bluuebunny/crossref_metadata_2025 huggingface dataset:
Evil and embodiment: towards a Latter-day Saint non-identity theodicy
Authors: Haderlie Derek Christian , Miller Taylor-Grey Edward
Published: January 2024

We offer an account of the metaphysics of persons rooted in Latter-day Saint scripture that vindicates the essentiality of origins. We then give theological support for the claim that prospects for the success of God's soul making project are bound up in God creating particular persons. We observe that these persons would not have existed were it not for the occurrence of a variety of evils (of even the worst kinds), and we conclude that Latter-day saint theology has the resources to endorse a strong soul-making non-identity theodicy. We then introduce two complications for this account rooted in the problem of horrendous evils. First, horrendous evils threaten to undermine our confidence that God is good to each created person within the context of their life. And second, horrendous evils raise concerns about the value of persons whose existence depends on the occurrence of those evils. We may wonder whether those whose existence depends on the occurrence of horrendous evils are valuable enough to motivate God's allowance of those evils. We show that by attending to important structural features of a post-mortem, pre-eschatological state called the spirit world, Latter-day Saints can ameliorate these concerns about horrendous evils.
Unconventional policy instruments in the New Keynesian model
Authors: Alla Zineddine , Espinoza Raphael A. , Ghosh Atish R.
Published: January 2024

This paper analyzes the use of unconventional policy instruments in New Keynesian setups in which the “divine coincidence” breaks down. The paper discusses the role of a second instrument that, in addition to the effect of conventional interest rate policy, may enter the Phillips curve, the investment–saving (IS) curve, and the welfare function, thus influencing inflation and output. The paper presents theoretical results on equilibrium determinacy, the inflation bias, the stabilization bias, and the optimal central banker’s preferences when both instruments are available. We show that the use of an unconventional instrument reduces the zone of equilibrium indeterminacy and may reduce the volatility of the economy. However, in some circumstances, committing to not use the second instrument may be welfare-improving (a result akin to Rogoff (Journal of International Economics 18(3-4), 199–217, 1985) example of counterproductive coordination). We also show that the optimal central banker should be both aggressive against inflation and interventionist in using the unconventional policy instrument, and we analyze the optimal central banker’s preferences when social preferences would yield equilibrium indeterminacy.
THE RIEFFEL CORRESPONDENCE FOR EQUIVALENT FELL BUNDLES
Authors: KALISZEWSKI S. , QUIGG JOHN , WILLIAMS DANA P.
Published: January 2024

We establish a generalized Rieffel correspondence for ideals in equivalent Fell bundles.
Double positivity for rheumatoid factor and anti-CCP autoantibodies: improving referral from primary care of patients suspected of having rheumatoid arthritis
Authors: Salinas Maria , Blasco Álvaro , Flores Emilio , Minguez Mauricio , Leiva-Salinas Carlos
Published: January 2024

Background:

Rheumatoid arthritis (RA) is a chronic progressive autoimmune inflammatory disease with significant morbidity and mortality. The course of the disease can be modified if diagnosis is early and treatment appropriate.

Aim:

In this study, we aimed to evaluate a new strategy for early identification of RA patients in primary care settings (the ‘diagnostic bottleneck’) based on serological biomarkers and to manage inappropriate rheumatoid factor (RF) laboratory test requests.

Method:

A two-arm study was carried out. The first arm corresponded to a retrospective observational descriptive study of patients referred for RF testing from primary care using the current laboratory workflow. The second arm included the following prospective interventions: cancelation of RF requests corresponding to patients with previous negative results for RF over a one-year period; and automatic reflex testing antibodies against cyclic citrullinated proteins (anti-CCP) for patients displaying RF values >30 IU/ml. Outcomes from both arms were then compared.

Findings:

As double positivity for RF and anti-CCP notably increases the positive likelihood ratio of RA. The intervention enabled a reduction of 2813 tests in 22 months. Moreover, the frequency of unnecessary referrals was reduced from 22% to 8.2%, while that of missed patients decreased slightly (from 21% to 16%), with the number of patients diagnosed per RF request remaining unchanged. In terms of costs, we saved 19.4 RF tests per anti-CCP test added.

We developed a simple and cost-effective strategy for reducing the time to diagnosis of RA that can improve patients’ quality of life. This approach was supported by primary and specialised care.
Could polyphenols be an effective treatment in the management of polycystic ovary syndrome?
Authors: Irmak Esra , Tunca Sanlier Nazli , Sanlier Nevin
Published: January 2024

Abstract: Polycystic ovary syndrome (PCOS), is a health problem observed in women of reproductive age. Different diets, physical activity recommendations and lifestyle changes can be effective in dealing with the symptoms of PCOS. Nutrition is indeed an essential part of the treatment of the disease as it directly affects body weight loss, insulin resistance, lipid profile, hormones, and dermatological complaints such as acne. Polyphenols, simply classified as flavonoids and non-flavonoids, are bioactive components found in plant-based foods. The most common polyphenols in the diet are flavanols, flavonols, flavanone, anthocyanins. In particular, polyphenols which are compounds naturally found in foods, have antioxidant, anticancer, anti-inflammatory, antimutagenic benefits along with many other ones. In the treatment of PCOS, polyphenols may help reduce the symptoms, improve insulin resistance and poor lipid profile, and cure hormonal disorders. It has been reported that polyphenols are influential in menstrual cycle disorders and enable a decrease in body weight, hyperandrogenism, estrogen, testosterone, luteinizing hormone (LH)/follicle stimulating hormone (FSH) ratios and LH. For adequate daily intake of polyphenols, which are found in high amounts in fruits and vegetables, at least 5 portions of fruits and vegetables should be consumed in addition to a healthy nutrition pattern. In this review, the effects of various polyphenols on polycystic ovary syndrome are discussed.
Uncertainties of Annual Suspended Sediment Transport Estimates Driven by Temporal Variability
Authors: Slabon Aron , Hoffmann Thomas
Published: January 2024

