bluuebunny/crossref_metadata_2025 huggingface dataset:
Multi-omics approaches define novel aphid effector candidates associated with virulence and avirulence phenotypes
Authors: Thorpe Peter , Altmann Simone , Lopez-Cobollo Rosa , Douglas Nadine , Iqbal Javaid , Kanvil Sadia , Simon Jean-Christophe , Carolan James C. , Bos Jorunn , Turnbull Colin
Published: July 2024

Background

Compatibility between plant parasites and their hosts is genetically determined by both interacting organisms. For example, plants may carry resistance (R) genes or deploy chemical defences. Aphid saliva contains many proteins that are secreted into host tissues. Subsets of these proteins are predicted to act as effectors, either subverting or triggering host immunity. However, associating particular effectors with virulence or avirulence outcomes presents challenges due to the combinatorial complexity. Here we use defined aphid and host genetics to test for co-segregation of expressed aphid transcripts and proteins with virulent or avirulent phenotypes.

Results

We compared virulent and avirulent pea aphid parental genotypes, and their bulk segregant F1 progeny onMedicago truncatulagenotypes carrying or lacking theRAP1resistance quantitative trait locus. Differential gene expression analysis of whole body and head samples, in combination with proteomics of saliva and salivary glands, enabled us to pinpoint proteins associated with virulence/avirulence phenotypes. There was relatively little impact of host genotype, whereas large numbers of transcripts and proteins were differentially expressed between parental aphids, likely a reflection of their classification as divergent biotypes within the pea aphid species complex. Many fewer transcripts intersected with the equivalent differential expression patterns in the bulked F1 progeny, providing an effective filter for removing genomic background effects. Overall, there were more upregulated genes detected in the F1 avirulent dataset compared with the virulent one. Some genes were differentially expressed both in the transcriptome and in the proteome datasets, with aminopeptidase N proteins being the most frequent differentially expressed family. In addition, a substantial proportion (27%) of salivary proteins lack annotations, suggesting that many novel functions remain to be discovered.

Conclusions

Especially when combined with tightly controlled genetics of both insect and host, multi-omics approaches are powerful tools for revealing and filtering candidate lists down to plausible genes for further functional analysis as putative aphid effectors.
Proteomic changes orchestrate metabolic acclimation of a unicellular diazotrophic cyanobacterium during light-dark cycle and nitrogen fixation states
Authors: Panda Punyatoya , Giri Swagarika J. , Sherman Louis A. , Kihara Daisuke , Aryal Uma K.
Published: July 2024

Cyanobacteria have developed an impressive array of proteins and pathways, each tailored for specific metabolic attributes, to execute photosynthesis and biological nitrogen (N2)-fixation. An understanding of these biologically incompatible processes provides important insights into how they can be optimized for renewable energy. To expand upon our current knowledge, we performed label-free quantitative proteomic analysis of the unicellular diazotrophic cyanobacteriumCrocosphaera subtropicaATCC 51142 grown with and without nitrate under 12-hour light-dark cycles. Results showed significant shift in metabolic activities including photosynthesis, respiration, biological nitrogen fixation (BNF), and proteostasis to different growth conditions. We identified 14 nitrogenase enzymes which were among the most highly expressed proteins in the dark under nitrogen-fixing conditions, emphasizing their importance in BNF. Nitrogenase enzymes were not expressed under non nitrogen fixing conditions, suggesting a regulatory mechanism based on nitrogen availability. The synthesis of key respiratory enzymes and uptake hydrogenase (HupSL) synchronized with the synthesis of nitrogenase indicating a coordinated regulation of processes involved in energy production and BNF. Data suggests alternative pathways that cells utilize, such as oxidative pentose phosphate (OPP) and 2-oxoglutarate (2-OG) pathways, to produce ATP and support bioenergetic BNF. Data also indicates the important role of uptake hydrogenase for the removal of O2to support BNF. Overall, this study expands upon our knowledge regarding molecular responses ofCrocosphaera51142 to nitrogen and light-dark phases, shedding light on potential applications and optimization for renewable energy.
Reinforced polymer–nanoparticle hydrogels for subcutaneous and sustained delivery of trastuzumab
Authors: Bovone Giovanni , Bernhard Stéphane , Jacquot Guillaume , Mittelheisser Vincent , Mirjolet Céline , Guzzi Elia A. , Garau Paganella Lorenza , Liebi Luca , Lefebvre Olivier , Goetz Jacky , Charbonnière Loïc , Harlepp Sébastien , Pivot Xavier , Tibbitt Mark W. , Detappe Alexandre
Published: July 2024

