bluuebunny/crossref_metadata_2025 huggingface dataset:
Can meta-omics revolutionize our understanding of rumen methane emissions?
Authors: Zhao Huiying , Bai Sarula , Tan Jian , Liu Ming , Zhao Yuchao , Jiang Linshu
Published: September 2024

The global challenge of methane emissions from enteric fermentation is critical, as it contributes significantly to atmospheric greenhouse gases and represents a loss of energy that could otherwise be utilized by ruminants. With the increasing demand for dairy and meat products, finding effective methods to reduce methane production is essential. This review explores the use of advanced meta-omics techniques – including metagenomics, metatranscriptomics, metaproteomics, and metabolomics – to deepen our understanding of ruminal methane production and identify potential strategies for its mitigation. These high-throughput technologies provide comprehensive insights into the rumen microbial communities and their metabolic functions by analyzing DNA, RNA, proteins, and metabolites directly from environmental samples. Metagenomics and metatranscriptomics offer a detailed view of microbial diversity and gene expression, while metaproteomics can identify specific enzymes and proteins directly involved in methane production pathways, revealing potential targets for mitigation strategies. Integrating these meta-omics approaches allows for a holistic understanding of the microbial processes that drive methane emissions, enabling the development of more precise interventions, such as tailored dietary modifications and the use of specific inhibitors. This review underscores the importance of a multi-omics strategy in characterizing microbial roles and interactions within the rumen, which is crucial for devising effective and sustainable methods to reduce methane emissions without compromising livestock productivity.
Real-world effectiveness of fidaxomicin in patients at high risk of Clostridioides difficile recurrence
Authors: Colwell Benjamin , Aguilar Jennifer , Hughes Frances , Goriacko Pavel , Chen Victor , Chang Mei , Bartash Rachel , Guo Yi
Published: September 2024

Objective:

Compare the real-world impact of fidaxomicin (FDX) and vancomycin (VAN) on Clostridioides difficile infection (CDI) recurrence in a high-risk patient population.

Design:

A retrospective, matched-cohort study evaluating hospitalized patients with CDI from January 1, 2016, to November 1, 2022, within a tertiary academic medical center.

Patients:

Adult patients with at least 1 prior CDI case who received either FDX or VAN for non-fulminant CDI while admitted, and had at least 1 additional risk factor for recurrence. Risk factors included age >70, solid organ or bone marrow transplant recipients, broad-spectrum antibiotic use within 30 days, or receipt of chemotherapy/immune-modulating agents within 30 days of admission. FDX and VAN patients were matched according to risk factors.

Results:

A total of 415 patient admissions were identified. After the exclusion of 92 patients for fulminant CDI, diarrhea from another cause, or use of VAN taper therapy, and 15 unmatched patients, 308 patient admissions were included (68 FDX and 240 VAN patients). There were no significant differences in 4-week recurrence (26% vs 23%; OR 1.1; P = .51), 90-day CDI readmission (29% vs 23%; P = .65), or 90-day all-cause readmission (54% vs 53%; P = .91). There was a significant 17% decrease in 90-day mortality associated with the use of FDX (OR .3; P = .04).

Conclusions:

In a real-world high-risk patient population, the use of FDX compared to oral VAN did not result in decreased CDI recurrence within 4 weeks or fewer hospital readmissions within 90 days. Further research is needed to better assess the value of FDX in this patient population.
Duty and Deontology
Authors: Herman Barbara
Published: September 2024

A too rarely emphasized feature of modern deontological ethics is the structure of its directives. Faced with alternatives, the question for the moral agent is “which, if either, must I perform (or avoid)?” Getting it right, one is, morally speaking, done…until the next set of freighted options presents. We should wonder whether this makes sense: whether there is not a more complex structure to deontological requirements that resists the “one and done” idea. Rehabilitating the Kantian idea of duty as a value-based deliberative principle, I argue for a more plausible deontology whose requirements are often temporally extended and interpersonally complex.
Sentiment analysis of code-mixed Dravidian languages leveraging pretrained model and word-level language tag
Authors: Chanda Supriya , Mishra Anshika , Pal Sukomal
Published: September 2024

The exponential growth of social media data in the era of Web 2.0 has necessitated advanced techniques for sentiment analysis. While sentiment analysis in monolingual datasets has received significant attention that in code-mixed datasets still need to be studied more. Code-mixed data often contain a mixture of monolingual content (might be in transliterated form), single-script but multilingual content, and multi-script multilingual content. This paper explores the issue from three important angles. What will be the best strategy to deal with the data for sentiment detection? Whether to train the classifier with the whole of the dataset or only with the pure code-mixed subset from the dataset? How much important is the language identification (LID) for the task? If LID is to be done, how, and when will it be used to yield the best performance? We explore the questions in the light of three datasets of Tamil–English, Kannada–English, and Malayalam–English YouTube social media comments. Our solution incorporated mBERT and an optional LID module. We report our results using a set of metrics like precision, recall,
$F_1$
score, and accuracy. The solutions provide considerable performance gain and some interesting insights for sentiment analysis from code-mixed data.
First report of the association between Wolbachia and Cotesia flavipes (Hymenoptera: Braconidae): effect on life history parameters of the parasitoid
Authors: Silva Nadja Nara P. , Carvalho Vanessa R. , Silva Carolane B. , Bomfim João Pedro A. , Ramos Gabryele S. , Oliveira Regiane C.
Published: September 2024

