bluuebunny/crossref_metadata_2025 huggingface dataset:
PMiSLocMF: predicting miRNA subcellular localizations by incorporating multi-source features of miRNAs
Authors: Chen Lei , Gu Jiahui , Zhou Bo
Published: August 2024

The microRNAs (miRNAs) play crucial roles in several biological processes. It is essential for a deeper insight into their functions and mechanisms by detecting their subcellular localizations. The traditional methods for determining miRNAs subcellular localizations are expensive. The computational methods are alternative ways to quickly predict miRNAs subcellular localizations. Although several computational methods have been proposed in this regard, the incomplete representations of miRNAs in these methods left the room for improvement. In this study, a novel computational method for predicting miRNA subcellular localizations, named PMiSLocMF, was developed. As lots of miRNAs have multiple subcellular localizations, this method was a multi-label classifier. Several properties of miRNA, such as miRNA sequences, miRNA functional similarity, miRNA-disease, miRNA-drug, and miRNA–mRNA associations were adopted for generating informative miRNA features. To this end, powerful algorithms [node2vec and graph attention auto-encoder (GATE)] and one newly designed scheme were adopted to process above properties, producing five feature types. All features were poured into self-attention and fully connected layers to make predictions. The cross-validation results indicated the high performance of PMiSLocMF with accuracy higher than 0.83, average area under the receiver operating characteristic curve (AUC) and area under the precision-recall curve (AUPR) exceeding 0.90 and 0.77, respectively. Such performance was better than all previous methods based on the same dataset. Further tests proved that using all feature types can improve the performance of PMiSLocMF, and GATE and self-attention layer can help enhance the performance. Finally, we deeply analyzed the influence of miRNA associations with diseases, drugs, and mRNAs on PMiSLocMF. The dataset and codes are available at https://github.com/Gu20201017/PMiSLocMF.
A systematic evaluation of computational methods for cell segmentation
Authors: Wang Yuxing , Zhao Junhan , Xu Hongye , Han Cheng , Tao Zhiqiang , Zhou Dawei , Geng Tong , Liu Dongfang , Ji Zhicheng
Published: August 2024

Cell segmentation is a fundamental task in analyzing biomedical images. Many computational methods have been developed for cell segmentation and instance segmentation, but their performances are not well understood in various scenarios. We systematically evaluated the performance of 18 segmentation methods to perform cell nuclei and whole cell segmentation using light microscopy and fluorescence staining images. We found that general-purpose methods incorporating the attention mechanism exhibit the best overall performance. We identified various factors influencing segmentation performances, including image channels, choice of training data, and cell morphology, and evaluated the generalizability of methods across image modalities. We also provide guidelines for choosing the optimal segmentation methods in various real application scenarios. We developed Seggal, an online resource for downloading segmentation models already pre-trained with various tissue and cell types, substantially reducing the time and effort for training cell segmentation models.
Application of singular spectrum analysis to InSAR time-series for constraining the post-seismic deformation due to moderate magnitude earthquakes: the case of 2019 Mw 6 Mirpur earthquake, NW Himalaya
Authors: Jasir M C M , Sreejith K M , Agrawal R , Begum S K
Published: August 2024

Detection and separation of the subtle post-seismic deformation signals associated with moderate magnitude earthquakes from interferometric synthetic aperture radar (InSAR) time-series is often challenging. Singular spectrum analysis (SSA) is a statistical non-parametric technique used to decompose and reconstruct signals from complex time-series data. We show that the SSA analysis effectively distinguished the post-seismic signal associated with the 2019 Mw 6 Mirpur earthquake from periodic and noise components. The SSA-derived post-seismic deformation signal is smoother and fits better to an exponential model with a decay time of 34 d. The post-seismic deformation is confined to the southeast of the rupture area and lasted for ∼90 d following the main shock. Inversion of the post-seismic deformation suggests an afterslip mechanism with a maximum slip of ∼0.07 m on the shallow, updip portions of the Main Himalayan Thrust. The 2019 Mirpur earthquake and afterslip together released less than 12 per cent of the accumulated strain energy since the 1555 Kashmir earthquake and implies continued seismic hazard in the future.
The effects of global populism: assessing the populist impact on international affairs
Authors: Wajner Daniel F , Destradi Sandra , Zürn Michael
Published: August 2024

With the global rise to power of populist leaders over the past decade, research on populism, including its international implications, has flourished. However, we still lack a nuanced understanding of the international effects of this new populist wave. The special section that this article introduces seeks to bridge this gap by systematically examining three types of international effects of populism. One group of contributions addresses the impact of populism on the processes of foreign policy-making in countries governed by populists (politics). Another group focuses on effects in terms of foreign policy agenda and its substantive outcomes (policies). A third group of contributions studies the impact of populism on states' stances towards international institutions (international polity). This introduction proposes a theoretical framework that takes into account the existent diversity among populist governments, specifically addressing how the more or less authoritarian character of populism explains variations in international outcomes across politics, policies and polities. A better understanding of these varied characters and effects can contribute new insights to lively debates about the potential challenges posed by populism and populists in the contemporary international order, and the prospects for mitigation.
On the p-irreducibility of quintic positive polynomials
Authors: Kamizawa Takeo , Jamiołkowski Andrzej , Matsuoka Takashi , Watanabe Noboru
Published: August 2024

In this paper we will discuss the p-reducibility/irreducibility of positive polynomials, and we will give some sufficient conditions for quintic polynomials to be p-reducible/irreducible. This research is closely related to some problems in bio-chemistry, especially to the cooperativity in bio-systems. We will study some applications of our results to these problems.
Whole-body urea kinetics and functional roles of urea transporters and aquaporins in urea secretion into the rumen in sheep fed diets varying in crude protein content and corn grain processing method
Authors: Burns Kaitlin S , Penner Gregory B , Hogan Natacha S , Mutsvangwa Timothy
Published: August 2024

