Browse Articles

Evaluating interdisciplinary research: Disparate outcomes for topic and knowledge base

Interdisciplinary research is essential for addressing complex global challenges, but there are concerns that scientific institutions like journals select against it. Prior work has focused largely on how interdisciplinarity relates to outcomes for published papers, but which papers get accepted for publication in the first place is unclear. Furthermore, journals may evaluate two key dimensions of interdisciplinarity,—topic and knowledge base,—differently. Topic interdisciplinarity (measured through title and abstract) may incur evaluation penalties by cutting across disciplinary evaluation standards and threatening symbolic boundaries, while knowledge-base interdisciplinarity (measured through references) may incur benefits by combining a large pool of nonredundant information. Evaluations may also depend on how well these dimensions align with each other and the intended audience. We test these arguments using data on 128,950 submissions to 62 journals across STEM disciplines, including both accepted and rejected manuscripts. We find that a 1SD increase in knowledge-base interdisciplinarity is associated with a 0.9 percentage-point higher acceptance probability, while a 1SD increase in topic interdisciplinarity corresponds to a 1.2 percentage-point lower acceptance probability. However, the penalty for high topic-interdisciplinarity diminishes when knowledge-base interdisciplinarity is also high, and when submitted to journals designated as “interdisciplinary.” These findings challenge the narrative of a uniform bias against interdisciplinary research and highlight the importance of distinguishing between its dimensions, as well as their alignment with each other and the intended audience.

Impact of altitudinal variations on plant growth dynamics, nutritional composition, and free living rhizospheric N2 fixing bacterial community of Eruca sativa

ATM priming and end resection–coupled phosphorylation of MRE11 is important for fork protection and replication restart

The MRE11/RAD50/NBS1 (MRN) complex plays multiple roles in the maintenance of genome stability. MRN is associated with replication forks to preserve fork integrity and is also required for end resection at double-strand breaks (DSBs) to facilitate homologous recombination (HR). The critical need for proper control of the MRE11 nuclease activity is highlighted by the extensive nascent strand DNA degradation driven by MRE11 in BRCA-deficient cells, leading to genome instability and increased sensitivity to chemotherapeutics. In this study, we identified a tightly controlled mechanism, elicited by sequential phosphorylation of MRE11 by ATM and ATR to regulate MRE11 nuclease activities through its DNA binding. Specifically, at DSBs, MRE11 phosphorylation by ATM at the C-terminal S676/S678 primes it for subsequent phosphorylation by ATR, whose activation is triggered by end resection which requires the MRE11 nuclease activity. This ATR-mediated phosphorylation in turn induces MRE11 dissociation from DNA, providing a feedback mechanism to regulate the extent of end resection. At stalled replication forks, however, without ATM priming, MRN is stably associated with forks despite ATR activation. Furthermore, the ATR phosphorylation–defective MRE11 mutants are retained at single-ended DSBs formed by fork reversal upon replication stress, leading to extensive degradation of nascent DNA strands. Importantly, this end resection–coupled MRE11 phosphorylation elicits another critical layer of fork protection of nascent DNA in addition to BRCA2, ensuring proper end resection that is sufficient for replication restart at reversed forks while maintaining fork stability.

Deep learning-aided segmentation combined with finite element analysis reveals a more natural biomechanic of dinosaur fossil

The pentameric chloride channel BEST1 is activated by extracellular GABA

Bestrophin-1 (BEST1) is a chloride channel expressed in the eye and other tissues of the body. A link between BEST1 and the principal inhibitory neurotransmitter γ -aminobutyric acid (GABA) has been proposed. The most appreciated receptors for extracellular GABA are the GABA B G-protein-coupled receptors and the pentameric GABA A chloride channels, both of which have fundamental roles in the central nervous system. Here, we demonstrate that BEST1 is directly activated by GABA. Through functional studies and atomic-resolution structures of human and chicken BEST1, we identify a GABA binding site on the channel’s extracellular side and determine the mechanism by which GABA binding stabilizes opening of the channel’s central gate. This same gate, “the neck,” is activated by intracellular [Ca 2+ ], indicating that BEST1 is controlled by ligands from both sides of the membrane. The studies demonstrate that BEST1, which shares no structural homology with GABA A receptors, is a GABA-activated chloride channel. The physiological implications of this finding remain to be studied.