The symbiosis between microorganisms and host arthropods can cause biological, physiological, and reproductive changes in the host population. The present study aimed to survey facultative symbionts of the genera Wolbachia, Arsenophonus, Cardinium, Rickettsia, and Nosema in Cotesia flavipes (Cameron) (Hymenoptera: Braconidae) and Diatraea saccharalis (Fabricius) (Lepidoptera: Crambidae) in the laboratory and evaluate the influence of infection on the fitness of these hosts. For this purpose, 16S rDNA primers were used to detect these facultative symbionts in the host species, and the hosts' biological and morphological features were evaluated for changes resulting from the infection caused by these microorganisms. The bacterial symbionts studied herein were not detected in the D. saccharalis samples analysed, but the endosymbiont Wolbachia was detected in C. flavipes and altered the biological and morphological aspects of this parasitoid insect. The results of this study may help to elucidate the role of Wolbachia in maintaining the quality of populations/lineages of C. flavipes.
Performance and trust in child protection systems: a comparative analysis of England and Norway
Authors: Hassan Bilal
Published: September 2024

Research on the relationship between performance and trust is commonplace in social sciences, yet trust in child protection systems (CPS) remains an emerging area of study. This research delves into how three dimensions of performance – distributive justice, procedural fairness, and functional effectiveness – affect trust in CPS in England and Norway, drawing insights from organisational and social psychology literature. A cross-sectional survey collected data from 981 individuals in England and 1,140 in Norway. Results suggest that procedural fairness and the competences indicator of functional effectiveness significantly and positively impact trust in CPS in both countries. Resources significantly influence trust in Norway’s CPS, while distributive justice has no impact on trust in either country’s CPS. These findings hold theoretical and practical implications for trust in CPS.
Constraints on verbal -s/zero marking: New insights from Norwich
Authors: Britain David , Rupp Laura
Published: September 2024

Here we investigate present tense verbal -s/zero variability in a dialect of Eastern England in which -s marking can only appear in third-person singular contexts. Our objective is to explore constraints on -s/zero marking, and to consider the grammatical function of -s in such a variety. In order to investigate this, we reanalyzed verbal -s/zero marking in 63 sociolinguistic interviews found in Peter Trudgill’s (1974) corpus from Norwich. The results show not only a significant role for subject animacy (animate subjects mark -s less than inanimates) and lexical (punctual verbs mark -s less than duratives) and structural aspect (punctual and habitual events mark less -s than durative ones), but also an interaction between animacy and aspect. To account for the findings, we draw upon the notion of differential subject marking (e.g., Aissen, 2003), which considers the role of the canonicity of arguments in accounting for morphological marking.
Tracking Agulhas Leakage in the South Atlantic Using Modern Planktic Foraminifera Nitrogen Isotopes
Authors: Granger R. , Smart S. M. , Foreman A. , Auderset A. , Campbell E. C. , Marshall T. A. , Haug G. H. , Sigman D. M. , Martínez‐García A. , Fawcett S. E.
Published: September 2024

Seawater transported into the South Atlantic from the Indian Ocean via “Agulhas leakage” modulates global ocean circulation and has been linked to glacial‐interglacial climate cycles. However, constraining past Agulhas leakage has been a challenge. We sampled a transect of the Cape Basin in winter 2017 that intersected a mature Agulhas eddy and found that the 15N/14N ratio (δ15N) of mixed‐layer nitrate, zooplankton, and foraminifera (tissue and shells) was 2‰–3‰ lower in the eddy than in the background Atlantic even though the δ15N of the underlying thermocline nitrate was indistinguishable between the two settings. We suggest that the δ15N of foraminifera and other zooplankton in the eddy reflects the original Agulhas Current thermocline nitrate, which is ∼2‰ lower than that of the South Atlantic due to N2 fixation that occurs in the Indian Ocean. Foraminifera δ15N may have been lowered further during eddy migration by in situ N2 fixation and/or recycling of low‐δ15N ammonium. The absence of low‐δ15N Agulhas nitrate in the eddy thermocline can be explained by partial assimilation of the nitrate as it was mixed into the euphotic zone during and after eddy formation, raising its δ15N. The low δ15N of eddy foraminifera, apparent even after several months of eddy migration across the Cape Basin, suggests that fossil foraminifer‐bound δ15N from the region could record variations in past Agulhas leakage.
A Lake at the Mt. Fuji (Lake Motosu) Recording Prolonged Negative Arctic Oscillation as Reduction of Aeolian Dust Due To Westerly Pathways During the Holocene
Authors: Nemoto Karin , Yokoyama Yusuke , Obrochta Stephen P. , Miyairi Yosuke , Fujiwara Osamu , Yamamoto Shinya , Nakamura Atsunori , Hubert‐Ferrari Aurélia , Heyvaert Vanessa , De Batist Marc
Published: September 2024

East Asia is a major source of dust accounting for 20% of the global dust emission. Work on reconstructing past changes in dust transport in East Asia is complicated by difficulties in distinguishing local sedimentation from aerial material and lack of suitable material for age determination. Here, we address these issues and present a new dust proxy record from Lake Motosu, located on the Pacific side of Japan. The record is anchored by a high‐quality tephra and radiocarbon chronology. Because Lake Motosu is situated in a quartz‐free basaltic volcanic province, all quartz deposited in the lake is likely to be aerially sourced, and variations in quartz content should reflect past changes in dust transport. Our new record detects a low dust deposition event from 3.0 to 2.0 ka. This event corresponds to elevated sea surface temperature in the Sea of Japan and climate conditions similar to a negative phase of the Arctic Oscillation, indicating an association with the weakened Westerlies and with less frequent dust storms in the source region. The increase in spatial resolution of past dust transport reconstructions will further improve our understanding of the mechanism related to dust emission from East Asia.
Three Atmospheric Patterns Dominate Decadal North Atlantic Overturning Variability
Authors: Stephenson Dafydd , Amrhein Daniel E. , Thompson LuAnne
Published: September 2024