The majority of sediment transported from rivers to the global oceans is moved in suspension as fine particles. Thereby, the transported sediment shapes the physical environment regarding erosive and accumulative processes. Temporal variations in sediment supply and transport lead to unquantified uncertainties in annual load estimates, requiring high‐resolution data sets and a sound understanding of site‐specific catchment characteristics. We investigate the temporal variability of suspended sediment transport in four catchments in Germany with highly different discharge regimes and catchment sizes (<1,000 km2 to >100,000 km2). The data set consists of high‐resolution 15‐min turbidity measurements with daily discharge and frequent manual sampling. Utilizing a bootstrap approach based on the 15‐min time series, we assessed the impact of the sampling interval on annual load estimates for less frequent data sets. We use the sediment load exceedance time (Ts80%) as a measure of variability and relate it to uncertainties in annual load estimates. Since low‐frequency data sets rely on sediment rating curves, we performed a sensitivity analysis of the rating parameters a, b, and ε. Our results indicate a negative exponential relationship between Ts80% and uncertainties in annual load estimates. Based on the Ts80%, we can derive the shortest sampling frequency necessary to obtain annual load estimates with an error of <20% over varying discharge regimes. Additionally, Ts80% is linked to rating exponent b, with low b‐values indicating high Ts80%‐values and lower variability, and high b‐values indicating higher variability.
Impact of Anthropogenic Warming on Future Unprecedented Droughts in California: Insights From Multiple Indices and Multi‐Model Projections
Authors: Zhou Zixuan , Kim Yong‐Tak , Im Eun‐Soon , Kwon Hyun‐Han
Published: January 2024

So‐called hot droughts are seen as one of the very foreseeable extremes amid the faster‐than‐expected pace of global warming. In particular, the western part of North America has been pummeled by severe droughts due to a lack of precipitation as well as record‐breaking hot temperatures. This study assesses the joint return period of drought severity and duration using the COordinated Regional Climate Downscaling EXperiment‐COmmon Regional Experiment (CORDEX‐CORE) simulations over the California domain. Six dynamically downscaled simulations with 25 km resolution are analyzed for the historical (1956–2005) and future (2050–2099) periods, whose warming sensitivities differ based on three global climate models (GCMs) driving two regional climate models (RCMs). Our focus is on estimating the joint probabilities of the drought duration and severity constructed from multiple drought indices such as the Palmer Drought Severity Index (PDSI) (with original temperature (PDSI) and its detrended counterpart (PDSI_detrended)) and Standardized Precipitation Index (SPI). Under the RCP8.5 scenario, an unprecedented level of droughts in terms of both duration and severity is likely to emerge only when the drought is characterized by PDSI. A comparison of PDSI and PDSI_detrended explicitly reveals that the occurrence of severe and prolonged droughts is mainly attributed to the warming trend of temperature. Both PDSI_detrended and SPI, which do not incorporate the warming effect explicitly, barely differentiate the joint distributions from the historical and future simulations. Unlike the PDSI based on water budget, the SPI, based on solely accumulated precipitation, shows a loosely coupled joint structure between the severity and duration of droughts, with marked differences in their marginal distributions.
On the Effects of Turbulence Modulation Driven by Suspended Sediment Stratification in Emergent Rigid Canopies
Authors: Ranjan Pallav , Tinoco Rafael O.
Published: January 2024

Aquatic vegetation has the potential to increase suspended sediment capture while also increasing sediment resuspension and bedload transport. Suspended sediment can induce density stratification, which modulates the turbulence in the water column. We derive a Rouse‐based formulation for suspended sediment concentration (SSC) including the effect of sediment‐induced density stratification. We perform Large Eddy Simulations of vegetated and non‐vegetated channels to explicitly highlight the effect of stratification on SSC profiles. We found that the impact of stratification is dominant in the near‐bed region within the bottom boundary layer, affecting both sediment resuspension and bedload transport. Stratification reduces the likelihood of both dominant sweep and ejection events in the near the bed region which may affect sediment entrainment and bedload transport. Modifications to existing models of sediment entrainment and bedload transport are suggested to account for the effects of sediment induced stratification in vegetated and non‐vegetated channels.
Pore‐Scale Modeling of Water and Ion Diffusion in Partially Saturated Clays
Authors: Yang Yuankai , Churakov Sergey V. , Patel Ravi A. , Prasianakis Nikolaos , Deissmann Guido , Bosbach Dirk , Poonoosamy Jenna
Published: January 2024