In oncology, the advent of monoclonal antibody (mAbs) therapeutics represents a major breakthrough in various cancer diseases. However, these biotherapies often necessitate iterative hospital visits for intravenous infusion that can alter patient’s quality of life and contribute to the chronic saturation of hospitals. Interestingly, subcutaneous formulations of various mAbs offer a promising alternative facilitating faster administration compared with traditional intravenous methods, while still maintaining the same dosing schedule and providing time-saving advantages. Here, we developed an injectable mAb delivery platform using α-cyclodextrin (αCD)-reinforced polymer–nanoparticle hydrogels to perform a subcutaneous injection but also to delay the release of mAbs. By leveraging the versatility of our platform, we formulated hyaluronic acid- and alginate-based injectable drug depots by simply mixing components that are generally regarded as safe (GRAS). We used trastuzumab for the polymer–antibody complexation. The hydrogel depots delayed mAb release up to at least 3 days in both in vitro and in vivo mice models, outperforming clinically approved Herceptin subcutaneous formulation composed of trastuzumab with recombinant human hyaluronidase (rHuPH20).
Cortical Acetylcholine Response to Deep Brain Stimulation of the Basal Forebrain
Authors: Shanazz Khadijah , Xie Kun , Oliver Tucker , Bogan Jamal , Vale Fernando , Sword Jeremy , Kirov Sergei A. , Terry Alvin , O’Herron Philip , Blake David T
Published: July 2024

Background

Deep brain stimulation (DBS), the direct electrical stimulation of neuronal tissue in the basal forebrain to enhance release of the neurotransmitter acetylcholine, is under consideration as a method to improve executive function in patients with dementia. While some small studies indicate a positive response in the clinical setting, the relationship between DBS and acetylcholine pharmacokinetics is incompletely understood.

Objective

We examined the cortical acetylcholine response to different stimulation parameters of the basal forebrain.

Methods

2-photon imaging was combined with deep brain stimulation. Stimulating electrodes were implanted in the subpallidal basal forebrain, and the ipsilateral somatosensory cortex was imaged. Acetylcholine activity was determined using the GRABACh-3.0muscarinic acetylcholine receptor sensor, and blood vessels were imaged with Texas red.

Results

Experiments manipulating pulse train frequency demonstrated that integrated acetylcholine induced fluorescence was insensitive to frequency, and that peak levels were achieved with frequencies from 60 to 130 Hz. Altering pulse train length indicated that longer stimulation resulted in higher peaks and more activation with sublinear summation. The acetylcholinesterase inhibitor donepezil increased the peak response to 10s of stimulation at 60Hz, and the integrated response increased 57% with the 2 mg/kg dose, and 126% with the 4 mg/kg dose. Acetylcholine levels returned to baseline with a time constant of 14 to 18 seconds in all experiments.

Conclusions

These data demonstrate that acetylcholine receptor activation is insensitive to frequency between 60 and 130 Hz. High peak responses are achieved with up to 900 pulses. Donepezil increases total acetylcholine receptor activation associated with DBS but did not change temporal kinetics. The long time constants observed in the cerebral cortex add to the evidence supporting volume in addition to synaptic transmission.

Graphical Abstract
Cell-type specific epigenetic clocks to quantify biological age at cell-type resolution
Authors: Tong Huige , Guo Xiaolong , Jacques Macsue , Luo Qi , Eynon Nir , Teschendorff Andrew E.
Published: July 2024

The ability to accurately quantify biological age could help monitor and control healthy aging. Epigenetic clocks have emerged as promising tools for estimating biological age, yet they have been developed from heterogeneous bulk tissues, and are thus composites of two aging processes, one reflecting the change of cell-type composition with age and another reflecting the aging of individual cell-types. There is thus a need to dissect and quantify these two components of epigenetic clocks, and to develop epigenetic clocks that can yield biological age estimates at cell-type resolution. Here we demonstrate that in blood and brain, approximately 39% and 12% of an epigenetic clock’s accuracy is driven by underlying shifts in lymphocyte and neuronal subsets, respectively. Using brain and liver tissue as prototypes, we build and validate neuron and hepatocyte specific DNA methylation clocks, and demonstrate that these cell-type specific clocks yield improved estimates of chronological age in the corresponding cell and tissue-types. We find that neuron and glia specific clocks display biological age acceleration in Alzheimer’s Disease with the effect being strongest for glia in the temporal lobe. Moreover, CpGs from these clocks display a small but significant overlap with the causal DamAge-clock, mapping to key genes implicated in neurodegeneration. The hepatocyte clock is found accelerated in liver under various pathological conditions. In contrast, non-cell-type specific clocks do not display biological age-acceleration, or only do so marginally. In summary, this work highlights the importance of dissecting epigenetic clocks and quantifying biological age at cell-type resolution.
Brain-responsive music enables non-invasive, targeted and unobtrusive neurostimulation
Authors: Zaaimi Boubker , Clay Rosie , Shivakumar Abhishek , Rickert Joern , Jackson Andrew
Published: July 2024

Objective

We are developing a new closed-loop brain stimulation method by embedding, within music, auditory elements that respond to the listener’s brain activity. Here we show that this brain-responsive music has systematic and targeted effects on neural oscillations implicated in a variety of neurological and mental health disorders.

Approach

We recorded magnetoencephalogram (MEG) or electroencephalogram (EEG) signals from participants as they listened to music synthesized by commercial audio software. Brain signals were bandpass filtered, phase-shifted and used to control the timbre and/or timing of notes within the music.