Atlantic Meridional Overturning Circulation (AMOC) variability originates from a large number of interacting processes with multiple time scales, with dominant processes dependent on both the latitude and timescale of interest. Here, we isolate the optimal atmospheric modes driving climate‐relevant decadal AMOC variability using a novel approach combining dynamical and statistical attribution (dynamics‐weighted principal component, or DPC analysis). We find that for both the subpolar (55°N) and subtropical (25°N) AMOC, the most effective independent mode of heat flux forcing closely resembles the North Atlantic Oscillation, and drives meridionally coherent AMOC anomalies through western boundary density anomalies. Conversely, established modes of wind stress variability possess limited quantitative similarity to the optimal wind stress patterns, which generate low‐frequency AMOC fluctuations by rearranging the ocean buoyancy field. We demonstrate (by running a modified version of the ECCOv4r4 state estimate) that most AMOC variability on decadal time scales can be explained by the DPCs.
Full Waveform Inversion Based on Dynamic Time Warping and Application to Reveal the Crustal Structure of Western Yunnan, Southwest China
Authors: Tan Jiayan , Wang Weitao , Langston Charles
Published: September 2024

We develop a 3D full waveform inversion (FWI) method based on dynamic time warping (DTW) to address the issue of cycle‐skipping, which can prohibit the convergence of conventional FWI methods. DTW globally compares data samples at different time steps in 2D matrices against the time shifts of waveforms. We introduce the concept of shape descriptors into softDTW, creating a soft‐shapeDTW objective function within our waveform inversion process to improve alignment accuracy. Additionally, including constraints from Sakoe‐Chiba bands in the inversion further enhances efficiency and overall performance. A synthetic test has shown that the soft‐shapeDTW inversion outperforms conventional waveform inversions in overcoming the cycle‐skipping challenges that arise from poor initial models. This method was applied to fit observed seismograms to reveal western Yunnan's crustal structure. Seismic waveforms were recorded by 88 broadband stations from 10 local earthquakes, which were then denoised using a continuous wavelet transform method. Generalized cut and paste waveform inversions were used to determine the source parameters of these seismic events. Our inversion well‐aligned various seismic phases in the selected time windows of seismograms, and the resolved velocity models well associate with local geological structure. Results suggest that the soft‐shapeDTW inversion offers a robust alternative to FWI, reducing the reliance on accurate starting models.
Wind‐Driven Along‐Coast Pressure Gradients in the Middle Atlantic Bight
Authors: Lentz Steven J.
Published: September 2024

Along‐shelf wind stresses drive substantial along‐coast variations in sea level that result in significant along‐coast pressure gradients in the Middle Atlantic Bight (MAB) at time scales from days to years. Forty years of sea‐level data and reanalysis wind stresses are examined to determine the characteristics and dynamics of pressure gradients along the New England and Central MAB coasts. Along‐coast dynamic sea level (pressure) gradients often exceed 5 cm/100 km at daily time scales, 2 cm/100 km at monthly time scales and 0.2 cm/100 km at yearly time scales. Along‐shelf wind stresses account for more than 50% of the along‐coast pressure gradient variance at daily and monthly time scales and more than 25% at yearly time scales. Pressure gradients along the New England coast are primarily driven by local wind stresses along the New England shelf, while pressure gradients along the Central MAB shelf are driven by both local wind stresses along the Central MAB shelf and remote wind stresses along the New England shelf. A steady depth‐average model (Csanady, 1978, https://doi.org/10.1175/1520‐0485(1978)008<0047:tatw>2.0.co;2) accurately reproduces the wind‐driven along‐coast pressure gradients in both regions. The along‐coast pressure gradients typically oppose the local wind stress and, in the along‐shelf momentum balance, are 50%–80% of the along‐shelf wind stress over the inner shelf (water depth 15 m).
Determinants of survival after first relapse of acute lymphoblastic leukemia: a Children’s Oncology Group study
Authors: Rheingold Susan R. , Bhojwani Deepa , Ji Lingyun , Xu Xinxin , Devidas Meenakshi , Kairalla John A. , Shago Mary , Heerema Nyla A. , Carroll Andrew J. , Breidenbach Heather , Borowitz Michael , Wood Brent L. , Angiolillo Anne L. , Asselin Barbara L. , Bowman W. Paul , Brown Patrick , Dreyer ZoAnn E. , Dunsmore Kimberly P. , Hilden Joanne M. , Larsen Eric , Maloney Kelly , Matloub Yousif , Mattano Leonard A. , Winter Stuart S. , Gore Lia , Winick Naomi J. , Carroll William L. , Hunger Stephen P. , Raetz Elizabeth A. , Loh Mignon L.
Published: September 2024