The objectives were to determine the effects of dietary crude protein (CP) content and corn grain processing on whole-body urea kinetics and the functional roles of urea transporter-B (UT-B) and aquaporins (AQP) in serosal-to-mucosal urea flux (Jsm-urea) in ovine ruminal epithelia. Thirty-two Rideau-Arcott ram lambs were blocked by bodyweight into groups of 4 and then randomly allocated within blocks to 1 of 4 diets (n = 8) in a 2 × 2 factorial design. Dietary factors were CP content (11% [LP] vs. 16% [HP]) and corn grain processing (whole-shelled [WSC] vs. steam-flaked [SFC] corn). Whole-body urea kinetics and N balance were determined using 4-d continuous intrajugular infusions of [15N15N]-urea with concurrent collections of urine and feces with four blocks of lambs (n = 4). After 23 d on diets, lambs were killed to collect ruminal epithelia for mounting in Ussing chambers to determine Jsm-urea and the measurement of mRNA abundance of UT-B and AQP. Serosal and mucosal additions of phloretin and NiCl2 were used to inhibit UT-B- and AQP-mediated urea transport, respectively. Lambs fed HP had a greater (P < 0.01) N intake (29.4 vs. 19.1 g/d) than those fed LP; however, retained N (g/d or % of N intake) was not different. As a % of N intake, lambs fed SFC tended (P = 0.09) to have a lower N excretion (72.2 vs. 83.5%) and a greater N retention (27.8 vs. 16.6%) compared to those fed WSC. Endogenous urea-N production (UER) was greater in lambs fed HP compared to those fed LP (29.9 vs. 20.6 g/d; P = 0.02), whereas urea-N secreted into the gut (GER; g/d) and urea-N used for anabolic purposes (UUA; g/d) were similar. Lambs fed LP tended (P = 0.05) to have greater GER:UER (0.78 vs. 0.66) and UUA:GER (0.23 vs. 0.13) ratios, and a greater Jsm-urea (144.7 vs. 116.1 nmol/[cm2 × h]; P = 0.07) compared to those fed HP. Lambs fed SFC tended to have a lower NiCl2-insensitive Jsm-urea (117.4 vs. 178.4 nmol/[cm2 × h]; P = 0.09) and had a lower phloretin-insensitive Jsm-urea (87.1 vs. 143.1 nmol/[cm2 × h]; P = 0.02) compared to those fed WSC. The mRNA abundance of UT-B (0.89 vs. 1.07; P = 0.08) and AQP-3 (0.90 vs. 1.05; P = 0.07) tended to be lower in lambs fed SFC compared to those fed WSC. Overall, reducing CP content tended to increase the GER:UER ratio with no changes in the expression or function of UT-B and AQP. Although corn grain processing had no effects on GER, feeding SFC increased the portion of urea secretion into the rumen that was mediated via UT-B and AQP.
External Validation of a Commercial Artificial Intelligence Algorithm on a Diverse Population for Detection of False Negative Breast Cancers
Authors: Plimpton S Reed , Milch Hannah , Sears Christopher , Chalfant James , Hoyt Anne , Fischer Cheryce , Hsu William , Joines Melissa
Published: August 2024

Objective

There are limited data on the application of artificial intelligence (AI) on nonenriched, real-world screening mammograms. This work aims to evaluate the ability of AI to detect false negative cancers not detected at the time of screening when reviewed by the radiologist alone.

Methods

A commercially available AI algorithm was retrospectively applied to patients undergoing screening full-field digital mammography (FFDM) or digital breast tomosynthesis (DBT) at a single institution from 2010 to 2019. Ground truth was established based on 1-year follow-up data. Descriptive statistics were performed with attention focused on AI detection of false negative cancers within these subsets.

Results

A total of 26 694 FFDM and 3183 DBT examinations were analyzed. Artificial intelligence was able to detect 7/13 false negative cancers (54%) in the FFDM cohort and 4/10 (40%) in the DBT cohort on the preceding screening mammogram that was interpreted as negative by the radiologist. Of these, 4 in the FFDM cohort and 4 in the DBT cohort were identified in breast densities of C or greater. False negative cancers detected by AI were predominantly luminal A invasive malignancies (9/11, 82%). Artificial intelligence was able to detect these false negative cancers a median time of 272 days sooner in the FFDM cohort and 248 days sooner in the DBT cohort compared to the radiologist.

Conclusion

Artificial intelligence was able to detect cancers at the time of screening that were missed by the radiologist. Prospective studies are needed to evaluate the synergy of AI and the radiologist in real-world settings, especially on DBT examinations.
Collimation principles of a hollow X-ray microbeam for high-contrast cytoplasm irradiation
Authors: Cheng Qinqin , Zhao Ruifeng , Wang Xiaowa , Wang Xufei
Published: August 2024

A Monte Carlo simulation was used to assess the performance of a collimated hollow X-ray microbeam for subcellular cytoplasm irradiation. A high-Z coaxial collimation structure with an inner core for nucleus shielding was investigated. Two key performances, the extraction efficiency (cytoplasm dose per unit incident fluence) and the dose contrast (cytoplasm-to-nucleus dose ratio), were evaluated regarding the influences of the material, geometry and physical arrangements of the collimator, target dish and incident beam source. Simulation results demonstrate that a gold coaxial structure with a practical collimation geometry of a 1-mm length, 10-μm inner diameter and 200-μm outer diameter, with the top exit closely attached (with a minimized air gap) to the bottom of a cell dish with a 3-μm thick Mylar film is recommended for cytoplasm irradiation of adherent mammalian cells. For a synchrotron source in the energy range < 10 keV, a dose contrast of approximately 100 can be achieved. For a bremsstrahlung source <30-kV tube voltage, a dose contrast of approximately 50–100 can still be achieved. General principles are summarized with further explanations of the performance of the hollow X-ray microbeam.
Dosimetric impact of calibration coefficients determined using linear accelerator photon and electron beams for ionization chamber in an on-site dosimetry audit
Authors: Tani Kensuke , Wakita Akihisa , Tohyama Naoki , Fujita Yukio
Published: August 2024