Main results

Listening to brain-responsive music induced peaks and troughs in spectral power at frequencies that depended systematically on the phase-shift applied to the brain signal. Phase-dependent modulation was greatest at the centre frequency of the filter. As a result, by calibrating these parameters we could achieve selective enhancement or suppression of either theta (5 Hz) or alpha (10 Hz) oscillations. Moreover, by chosing different sensor locations we could target power modulation to either frontal or temporal cortex. The phase-dependent power modulation observed with brain-responsive music was significantly attenuated when participants listened to identical music as a conventional, open-loop stimulus. Finally, we demonstrate that brain activity could be modulated by more complex compositions combining a variety of brain-responsive musical elements controlled by a wireless, wearable EEG headband suitable for home use.

Significance

Brain-responsive music provides an unobtrusive and targeted method of modulating neural oscillations in the listener’s brain, and may enable both creative and therapeutic applications of Brain Computer Interface technologies.
Dynamic network features of functional and structural brain networks support visual working memory in aging adults
Authors: Neudorf Josh , Shen Kelly , McIntosh Anthony R.
Published: July 2024

In this work, we investigated the relationship between structural connectivity and the dynamics of functional connectivity and how this relationship changes with age to benefit cognitive functions. Visual working memory (VWM) is an important brain function that allows us to maintain a mental representation of the world around us, but its capacity and precision peaks by around 20 years old and decreases steadily throughout the rest of our lives. This research examined the functional brain network dynamics associated with VWM throughout the lifespan and found that Default Mode Network and Fronto-Parietal Network states were more well represented in individuals with better VWM. Furthermore, transitions between the Visual/Somatomotor Network state and the Attention Network state were more well-represented in older adults, and a network control theory simulation demonstrated that structural connectivity differences supporting this transition were associated with better VWM, especially in middle-aged individuals. The structural connectivity of regions from all states was important for supporting this transition in younger adults, while regions within the Visual/Somatomotor and Attention Network states were more important in older adults. These findings demonstrate that structural connectivity supports flexible, functional dynamics that allow for better VWM with age and may lead to important interventions to uphold healthy VWM throughout the lifespan.
In situdeposition of nanobodies by an engineered commensal microbe promotes survival in a mouse model of enterohemorrhagicE. coli
Authors: Srivastava Rajkamal , González-Prieto Coral , Lynch Jason P , Muscolo Michele , Lin Catherine Y , Brown Markus A , Lemos Luisa , Shrestha Anishma , Osburne Marcia S , Leong John M , Lesser Cammie F
Published: July 2024

Engineered smart microbes that deliver therapeutic payloads are emerging as treatment modalities, particularly for diseases with links to the gastrointestinal tract. EnterohemorrhagicE coli(EHEC) is a causative agent of potentially lethal hemolytic uremic syndrome. Given concerns that antibiotic treatment increases EHEC production of Shiga toxin (Stx), which is responsible for systemic disease, novel remedies are needed. EHEC encodes a type III secretion system (T3SS) that injects Tir into enterocytes. Tir inserts into the host cell membrane, exposing an extracellular domain that subsequently binds intimin, one of its outer membrane proteins, triggering the formation of attaching and effacing (A/E) lesions that promote EHEC mucosal colonization.Citrobacter rodentium(Cr), a natural A/E mouse pathogen, similarly requires Tir and intimin for its pathogenesis. Mice infected with Cr(ΦStx2dact), a variant lysogenized with an EHEC-derived phage that produces Stx2dact, develop intestinal A/E lesions and toxin-dependent disease. Stx2a is more closely associated with human disease. By developing an efficient approach to seamlessly modify theC. rodentiumgenome, we generated Cr_Tir-MEHEC(ΦStx2a), a variant that expresses Stx2a and the EHEC extracellular Tir domain. We found that mouse pre-colonization with HS-PROT3EcT-TD4, a human commensalE. colistrain (E. coliHS) engineered to efficiently secrete- an anti-EHEC Tir nanobody, delayed bacterial colonization and improved survival after challenge with Cr_Tir-MEHEC(ΦStx2a). This study provides the first evidence to support the efficacy of engineered commensalE. colito intestinally deliver therapeutic payloads that block essential enteric pathogen virulence determinants, a strategy that may serve as an antibiotic-independent antibacterial therapeutic modality.

Significance Statement

Engineered smart microbes that secrete therapeutics are emerging as treatment modalities, particularly for gut-based diseases. With the growing threat of multidrug-resistant infection, non-antibiotic treatments are urgently needed. The gastrointestinal pathogen enterohemorrhagicE coli(EHEC) can cause the potentially lethal hemolytic uremic syndrome, a toxin-driven disease. Given concerns that antibiotics increase toxin release, treatment is largely limited to supportive care. Here, we show that pre-treatment with a commensalE. coli(HS-PROT3EcT) engineered to secrete an antibody that blocks an essential EHEC virulence factor delays the establishment of an EHEC-like infection in mice. This study strongly suggests that smart microbes that deliver payloads that block colonization factors of gut pathogens can be developed as critically needed alternatives to antibiotics for fighting bacterial infections.
Event boundaries drive norepinephrine release and distinctive neural representations of space in the rodent hippocampus
Authors: McKenzie Sam , Sommer Alexandra L. , Donaldson Tia N. , Pimentel Infania , Kakani Meenakshi , Choi Irene Jungyeon , Newman Ehren L. , English Daniel F.
Published: July 2024