Limited prognostic factors have been associated with overall survival (OS) post-relapse in childhood Acute Lymphoblastic Leukemia (ALL). Patients enrolled on 12 Children’s Oncology Group frontline ALL trials (1996–2014) were analyzed to assess for additional prognostic factors associated with OS post-relapse. Among 16,115 patients, 2053 (12.7%) relapsed. Relapse rates were similar for B-ALL (12.5%) and T-ALL (11.2%) while higher for infants (34.2%). Approximately 50% of B-ALL relapses occurred late (≥36 months) and 72.5% involved the marrow. Conversely, 64.8% of T-ALL relapses occurred early (<18 months) and 47.1% involved the central nervous system. The 5-year OS post-relapse for the entire cohort was 48.9 ± 1.2%; B-ALL:52.5 ± 1.3%, T-ALL:35.5 ± 3.3%, and infant ALL:21.5 ± 3.9%. OS varied by early, intermediate and late time-to-relapse; 25.8 ± 2.4%, 49.5 ± 2.2%, and 66.4 ± 1.8% respectively for B-ALL and 29.8 ± 3.9%, 33.3 ± 7.6%, 58 ± 9.8% for T-ALL. Patients with ETV6::RUNX1 or Trisomy 4 + 10 had median time-to-relapse of 43 months and higher OS post-relapse 74.4 ± 3.1% and 70.2 ± 3.6%, respectively. Patients with hypodiploidy, KMT2A-rearrangement, and TCF3::PBX1 had short median time-to-relapse (12.5-18 months) and poor OS post-relapse (14.2 ± 6.1%, 31.9 ± 7.7%, 36.8 ± 6.6%). Site-of-relapse varied by cytogenetic subtype. This large dataset provided the opportunity to identify risk factors for OS post-relapse to inform trial design and highlight populations with dismal outcomes post-relapse.
A simple and rapid simultaneous measurement strategy for optical rotatory dispersion and circular dichroism
Authors: Du Junjie
Published: September 2024

A simple cavity-based technology capable of simultaneously measuring optical rotary dispersion and circular dichroism within milliseconds offers ultra-high sensitivity and unprecedented spectral resolution. This advancement holds significant potential for various biochemical applications, including drug development, clinical diagnosis, and food science and safety.
Large-scale brain connectivity changes following the administration of lysergic acid diethylamide, d-amphetamine, and 3,4-methylenedioxyamphetamine
Authors: Avram Mihai , Fortea Lydia , Wollner Lea , Coenen Ricarda , Korda Alexandra , Rogg Helena , Holze Friederike , Vizeli Patrick , Ley Laura , Radua Joaquim , Müller Felix , Liechti Matthias E. , Borgwardt Stefan
Published: September 2024

Psychedelics have recently attracted significant attention for their potential to mitigate symptoms associated with various psychiatric disorders. However, the precise neurobiological mechanisms responsible for these effects remain incompletely understood. A valuable approach to gaining insights into the specific mechanisms of action involves comparing psychedelics with substances that have partially overlapping neurophysiological effects, i.e., modulating the same neurotransmitter systems. Imaging data were obtained from the clinical trial NCT03019822, which explored the acute effects of lysergic acid diethylamide (LSD), d-amphetamine, and 3,4-methylenedioxymethamphetamine (MDMA) in 28 healthy volunteers. The clinical trial employed a double-blind, placebo-controlled, crossover design. Herein, various resting-state connectivity measures were examined, including within-network connectivity (integrity), between-network connectivity (segregation), seed-based connectivity of resting-state networks, and global connectivity. Differences between placebo and the active conditions were assessed using repeated-measures ANOVA, followed by post-hoc pairwise t-tests. Changes in voxel-wise seed-based connectivity were correlated with serotonin 2 A receptor density maps. Compared to placebo, all substances reduced integrity in several networks, indicating both common and unique effects. While LSD uniquely reduced integrity in the default-mode network (DMN), the amphetamines, in contrast to our expectations, reduced integrity in more networks than LSD. However, LSD exhibited more pronounced segregation effects, characterized solely by decreases, in contrast to the amphetamines, which also induced increases. Across all substances, seed-based connectivity mostly increased between networks, with LSD demonstrating more pronounced effects than both amphetamines. Finally, while all substances decreased global connectivity in visual areas, compared to placebo, LSD specifically increased global connectivity in the basal ganglia and thalamus. These findings advance our understanding of the distinctive neurobiological effects of psychedelics, prompting further exploration of their therapeutic potential.
Impact of blood glucose on cognitive function in insulin resistance: novel insights from ambulatory assessment
Authors: Gruber Judith R. , Ruf Alea , Süß Elena D. , Tariverdian Sewin , Ahrens Kira F. , Schiweck Carmen , Ebner-Priemer Ulrich , Edwin Thanarajah Sharmili , Reif Andreas , Matura Silke
Published: September 2024

Background/objectives

Insulin resistance (IR)-related disorders and cognitive impairment lead to reduced quality of life and cause a significant strain on individuals and the public health system. Thus, we investigated the effects of insulin resistance (IR), and blood glucose fluctuations on cognitive function under laboratory and free-living conditions, using ecological momentary assessment (EMA).

Subjects/methods

Baseline assessments included neuropsychological tests and blood analysis. Individuals were classified as either insulin-sensitive (<2) or insulin-resistant (≥2), based on their Homeostatic Model Assessment (HOMA-IR) values. Continuous glucose monitoring (CGM) using a percutaneous sensor was performed for 1 week. Using multiple linear regression, we examined the effects of HOMA-IR and CGM metrics on cognitive domains. Working memory (WM) performance, which was assessed using EMA, 4 times a day for 3 consecutive days, was matched to short-term pre-task CGM metrics. Multilevel analysis was used to map the within-day associations of HOMA-IR, short-term CGM metrics, and WM.

Results

Analyses included 110 individuals (mean age 48.7 ± 14.3 years, 59% female, n = 53 insulin-resistant). IR was associated with lower global cognitive function (b = −0.267, P = 0.027), and WM (b = −0.316; P = 0.029), but not with executive function (b = −0.216; P = 0.154) during baseline. EMA showed that higher HOMA-IR was associated with lower within-day WM performance (β = −0.20, 95% CI −0.40 to −0.00). CGM metrics were not associated with cognitive performance.