This study aimed to clarify the dosimetric impact of calibration beam quality for calibration coefficients of the absorbed dose to water for an ionization chamber in an on-site dosimetry audit. Institution-measured doses of 200 photon and 184 electron beams were compared with the measured dose using one year data before and after the calibration of the ionization chamber used. For photon and electron reference dosimetry, the agreements of the institution-measured dose against two measured doses in this audit were evaluated using the calibration coefficients determined using 60Co (${N}_{D,\mathrm{w},{}^{60}\mathrm{Co}}$) and linear accelerator (linac) (${N}_{D,\mathrm{w},Q}$) beams. For electron reference dosimetry, the agreement of two institution-measured doses against the measured dose was evaluated using${N}_{D,\mathrm{w},Q}$. Institution-measured doses were evaluated using direct- and cross-calibration coefficients. For photon reference dosimetry, the mean differences and standard deviation (SD) of institution-measured dose against the measured dose using ${N}_{D,\mathrm{w},{}^{60}\mathrm{Co}}$ and ${N}_{D,\mathrm{w},Q}$ were −0.1% ± 0.4% and −0.3% ± 0.4%, respectively. For electron reference dosimetry, the mean differences and SD of institution-measured dose using the direct-calibration coefficient against the measured dose using ${N}_{D,\mathrm{w},{}^{60}\mathrm{Co}}$ and ${N}_{D,\mathrm{w},Q}$ were 1.3% ± 0.8% and 0.8% ± 0.8%, respectively. Further, the mean differences and SD of institution-measured dose using the cross-calibration coefficient against the measured dose using ${N}_{D,\mathrm{w},Q}$ were −0.1% ± 0.6%. For photon beams, the dosimetric impact of introducing calibration coefficients determined using linac beams was small. For electron beams, it was larger, and the measured dose using ${N}_{D,\mathrm{w},Q}$ was most consistent with the institution-measured dose, which was evaluated using a cross-calibration coefficient.
Impact of neoadjuvant androgen deprivation therapy on toxicity in intensity-modulated radiation therapy for prostate cancer
Authors: Serizawa Itsuko , Kozuka Takuyo , Soyano Takashi , Sasamura Kazuma , Kamima Tatsuya , Kunogi Hiroaki , Numao Noboru , Yamamoto Shinya , Yonese Junji , Yoshioka Yasuo
Published: August 2024

This study aimed to compare toxicities, prostate volume and dosimetry, between patients who underwent intensity-modulated radiation therapy (IMRT) combined with ≥3 months of neoadjuvant androgen deprivation therapy (NADT) and those without NADT for prostate cancer. In total, 449 patients with intermediate- and high-risk prostate cancer received 78 Gy IMRT in 39 fractions, of which 129 were treated without any ADT (non-ADT group) and 320 with NADT ≥3 months (NADT group). Adverse events and dose-volume indices were compared between the two groups retrospectively. The NADT group had a lower rate of acute grade 2 gastrointestinal (GI) toxicities (17% vs 25%, P = 0.063) and late grade 2 GI toxicities (P = 0.055), including a significantly lower rate of late grade 2 rectal hemorrhage (P = 0.033), compared with the non-ADT group. There were no cases of late grade 3 or higher GI toxicities. The average volume of the prostate in the NADT group was 38% smaller than that in the non-ADT group (43.7 vs 27.0 cm3, P < 0.001). Bladder V40Gy and V50Gy, and rectum V40Gy, V50Gy, V60Gy and V70Gy were significantly smaller in the NADT group. In the NADT group, no significant difference was observed in adverse events or dosimetry between the subgroups with NADT ≥12 and <12 months. Acute and late rectal toxicities were reduced by NADT within ≥3 months in accordance with reduced prostate volume and improved rectal dosimetry. This suggests a merit of administering neoadjuvant ADT ≥3 months for reducing rectal toxicities.
Craniospinal irradiation for leptomeningeal metastasis of solid tumors: survival analysis and prognostic factors
Authors: Takeda Kazuya , Umezawa Rei , Yamamoto Takaya , Takahashi Noriyoshi , Jingu Keiichi
Published: August 2024

We conducted a study to examine the treatment outcomes and prognostic factors for patients who underwent craniospinal irradiation (CSI) for leptomeningeal metastasis of solid tumors. This retrospective study included patients who received CSI for leptomeningeal metastasis at a single institute between 2010 and 2021. Data from clinical records and the radiation information system were obtained and analyzed. A total of 25 patients were included in the study. Eighteen patients (72%) completed the scheduled CSI. The median overall survival (OS) period was 4.8 months (95% confidence interval (CI): 3.2–10.0 months). Symptom relief was achieved in four out of 23 symptomatic patients (17%). Non-hematological adverse events occurred in 12 patients (48%), with 1 patient (4%) developing Grade 3 bacterial meningitis and the other patients having Grade 1–2 events. Twenty patients (80%) had hematological adverse events of Grade 3 or higher. Grade 4 hematologic toxicities occurred in 3 patients (12%) due to neutropenia and in 11 patients (44%) due to lymphopenia. In multivariate Cox regression analysis, the systemic immune-inflammation index (SII) was identified as the only significant parameter for predicting OS. The median OS periods for patients with SII < 607 and SII ≥ 607 were 6.1 and 2.1 months, respectively (P = 0.003). In conclusion, this study showed the treatment outcomes of CSI for leptomeningeal metastasis of solid tumors. It was shown that a high baseline SII was associated with shorter OS after CSI. The findings will contribute to the evaluation of prognosis after CSI.
Molecular epidemiological investigation of Cryptococcus spp. isolated from cats in Japan using multi-locus sequence typing
Authors: Omura Miki , Komori Aya , Tamura Takashi , Han Hock Siew , Kano Rui , Makimura Koichi
Published: August 2024