Episodic memories are temporally segmented around event boundaries that tend to coincide with moments of environmental change. During these times, the state of the brain should change rapidly, or reset, to ensure that the information encountered before and after an event boundary is encoded in different neuronal populations. Norepinephrine (NE) is thought to facilitate this network reorganization. However, it is unknown whether event boundaries drive NE release in the hippocampus and, if so, how NE release relates to changes in hippocampal firing patterns. The advent of the new GRABNEsensor now allows for the measurement of NE binding with sub-second resolution. Using this tool in mice, we tested whether NE is released into the dorsal hippocampus during event boundaries defined by unexpected transitions between spatial contexts and presentations of novel objections. We found that NE binding dynamics were well explained by the time elapsed after each of these environmental changes, and were not related to conditioned behaviors, exploratory bouts of movement, or reward. Familiarity with a spatial context accelerated the rate in which phasic NE binding decayed to baseline. Knowing when NE is elevated, we tested how hippocampal coding of space differs during these moments. Immediately after context transitions we observed relatively unique patterns of neural spiking which settled into a modal state at a similar rate in which NE returned to baseline. These results are consistent with a model wherein NE release drives hippocampal representations away from a steady-state attractor. We hypothesize that the distinctive neural codes observed after each event boundary may facilitate long-term memory and contribute to the neural basis for the primacy effect.
Lineage-specific patterns of sexually dimorphic antennal transcription in the paper waspPolistes fuscatus
Authors: Legan Andrew W , Sheehan Michael J
Published: July 2024

Olfaction mediates many behaviors in social Hymenoptera, with sexual dimorphism in antennal transcription associated with different behaviors between sexes. Females display coordinated social behaviors within colonies, while males exhibit limited social behavior but are selected for finding mates. The expanded "9-exon" odorant receptor (OR) gene subfamily is associated with chemical communication and exhibits strongly female biased antennal transcription in ants and honey bees. Polistine wasps represent an independent evolution of sociality and associated expansion of 9-exon ORs, though antennal expression patterns are unknown. Here, we report distinct patterns of sexually dimorphic OR transcription inPolistes fuscatuscompared to ants and bees. MostP. fuscatus9-exon transcripts were detected at similar levels in males and females, and some were male biased. We also report differential antennal transcription of cytochromes P450 and muscle-related genes between sexes. We discuss these patterns in the context of the unique sexual and social behaviors ofPolisteswasps, including prolonged male mating aggregations and male antennal tapping and curling during courtship and copulation. These results call attention to the lineage-specific selective pressures shaping sexually dimorphic antennal transcription in social insects.
How different immersive environments affect intracortical brain computer interfaces
Authors: Tortolani Ariana F , Kunigk Nicolas G , Sobinov Anton R , Boninger Michael L , Bensmaia Sliman J , Collinger Jennifer L , Hatsopoulos Nicholas G , Downey John E
Published: July 2024

Abstract

As brain-computer interface (BCI) research advances, many new applications are being developed. Tasks can be performed in different environments, and whether a BCI user can switch environments seamlessly will influence the ultimate utility of a clinical device. Here we investigate the importance of the immersiveness of the virtual environment used to train BCI decoders on the resulting decoder and its generalizability between environments. Two participants who had intracortical electrodes implanted in their precentral gyrus used a BCI to control a virtual arm, either viewed immersively through virtual reality goggles or at a distance on a flat television monitor. Each participant performed better with a decoder trained and tested in the environment they had used the most prior to the study, one for each environment type. The neural tuning to the desired movement was minimally influenced by the immersiveness of the environment. Finally, in further testing with one of the participants, we found that decoders trained in one environment generalized well to the other environment, but the order in which the environments were experienced within a session mattered. Overall, experience with an environment was more influential on performance than the immersiveness of the environment, but BCI performance generalized well after accounting for experience.
Effects of unconscious tactile stimuli on autonomic nervous activity and afferent signal processing
Authors: Sakuragi Mai , Tanaka Yuto , Shinagawa Kazushi , Tsuji Koki , Umeda Satoshi
Published: July 2024

Autonomic nervous system (ANS) is a mechanism that regulates our internal environment. In recent years, the interest in how tactile stimuli presented directly to the body affect ANS function and cortical processing in humans has been renewed. However, it is not yet clear how subtle tactile stimuli below the level of consciousness affect human heart rate and cortical processing. To examine this, subthreshold electrical stimuli were presented to the left forearm of 43 participants during an image-viewing task, and electrocardiogram (ECG) and electroencephalogram (EEG) data were collected. The changes in the R-wave interval of the ECG immediately after the subthreshold electrical presentation and heartbeat-evoked potential (HEP), the afferent signal processing of cardiac activity, were measured. The results showed that heart rate decelerated immediately after the presentation of subthreshold electrical stimuli. The HEP during stimulus presentation was amplified for participants with greater heart rate acceleration immediately after this deceleration. The magnitude of these effects depended on the type of the subthreshold tactile stimuli. The results suggest that even with subthreshold stimulation, the changes in autonomic activity associated with orienting response and related afferent signal processing differ depending on the clarity of the tactile stimuli.
Structural insights into the assembly mechanism of the flagellar MS-ring with three different symmetries
Authors: Kinoshita Miki , Makino Fumiaki , Miyata Tomoko , Imada Katsumi , Namba Keiichi , Minamino Tohru
Published: July 2024