Conclusions

The results confirm the association between IR and decrements in global cognitive functioning and WM, while no effects of CGM metrics were observed, making IR a crucial time point for intervention. Targeting underlying mechanisms (e.g., inflammation) in addition to glycemia could be promising to minimize adverse cognitive effects. Registered under https://drks.de/register/de identifier no. DRKS00022774.
Traumatic spinal cord injury and its correlation to risk of autoimmune/-inflammatory disease
Authors: Nielsen Tim Damgaard , Laursen Thomas Munk , Bech Bodil Hammer , Rasmussen Mikkel Mylius
Published: September 2024

Study design

Nationwide epidemiological open cohort study.

Objectives

To evaluate whether individuals with traumatic spinal cord injury (TSCI) are more prone to develop autoimmune diseases compared to a general non-TSCI population.

Setting

Danish public national registries.

Methods

An open nationwide cohort, including individuals born in Denmark from or alive during 1945-2018 was collected and the study period was 1980-2018. Poissons Log-linear regression estimated the incidence rate ratio (IRR) for developing eight groups of autoimmune diseases. A dose-response relationship based on the cervical/thoracic level of injury was assessed by stratification.

Results

The cohort included 3,272 individuals with TSCI and 4.8 million background individuals, accounting for 50,865 and 140 million person-years respectively. The TSCI population had an overall IRR of 1.81 (95% CI, 1.59 to 2.05) of getting any autoimmune disease. Subgroup analysis found positive associations for; a) Other neurologic IRR 5.19 (95% CI, 2.79 to 9.65), b) multiple sclerosis IRR 3.70 (95% CI, 2.54 to 5.40), c) Dermatologic IRR 2.57 (95% CI, 1.86 to 3.55), d) Type 1 diabetes mellitus IRR 2.01 (95% CI, 1.54 to 2.61), e) Systemic 1.92 (95% CI, 1.44 to 2.55), and f) Gastroenterologic IRR 1.42 (95% CI, 1.05 to 1.92). Cervical levels of TSCI showed an IRR of 1.70 (95% CI, 1.43 to 2.02), while thoracic levels had an IRR 1.98 (95% CI, 1.63 to 2.39).

Conclusions

TSCI may be an individual risk factor of developing an autoimmune disease. There does not appear to exist a dose-response relationship from the level of injury.

Sponsorship

None.
Association of ADAM family members with proliferation signaling and disease progression in multiple myeloma
Authors: Evers Marietheres , Stühmer Thorsten , Schreder Martin , Steinbrunn Torsten , Rudelius Martina , Jundt Franziska , Ebert Regina , Hartmann Tanja Nicole , Bargou Ralf Christian , Rosenwald Andreas , Leich Ellen
Published: September 2024

Multiple myeloma (MM) is a hematological malignancy whose curability is greatly challenged by recurrent patient relapses and therapy resistance. We have previously proposed the high expression of ADAM8, ADAM9 and ADAM15 (A Disintegrin And Metalloproteinase 8/9/15) as adverse prognostic markers in MM. This study focused on the so far scarcely researched role of ADAM8/9/15 in MM using two patient cohorts and seven human MM cell lines (HMCL). High ADAM8/9/15 expression was associated with high-risk cytogenetic abnormalities and extramedullary disease. Furthermore, ADAM8/15 expression increased with MM progression and in relapsed/refractory MM compared to untreated patient samples. RNA sequencing and gene set enrichment analysis comparing ADAM8/9/15high/low patient samples revealed an upregulation of proliferation markers and proliferation-associated gene sets in ADAM8/9/15high patient samples. High ADAM8/9/15 expression correlated with high Ki67 and high ADAM8/15 expression with high MYC protein expression in immunohistochemical stainings of patient tissue. Conversely, siRNA-mediated knockdown of ADAM8/9/15 in HMCL downregulated proliferation-related gene sets. Western blotting revealed that ADAM8 knockdown regulated IGF1R/AKT signaling and ADAM9 knockdown decreased mTOR activation. Lastly, high ADAM8/9/15 expression levels were verified as prognostic markers independent of Ki67/MYC expression and/or high-risk abnormalities. Overall, these findings suggest that ADAM8/9/15 play a role in MM progression and proliferation signaling.
A bird’s eye view of mitochondrial unfolded protein response in cancer: mechanisms, progression and further applications
Authors: Zhang Xinyu , Fan Yumei , Tan Ke
Published: September 2024

Mitochondria are essential organelles that play critical roles in energy metabolism, apoptosis and various cellular processes. Accumulating evidence suggests that mitochondria are also involved in cancer development and progression. The mitochondrial unfolded protein response (UPRmt) is a complex cellular process that is activated when the protein-folding capacity of the mitochondria is overwhelmed. The core machinery of UPRmt includes upstream regulatory factors, mitochondrial chaperones and proteases. These components work together to eliminate misfolded proteins, increase protein-folding capacity, and restore mitochondrial function. Recent studies have shown that UPRmt is dysregulated in various cancers and contributes to tumor initiation, growth, metastasis, and therapeutic resistance. Considering the pivotal role of the UPRmt in oncogenesis, numerous compounds and synthetic drugs targeting UPRmt-related components induce cancer cell death and suppress tumor growth. In this review, we comprehensively summarize recent studies on the molecular mechanisms of UPRmt activation in C. elegans and mammals and elucidate the conceptual framework, functional aspects, and implications of the UPRmt for cancer therapy. In summary, we paint a developmental landscape of the UPRmt in different types of cancer and offer valuable insights for the development of novel cancer treatment strategies by targeting the UPRmt.
RNA-mediated double-strand break repair by end-joining mechanisms
Authors: Jeon Youngkyu , Lu Yilin , Ferrari Margherita Maria , Channagiri Tejasvi , Xu Penghao , Meers Chance , Zhang Yiqi , Balachander Sathya , Park Vivian S. , Marsili Stefania , Pursell Zachary F. , Jonoska Nataša , Storici Francesca
Published: September 2024