Prognostic value of residual cancer burden after neoadjuvant chemotherapy in breast cancer: a comprehensive subtype-specific analysis

Abstract This study evaluated the prognostic impact of residual cancer burden (RCB) on breast cancer subtypes following neoadjuvant chemotherapy (NAC). We retrospectively examined 2,416 breast cancer patients treated with NAC and surgery at Asan Medical Center (2015–2020). Baseline characteristics, clinicopathological parameters, recurrence, and survival outcomes were analyzed using Kaplan-Meier and Cox regression methods to assess RCB’s prognostic significance across subtypes. Pathologic complete response (pCR) was achieved in 25.6% (619) of patients. RCB2 was the most common (44.0%, 1,063), followed by RCB3 (19.6%, 474) and RCB1 (10.8%, 260). Among HR-/HER2 + patients, 67% had RCB0/1, while 87% of HR+/HER2- patients had RCB2/3. Higher RCB was significantly associated with worse overall survival (OS) and disease-free survival (DFS) across all subtypes. Subtype-specific analysis revealed that HR-/HER2 + patients with RCB3 and HR-/HER2- patients with RCB2/3 had significantly worse OS and DFS. Multivariate analysis revealed that RCB2/3 (vs. RCB0), total mastectomy (vs. breast-conserving surgery), axillary lymph node dissection (ALND), lymphovascular invasion (LVI), high Ki-67 index (≥ 20), HR negativity, and HER2 negativity were linked to higher risks of recurrence and death (p < 0.05). Factors associated with higher RCB included ALND, LVI, higher Ki-67, and HR+/HER2- subtype. RCB classification is a strong prognostic indicator across all subtypes. Patients with RCB2/3 in the HR-/HER2- and RCB3 in the HR-/HER2 + subtypes had particularly poor outcomes, suggesting benefits from additional treatments beyond standard care.

Structural basis of excitatory amino acid transporter 3 substrate recognition

Excitatory amino acid transporters (EAATs) reside on cell surfaces and uptake substrates, including L-glutamate, L-aspartate, and D-aspartate, using ion gradients. Among five EAATs, EAAT3 is the only isoform that can efficiently transport L-cysteine, a substrate for glutathione synthesis. Recent studies suggest that EAAT3 also transports the oncometabolite R-2-hydroxyglutarate (R-2HG). Here, we examined the structural basis of substrate recognition by determining the cryogenic electron microscopy (cryo-EM) structures of EAAT3 bound to different substrates. We found that L-cysteine binds to EAAT3 in thiolate form, and EAAT3 recognizes different substrates by fine-tuning local conformations of the coordinating residues. However, using purified human EAAT3, we could not observe R-2HG binding or transport. Imaging of EAAT3 bound to L-cysteine revealed several conformational states, including an outward-facing state with a semi-open gate and a disrupted sodium-binding site. These structures demonstrate that the full gate closure, coupled with the binding of the last sodium ion, occurs after substrate binding. Furthermore, we observed that different substrates affect how the transporter distributes between a fully outward-facing conformation and intermediate occluded states on a path to the inward-facing conformation, suggesting that translocation rates are substrate-dependent.

Impact of primary entry tear locations on outcomes in acute type A aortic dissection

Correction for Gasparin et al., Combining exchangeable <i>P</i> -values

Understanding zoonotic disease spread with a fractional order epidemic model

Mapping global brain reconfigurations following local targeted manipulations

Understanding how localized brain interventions influence whole-brain dynamics is essential for deciphering neural function and designing therapeutic strategies. Using longitudinal functional MRI datasets collected from mice, we investigated the effects of focal interventions, such as thalamic lesions and chemogenetic silencing of cortical hubs. We found that these local manipulations disrupted the brain’s ability to sustain network-wide activity, leading to global functional connectivity (FC) reconfigurations. Personalized mouse brain simulations based on experimental data revealed that alterations in local excitability modulate firing rates and frequency content across distributed brain regions, driving these FC changes. Notably, the topography of the affected brain regions depended on the intervention site, serving as distinctive signatures of localized perturbations. These findings suggest that focal interventions produce consistent yet region-specific patterns of global FC reorganization, providing an explanation for the seemingly paradoxical observations of hypo- and hyperconnectivity reported in the literature. This framework offers mechanistic insights into the systemic effects of localized neural modulation and holds potential for refining clinical diagnostics in focal brain disorders and advancing personalized neuromodulation strategies.

Genomic prediction and genetic parameter estimation for unsaturated and saturated fatty acids in Canadian dairy cattle

Correction for Yardeni et al., Mitochondrial DNA lineages determine tumor progression through T cell reactive oxygen signaling

Development and validation of a nomogram for predicting antibiotic treatment duration in patients with liver abscess complicated by diabetes

CB-1 receptor agonist drastically changes oscillatory activity, defining active sleep

Brain oscillations in different behavioral states are essential for cognition, and oscillopathies contribute to cognitive dysfunction in neuropsychiatric diseases. Cannabis-1 receptor (CB1-R) activation was reported to suppress theta and fast gamma activities in rats during waking exploration, and here, we show that cannabis fundamentally alters network activity during sleep as well. Prominent theta rhythm is present in rapid eye movement sleep (REMS), whereas fast oscillations appear as regular sequences of sleep spindles during intermediate sleep (IS)—both implicated in dreaming and memory consolidation. The CB1-R agonist disrupted these mechanisms, restructuring IS-REMS episodes; IS lengthened sixfold and intruded REMS, where ongoing theta was drastically reduced. The spindle architecture was also affected; its amplitude increased, and its peak frequency downshifted into the theta range. Cannabis is known to induce psychotic-like conditions and cognitive deficits; thus, our results may help in understanding the dual effect of cannabis on cognitive states and the role of network oscillations in psychiatric pathology.