The flagellar basal body MS-ring, formed by 34 FliF subunits, is the core of the flagellar motor as well as the base for flagellar assembly. The MS-ring is also a housing for the flagellar protein export gate complex that is required for construction of the flagellum on the cell surface. A large periplasmic region of FliF contains three ring-building motifs named RBM1, RBM2, and RBM3. RBM3 forms the S-ring and β-collar with C34 symmetry. RBM2 forms the inner core ring of the M-ring with C23 symmetry surrounded by 11 cog-like structures formed by RBM1 and RBM2. However, it remains unknown how FliF assembles to generate these three different symmetries within the MS-ring. Here, we report the two cryoEM structures of the MS-ring formed by FliF co-expressed with FliG and transmembrane export gate proteins. Structural comparison of 33-mer and 34-mer MS-rings revealed that a subtle change in the conformation of RBM3 produces the different rotational symmetries. Combination of cryoEM structural and mutational analyses of the MS-ring with C33 symmetry provides evidence that the well-conserved DQxGxxL motif within a flexible loop connecting RBM2 and RBM3 allows RBM2 to take two different orientations relative to RBM3 to form not only 11 cog-like structures just outside the inner core ring with C22 symmetry but also an appropriately sized central pore in the inner core ring to accommodate the export gate complex.

IMPORTANCE

The flagellar MS-ring is the core of the flagellar motor and serves not only as an initial template for flagellar assembly but also as a base to accommodate the flagellar protein export complex. The MS-ring is formed by 34 subunits of FliF with two transmembrane helices and a large periplasmic region containing ring-building motifs, RBM1, RBM2, and RBM3. FliF adopts two different conformations in the MS-ring to generate three different rotational symmetries, C34, C23, and C11. However, how FliF assembles to produce these three symmetries remains a mystery. Combination of cryoEM structural and mutational analyses has provided evidence that the well-conserved DQxGxxL motif within a hinge loop connecting RBM2 and RBM3 allows RBM2 to take two different orientations relative to RBM3, allowing 23 RBM2 domains of 34 subunits to form the inner core ring with a properly sized central pore to accommodate the flagellar protein export complex.
Introducing ‘identification probability’ for automated and transferable assessment of metabolite identification confidence in metabolomics and related studies
Authors: Metz Thomas O. , Chang Christine H. , Gautam Vasuk , Anjum Afia , Tian Siyang , Wang Fei , Colby Sean M. , Nunez Jamie R. , Blumer Madison R. , Edison Arthur S. , Fiehn Oliver , Jones Dean P. , Li Shuzhao , Morgan Edward T. , Patti Gary J. , Ross Dylan H. , Shapiro Madelyn R. , Williams Antony J. , Wishart David S.
Published: July 2024

Methods for assessing compound identification confidence in metabolomics and related studies have been debated and actively researched for the past two decades. The earliest effort in 2007 focused primarily on mass spectrometry and nuclear magnetic resonance spectroscopy and resulted in four recommended levels of metabolite identification confidence – the Metabolite Standards Initiative (MSI) Levels. In 2014, the original MSI Levels were expanded to five levels (including two sublevels) to facilitate communication of compound identification confidence in high resolution mass spectrometry studies. Further refinement in identification levels have occurred, for example to accommodate use of ion mobility spectrometry in metabolomics workflows, and alternate approaches to communicate compound identification confidence also have been developed based on identification points schema. However, neither qualitative levels of identification confidence nor quantitative scoring systems address the degree of ambiguity in compound identifications in context of the chemical space being considered, are easily automated, or are transferable between analytical platforms. In this perspective, we propose that the metabolomics and related communities consider identification probability as an approach for automated and transferable assessment of compound identification and ambiguity in metabolomics and related studies. Identification probability is defined simply as 1/N, where N is the number of compounds in a reference library or chemical space that match to an experimentally measured molecule within user-defined measurement precision(s), for example mass measurement or retention time accuracy, etc. We demonstrate the utility of identification probability in anin silicoanalysis of multi-property reference libraries constructed from the Human Metabolome Database and computational property predictions, provide guidance to the community in transparent implementation of the concept, and invite the community to further evaluate this concept in parallel with their current preferred methods for assessing metabolite identification confidence.
Structural disconnections caused by white matter hyperintensities in post-stroke spatial neglect
Authors: Röhrig Lisa , Karnath Hans-Otto
Published: July 2024