An accurate mechanistic understanding of solute diffusion in partially saturated clays is critical for assessing the safety of deep geological repositories for radioactive waste. In this study, a pore‐scale numerical framework is developed to simulate water and ion diffusion in partially saturated clays. First, the two‐phase Shan‐Chen Lattice Boltzmann method is employed to establish the liquid‐gas distribution in a reconstructed three‐dimensional pore geometry of a clay. An equivalent solute method is also developed and validated to improve the numerical stability of the solution at the liquid/gas interface corresponding to steep variations of the concentration and diffusion coefficient of the water tracer. By using a mobility‐distance relationship from molecular simulations, Fick's law is numerically solved to simulate water diffusion in nanopores, while the coupled Poisson‐Boltzmann‐Nernst‐Planck equations are solved to simulate ion diffusion under the influence of the electrical double layer (EDL). Our model reveals that the decrease of relative effective diffusion coefficients during the desaturation is more pronounced for ions than for water, due to the additional transport pathway of water tracers in the gas phase. The obtained effective diffusion coefficients of tritiated water and ions agree well with reported data from compacted sedimentary rocks. By comparing the local electric potential and the distribution of ion concentrations in single pores, the simulation results suggest that the EDL in unsaturated clays has a more complex influence on ion distribution than under fully water‐saturated conditions. This study provides critical insights into the coupled transport processes of solutes in partially saturated clays.
Reconstruction of the Pleistocene Paleoclimate From Deep Groundwater in Southern Germany From Noble Gas Temperatures Linked With Organic Radiocarbon Dating
Authors: Winter Theis , Aeschbach Werner , Einsiedl Florian
Published: January 2024

This study presents a 25 ka reconstruction of the Pleistocene paleoclimate in the South German Molasse Basin. Deep groundwater was sampled at 19 wells in the Upper Jurassic aquifer (UJA). Calculating gas temperatures (NGT) using the UA model with the noble gases Ar, Kr, and Xe led to groundwater recharge temperatures between 0.4 and 4.7°C. Combined with innovative 14CDOC groundwater dating, calculated NGTs revealed up to 8°C cooler soil temperatures during the Pleistocene compared with modern soil temperature. This interpretation agrees well with the observed depleted stable water isotope signature ranging from −83.3 to −86.1 for δ2H and from −10.66 to −11.77 for δ18O, which is characteristic of groundwater of Pleistocene origin in Southern Germany. The temperature differences (∆T) agree remarkably well with calculated NGTs within other European basins (∆T 6–9.5°C) and suggest widespread pronounced terrestrial cooling during the Last Glacial Maximum through the interior of the European continent.
Hybrid Discrete Fracture Network Inversion of Hydraulic Tomography Data From a Fractured‐Porous Field Site
Authors: Römhild Lukas , Ringel Lisa Maria , Liu Quan , Hu Linwei , Ptak Thomas , Bayer Peter
Published: January 2024

The accurate characterization of hydraulic conductivity heterogeneities in an aquifer is crucial for predicting flow and transport processes correctly. Hydraulic tomography (HT) experiments are often used to infer the hydraulically relevant features, but the correct inversion of the data remains a challenging task. We implemented a discrete fracture network (DFN) inversion approach that is expanded by considering a nonzero matrix permeability. The hybrid model allows the accurate characterization of fractured‐porous sites by taking into account both matrix and fracture flow. This novel inversion algorithm is successfully applied to HT data acquired at a field site in Goettingen (Germany), and the results are compared with those of a standard travel time inversion. Furthermore, we validate the inversion results by using them as the underlying material parameters for simulating heat tracer experiments and comparing the modeled temperature responses with those of heat tracer tests actually conducted at the site. It is shown that the DFN ensemble predicts the thermal response of the experiments correctly for the two major fractures in terms of location, amplitude, and time‐dependent behavior of the temperature anomaly, as long as the stochastic nature of the results is taken into account. We conclude that considering both matrix and fracture flow in a hybrid DFN inversion approach can lead to significant improvements in flow and transport modeling at fractured‐porous sites.
Stochastic Inversion of a Tomographic Pumping Test: Identifying Conductivity Horizontal Correlation and Longitudinal Macrodispersivity
Authors: Cheng Kan Bun , Rabinovich Avinoam , Dagan Gedeon
Published: January 2024

Two important properties for modeling flow and transport in heterogeneous aquifers are the horizontal integral scale (Ih) of hydraulic logconductivity (Y = ln K) and the longitudinal macrodispersivity (αL). Estimating the former generally requires K measurements in many wells, which are typically not available. In this work, we present a method for estimating Ih and αL from hydraulic tomography (HT) pumping tests. The approach is based on stochastic inversion, assuming head and K are stationary random space functions. Head variance and mean head gradient are calculated from measured head data at large distances from the pumping well and for large times from the start of pumping. These are then used in a theoretical formula for head variance in uniform mean flow to obtain Ih and subsequently αL, requiring only previous knowledge of the vertical integral scale (Iv) and the logconductivity variance . The method is applied to data from an HT pumping test at the Boise Hydrogeophysical Research site and results for Ih and αL are in the range previously reported in the literature. Particularly promising results are found for αL, which is seen to be robust, with relatively little variation for different values of Iv and .
Highly-coherent second-harmonic generation in a chip-scale source
Authors: Liu Xuanyi , Fu Hongyan
Published: January 2024

A highly efficient second-harmonic source is integrated into a silicon nitride microring resonator, unlocking the potential for advanced chip-scale devices such as miniaturized atomic clocks and fully integrated self-referenced microcombs.
Revolutionizing solid-state single-photon sources with multifunctional metalenses
Authors: Ding Fei
Published: January 2024

Ultrathin multifunctional metalenses are demonstrated to control the multiple degrees of freedom of a single-photon source in hexagonal boron nitride.
An in vitro demonstration of a passive, acoustic metamaterial as a temperature sensor with mK resolution for implantable applications
Authors: Maini Lucrezia , Genovés Vicente , Furrer Roman , Cesarovic Nikola , Hierold Christofer , Roman Cosmin
Published: January 2024