Double-strand breaks (DSBs) in DNA are challenging to repair. Cells employ at least three DSB-repair mechanisms, with a preference for non-homologous end joining (NHEJ) over homologous recombination (HR) and microhomology-mediated end joining (MMEJ). While most eukaryotic DNA is transcribed into RNA, providing complementary genetic information, much remains unknown about the direct impact of RNA on DSB-repair outcomes and its role in DSB-repair via end joining. Here, we show that both sense and antisense-transcript RNAs impact DSB repair in a sequence-specific manner in wild-type human and yeast cells. Depending on its sequence complementarity with the broken DNA ends, a transcript RNA can promote repair of a DSB or a double-strand gap in its DNA gene via NHEJ or MMEJ, independently from DNA synthesis. The results demonstrate a role of transcript RNA in directing the way DSBs are repaired in DNA, suggesting that RNA may directly modulate genome stability and evolution.
IL-1β promotes adipogenesis by directly targeting adipocyte precursors
Authors: Hofwimmer Kaisa , de Paula Souza Joyce , Subramanian Narmadha , Vujičić Milica , Rachid Leila , Méreau Hélène , Zhao Cheng , Dror Erez , Barreby Emelie , Björkström Niklas K. , Wernstedt Asterholm Ingrid , Böni-Schnetzler Marianne , Meier Daniel T. , Donath Marc Y. , Laurencikiene Jurga
Published: September 2024

Postprandial IL-1β surges are predominant in the white adipose tissue (WAT), but its consequences are unknown. Here, we investigate the role of IL-1β in WAT energy storage and show that adipocyte-specific deletion of IL-1 receptor 1 (IL1R1) has no metabolic consequences, whereas ubiquitous lack of IL1R1 reduces body weight, WAT mass, and adipocyte formation in mice. Among all major WAT-resident cell types, progenitors express the highest IL1R1 levels. In vitro, IL-1β potently promotes adipogenesis in murine and human adipose-derived stem cells. This effect is exclusive to early-differentiation-stage cells, in which the adipogenic transcription factors C/EBPδ and C/EBPβ are rapidly upregulated by IL-1β and enriched near important adipogenic genes. The pro-adipogenic, but not pro-inflammatory effect of IL-1β is potentiated by acute treatment and blocked by chronic exposure. Thus, we propose that transient postprandial IL-1β surges regulate WAT remodeling by promoting adipogenesis, whereas chronically elevated IL-1β levels in obesity blunts this physiological function.
Omicron COVID-19 immune correlates analysis of a third dose of mRNA-1273 in the COVE trial
Authors: Zhang Bo , Fong Youyi , Fintzi Jonathan , Chu Eric , Janes Holly E. , Kenny Avi , Carone Marco , Benkeser David , van der Laan Lars W. P. , Deng Weiping , Zhou Honghong , Wang Xiaowei , Lu Yiwen , Yu Chenchen , Borate Bhavesh , Chen Haiyan , Reeder Isabel , Carpp Lindsay N. , Houchens Christopher R. , Martins Karen , Jayashankar Lakshmi , Huynh Chuong , Fichtenbaum Carl J. , Kalams Spyros , Gay Cynthia L. , Andrasik Michele P. , Kublin James G. , Corey Lawrence , Neuzil Kathleen M. , Priddy Frances , Das Rituparna , Girard Bethany , El Sahly Hana M. , Baden Lindsey R. , Jones Thomas , Donis Ruben O. , Koup Richard A. , Gilbert Peter B. , Follmann Dean ,   On behalf of the United States Government (USG) COVID-19 Immune Assays Team,   Moderna, Inc. Team,   Coronavirus Vaccine Prevention Network (CoVPN)/Coronavirus Efficacy (COVE) Team,   USG/CoVPN Biostatistics Team, van der Laan Lars W. P.
Published: September 2024

In the phase 3 Coronavirus Efficacy (COVE) trial (NCT04470427), post-dose two Ancestral Spike-specific binding (bAb) and neutralizing (nAb) antibodies were shown to be correlates of risk (CoR) and of protection against Ancestral-lineage COVID-19 in SARS-CoV-2 naive participants. In the SARS-CoV-2 Omicron era, Omicron subvariants with varying degrees of immune escape now dominate, seropositivity rates are high, and booster doses are administered, raising questions on whether and how these developments affect the bAb and nAb correlates. To address these questions, we assess post-boost BA.1 Spike-specific bAbs and nAbs as CoRs and as correlates of booster efficacy in COVE. For naive individuals, bAbs and nAbs inversely correlate with Omicron COVID-19: hazard ratios (HR) per 10-fold marker increase (95% confidence interval) are 0.16 (0.03, 0.79) and 0.31 (0.10, 0.96), respectively. In non-naive individuals the analogous results are similar: 0.15 (0.04, 0.63) and 0.28 (0.07, 1.08). For naive individuals, three vs two-dose booster efficacy correlates with predicted nAb titer at exposure, with estimates -8% (-126%, 48%), 50% (25%, 67%), and 74% (49%, 87%), at 56, 251, and 891 Arbitrary Units/ml. These results support the continued use of antibody as a surrogate endpoint.
The Polycomb system sustains promoters in a deep OFF state by limiting pre-initiation complex formation to counteract transcription
Authors: Szczurek Aleksander T. , Dimitrova Emilia , Kelley Jessica R. , Blackledge Neil P. , Klose Robert J.
Published: September 2024