White matter hyperintensities (WMH), a common feature of cerebral small vessel disease, affect a wide range of cognitive dysfunctions, including spatial neglect. The latter is a disorder of spatial attention and exploration typically after right hemisphere brain damage. To explore the impact of WMH on neglect-related structural disconnections, the present study investigated the indirectly quantified structural disconnectome induced by either stroke lesion alone, WMH alone, or their combination. Further, we compared different measures of structural disconnections – voxel-wise, pairwise, tract-wise, and parcel-wise – to identify neural correlates and predict acute neglect severity. We observed that WMH-derived disconnections alone were not associated to neglect behavior. However, when combined with disconnections derived from individual stroke lesions, pre-stroke WMH contributed to post-stroke neglect severity by affecting right frontal and subcortical substrates, like the middle frontal gyrus, basal ganglia, thalamus, and the fronto-pontine tract. Predictive modeling demonstrated that voxel-wise disconnection data outperformed other measures of structural disconnection, explaining 42% of the total variance. Compared to using stroke lesion anatomy, prediction performance can be improved by either estimating stroke-based structural disconnections or delineating the combined anatomy of stroke lesion and WMH. We conclude that pre-stroke alterations in the white matter microstructure due to WMH contribute to post-stroke deficits in spatial attention, likely by impairing the integrity of human attention networks.
The Serine Shunt enables formate conversion to formaldehydein vivo
Authors: Schann Karin , Wenk Sebastian
Published: July 2024

Microbial valorization of CO2-derived substrates has emerged as a promising approach to address climate change and resource scarcity. Formate, which can be efficiently produced from CO2, shows great potential as a sustainable feedstock for biotechnological production. However, the scope of formate assimilation pathways is restricted by the limited number of natural formate-assimilating enzymes. To overcome this limitation, several new-to-nature routes for formate assimilation based on its reduction to formaldehyde have been proposed, but they suffer from low catalytic efficiencies and cannot yet support bacterial growth. Here, we propose the Serine Shunt as a novel formate reduction route and demonstrate its activityin vivo. In this pathway, formate is attached to glycine to form serine, which is subsequently cleaved into formaldehyde and glycine, thereby effectively converting formate to formaldehyde. Unlike other formate reduction routes, the Serine Shunt mainly utilizes natural reactions with favorable enzyme kinetics, while requiring the same amount of ATP and NAD(P)H as the most efficient new-to-nature route. We implemented the Serine Shunt in engineeredE. colistrains using a step-wise approach by dividing the pathway into metabolic modules. After validating the individual module activities, we demonstrated thein vivoactivity of the complete Serine Shunt by measuring intracellular formaldehyde production with a GFP sensor and coupling its activity to cell growth. Our results indicate that the Serine Shunt could be applied as a novel formate reduction route in methylotrophic hosts relevant for biotechnology.
Enhanced and idiosyncratic neural representations of personally typical scenes
Authors: Wang Gongting , Chen Lixiang , Cichy Radoslaw Martin , Kaiser Daniel
Published: July 2024

Previous research shows that the typicality of visual scenes (i.e., if they are good examples of a category) determines how easily they can be perceived and represented in the brain. However, the unique visual diets individuals are exposed to across their lifetimes should sculpt very personal notions of typicality. Here, we thus investigated whether scenes that are more typical to individual observers are more accurately perceived and represented in the brain. We used drawings to enable participants to describe typical scenes (e.g., a kitchen) and converted these drawings into 3D renders. These renders were used as stimuli in a scene categorization task, during which we recorded EEG. In line with previous findings, categorization was most accurate for renders resembling the typical scene drawings of individual participants. Our EEG analyses reveal two critical insights on how these individual differences emerge on the neural level: First, personally typical scenes yielded enhanced neural representations from around 200 ms after onset. Second, personally typical scenes were represented in idiosyncratic ways, with reduced dependence on high-level visual features. We interpret these findings in a predictive processing framework, where individual differences in internal models of scene categories formed through experience shape visual analysis in idiosyncratic ways.
Honey bulk DNA metagenomic analysis to identify honey biological composition and monitor honey bee pathogens
Authors: Paluoja Priit , Vaher Mihkel , Teder Hindrek , Krjutškov Kaarel , Salumets Andres , Raime Kairi
Published: July 2024

Honey’s DNA mixture originates from various organismal groups like plants, arthropods, fungi, bacteria, and viruses. Conventional methods like melissopalynological analysis and targeted honey DNA metabarcoding offer a limited view of honey’s biological composition. We conducted a honey bulk DNA metagenomic analysis to characterize the honey’s taxonomic composition and identify honey bee-related pathogens and parasites based on 266 Estonian and 103 foreign honey samples. 70.4% of the DNA in Estonian honey was derived from green plant families likeBrassicaceae,Rosaceae,Fabaceae, andPinaceae. Geographical distribution analysis revealed distinct botanical compositions between Estonian mainland and island samples. The bacterial familyLactobacillaceaewas prevalent overall, reflecting the honey bee microbiota in honey. We detected 12 honey bee pathogens and parasites, includingPaenibacillus larvaeandNosema ceranae. In conclusion, the study underscores the potential of bulk DNA-based and non-targeted metagenomic approaches for monitoring honey bee health, environmental quality, and honey composition, origin, and authenticity.
PARP inhibition enhances exemestane efficacy in triple-negative breast cancer
Authors: Yusoh Nur Aininie , Su Liping , Chia Suet Lin , Tian Xiaohe , Ahmad Haslina , Gill Martin R.
Published: July 2024