Cryptococcosis is an important fungal infection for both humans and cats, but molecular epidemiological studies on strains isolated from cats are limited. We conducted multi-locus sequence typing analysis and antifungal susceptibility testing of 14 Cryptococcus spp. strains from domestic cats in Japan and one strain isolated from a cat in Singapore. All 14 strains from domestic cats in Japan were identified as Cryptococcus neoformans molecular type VNI. The sequence types (STs) included eight cases of ST5, five cases of ST31, and one novel ST. VNI ST5 is the most frequently isolated strain in Japanese patients as well, while there are no records of VNI ST31 being isolated from Japanese patients. The Singaporean cat strain was identified as C. gattii VGIIb (C. deuterogattii), ST7. We compared these results with strains previously reported to have been isolated from cats. This comparison suggested that molecular types of Cryptococcus spp. isolated from cats may differ depending on the country. In the antifungal susceptibility testing of C. neoformans, one strain each exceeded the epidemiological cutoff value (ECV) for amphotericin B and 5-fluorocytosine, while two strains exceeded the ECV for fluconazole. This study reveals the molecular epidemiology of Cryptococcus spp. isolated from cats with cryptococcosis in Japan. It suggests that investigating Cryptococcus spp. carried by cats, which share close living environments with humans, may contribute to the health of both cats and human populations.
ALMA follow-up of ~3000 red-Herschel galaxies: the nature of extreme submillimetre galaxies
Authors: Quirós-Rojas Marianela , Montaña Alfredo , Zavala Jorge A , Aretxaga Itziar , Hughes David H
Published: August 2024

We present the analysis of over 3000 red-Herschel sources ($S_{\mathrm{250\, \mu m}}\lt S_{\mathrm{350\, \mu m}}\lt S_{\mathrm{500\, \mu m} }$) using public data from the ALMA archive and the Herschel-ATLAS survey. This represents the largest sample of red-Herschel sources with interferometric follow-up observations to date. The high ALMA angular resolution and sensitivity ($\theta _{\rm FWHM}\sim$1 arcsec; $\sigma _{1.3\mathrm{\, mm}}\sim 0.17$ mJy beam$^{-1}$) allow us to classify the sample into individual sources, multiple systems, and potential lenses and/or close mergers. Interestingly, even at this high angular resolution, 73 per cent of our detections are single systems, suggesting that most of these galaxies are isolated and/or post-merger galaxies. For the remaining detections, 20 per cent are classified as multiple systems, 5 per cent as lenses and/or mergers, and 2 per cent as low-z galaxies or active galactic nuclei. Combining the Herschel/SPIRE and ALMA photometry, these galaxies are found to be extreme and massive systems with a median star formation rate of $\sim$1500 $\mathrm{M_{\odot }\, yr^{-1}}$ and molecular gas mass of $M_{\mathrm{gas}}\sim 10^{11}$ $\mathrm{M_{\odot }}$. The median redshift of individual sources is $z\approx 2.8$, while the likely lensed systems are at $z\approx 3.3$, with redshift distributions extending to $z\sim 6$. Our results suggest a common star formation mode for extreme galaxies across cosmic time, likely triggered by close interactions or disc-instabilities, and with short depletion times consistent with the starburst-type population. Moreover, all galaxies with $S_{\mathrm{1.3mm}}\ge 13$ mJy are gravitationally amplified which, similar to the established $S_{500\mathrm{ \, \mu m}}\gt 100$ mJy threshold, can be used as a simple criterion to identify gravitationally lensed galaxies.
The physical mechanism of the streaming instability
Authors: Magnan Nathan , Heinemann Tobias , Latter Henrik N
Published: August 2024

The main hurdle of planet formation theory is the metre-scale barrier. One of the most promising ways to overcome it is via the streaming instability (SI). Unfortunately, the mechanism responsible for the onset of this instability remains mysterious. It has recently been shown that the SI is a Resonant Drag Instability (RDI) involving inertial waves. We build on this insight and clarify the physical picture of how the SI develops, while bolstering this picture with transparent mathematics. Like all RDIs, the SI is built on a feedback loop: in the ‘forward action’, an inertial wave concentrates dust into clumps; in the ‘backward reaction’, those drifting dust clumps excite an inertial wave. Each process breaks into two mechanisms, a fast one and a slow one. At resonance, each forward mechanism can couple with a backward mechanism to close a feedback loop. Unfortunately, the fast-fast loop is stable, so the SI uses the fast-slow and slow-fast loops. Despite this last layer of complexity, we hope that our explanation will help understand how the SI works, in which conditions it can grow, how it manifests itself, and how it saturates.
Searching for the imprints of AGN feedback on the Lyman alpha forest around luminous red galaxies
Authors: Khaire Vikram , Hu Teng , Hennawi Joseph F , Burchett Joseph N , Walther Michael , Davies Frederick
Published: August 2024