The Polycomb system has fundamental roles in regulating gene expression during mammalian development. However, how it controls transcription to enable gene repression has remained enigmatic. Here, using rapid degron-based depletion coupled with live-cell transcription imaging and single-particle tracking, we show how the Polycomb system controls transcription in single cells. We discover that the Polycomb system is not a constitutive block to transcription but instead sustains a long-lived deep promoter OFF state, which limits the frequency with which the promoter can enter into a transcribing state. We demonstrate that Polycomb sustains this deep promoter OFF state by counteracting the binding of factors that enable early transcription pre-initiation complex formation and show that this is necessary for gene repression. Together, these important discoveries provide a rationale for how the Polycomb system controls transcription and suggests a universal mechanism that could enable the Polycomb system to constrain transcription across diverse cellular contexts.
One month convection timescale on the surface of a giant evolved star
Authors: Vlemmings Wouter , Khouri Theo , Bojnordi Arbab Behzad , De Beck Elvire , Maercker Matthias
Published: September 2024

The transport of energy through convection is important during many stages of stellar evolution1,2, and is best studied in our Sun3 or giant evolved stars4. Features that are attributed to convection are found on the surface of massive red supergiant stars5–8. Also for lower-mass evolved stars, indications of convection are found9–13, but convective timescales and sizes remain poorly constrained. Models indicate that convective motions are crucial to produce strong winds that return the products of stellar nucleosynthesis into the interstellar medium14. Here we report a series of reconstructed interferometric images of the surface of the evolved giant star R Doradus. The images reveal a stellar disk with prominent small-scale features that provide the structure and motions of convection on the stellar surface. We find that the dominant structure size of the features on the stellar disk is 0.72 ± 0.05 astronomical units. We measure the velocity of the surface motions to vary between −18 and +20 km s−1, which means that the convective timescale is approximately one month. This indicates a possible difference between the convection properties of low-mass and high-mass evolved stars.
Brain-wide dynamics linking sensation to action during decision-making
Authors: Khilkevich Andrei , Lohse Michael , Low Ryan , Orsolic Ivana , Bozic Tadej , Windmill Paige , Mrsic-Flogel Thomas D.
Published: September 2024

Perceptual decisions rely on learned associations between sensory evidence and appropriate actions, involving the filtering and integration of relevant inputs to prepare and execute timely responses1,2. Despite the distributed nature of task-relevant representations3–10, it remains unclear how transformations between sensory input, evidence integration, motor planning and execution are orchestrated across brain areas and dimensions of neural activity. Here we addressed this question by recording brain-wide neural activity in mice learning to report changes in ambiguous visual input. After learning, evidence integration emerged across most brain areas in sparse neural populations that drive movement-preparatory activity. Visual responses evolved from transient activations in sensory areas to sustained representations in frontal-motor cortex, thalamus, basal ganglia, midbrain and cerebellum, enabling parallel evidence accumulation. In areas that accumulate evidence, shared population activity patterns encode visual evidence and movement preparation, distinct from movement-execution dynamics. Activity in movement-preparatory subspace is driven by neurons integrating evidence, which collapses at movement onset, allowing the integration process to reset. Across premotor regions, evidence-integration timescales were independent of intrinsic regional dynamics, and thus depended on task experience. In summary, learning aligns evidence accumulation to action preparation in activity dynamics across dozens of brain regions. This leads to highly distributed and parallelized sensorimotor transformations during decision-making. Our work unifies concepts from decision-making and motor control fields into a brain-wide framework for understanding how sensory evidence controls actions.
Ultrahigh electromechanical response from competing ferroic orders
Authors: Lin Baichen , Ong Khuong Phuong , Yang Tiannan , Zeng Qibin , Hui Hui Kim , Ye Zhen , Sim Celine , Yen Zhihao , Yang Ping , Dou Yanxin , Li Xiaolong , Gao Xingyu , Tan Chee Kiang Ivan , Lim Zhi Shiuh , Zeng Shengwei , Luo Tiancheng , Xu Jinlong , Tong Xin , Li Patrick Wen Feng , Ren Minqin , Zeng Kaiyang , Sun Chengliang , Ramakrishna Seeram , Breese Mark B. H. , Boothroyd Chris , Lee Chengkuo , Singh David J. , Lam Yeng Ming , Liu Huajun
Published: September 2024

Materials with electromechanical coupling are essential for transducers and acoustic devices as reversible converters between mechanical and electrical energy1–6. High electromechanical responses are typically found in materials with strong structural instabilities, conventionally achieved by two strategies—morphotropic phase boundaries7 and nanoscale structural heterogeneity8. Here we demonstrate a different strategy to accomplish ultrahigh electromechanical response by inducing extreme structural instability from competing antiferroelectric and ferroelectric orders. Guided by the phase diagram and theoretical calculations, we designed the coexistence of antiferroelectric orthorhombic and ferroelectric rhombohedral phases in sodium niobate thin films. These films show effective piezoelectric coefficients above 5,000 pm V−1 because of electric-field-induced antiferroelectric–ferroelectric phase transitions. Our results provide a general approach to design and exploit antiferroelectric materials for electromechanical devices.
Connectome-constrained networks predict neural activity across the fly visual system
Authors: Lappalainen Janne K. , Tschopp Fabian D. , Prakhya Sridhama , McGill Mason , Nern Aljoscha , Shinomiya Kazunori , Takemura Shin-ya , Gruntman Eyal , Macke Jakob H. , Turaga Srinivas C.
Published: September 2024