Triple negative breast cancer (TNBC) remains the breast cancer subtype with the poorest prognosis and median survival rate. Targeting PARP1/2 with PARP inhibitors (PARPi) and achieving synthetic lethality is an effective strategy for TNBCs with BRCA1/2 mutations, however, the majority of TNBCs are BRCA1/2 wild type. Synergistic drug combinations with PARPi offers the potential to expand the use of PARPi towards BRCA-proficient cancers, including TNBC. To identify new PARPi combinations, we screened a library of 166 FDA-approved oncology drugs for synergy with the PARPi Olaparib in TNBC cells. We found that Exemestane, an aromatase inhibitor, synergised with Olaparib with a significant decrease in IC50values and clonogenicity accompanied by elevated DNA damage and apoptosis seen in combination treatment. The mechanistic basis for synergy was rationalised by the previously unreported ability of Exemestane to induce replication stress, as evidenced by ATR pathway activation and RPA foci formation. Low impact of this combination towards normal breast epithelial cells was observed and Exemestane has no reported severe toxicity as a monotherapy. This combination was able to achieve enhanced tumor growth inhibition in a murine xenograft model, greater than either drug employed as a single-agent. GO and KEGG enrichment analysis of differential genes indicated alterations in pathways associated with cell death in response to Exemestane and Olaparib treatment.
Delayed post-juvenile moult in malaria-infected European blackcaps
Authors: Remacha Carolina , de la Hera Iván , Ramírez Álvaro , Pérez-Tris Javier
Published: July 2024

Parasites have their strongest impact on fitness when host defences limit the quantity of resources available for other critical life-history stages, such as development, breeding or migration. One greatly neglected stage that could be altered by parasites is the post-juvenile moult (PJM) of birds, through which inexperienced yearlings replace their weak and fast-generated juvenile feathers by adult-like feathers. The earlier juvenile birds complete PJM, the earlier they will be prepared to withstand forthcoming adverse conditions, especially if they migrate short after moulting. We used data from 435 juvenile European blackcaps (Sylvia atricapilla) sampled during three years in 26 localities spanning the wide range of environmental conditions across Iberian Spain to test whether haemosporidian infections (presence and abundance in blood of parasites of the generaHaemoproteus, PlasmodiumandLeucocytozoon) were related to delayed PJM. Controlling for body condition, sex, year and date of capture, infected blackcaps (single-infected or coinfected) had lower moult scores indicative of delayed moult, especially when birds hadPlasmodiuminfections or higher intensity ofHaemoproteusparasites. Our results broaden the range of fitness costs that haemosporidian parasites may have on birds, as delayed plumage maturation prolongs the period during which juvenile birds lack a fully functional plumage.
Cholecystokinin modulates age-dependent Thalamocortical Neuroplasticity
Authors: Li Xiao , Feng Jingyu , Hu Xiaohan , Zhou Peipei , Chen Tao , Zheng Xuejiao , Jendrichovsky Peter , Wang Xue , Chen Mengying , Li Hao , Chen Xi , Zeng Dingxuan , Zhang Mengfan , Xiao Zhoujian , He Ling , Bello Stephen Temitayo , He Jufang
Published: July 2024

The thalamocortical pathway exhibits neuroplasticity not only during the critical period but also in adulthood. Here, we aimed to investigate the modulation of age-dependent thalamocortical plasticity by cholecystokinin (CCK). Our findings revealed the expression of CCK in thalamocortical neurons, and high-frequency stimulation (HFS) of the thalamocortical pathway elicited the release of CCK in auditory cortex (ACx), as evidenced by CCK sensor. HFS of the medial geniculate body (MGB) induced thalamocortical long-term potentiation (LTP) in wildtype young adult mice. However, knockdown of Cck expression in MGB neurons or blockade of the CCK-B receptor (CCKBR) in ACx effectively abolished HFS-induced LTP. Notably, this LTP could not be elicited in both juvenile mice (week 3) and mice over 18 months old, due to the absence of CCKBR in juvenile mice and the inability of CCK to be released in aged mice. Remarkably, the administration of exogenous CCK into the auditory cortex of the aged mice restored this LTP, accompanied by a significant improvement in frequency discrimination. These findings suggest the potential of CCK as a therapeutic intervention for addressing neurodegenerative deficits associated with thalamocortical neuroplasticity.
Phase transitions and composite order in
U(1)N
lattice London models
Authors: Weston Daniel , Sellin Karl , Babaev Egor
Published: July 2024

The phase diagrams and the nature of the phase transitions in multicomponent gauge theories with an Abelian gauge field are important topics with various physical applications. While an early renormalization-group-based study indicated that the direct transition from a fully ordered to a fully disordered state is continuous for N=1 and N>183, recently it was demonstrated that the transition is discontinuous for N=2. We quantitatively study the dependence on N of the degree of discontinuity of this transition. Our results suggest that the transition is discontinuous at least up to N=7. Furthermore, we demonstrate that, at increased coupling strength, the phase transitions of the neutral and charged sectors of the model split, which for N>2 yields a new phase with composite order. The transition from the composite-order phase to the fully disordered phase is then also discontinuous, at least for N=3 and N=4. Via a duality argument, this indicates that van der Waals–type interaction between directed loops may be responsible for the discontinuous phase transitions in these models.