Wireless medical sensors typically utilize electromagnetic coupling or ultrasound for energy transfer and sensor interrogation. Energy transfer and management is a complex aspect that often limits the applicability of implantable sensor systems. In this work, we report a new passive temperature sensing scheme based on an acoustic metamaterial made of silicon embedded in a polydimethylsiloxane matrix. Compared to other approaches, this concept is implemented without additional electrical components in situ or the need for a customized receiving unit. A standard ultrasonic transducer is used for this demonstration to directly excite and collect the reflected signal. The metamaterial resonates at a frequency close to a typical medical value (5 MHz) and exhibits a high-quality factor. Combining the design features of the metamaterial with the high-temperature sensitivity of the polydimethylsiloxane matrix, we achieve a temperature resolution of 30 mK. This value is below the current standard resolution required in infrared thermometry for monitoring postoperative complications (0.1 K). We fabricated, simulated, in vitro tested, and compared three acoustic sensor designs in the 29–43 °C (~302–316 K) temperature range. With this concept, we demonstrate how our passive metamaterial sensor can open the way toward new zero-power smart medical implant concepts based on acoustic interrogation.
High-resolution tracking of unconfined zebrafish behavior reveals stimulatory and anxiolytic effects of psilocybin
Authors: Braun Dotan , Rosenberg Ayelet M. , Rabaniam Elad , Haruvi Ravid , Malamud Dorel , Barbara Rani , Aiznkot Tomer , Levavi-Sivan Berta , Kawashima Takashi
Published: January 2024

Serotonergic psychedelics are emerging therapeutics for psychiatric disorders, yet their underlying mechanisms of action in the brain remain largely elusive. Here, we developed a wide-field behavioral tracking system for larval zebrafish and investigated the effects of psilocybin, a psychedelic serotonin receptor agonist. Machine learning analyses of precise body kinematics identified latent behavioral states reflecting spontaneous exploration, visually-driven rapid swimming, and irregular swim patterns following stress exposure. Using this method, we found that acute psilocybin treatment has two behavioral effects: [i] facilitation of spontaneous exploration (“stimulatory”) and [ii] prevention of irregular swim patterns following stress exposure (“anxiolytic”). These effects differed from the effect of acute SSRI treatment and were rather similar to the effect of ketamine treatment. Neural activity imaging in the dorsal raphe nucleus suggested that psilocybin inhibits serotonergic neurons by activating local GABAergic neurons, consistent with psychedelic-induced suppression of serotonergic neurons in mammals. These findings pave the way for using larval zebrafish to elucidate neural mechanisms underlying the behavioral effects of serotonergic psychedelics.
Lung microbiome: new insights into the pathogenesis of respiratory diseases
Authors: Li Ruomeng , Li Jing , Zhou Xikun
Published: January 2024

The lungs were long thought to be sterile until technical advances uncovered the presence of the lung microbial community. The microbiome of healthy lungs is mainly derived from the upper respiratory tract (URT) microbiome but also has its own characteristic flora. The selection mechanisms in the lung, including clearance by coughing, pulmonary macrophages, the oscillation of respiratory cilia, and bacterial inhibition by alveolar surfactant, keep the microbiome transient and mobile, which is different from the microbiome in other organs. The pulmonary bacteriome has been intensively studied recently, but relatively little research has focused on the mycobiome and virome. This up-to-date review retrospectively summarizes the lung microbiome’s history, composition, and function. We focus on the interaction of the lung microbiome with the oropharynx and gut microbiome and emphasize the role it plays in the innate and adaptive immune responses. More importantly, we focus on multiple respiratory diseases, including asthma, chronic obstructive pulmonary disease (COPD), fibrosis, bronchiectasis, and pneumonia. The impact of the lung microbiome on coronavirus disease 2019 (COVID-19) and lung cancer has also been comprehensively studied. Furthermore, by summarizing the therapeutic potential of the lung microbiome in lung diseases and examining the shortcomings of the field, we propose an outlook of the direction of lung microbiome research.
Cdk5-dependent rapid formation and stabilization of dendritic spines by corticotropin-releasing factor
Authors: Vandael Dorien , Vints Katlijn , Baatsen Pieter , Śliwińska Małgorzata A. , Gabarre Sergio , De Groef Lies , Moons Lieve , Rybakin Vasily , Gounko Natalia V.
Published: January 2024

The neuropeptide corticotropin-releasing factor (CRF) exerts a pivotal role in modulating neuronal activity in the mammalian brain. The effects of CRF exhibit notable variations, depending on factors such as duration of exposure, concentration, and anatomical location. In the CA1 region of the hippocampus, the impact of CRF is dichotomous: chronic exposure to CRF impairs synapse formation and dendritic integrity, whereas brief exposure enhances synapse formation and plasticity. In the current study, we demonstrate long-term effects of acute CRF on the density and stability of mature mushroom spines ex vivo. We establish that both CRF receptors are present in this hippocampal region, and we pinpoint their precise subcellular localization within synapses by electron microscopy. Furthermore, both in vivo and ex vivo data collectively demonstrate that a transient surge of CRF in the CA1 activates the cyclin-dependent kinase 5 (Cdk5)-pathway. This activation leads to a notable augmentation in CRF-dependent spine formation. Overall, these data suggest that upon acute release of CRF in the CA1-SR synapse, both CRF-Rs can be activated and promote synaptic plasticity via activating different downstream signaling pathways, such as the Cdk5-pathway.
Mode of progression in smoldering multiple myeloma: a study of 406 patients
Authors: Abdallah Nadine H. , Lakshman Arjun , Kumar Shaji K. , Cook Joselle , Binder Moritz , Kapoor Prashant , Dispenzieri Angela , Gertz Morie A. , Lacy Martha Q. , Hayman Suzanne R. , Buadi Francis K. , Dingli David , Lin Yi , Kourelis Taxiarchis , Warsame Rahma , Bergsagel Leif , Rajkumar S. Vincent
Published: January 2024