People adhere to content warning labels even when they are wrong due to ecologically rational adaptations

Intraflagellar transport trains can switch rails and move along multiple microtubules in intact primary cilia

Structural homeostasis and proper distributions of signaling molecules in cilia require a constant flow of cargoes carried by intraflagellar transport (IFT) trains in both anterograde and retrograde directions within the thin, long ciliary shafts. In the motile cilium framework, the nine microtubule doublets of the same length serve as the transportation rails, and a preferential association to the two subtubules of the microtubule doublets prevents collisions among the IFT trains that move in opposite directions. However, this mechanism is incompatible with the primary cilia structure, where most of the nine microtubule doublets terminate in the ciliary shafts—only several of them reach the ciliary tip and only in a singlet form. Here, we demonstrate that anterograde and retrograde trains in primary cilia interact with both subtubules of the microtubule doublets without apparent preference. They can switch microtubules, and they may simultaneously interact with multiple microtubules to facilitate their movement. This architecture makes the collisions inevitable, and live-cell recordings reveal that anterograde and retrograde trains tend to pause when they come into direct contact. We also find that the velocity of the train’s movement often changes after the pause. Thus, the motion behaviors of IFT trains in primary cilia are distinctive from those of motile cilia, and our data offer an essential foundation for understanding proper signaling molecule distributions in primary cilia.

Declining urban density attenuates rising population exposure to surface heat extremes

Flocking and giant fluctuations in epithelial active solids

The collective motion of epithelial cells is a fundamental biological process which plays a significant role in embryogenesis, wound healing, and tumor metastasis. While it has been broadly investigated for over a decade both in vivo and in vitro, large-scale coherent flocking phases remain underexplored and have so far been mostly described as fluid. In this work, we report an additional mode of large-scale collective motion for different epithelial cell types in vitro with distinctive features. By tracking individual cells, we show that cells move over long time scales coherently not as a fluid, but as a polar elastic solid with negligible cell rearrangements. Our analysis reveals that this solid flocking phase exhibits signatures of long-range polar order, accompanying with scale-free correlations of the transverse component of velocity fluctuations, anomalously large density fluctuations, and shear waves. Based on a general theory of active polar solids, we argue that these features result from massless orientational Goldstone mode, which, in contrast to polar fluids where they are generic, require the decoupling of global rotations of the polarity and in-plane elastic deformations in polar solids. We theoretically show and consistently observe in experiments that the fluctuations of elastic deformations diverge for large system sizes in such polar active solid phases, leading eventually to rupture and thus potentially loss of tissue integrity at large scales.

Three-dimensional bioprinted in vitro glioma tumor constructs for synchrotron microbeam radiotherapy dosimetry and biological study using gelatin methacryloyl hydrogel

Abstract Synchrotron microbeam radiotherapy (MRT) is an innovative cancer treatment that uses micron-sized of ultra-high dose rate spatially fractionated X-rays to effectively control cancer growth while reducing the damage to surrounding healthy tissue. However, the current pre-clinical experiments are commonly limited with the use of conventional two-dimensional cell cultures which cannot accurately model in vivo tissue environment. This study aims to propose a three-dimensional (3D) bioprinting gelatin methacryloyl (GelMA) hydrogel protocol and to characterize 3D bioprinted glioma relative to cell monolayer and spheroid models for experimental MRT using 9L rat gliosarcoma and U87 human glioma. Synchrotron broad-beam (SBB) and MRT beams were delivered to all cell models using 5, 10, and 20 Gy. 3D bioprinting enables the creation of 3D cell models that mimic in vivo conditions using bioinks, biomaterials, and cells. Synchrotron dosimetry, Monte Carlo simulation, in vitro cell viability, and fluorescence microscopy were performed to understand the relationship of the radiation dosimetry with the radiobiological response of different cancer models. Encapsulated gliomas were placed inside 3D printed human and rat phantoms to mimic scattering conditions. Results showed that MRT kills more gliomas relative to SBB for all cell models. The 3D bioprinted culture detected the spatial clustering of dead cells due to MRT high peak doses as seen in fluorescence imaging. The result of this study progresses MRT research by integrating 3D bioprinting techniques in radiobiological experiments. The study’s bioprinting protocol and results will help in reducing the use of animal experiments and possibly in clinical translation of MRT.