Published by the American Physical Society
2024
QCD with an infrared fixed point and a dilaton
Authors: Zwicky Roman
Published: July 2024

Following previous work we further explore the possibility that the chirally broken phase of gauge theories admits an infrared fixed point interpretation. The slope of the β function, β*′, is found to vanish at the infrared fixed point which has several attractive features such as logarithmic running. We provide a more in-depth analysis of our previous result that the mass anomalous assumes γ*=1 at the fixed point. The results are found to be consistent with N=1 supersymmetric gauge theories. In a second part the specific properties of a dilaton, the (pseudo-) Goldstone, due to spontaneous symmetry breaking are investigated. Dilaton soft theorems indicate that a soft dilaton mass can only originate from an operator of scaling dimension two. In the gauge theory this role is taken on by the q¯q-operator. The quantum chromodynamics (QCD) dilaton candidate, the σ=f0(500) meson is investigated and the singlet-octet mixing is found to be relevant. We briefly discuss the dilaton as a candidate for the Higgs boson, which relies on the ratio of dilaton to pion decay constant being close to unity. In QCD this is approximately satisfied but it is remains unclear if this is accidental or whether there is yet to be uncovered principle behind it.

Published by the American Physical Society
2024
Light long-lived particles at the FCC-hh with the proposal for a dedicated forward detector FOREHUNT and a transverse detector DELIGHT
Authors: Bhattacherjee Biplob , Dreiner Herbi K. , Ghosh Nivedita , Matsumoto Shigeki , Sengupta Rhitaja , Solanki Prabhat
Published: July 2024

In this paper, we propose a dedicated forward detector, FOREHUNT (FORward Experiment for HUNdred TeV), for 100 TeV FCC-hh for the detection of light long-lived particles (LLP) coming from B-meson decay. We calculate the signal acceptance as a function of mass and proper decay length of the LLP for 100 TeV and interpret our result in terms of model parameters for models of dark Higgs scalar and heavy neutral leptons. We also compare the sensitivity with proposed transverse detectors like MATHUSLA, CODEX-b for HL-LHC, and DELIGHT (Detector for long-lived particles at high energy of 100 TeV) for FCC-hh. Our analysis reveals that if the LLP is light (≲4.4  GeV) and has a low proper decay length (<10  m), a forward detector like FOREHUNT is the best option to look for the decaying LLP, while DELIGHT is preferable for higher proper decay lengths.

Published by the American Physical Society
2024
How caged motion in the contact layer enhances thermal tunneling across a liquid/solid interface
Authors: Kaifu Hiroki , Troian Sandra M. , Baskin Artem I.
Published: July 2024

Ever more powerful and densely packed chips for applications like cryptocurrency mining and artificial intelligence generate such enormous heat fluxes that designers are pivoting from gas to liquid cooling to forestall damage from thermal runaway. Even with optimal flow patterns, however, the intrinsic thermal boundary resistance at the liquid/solid (L/S) interface poses an additional source of thermal impedance. There is a lingering misconception in the field that the higher the liquid contact density, the more frequent the L/S collision rate and the smaller the thermal slip length. Here we present an insightful counterexample based on nonequilibrium molecular dynamics simulations of a simple liquid confined between two face centered cubic crystals at different temperatures aligned with the [001], [011] or [111] facet plane. Measurements of various static and dynamic quantities of the contact layer reveal the ways in which long-range order, anisotropy of the L/S potential, and correlated motion act to reduce thermal boundary resistance. Systems with the smallest thermal slip length exhibit two distinct features: 2D caged motion with stringlike alignment of liquid particles, unlike that observed in glassy systems, and larger nonergodicity parameter with shorter, not longer, caging times. This trapping and release mechanism suggests a paradigm for the design of L/S interfaces to maximize thermal exchange across a classical L/S interface.

Published by the American Physical Society
2024
Non-self-similar light transport in scattering media
Authors: Pini Ernesto , Mazzamuto Giacomo , Riboli Francesco , Wiersma Diederik S. , Pattelli Lorenzo
Published: July 2024

Transport processes underpin a wide variety of phenomena, ranging from chemistry, to physics and ecology. Despite their pervasiveness, however, several distinctive features of these processes are still elusive, making it difficult to recognize and classify the associated transport regimes. Using light scattering as a probe to explore different propagation regimes, we report on the experimental observation of non-self-similar light transport through turbid membranes. Our results show that a breakdown of self-similarity can arise for light waves even in the presence of isotropic and homogeneous disorder, and can be tuned by varying the turbidity of the system. By introducing the concept of self-similarity for light propagation, we provide a unified framework for the classification of light transport regimes—overcoming the dichotomy between normal and anomalous diffusion—and show that non-self-similar propagation is a common and experimentally accessible phenomenon. This insight can help to understand and model other scenarios where light transport is dominated by rare propagation events, such as in nonlinear and active media, but also in other fields of research beyond optics.

Published by the American Physical Society
2024