The approach to patients with high-risk smoldering multiple myeloma (SMM) varies among clinicians; while some advocate early intervention, others reserve treatment at progression to multiple myeloma (MM). We aimed to describe the myeloma-defining events (MDEs) and clinical presentations leading to MM diagnosis among SMM patients seen at our institution. We included 406 patients diagnosed with SMM between 2013–2022, seen at Mayo Clinic, Rochester, MN. The 2018 Mayo 20/2/20 criteria were used for risk stratification. Median follow-up was 3.9 years. Among high-risk patients who did not receive treatment in the SMM phase (n = 71), 51 progressed by last follow-up; the MDEs included: bone lesions (37%), anemia (35%), hypercalcemia (8%), and renal failure (6%); 24% met MM criteria based on marrow plasmacytosis (≥60%) and/or free light chain ratio (>100); 45% had clinically significant MDEs (hypercalcemia, renal insufficiency, and/or bone lesions). MM diagnosis was made based on surveillance labs/imaging(45%), testing obtained due to provider suspicion for progression (14%), bone pain (20%), and hospitalization/ED presentations due to MM complications/symptoms (4%). The presentation was undocumented in 14%. A high proportion (45%) of patients with high-risk SMM on active surveillance develop end-organ damage at progression. About a quarter of patients who progress to MM are not diagnosed based on routine interval surveillance testing.
Soluble lymphocyte activation gene-3 (sLAG3) and CD4/CD8 ratio dynamics as predictive biomarkers in patients undergoing immune checkpoint blockade for solid malignancies
Authors: Gorgulho Joao , Roderburg Christoph , Beier Fabian , Bokemeyer Carsten , Brümmendorf Tim H. , Loosen Sven H. , Luedde Tom
Published: January 2024

Background

The search for biomarkers to identify suitable candidates for immune checkpoint inhibitor (ICI) therapy remains ongoing. We evaluate how soluble levels of the next generation immune checkpoint Lymphocyte Activation Gene-3 (sLAG-3) and its association with circulating T lymphocyte subsets could pose as a novel biomarker to predict outcome to ICI therapy.

Methods

Circulating levels of sLAG3 were analyzed using multiplex immunoassay in n = 84 patients undergoing ICI therapy for advanced solid cancer, accompanied by flow cytometry analyses of peripheral blood mononuclear cells (PBMCs).

Results

Uni- and multivariate analysis shows that patients with higher sLAG3 concentrations before ICI therapy had a significantly impaired progression-free (PFS) and overall survival (OS) (HRPFS: 1.005 [95%CI: 1.000–1.009], p = 0.039; HROS: 1.006 [95%CI: 1.001–1.011], p = 0.015). The CD4/CD8 cell ratio and its dynamics during therapy were strong predictors of PFS and OS with patients with a decreasing ratio between baseline and after 1–2 cycles having an improved median OS compared to patients with increasing values (p = 0.012, HR: 3.32). An immunological score combining sLAG3 and the CD4/CD8 ratio showed the highest predictive potential (HROS: 10.3).

Conclusion

Pending prospective validation, sLAG3 and correlating circulating T-cell subsets can be used as a non-invasive predictive marker to predict outcome to ICI therapy to help identifying ideal ICI candidates in the future.
FKBP10 promotes clear cell renal cell carcinoma progression and regulates sensitivity to the HIF2α blockade by facilitating LDHA phosphorylation
Authors: Liu Ren , Zou Zhihao , Chen Lingwu , Feng Yuanfa , Ye Jianheng , Deng Yulin , Zhu Xuejin , Zhang Yixun , Lin Jundong , Cai Shanghua , Tang Zhenfeng , Liang Yingke , Lu Jianming , Zhuo Yangjia , Han Zhaodong , Ling Xiaohui , Liang Yuxiang , Wang Zongren , Zhong Weide
Published: January 2024

Renal cell carcinoma (RCC) is one of the three major malignant tumors of the urinary system and originates from proximal tubular epithelial cells. Clear cell renal cell carcinoma (ccRCC) accounts for approximately 80% of RCC cases and is recognized as a metabolic disease driven by genetic mutations and epigenetic alterations. Through bioinformatic analysis, we found that FK506 binding protein 10 (FKBP10) may play an essential role in hypoxia and glycolysis pathways in ccRCC progression. Functionally, FKBP10 promotes the proliferation and metastasis of ccRCC in vivo and in vitro depending on its peptidyl-prolyl cis-trans isomerase (PPIase) domains. Mechanistically, FKBP10 binds directly to lactate dehydrogenase A (LDHA) through its C-terminal region, the key regulator of glycolysis, and enhances the LDHA-Y10 phosphorylation, which results in a hyperactive Warburg effect and the accumulation of histone lactylation. Moreover, HIFα negatively regulates the expression of FKBP10, and inhibition of FKBP10 enhances the antitumor effect of the HIF2α inhibitor PT2385. Therefore, our study demonstrates that FKBP10 promotes clear cell renal cell carcinoma progression and regulates sensitivity to HIF2α blockade by facilitating LDHA phosphorylation, which may be exploited for anticancer therapy.
Improving the marine biodegradability of poly(alkylene succinate)-based copolymers
Authors: Kumagai Sumito , Hayashi Senri , Katsuragi Atsushi , Imada Motosuke , Sato Kaoko , Abe Hideki , Asakura Noriyuki , Takenaka Yasumasa
Published: January 2024

