bluuebunny/crossref_metadata_2025_split 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

ABSTRACTBackgroundCompatibility 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.ResultsWe 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.ConclusionsEspecially 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

AbstractCyanobacteria 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

AbstractIn 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

AbstractBackgroundDeep 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.ObjectiveWe examined the cortical acetylcholine response to different stimulation parameters of the basal forebrain.Methods2-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.ResultsExperiments 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.ConclusionsThese 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

AbstractThe 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

AbstractObjectiveWe 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.ApproachWe 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 resultsListening 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.SignificanceBrain-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

AbstractIn 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

AbstractEngineered 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 StatementEngineered 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

AbstractEpisodic 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.
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

AbstractAs 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

AbstractAutonomic 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.