereas a majority of panel groups had experience of working together as a panel in the past, the process of introducing new members in an online environment was problematic. These preliminary results indicate that more evidence is needed about how the virtual environment influences peer review processes before a more permanent change is adopted by funding agencies.
Menopausal hormone therapy and the risk of systemic lupus erythematosus and systemic sclerosis: a population-based nested case-control study
Authors: Patasova Karina , Dehara Marina , Mantel Ängla , Bixo Marie , Arkema Elizabeth V , Holmqvist Marie
Published: January 2025

Objectives

SLE and SSc are more common in women, partly due to differences in female sex hormones. Menopausal hormone therapy (MHT) is widely used to alleviate climacteric symptoms. Here, the relationship between MHT and SLE/SSc was investigated in a nested case-control study.

Methods

Women with SLE or SSc and controls, matched 1 up to 10 on sex, birth year and region, from the general population of Sweden. Data on exposures and potential confounders were obtained from the National Patient and Prescribed Drug Register as well as the Longitudinal Integration Database for Health Insurance and Labour Market Studies. Exposure was defined as the dispensation of any MHT medication prior to the diagnosis/matching. The association between MHT and SLE/SSc, and whether the strength of the association, expressed as odds ratios (OR) and 95% CI, varied by type, route of administration, and duration of use, was assessed using conditional logistic regression, adjusted for education, income and sick leave.

Results

In total, 943 women with SLE and 733 women with SSc were identified between 2009 and 2019. We detected a significant association between MHT use and risk of SLE (OR = 1.3; 95% CI: 1.1–1.6), and SSc (OR = 1.4; 95% CI: 1.2–1.7). Women who had both systemic and local MHT medications dispensed exhibited the highest risk of SLE (OR = 1.9; 95% CI: 1.4–2.7) and SSc (OR = 1.8; 95% CI: 1.2–2.5).

Conclusion

These findings indicate an association between MHT and SLE/SSc, independent of socioeconomic factors, warranting further investigation into the role of exogenous female sex hormones in SLE/SSc pathogenesis.
Amitriptyline for the prevention of post-herpetic neuralgia: study protocol for the ATHENA study
Authors: Wells Sian , MacNeill Stephanie J , Liu Yumeng , Gilbertson Anna , Everitt Hazel , van Hecke Oliver , Banks Jonathan , Rees Sophie , Kandiyali Rebecca , Garfield Kirsty , Hunt Lorelei , Fodor Ioana , Wylde Vikki , Johnson Robert , Hay Alastair D , Pickering Anthony E , Ridd Matthew J
Published: January 2025

Background

Post-herpetic neuralgia (PHN) is the most common complication of herpes zoster, also known as shingles. Amitriptyline has been postulated to prevent PHN. The objective was to determine whether prophylactic low-dose amitriptyline prevents PHN in patients newly diagnosed with shingles.

Methods

Multi-centre, individually randomized, pragmatic, placebo-controlled superiority trial with health economic analysis and nested qualitative study. Patients with new onset shingles are screened by treating clinicians in participating general practitioner surgeries. Key eligibility criteria are: age ≥50 years, ≤6 days since rash onset and not already taking (and no contraindication to) amitriptyline. Participants are randomized 1:1 to amitriptyline 10 mg or matched placebo tablets (dose escalated as tolerated to maximum three tablets daily for 70 days). Resource-use data (including health, social and informal care, personal expenses and usual activities) is collected from electronic medical records and participant questionnaires. A sample of recruitment conversations are audio-recorded and interviews conducted with recruiters and patients, including those who decline to participate or who withdraw from the trial.

Results

The primary outcome is presence of PHN (≥3/10 worst pain on Zoster Brief Pain Inventory) at 90 days after rash onset. Primary health economic analyses will present cost per case of PHN prevented and cost per quality-adjusted life year. Qualitative data will be analysed to optimize trial delivery and to aid interpretation and implementation of the trial findings.

Conclusions

This is the largest trial to date evaluating the clinical/cost effectiveness and acceptability of prophylactic low-dose amitriptyline for the prevention of PHN.
Silicon reduces lead accumulation in Moso bamboo via immobilization and suppression of metal cation transporter genes in roots
Authors: Yang Fan , Xie Xuanhong , Zhao Yu , Jin Zetao , Pan Xianyu , Shen Zhenming , Hu Lin , Yu Xuejun , Shao Ji Feng
Published: January 2025

Lead (Pb) is a hazardous element that affects the growth and development of plants, while silicon (Si) is a beneficial element for alleviating the stress caused by heavy metals, including Pb. However, the mechanisms by which Si reduces Pb accumulation in Moso bamboo (Phyllostachys edulis (Carr ·) H · de Lehaie) remain unclear. In this study, physiological assessments and transcriptome analyses were conducted to investigate the interaction between Si and Pb. Our findings showed that Si application has no significant effect on alleviating Pb-induced inhibition of root elongation and dry weight in short-term and long-term experiments, respectively. However, it did rescue leaf yellowing and reduce Pb accumulation, particularly in the shoot. Pre-treatment with Si led to a reduction in Pb uptake, translocation and accumulation, coupled with an increase in Pb fixation within the hemicellulose of the root cell wall, resulting in a lower Pb concentration in the cell sap. At the cellular level, Pb was found to be distributed in all cells of roots, and Si pretreatment did not alter Pb distribution. Additionally, Si application downregulated the expression of genes related to ABC and metal cation transporters. These findings indicate that Si reduces Pb accumulation in Moso bamboo by immobilizing Pb in the hemicellulose of root cell walls and downregulating the expression of transporter genes involved in Pb uptake and transport.
Virulence Characterization and Population Structure of Puccinia striiformis f. sp. tritici in Henan Province, China
Authors: Ma Mengjie , Jin Yongjin , Chen Xianming , Wang Jie , Liu Xinyun , Geng Li , Zheng Wenming , Huang Lili , Kang Zhensheng , Zhan Gangming
Published: January 2025

Wheat stripe rust, caused by Puccinia striiformis f. sp. tritici (Pst), poses a significant threat to wheat production, particularly in Henan province, which produces more than 36 million tons of wheat grain every year, the highest production among all provinces in China. This study characterized 219 Pst isolates collected from the five regions of Henan through virulence testing using two sets of wheat differentials and genotyping with 23 Kompetitive allele-specific PCR (KASP) markers developed from single-nucleotide polymorphism (SNP) markers. Based on the virulence phenotypes on the Chinese differentials, 37 races were identified, including 17 new races. CYR34, CYR32, and G22-14 were the top three most prevalent races across the province. The virulence profiles varied among the five regions. The tests of the isolates with the Yr single-gene differentials revealed 75 races. None of the isolates were virulent to either Yr5 or Yr15, whereas the virulence frequencies to the other 16 Yr genes varied from 10% to 85% in the province and slightly different among the five regions for each virulence factors. The Pst populations from the five regions were clustered into two major groups based on the two sets of differentials and the KASP-SNP marker data. These findings provide valuable insights for developing wheat cultivars with effective resistance for enhancing stripe rust management and improving wheat yields in Henan province and the country.