We report the syntheses of novel marine biodegradable poly(ethylene succinate) (PES)- and poly(butylene succinate) (PBS)-based copolymers containing different dicarboxylic acid (DCA) units with various carbon numbers and different feed ratios. Biochemical oxygen demand tests demonstrated that some of the obtained PES- and PBS-based copolymers were biodegradable in seawater. Specifically, polymers with longer-chain DCA units, even at low contents, exhibited marine biodegradability. The thermomechanical properties of the copolymers, such as their thermal stabilities, melting points, glass transition temperatures, tensile moduli, strains at break, and stresses at break, also varied with the DCA contents. These results indicated that the thermomechanical properties and the marine biodegradabilities of the PES- and PBS-based copolymers were regulated by controlling their structures and DCA contents. The polymers obtained in this study may replace general-purpose polymers. Our approach may also be applicable to other polymeric materials. Furthermore, our findings pave the way for the rational design and preparation of polymeric materials that are biodegradable in environments other than oceans and have good thermomechanical properties.
Conserved chromatin and repetitive patterns reveal slow genome evolution in frogs
Authors: Bredeson Jessen V. , Mudd Austin B. , Medina-Ruiz Sofia , Mitros Therese , Smith Owen Kabnick , Miller Kelly E. , Lyons Jessica B. , Batra Sanjit S. , Park Joseph , Berkoff Kodiak C. , Plott Christopher , Grimwood Jane , Schmutz Jeremy , Aguirre-Figueroa Guadalupe , Khokha Mustafa K. , Lane Maura , Philipp Isabelle , Laslo Mara , Hanken James , Kerdivel Gwenneg , Buisine Nicolas , Sachs Laurent M. , Buchholz Daniel R. , Kwon Taejoon , Smith-Parker Heidi , Gridi-Papp Marcos , Ryan Michael J. , Denton Robert D. , Malone John H. , Wallingford John B. , Straight Aaron F. , Heald Rebecca , Hockemeyer Dirk , Harland Richard M. , Rokhsar Daniel S.
Published: January 2024

Frogs are an ecologically diverse and phylogenetically ancient group of anuran amphibians that include important vertebrate cell and developmental model systems, notably the genus Xenopus. Here we report a high-quality reference genome sequence for the western clawed frog, Xenopus tropicalis, along with draft chromosome-scale sequences of three distantly related emerging model frog species, Eleutherodactylus coqui, Engystomops pustulosus, and Hymenochirus boettgeri. Frog chromosomes have remained remarkably stable since the Mesozoic Era, with limited Robertsonian (i.e., arm-preserving) translocations and end-to-end fusions found among the smaller chromosomes. Conservation of synteny includes conservation of centromere locations, marked by centromeric tandem repeats associated with Cenp-a binding surrounded by pericentromeric LINE/L1 elements. This work explores the structure of chromosomes across frogs, using a dense meiotic linkage map for X. tropicalis and chromatin conformation capture (Hi-C) data for all species. Abundant satellite repeats occupy the unusually long (~20 megabase) terminal regions of each chromosome that coincide with high rates of recombination. Both embryonic and differentiated cells show reproducible associations of centromeric chromatin and of telomeres, reflecting a Rabl-like configuration. Our comparative analyses reveal 13 conserved ancestral anuran chromosomes from which contemporary frog genomes were constructed.
High-content screening identifies a small molecule that restores AP-4-dependent protein trafficking in neuronal models of AP-4-associated hereditary spastic paraplegia
Authors: Saffari Afshin , Brechmann Barbara , Böger Cedric , Saber Wardiya Afshar , Jumo Hellen , Whye Dosh , Wood Delaney , Wahlster Lara , Alecu Julian E. , Ziegler Marvin , Scheffold Marlene , Winden Kellen , Hubbs Jed , Buttermore Elizabeth D. , Barrett Lee , Borner Georg H. H. , Davies Alexandra K. , Ebrahimi-Fakhari Darius , Sahin Mustafa
Published: January 2024

Unbiased phenotypic screens in patient-relevant disease models offer the potential to detect therapeutic targets for rare diseases. In this study, we developed a high-throughput screening assay to identify molecules that correct aberrant protein trafficking in adapter protein complex 4 (AP-4) deficiency, a rare but prototypical form of childhood-onset hereditary spastic paraplegia characterized by mislocalization of the autophagy protein ATG9A. Using high-content microscopy and an automated image analysis pipeline, we screened a diversity library of 28,864 small molecules and identified a lead compound, BCH-HSP-C01, that restored ATG9A pathology in multiple disease models, including patient-derived fibroblasts and induced pluripotent stem cell-derived neurons. We used multiparametric orthogonal strategies and integrated transcriptomic and proteomic approaches to delineate potential mechanisms of action of BCH-HSP-C01. Our results define molecular regulators of intracellular ATG9A trafficking and characterize a lead compound for the treatment of AP-4 deficiency, providing important proof-of-concept data for future studies.
Effective binning of metagenomic contigs using contrastive multi-view representation learning
Authors: Wang Ziye , You Ronghui , Han Haitao , Liu Wei , Sun Fengzhu , Zhu Shanfeng
Published: January 2024