We explore the potential of using the low-redshift Lyman $\alpha$ (Ly $\alpha$) forest surrounding luminous red galaxies (LRGs) as a tool to constrain active galactic nuclei (AGNs) feedback models. Our analysis is based on snapshots from the Illustris and IllustrisTNG simulations at a redshift of $z=0.1$. These simulations offer an ideal platform for studying the influence of AGN feedback on the gas surrounding galaxies, as they share the same initial conditions and underlying code but incorporate different feedback prescriptions. Both simulations show significant impacts of feedback on the temperature and density of the gas around massive haloes. Following our previous work, we adjusted the UV background in both simulations to align with the observed number density of Ly $\alpha$ lines ($\rm dN/dz$) in the intergalactic medium and study the Ly $\alpha$ forest around massive haloes hosting LRGs, at impact parameters ($r_{\perp }$) ranging from 0.1 to 100 pMpc. Our findings reveal that $\rm dN/dz$, as a function of $r_{\perp }$, is approximately 1.5 to 2 times higher in IllustrisTNG compared to Illustris up to $r_{\perp }$ of $\sim 10$ pMpc. To further assess whether existing data can effectively discern these differences, we search for archival data containing spectra of background quasars probing foreground LRGs. Through a feasibility analysis based on these data, we demonstrate that ${\rm dN/dz} (r_{\perp })$ measurements can distinguish between feedback models of IllustrisTNG and Illustris with a precision exceeding 16$\sigma$. This underscores the potential of ${\rm dN/dz} (r_{\perp })$ measurements around LRGs as a valuable benchmark observation for discriminating between different feedback models.
Exploring the role of the halo-mass function for inferring astrophysical parameters during reionization
Authors: Greig Bradley , Prelogović David , Mirocha Jordan , Qin Yuxiang , Ting Yuan-Sen , Mesinger Andrei
Published: August 2024

Detecting the 21-cm signal at $z\gtrsim 6$ will reveal insights into the properties of the first galaxies responsible for driving reionization. To extract this information, we perform parameter inference with three-dimensional simulations of the 21-cm signal embedded within a Bayesian inference pipeline. Presently, when performing inference, we must choose which sources of uncertainty to sample and which to hold fixed. Since the astrophysics of galaxies is much more uncertain than that of the underlying halo-mass function (HMF), we typically parametrize and model the former while fixing the latter. However, doing so may bias our inference of the galaxy properties. In this work, we explore the consequences of assuming an incorrect HMF and quantify the relative biases on our inferred astrophysical model parameters when considering the wrong HMF. We then relax this assumption by constructing a generalized five parameter HMF model and simultaneously recover it with our underlying astrophysical model. For this, we use 21cmfast and perform simulation-based inference using marginal neural ratio estimation to learn the likelihood-to-evidence ratio with Swyft. Using a mock 1000-h observation of the 21-cm power spectrum from the forthcoming Square Kilometre Array, conservatively assuming foreground wedge avoidance, we find that assuming the incorrect HMF can bias the recovered astrophysical parameters by up to $\sim 3{\!-\!}4\sigma$ even when including independent information from observed luminosity functions. Using our generalized HMF model, although we recover our astrophysical parameters with a factor of $\sim 2{\!-\!}4$ larger marginalized uncertainties, the constraints are unbiased, agnostic to the underlying HMF and therefore more conservative.
Inferring astrophysical parameters using the 2D cylindrical power spectrum from reionization
Authors: Greig Bradley , Prelogović David , Qin Yuxiang , Ting Yuan-Sen , Mesinger Andrei
Published: August 2024

Enlightening our understanding of the first galaxies responsible for driving reionization requires detecting the 21-cm signal from neutral hydrogen. Interpreting the wealth of information embedded in this signal requires Bayesian inference. Parameter inference from the 21-cm signal is primarily restricted to the spherically averaged power spectrum (1D PS) owing to its relatively straightforward derivation of an analytic likelihood function enabling traditional Monte Carlo Markov Chain approaches. However, in recent years, simulation-based inference (SBI) has become feasible which removes the necessity of having an analytic likelihood, enabling more complex summary statistics of the 21-cm signal to be used for Bayesian inference. In this work, we use SBI, specifically marginal neural ratio estimation to learn the likelihood-to-evidence ratio with swyft, to explore parameter inference using the cylindrically averaged 2D PS. Since the 21-cm signal is anisotropic, the 2D PS should yield more constraining information compared to the 1D PS which isotropically averages the signal. For this, we consider a mock 1000 h observation of the 21-cm signal using the Square Kilometre Array and compare the performance of the 2D PS relative to the 1D PS. Additionally, we explore two separate foreground mitigation strategies, perfect foreground removal and wedge avoidance. We find the 2D PS outperforms the 1D PS by improving the marginalized uncertainties on individual astrophysical parameters by up to $\sim 30\!-\!40$ per cent irrespective of the foreground mitigation strategy. Primarily, these improvements stem from how the 2D PS distinguishes between the transverse, $k_{\perp }$, and redshift-dependent, $k_{\parallel }$, information which enables greater sensitivity to the complex reionization morphology.
Association of serum uric acid with male sexual hormones and erectile dysfunction: a bidirectional 2-sample Mendelian randomization analysis
Authors: Chen Hui , Feng Wei-Dong , Feng Jun-Long , Zhao Cong , Gao Zi-Xiang , Wang Bin
Published: August 2024

Background

Observational studies indicated that serum uric acid (SUA) was associated with male sexual hormones and erectile dysfunction (ED). However, their relationship was still heterogeneous.

Aim

This study conducted 2-sample univariate mendelian randomization (UVMR) and multivariate mendelian randomization (MVMR) to explore the causal relationship between SUA and sexual hormones as well as ED.