We can now measure the connectivity of every neuron in a neural circuit1–9, but we cannot measure other biological details, including the dynamical characteristics of each neuron. The degree to which measurements of connectivity alone can inform the understanding of neural computation is an open question10. Here we show that with experimental measurements of only the connectivity of a biological neural network, we can predict the neural activity underlying a specified neural computation. We constructed a model neural network with the experimentally determined connectivity for 64 cell types in the motion pathways of the fruit fly optic lobe1–5 but with unknown parameters for the single-neuron and single-synapse properties. We then optimized the values of these unknown parameters using techniques from deep learning11, to allow the model network to detect visual motion12. Our mechanistic model makes detailed, experimentally testable predictions for each neuron in the connectome. We found that model predictions agreed with experimental measurements of neural activity across 26 studies. Our work demonstrates a strategy for generating detailed hypotheses about the mechanisms of neural circuit function from connectivity measurements. We show that this strategy is more likely to be successful when neurons are sparsely connected—a universally observed feature of biological neural networks across species and brain regions.
Comparative phytochemical, antioxidant, and hemostatic studies of fractions from raw and roasted sea buckthorn seeds in vitro
Authors: Sławińska Natalia , Żuchowski Jerzy , Stochmal Anna , Olas Beata
Published: September 2024

Various seeds, including sea buckthorn (Hippophae rhamnoides L.) seeds, are sources of different bioactive compounds. They can show anti-inflammatory, hypoglycemic, anti-hyperlipidemic, antibacterial, antioxidant, or other biological properties in in vitro and in vivo models. Our preliminary in vitro results have demonstrated that the extracts from raw (no thermal processing) and roasted (thermally processed) sea buckthorn seeds have antioxidant potential and anticoagulant activity. However, it was unclear which compounds were responsible for these properties. Therefore, in continuation of our previous study, the extracts were fractionated by C18 chromatography. Phytochemical analysis of three fractions (a, b, and c) from raw sea buckthorn seeds and four fractions (d, e, f, and g) from roasted sea buckthorn seeds were performed. Several in vitro assays were also conducted to determine the antioxidant and procoagulant/anticoagulant potential of the fractions and two of their major constituents—isorhamnetin 3-O-β-glucoside7-O-α-rhamnoside and serotonin. LC–MS analyses showed that serotonin is the dominant constituent of fractions c and f, which was tentatively identified on the basis of its HRMS and UV spectra. Moreover, fractions c and f, as well as b and e, contained different B-type proanthocyanidins. Fractions b and e consisted mainly of numerous glycosides of kaempferol, quercetin, and isorhamnetin. The results of oxidative stress assays (measurements of protein carbonylation, lipid peroxidation, and thiol groups oxidation) showed that out of all the tested fractions, fraction g (isolated from roasted seeds and containing mainly dihexoses, and serotonin) demonstrated the strongest antioxidant properties.
ISB 2001 trispecific T cell engager shows strong tumor cytotoxicity and overcomes immune escape mechanisms of multiple myeloma cells
Authors: Carretero-Iglesia Laura , Hall Olivia J. , Berret Jérémy , Pais Daniela , Estoppey Carole , Chimen Myriam , Monney Thierry , Loyau Jeremy , Dreyfus Cyrille , Macoin Julie , Perez Cynthia , Menon Vinu , Gruber Isabelle , Laurendon Amélie , Caro Lydia N. , Gudi Girish S. , Matsuura Tomomi , van der Graaf Piet H. , Blein Stanislas , Mbow M. Lamine , Croasdale-Wood Rebecca , Srivastava Ankita , Dyson Michael R. , Matthes Thomas , Kaya Zeynep , Edwards Claire M. , Edwards James R. , Maiga Sophie , Pellat-Deceunynck Catherine , Touzeau Cyrille , Moreau Philippe , Konto Cyril , Drake Adam , Zhukovsky Eugene A. , Perro Mario , Pihlgren Maria
Published: September 2024

Despite recent advances in immunotherapies targeting single tumor-associated antigens, patients with multiple myeloma eventually relapse. ISB 2001 is a CD3+ T cell engager (TCE) co-targeting BCMA and CD38 designed to improve cytotoxicity against multiple myeloma. Targeting of two tumor-associated antigens by a single TCE resulted in superior cytotoxic potency across a variable range of BCMA and CD38 tumor expression profiles mimicking natural tumor heterogeneity, improved resistance to competing soluble factors and exhibited superior cytotoxic potency on patient-derived samples and in mouse models. Despite the broad expression of CD38 across human tissues, ISB 2001 demonstrated a reduced T cell activation profile in the absence of tumor cells when compared to TCEs targeting CD38 only. To determine an optimal first-in-human dose for the ongoing clinical trial (NCT05862012), we developed an innovative quantitative systems pharmacology model leveraging preclinical data, using a minimum pharmacologically active dose approach, therefore reducing patient exposure to subefficacious doses of therapies.
A novel synthesis method of medium- and long-chain triglyceride lipids from rubber seed oil catalyzed by enzymatic interesterification and its metabolism mechanism
Authors: Liu Jiahao , Zheng Yinghui , Zhang Renwei , Yu Yue , Wang Fang , Deng Li , Wu Kai
Published: September 2024

Medium- and long-chain triglyceride (MLCT) is a striking structural lipid for the supply of energy and essential fatty free acids (FFAs) in the food field.
A cerium-doped tungsten trioxide-functionalized sensing platform for photoelectrochemical detection of ascorbic acid with high sensitivity
Authors: Zhu Xueying , Liang Tikai , Tang Dianping
Published: September 2024

A highly efficient photoelectrochemical (PEC) strategy was proposed for the determination of ascorbic acid (AA).
Porous boron-doped graphitic carbon nitride-based label-free electrochemical immunoassay of vascular endothelial cadherin
Authors: Wang Xuan , He Mengting , Yu Rujie , Tan Liang
Published: September 2024

A glassy carbon electrode modified with porous boron-doped carbon nitride and gold nanoparticles was prepared. A label-free electrochemical method for the immunoassay of vascular endothelial cadherin was developed.