Contig binning plays a crucial role in metagenomic data analysis by grouping contigs from the same or closely related genomes. However, existing binning methods face challenges in practical applications due to the diversity of data types and the difficulties in efficiently integrating heterogeneous information. Here, we introduce COMEBin, a binning method based on contrastive multi-view representation learning. COMEBin utilizes data augmentation to generate multiple fragments (views) of each contig and obtains high-quality embeddings of heterogeneous features (sequence coverage and k-mer distribution) through contrastive learning. Experimental results on multiple simulated and real datasets demonstrate that COMEBin outperforms state-of-the-art binning methods, particularly in recovering near-complete genomes from real environmental samples. COMEBin outperforms other binning methods remarkably when integrated into metagenomic analysis pipelines, including the recovery of potentially pathogenic antibiotic-resistant bacteria (PARB) and moderate or higher quality bins containing potential biosynthetic gene clusters (BGCs).
VGLL1 cooperates with TEAD4 to control human trophectoderm lineage specification
Authors: Yang Yueli , Jia Wenqi , Luo Zhiwei , Li Yunpan , Liu Hao , Fu Lixin , Li Jinxiu , Jiang Yu , Lai Junjian , Li Haiwei , Saeed Babangida Jabir , Zou Yi , Lv Yuan , Wu Liang , Zhou Ting , Shan Yongli , Liu Chuanyu , Lai Yiwei , Liu Longqi , Hutchins Andrew P. , Esteban Miguel A. , Mazid Md. Abdul , Li Wenjuan
Published: January 2024

In contrast to rodents, the mechanisms underlying human trophectoderm and early placenta specification are understudied due to ethical barriers and the scarcity of embryos. Recent reports have shown that human pluripotent stem cells (PSCs) can differentiate into trophectoderm (TE)-like cells (TELCs) and trophoblast stem cells (TSCs), offering a valuable in vitro model to study early placenta specification. Here, we demonstrate that the VGLL1 (vestigial-like family member 1), which is highly expressed during human and non-human primate TE specification in vivo but is negligibly expressed in mouse, is a critical regulator of cell fate determination and self-renewal in human TELCs and TSCs derived from naïve PSCs. Mechanistically, VGLL1 partners with the transcription factor TEAD4 (TEA domain transcription factor 4) to regulate chromatin accessibility at target gene loci through histone acetylation and acts in cooperation with GATA3 and TFAP2C. Our work is relevant to understand primate early embryogenesis and how it differs from other mammalian species.
From chiral laser pulses to femto- and attosecond electronic chirality flips in achiral molecules
Authors: Chen Yunjiao , Haase Dietrich , Manz Jörn , Wang Huihui , Yang Yonggang
Published: January 2024

Chirality is an important topic in biology, chemistry and physics. Here we show that ultrashort circularly polarized laser pulses, which are chiral, can be fired on achiral oriented molecules to induce chirality in their electronic densities, with chirality flips within femtoseconds or even attoseconds. Our results, obtained by quantum dynamics simulations, use the fact that laser pulses can break electronic symmetry while conserving nuclear symmetry. Here two laser pulses generate a superposition of three electronic eigenstates. This breaks all symmetry elements of the electronic density, making it chiral except at the periodic rare events of the chirality flips. As possible applications, we propose the combination of the electronic chirality flips with Chiral Induced Spin Selectivity.
Structural polymorphism of amyloid fibrils in ATTR amyloidosis revealed by cryo-electron microscopy
Authors: Nguyen Binh An , Singh Virender , Afrin Shumaila , Yakubovska Anna , Wang Lanie , Ahmed Yasmin , Pedretti Rose , Fernandez-Ramirez Maria del Carmen , Singh Preeti , Pękała Maja , Cabrera Hernandez Luis O. , Kumar Siddharth , Lemoff Andrew , Gonzalez-Prieto Roman , Sawaya Michael R. , Eisenberg David S. , Benson Merrill Douglas , Saelices Lorena
Published: January 2024

ATTR amyloidosis is caused by the deposition of transthyretin in the form of amyloid fibrils in virtually every organ of the body, including the heart. This systemic deposition leads to a phenotypic variability that has not been molecularly explained yet. In brain amyloid conditions, previous studies suggest an association between clinical phenotype and the molecular structures of their amyloid fibrils. Here we investigate whether there is such an association in ATTRv amyloidosis patients carrying the mutation I84S. Using cryo-electron microscopy, we determined the structures of cardiac fibrils extracted from three ATTR amyloidosis patients carrying the ATTRv-I84S mutation, associated with a consistent clinical phenotype. We found that in each ATTRv-I84S patient, the cardiac fibrils exhibited different local conformations, and these variations can co-exist within the same fibril. Our finding suggests that one amyloid disease may associate with multiple fibril structures in systemic amyloidoses, calling for further studies.
Regulating Au coverage for the direct oxidation of methane to methanol
Authors: Xu Yueshan , Wu Daoxiong , Zhang Qinghua , Rao Peng , Deng Peilin , Tang Mangen , Li Jing , Hua Yingjie , Wang Chongtai , Zhong Shengkui , Jia Chunman , Liu Zhongxin , Shen Yijun , Gu Lin , Tian Xinlong , Liu Quanbing
Published: January 2024