Methods

Genetic variants associated with SUA were derived from the UK Biobank database (N = 437 354). Outcomes from the IEU Open GWAS and summary data sets were sexual hormones (sex hormone–binding globulin [SHBG], testosterone, estradiol [E2], follicle-stimulating hormone, luteinizing hormone) and ED, with 3301 to 625 650 participants. UVMR analysis primarily utilized the inverse variance weighted method, complemented by MVMR analysis. Thorough sensitivity analyses were carried out to ensure the reliability of results. Moreover, mediation analysis was conducted to estimate the mediated effect between SUA and outcomes.

Outcomes

The primary outcomes included results of UVMR and MVMR analysis and mediation analysis, along with sensitivity analyses involving the Cochran Q test, the MR Egger intercept test, leave-1-out analysis, and the MR-PRESSO method (mendelian randomization pleiotropy residual sum and outlier).

Results

UVMR analysis revealed that an elevated SUA level could decrease levels of SHBG (β = –0.10, P = 1.70 × 10–7) and testosterone (β = –0.10, P = 5.94 × 10–3) and had a positive causal effect on ED (odds ratio, 1.10; P = .018). According to reverse mendelian randomization results, increased levels of SHBG (β = –0.06, P = 4.82 × 10–4) and E2 (β = –0.04, P = .037) could also reduce SUA levels. As shown by MVMR analysis, SUA had a negative effect on SHBG and testosterone levels (P < .05), while the significant causal relationship between SUA and ED disappeared. Furthermore, SHBG mediated 98.1% of the effect of SUA on testosterone levels. Results of other mendelian randomization analyses were not statistically significant. No pleiotropy was found by sensitivity analysis in this study.

Clinical Implications

Given the causal relationship between SUA and sexual hormones, we must focus on SUA and E2 levels in men, especially patients with hypogonadism and ED.

Strengths and Limitations

This study evaluated the causal effect of SUA on male sexual hormones and ED genetically for the first time, clarifying the common biases in observational studies and confirming the negative relationship between SUA and testosterone level. Limitations include a population based on European ancestry, some crossover of the samples, and unobserved confounding factors.

Conclusion

Genetic studies provide evidence for the causal relationship between SUA and male sexual hormones (SHBG, testosterone, E2), while the relationship between SUA and ED should be further evaluated.
First Complete Genome Sequence of Nigrospora osmanthi: A Fundamental Resource for Studying the Plant Pathogenic Fungus
Authors: Huang Hui , Kong Jiajia , Lin Jingyu , Zhang Xiao , Xu Guoyong , Ding Weiwen , Jin Rui , Wang Wei , Chen Jianming , Lin Zhenyue
Published: August 2024

Nigrospora osmanthi strain Z1 is a potential bioherbicide for the biological control of water lettuce, one of the most common invasive weeds. Here, the first high-quality genome assembly of N. osmanthi was obtained by a combination of PacBio and Illumina sequencing technologies. Twelve contigs representing the nuclear genome and one mitochondrial DNA were generated, with a total length of 45.94 Mb, an N50 equal to 6.99 Mb, and a GC content of 57.91%; 9 of the 12 nuclear contigs represented chromosomes from telomere to telomere characterized by telomeric-like repeats. A total of 11,051 genes were predicted using a combination of gene prediction tools, including 336 noncoding RNAs, 1,298 genes encoding secretory proteins, 1,735 genes encoding carbohydrate-active enzymes, 1,955 fungal virulence factors, and 50 putative secondary metabolite gene clusters. This complete genome sequence can serve as a valuable resource for future comparative genomic studies of the fungus Nigrospora for effective application in the biocontrol of invasive species and the discovery of fungal secondary metabolites.

[Formula: see text] Copyright © 2024 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license .
Insomnia score: predictive ability of insomnia, high-diagnostic and prognostic value for cancer
Authors: Xiao Dan , Lan Yixin , Zhang Haohan , Li Siyu , Zhou Chuandong
Published: August 2024

Objective

This study utilized bioinformatics methods to investigate the association between insomnia and cancer.

Methods

We identified key insomnia-related genes and constructed an insomnia score (riskScore = ∑ Expressiongene* Coefficient) based on an insomnia dataset using differential analysis, Weighted Gene Co-expression Network Analysis (WGCNA), and Least Absolute Shrinkage and Selection Operator (LASSO) regression. The predictive ability of the insomnia score was validated in the insomnia dataset using Receiver Operating Characteristic (ROC) analysis. Finally, the diagnostic and prognostic value of the insomnia score was assessed in a pan-cancer cohort.

Results

Differential analysis, WGCNA, and LASSO screening of the insomnia dataset yielded three key insomnia-related genes (PTMA, NLRP8, and CCBE1). An insomnia score was then constructed using the formula: riskScore = -0.8039667 * ExpressionPTMA+ - 3.1975230 * ExpressionNLRP8+ -0.4957560 * ExpressionCCBE1. The ROC analysis demonstrated that the insomnia score has excellent predictive ability for insomnia. Furthermore, pan-cancer analysis illustrated the diagnostic and prognostic value of the insomnia score across various cancers.