The direct oxidation of methane to methanol under mild conditions is challenging owing to its inadequate activity and low selectivity. A key objective is improving the selective oxidation of the first carbon-hydrogen bond of methane, while inhibiting the oxidation of the remaining carbon-hydrogen bonds to ensure high yield and selectivity of methanol. Here we design ultrathin PdxAuy nanosheets and revealed a volcano-type relationship between the binding strength of hydroxyl radical on the catalyst surface and catalytic performance using experimental and density functional theory results. Our investigations indicate a trade-off relationship between the reaction-triggering and reaction-conversion steps in the reaction process. The optimized Pd3Au1 nanosheets exhibits a methanol production rate of 147.8 millimoles per gram of Pd per hour, with a selectivity of 98% at 70 °C, representing one of the most efficient catalysts for the direct oxidation of methane to methanol.
Accelerating the transition to cobalt-free batteries: a hybrid model for LiFePO4/graphite chemistry
Authors: Pozzato Gabriele , Li Xueyan , Lee Donghoon , Ko Johan , Onori Simona
Published: January 2024

The increased adoption of lithium-iron-phosphate batteries, in response to the need to reduce the battery manufacturing process’s dependence on scarce minerals and create a resilient and ethical supply chain, comes with many challenges. The design of an effective and high-performing battery management system (BMS) for such technology is one of those challenges. In this work, a physics-based model describing the two-phase transition operation of an iron-phosphate positive electrode—in a graphite anode battery—is integrated with a machine-learning model to capture the hysteresis and path-dependent behavior during transient operation. The machine-learning component of the proposed “hybrid” model is built upon the knowledge of the electrochemical internal states of the battery during charge and discharge operation over several driving profiles. The hybrid model is experimentally validated over 15 h of driving, and it is shown that the machine-learning component is responsible for a small percentage of the total battery behavior (i.e., it compensates for voltage hysteresis). The proposed modeling strategy can be used for battery performance analysis, synthetic data generation, and the development of reduced-order models for BMS design.
Exfoliation of an extruded Mg-4Li-1Ca alloy in presence of glucose and bovine serum albumin
Authors: Cai Lei , Zeng Mei-Qi , Liu Meng-Jie , Bao Jing-Yu , Ren Yu-Qian , Kannan M. Bobby , Cui Lan-Yue , Liu Cheng-Bao , Zhang Fen , Li Shuo-Qi , Zeng Rong-Chang
Published: January 2024

Exfoliation corrosion (EFC) on extruded Mg-4Li-1Ca alloys as bone implant materials has not been reported. This study aimed to elucidate the degradation mechanism of a corrosion type-exfoliation occurred on an extruded Mg-4Li-1Ca alloy under the interaction of glucose (Glu) and bovine serum albumin (BSA) in Hank’s solution. The alloy microstructure, chemical composition, texture, stress distribution and Volta potential maps were characterized using metallographic microscopy, scanning electron microscopy and electron backscattered diffraction, and scanning Kelvin Probe. The alloy corrosion behavior was investigated via electrochemical testing and hydrogen evolution rate methods. X-ray diffraction, Fourier transform infrared spectrometry, X-ray photoelectron spectrometer, and fluorescence microscopy were used to analyze the corrosion products and the adsorption of the organic molecules. The experimental results indicated that the anodic second phase (Mg2Ca) were distributed in lamellar and rod-like patterns along the extrusion direction of the alloy, a lower Volta potential for Mg2Ca, texture and residual stresses also promote EFC. An increase in Glu concentration exacerbated the EFC, whereas BSA inhibited the EFC of the alloy. Higher Glu concentrations in BSA in turn inhibited EFC since Glu can complex with amino acids in proteins to form Glu-amino acid amides, which promoted protein adsorption and thereby forming a dense protective film on the alloy surface. The preferential dissolution of the Mg2Ca phase particles led to the complexation and adsorption of Glu and protein. This study enriches the understanding of the corrosion types in biomedical Mg-4Li-1Ca alloy and paving the way for enhancing the EFC resistance of the alloy.
The network characteristics in schizophrenia with prominent negative symptoms: a multimodal fusion study
Authors: Kong Li , Zhang Yao , Wu Xu-ming , Wang Xiao-xiao , Wu Hai-su , Li Shuai-biao , Chu Min-yi , Wang Yi , Lui Simon S. Y. , Lv Qin-yu , Yi Zheng-hui , Chan Raymond C. K.
Published: January 2024

Previous studies on putative neural mechanisms of negative symptoms in schizophrenia mainly used single modal imaging data, and seldom utilized schizophrenia patients with prominent negative symptoms (PNS).This study adopted the multimodal fusion method and recruited a homogeneous sample with PNS. We aimed to identify negative symptoms-related structural and functional neural correlates of schizophrenia. Structural magnetic resonance imaging (sMRI) and resting-state functional MRI (rs-fMRI) were performed in 31 schizophrenia patients with PNS and 33 demographically matched healthy controls.Compared to healthy controls, schizophrenia patients with PNS exhibited significantly altered functional activations in the default mode network (DMN) and had structural gray matter volume (GMV) alterations in the cerebello-thalamo-cortical network. Correlational analyses showed that negative symptoms severity was significantly correlated with the cerebello-thalamo-cortical structural network, but not with the DMN network in schizophrenia patients with PNS.Our findings highlight the important role of the cerebello-thalamo-cortical structural network underpinning the neuropathology of negative symptoms in schizophrenia. Future research should recruit a large sample and schizophrenia patients without PNS, and apply adjustments for multiple comparison, to verify our preliminary findings.