Conclusion

We successfully constructed an insomnia score and demonstrated its diagnostic and prognostic value in multiple cancers.
Phosphoryl group wires stabilize pathological tau fibrils as revealed by multiple quantum spin counting NMR
Authors: Potnuru Lokeswara Rao , DuBose Austin , Nowotarski Mesopotamia S. , Vigers Michael , Zhang Boqin , Han Chung-Ta , Han Songi
Published: August 2024

Hyperphosphorylation of the protein tau is one of the biomarkers of neurodegenerative diseases in the category of tauopathies. However, the molecular level, mechanistic, role of this common post- translational modification (PTM) in enhancing or reducing the aggregation propensity of tau is unclear, especially considering that combinatorial phosphorylation of multiple sites can have complex, non-additive, effects on tau protein aggregation. Since tau proteins stack in register and parallel to elongate into pathological fibrils, phosphoryl groups from adjacent tau strands with 4.8 Å separation must find an energetically favorable spatial arrangement. At first glance, this appears to be an unfavorable configuration due to the proximity of negative charges between phosphate groups from adjacent neighboring tau fibrils. However, this study tests a counterhypothesis that phosphoryl groups within the fibril core-forming segments favorably assemble into highly ordered, hydrogen-bonded, one-dimensionally extended wires under biologically relevant conditions. We selected two phosphorylation sites associated with neurodegeneration, serine 305 (S305p) and tyrosine 310 (Y310p), on a model tau peptide jR2R3-P301L (tau295-313) spanning the R2/R3 splice junction of tau, that readily aggregate into a fibril with characteristics of a seed-competent mini prion. Using multiple quantum spin counting (MQ-SC) by31P solid-state NMR of phosphorylated jR2R3-P301L tau peptide fibrils, enhanced by dynamic nuclear polarization, we find that at least six phosphorous spins must neatly arrange in 1D within fibrils or in 2D within a protofibril to yield the experimentally observed MQ-coherence orders of four. We found that S305pstabilizes the tau fibrils and leads to more seeding-competent fibrils compared to jR2R3 P301L or Y310p. This study introduces a new concept that phosphorylation of residues within a core forming tau segment can mechanically facilitate fibril registry and stability due a hitherto unrecognized role of phosphoryl groups to form highly ordered, extended, 1D wires that stabilize pathological tau fibrils.

Graphical Abstract
C9orf72repeat expansion-carrying iPSC-microglia from FTD patients show increased phagocytic activity concomitantly with decreased number of autophagosomal-lysosomal vesicles
Authors: Rostalski Hannah , Hietanen Tomi , Hoffmann Dorit , Heikkinen Sami , Huber Nadine , Dhingra Ashutosh , Rodriguez-Nieto Salvador , Kuulasmaa Teemu , Ohtonen Sohvi , Jäntti Henna , Pekkala Viivi , Leskelä Stina , Mäkinen Petra , Katisko Kasper , Hartikainen Päivi , Lehtonen Šárka , Solje Eino , Koistinaho Jari , Malm Tarja , Portaankorva Anne M. , Natunen Teemu , Martiskainen Henna , Takalo Mari , Hiltunen Mikko , Haapasalo Annakaisa
Published: August 2024

C9orf72hexanucleotide repeat expansion (HRE) is a major genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. The role of microglia in theseC9orf72HRE-associated diseases is understudied. To elucidate effects ofC9orf72HRE on microglia, we have characterized human induced pluripotent stem cell-derived microglia (iMG) from behavioral variant frontotemporal dementia (bvFTD) patients carrying theC9orf72HRE.C9orf72HRE iMG were compared to iMG from healthy controls and sporadic bvFTD patients. The phenotypes of iMG were analyzed using bulk RNA sequencing, biochemical and immunofluorescence analyses, and live cell imaging.C9orf72HRE-carrying iMG showed nuclear RNA foci and poly-GP dipeptide repeat proteins but no decreased C9orf72 mRNA or protein expression. TDP-43 pathology was absent from all bvFTD iMG. As compared to healthy control iMG, quantitative immunofluorescence analyses indicated that all bvFTD iMG had reduced number, size, and intensity of LAMP2-A-positive vesicles.C9orf72HRE-carrying iMG additionally showed decreased number, size, and intensity of p62/SQSTM1-positive vesicles. These changes were accompanied by increased phagocytic activity of theC9orf72HRE-carrying iMG. Serum starvation increased phagocytic activity also in the iMG of sporadic bvFTD patients. RNA sequencing revealed that iMG ofC9orf72HRE-carrying bvFTD patients as compared to the iMG of sporadic bvFTD patients showed differential gene expression in pathways related to RNA and protein regulation and mitochondrial metabolism. Our data suggest potential alterations in the autophagosomal/lysosomal pathways in bvFTD patient iMG, which are further reinforced by theC9orf72HRE and functionally manifest as increased phagocytic activity.
Comparison of Fixed Single Cell RNA-seq Methods to Enable Transcriptome Profiling of Neutrophils in Clinical Samples
Authors: Hatje Klas , Schneider Kim , Danilin Sabrina , Koechl Fabian , Giroud Nicolas , Juglair Laurent , Marbach Daniel , Knuckles Philip , Bergauer Tobias , Metruccio Matteo , Garrido Alba , Zhang Jitao David , Sultan Marc , Bell Emma
Published: August 2024

Monitoring neutrophil gene expression is a powerful tool for understanding disease mechanisms, developing new diagnostics, therapies and optimizing clinical trials. Neutrophils are sensitive to the processing, storage and transportation steps that are involved in clinical sample analysis. This study is the first to evaluate the capabilities of technologies from 10X Genomics, PARSE Biosciences, and HIVE (Honeycomb Biotechnologies) to generate high-quality RNA data from human blood-derived neutrophils. Our comparative analysis shows that all methods produced high quality data, importantly capturing the transcriptomes of neutrophils. 10X FLEX cell populations in particular showed a close concordance with the flow cytometry data. Here, we establish a reliable single-cell RNA sequencing workflow for neutrophils in clinical trials: we offer guidelines on sample collection to preserve RNA quality and demonstrate how each method performs in capturing sensitive cell populations in clinical practice.
Identifying a gene signature of metastatic potential by linking pre-metastatic state to ultimate metastatic fate
Authors: Handler Jesse S , Li Zijie , Dveirin Rachel K , Fang Weixiang , Goodarzi Hani , Fertig Elana J , Kalhor Reza
Published: August 2024

Identifying the key molecular pathways that enable metastasis by analyzing the eventual metastatic tumor is challenging because the state of the founder subclone likely changes following metastatic colonization. To address this challenge, we labeled primary mouse pancreatic ductal adenocarcinoma (PDAC) subclones with DNA barcodes to characterize their pre-metastatic state using ATAC-seq and RNA-seq and determine their relativein vivometastatic potential prospectively. We identified a gene signature separating metastasis-high and metastasis-low subclones orthogonal to the normal-to-PDAC and classical-to-basal axes. The metastasis-high subclones feature activation of IL-1 pathway genes and high NF-κB and Zeb/Snail family activity and the metastasis-low subclones feature activation of neuroendocrine, motility, and Wnt pathway genes and high CDX2 and HOXA13 activity. In a functional screen, we validated novel mediators of PDAC metastasis in the IL-1 pathway, including the NF-κB targetsFosandIl23a, and beyond the IL-1 pathway includingMyo1bandTmem40. We scored human PDAC tumors for our signature of metastatic potential from mouse and found that metastases have higher scores than primary tumors. Moreover, primary tumors with higher scores are associated with worse prognosis. We also found that our metastatic potential signature is enriched in other human carcinomas, suggesting that it is conserved across epithelial malignancies. This work establishes a strategy for linking cancer cell state to future behavior, reveals novel functional regulators of PDAC metastasis, and establishes a method for scoring human carcinomas based on metastatic potential.
A nanobody-based proximity ligation assay detects constitutive and stimulus-regulated native Arc/Arg3.1 oligomers in hippocampal neuronal dendrites
Authors: Baldinotti Rodolfo , Pauzin Francois P. , Fevang Hauk , Ishizuka Yuta , Bramham Clive R.
Published: August 2024

Activity-regulated cytoskeleton-associated (Arc), the product of an immediate early gene, plays critical roles in synaptic plasticity and memory. Evidence suggests that Arc function is determined by its oligomeric state, however, methods for localization of native Arc oligomers are lacking. Here, we developed a nanobody-based proximity ligation assay (PLA) for detection, localization, and quantification of Arc-Arc complexes in primary rat hippocampal neuronal cultures. We used nanobodies with single, structurally defined epitopes in the bilobar Arc capsid domain. Nanobody H11 binds inside the N-lobe ligand pocket, while nanobody C11 binds to the C-lobe surface. For each nanobody, ALFA- and FLAG-epitope tags created a platform for antibody binding and PLA. Surprisingly, PLA puncta in neuronal dendrites revealed widespread constitutive Arc-Arc complexes. Treatment of cultures with tetrodotoxin or cycloheximide had no effect, suggesting stable complexes that are independent of recent neuronal activity and protein synthesis. To assess detection of oligomers, cultures were exposed to a cell-penetrating peptide inhibitor of the Arc oligomerization motif (OligoOFF). Arc-Arc complexes detected by H11 PLA were inhibited by OligoOff but not by control peptide. Notably, Arc complexes detected by C11 were unaffected by OligoOFF. Furthermore, we evaluated Arc complex formation after chemical stimuli that increase Arc synthesis. Brain-derived neurotrophic factor increased Arc-Arc signal detected by C11, but not H11. Conversely, dihydroxyphenylglycine (DHPG) treatment selectively enhanced H11 PLA signals. In sum, nanobody-based PLA reveals constitutive and stimulus-regulated Arc oligomers in hippocampal neuronal dendrites. A model is proposed based on detection of Arc dimer by C11 and higher-order oligomer by H11 nanobody.
Inhibition of glycolysis in tuberculosis-mediated metabolic rewiring reduces HIV-1 spread across macrophages
Authors: Vahlas Zoï , Faivre Natacha , Monard Sarah C. , Hertel Quentin , Maio Mariano , Barros Joaquina , Lucas Alexandre , Manh Thien-Phong Vu , Ben Neji Myriam , Corti Marcelo , Poincloux Renaud , Blanchet Fabien , Raynaud-Messina Brigitte , Letisse Fabien , Neyrolles Olivier , Lugo-Villarino Geanncarlo , Balboa Luciana , Vérollet Christel
Published: August 2024

Tuberculosis (TB) is a significant aggravating factor in individuals living with human immunodeficiency virus type 1 (HIV-1), the causative agent for acquired immunodeficiency syndrome (AIDS). BothMycobacterium tuberculosis(Mtb), the bacterium responsible for TB, and HIV-1 target macrophages. Understanding how Mtb subverts these cells may facilitate the identification of new druggable targets. Here, we explored how TB can induce macrophages to form tunneling nanotubes (TNT), promoting HIV-1 spread. We found that TB triggers metabolic rewiring of macrophages, increasing their glycolytic ATP production. Using pharmacological inhibitors and glucose deprivation, we discovered that disrupting aerobic glycolysis significantly reduces HIV-1 exacerbation in these macrophages. Glycolysis is essential for tunneling nanotubes (TNT) formation, which facilitates viral transfer and cell-to-cell fusion and induces the expression of the sialoadhesin Siglec-1, enhancing both HIV-1 binding and TNT stabilization. Glycolysis did not exacerbate HIV-1 infection when TNT formation was pharmacologically prevented, indicating that higher metabolic activity is not sufficient per se to make macrophages more susceptible to HIV-1. Overall, these data might facilitate the development of targeted therapies aimed at inhibiting glycolytic activity in TB-induced immunomodulatory macrophages to ultimately halt HIV-1 dissemination in co-infected patients.