bluuebunny/crossref_metadata_2025 huggingface dataset:
Sensory suppression and increased neuromodulation during actions disrupt memory encoding of unpredictable self-initiated stimuli
Authors: Paraskevoudi Nadia , SanMiguel Iria
Published: December 2021

Actions modulate sensory processing by attenuating responses to self- compared to externally-generated inputs, which is traditionally attributed to stimulus-specific motor predictions. Yet, suppression has been also found for stimuli merely coinciding with actions, pointing to unspecific processes that may be driven by neuromodulatory systems. Meanwhile, the differential processing for self-generated stimuli raises the possibility of producing effects also on memory for these stimuli, however, evidence remains mixed as to the direction of the effects. Here, we assessed the effects of actions on sensory processing and memory encoding of concomitant, but unpredictable sounds, using a combination of self-generation and memory recognition task concurrently with EEG and pupil recordings. At encoding, subjects performed button presses that half of the time generated a sound (motor-auditory; MA) and listened to passively presented sounds (auditory-only; A). At retrieval, two sounds were presented and participants had to respond which one was present before. We measured memory bias and memory performance by having sequences where either both or only one of the test sounds were presented at encoding, respectively. Results showed worse memory performance – but no differences in memory bias – and attenuated responses and larger pupil diameter for MA compared to A sounds. Critically, the larger the sensory attenuation and pupil diameter, the worse the memory performance for MA sounds. Nevertheless, sensory attenuation did not correlate with pupil dilation. Collectively, our findings suggest that sensory attenuation and neuromodulatory processes coexist during actions, and both relate to disrupted memory for concurrent, albeit unpredictable sounds.
Simple contextual cueing prevents retroactive interference in short-term perceptual training of orientation detection tasks
Authors: Huang Hui , Zhang Yangming , Li Sheng
Published: December 2021

Perceptual training of multiple tasks suffers from interference between the trained tasks. Here, we conducted four psychophysical experiments with separate groups of participants to investigate the possibility of preventing the interference in short-term perceptual training. We trained the participants to detect two orientations of Gabor stimuli in two adjacent days at the same retinal location and examined the interference of training effects between the two orientations. The results showed significant retroactive interference from the second orientation to the first orientation (Experiments 1 and 2). Introducing a 6-hour interval between the pre-test and training of the second orientation did not eliminate the interference effect, excluding the interpretation of disrupted reconsolidation as the pre-test of the second orientation may reactivate and destabilize the representation of the first orientation (Experiment 3). Finally, the training of the two orientations was accompanied by fixations in two colors, each served as a contextual cue for one orientation. The results showed that the retroactive interference was not evident after introducing these passively perceived contextual cues (Experiment 4). Our findings suggest that the retroactive interference effect in short-term perceptual training of orientation detection tasks was likely the result of higher-level factors such as shared contextual cues embedded in the tasks. The effect of multiple perceptual training could be facilitated by associating the trained tasks with different contextual cues.
Spatially bivariate EEG-neurofeedback can manipulate interhemispheric rebalancing of M1 excitability
Authors: Hayashi Masaaki , Okuyama Kohei , Mizuguchi Nobuaki , Hirose Ryotaro , Okamoto Taisuke , Kawakami Michiyuki , Ushiba Junichi
Published: December 2021

Human behavior requires interregional crosstalk to employ the sensorimotor processes in the brain. Although some external neuromodulation tools have been used to manipulate interhemispheric sensorimotor activity, a central controversy concerns whether this activity can be volitionally controlled. Experimental tools lack the power to up- or down-regulate the state of the targeted hemisphere over a large dynamic range and, therefore, cannot evaluate the possible volitional control of the activity. We overcame this difficulty by using the recently developed method of spatially bivariate electroencephalography (EEG)-neurofeedback to systematically enable participants to manipulate their bilateral sensorimotor activities. Herein, we report that bi-directional changes in ipsilateral excitability to the imagined hand (conditioning hemisphere) affect interhemispheric inhibition (IHI) assessed by paired-pulse transcranial magnetic stimulation paradigm. In addition, participants were able to robustly manipulate the IHI magnitudes. Further physiological analyses revealed that the self-manipulation of IHI magnitude reflected interhemispheric connectivity in EEG and TMS, which was accompanied by intrinsic bilateral cortical oscillatory activities. Our results provide clear neuroscientific evidence regarding the inhibitory interhemispheric sensorimotor activity and IHI manipulator, thereby challenging the current theoretical concept of recovery of motor function for neurorehabilitation.
isomiRs-specific differential expression is the rule, not the exception: Are we missing hundreds of species in microRNA analysis?
Authors: Schmauch Eloi , Laitinen Pia , Turunen Tiia A. , Väänänen Mari-Anna , Malm Tarja , Kellis Manolis , Kaikkonen Minna U , Linna-Kuosmanen Suvi
Published: December 2021

MicroRNAs (miRNAs) are small RNA molecules that act as regulators of gene expression through targeted mRNA degradation. They are involved in many biological and pathophysiological processes and are widely studied as potential biomarkers and therapeutics agents for human diseases, including cardiovascular disorders. Recently discovered isoforms of miRNAs (isomiRs) exist in high quantities and are very diverse. Despite having few differences with their corresponding reference miRNAs, they display specific functions and expression profiles, across tissues and conditions. However, they are still overlooked and understudied, as we lack a comprehensive view on their condition-specific regulation and impact on differential expression analysis. Here, we show that isomiRs can have major effects on differential expression analysis results, as their expression is independent of their host miRNA genes or reference sequences. We present two miRNA-seq datasets from human umbilical vein endothelial cells, and assess isomiR expression in response to senescence and compartment-specificity (nuclear/cytosolic) under hypoxia. We compare three different methods for miRNA analysis, including isomiR-specific analysis, and show that ignoring isomiRs induces major biases in differential expression. Moreover, isomiR analysis permits higher resolution of complex signal dissection, such as the impact of hypoxia on compartment localization, and differential isomiR type enrichments between compartments. Finally, we show important distribution differences across conditions, independently of global miRNA expression signals. Our results raise concerns over the quasi exclusive use of miRNA reference sequences in miRNA-seq processing and experimental assays. We hope that our work will guide future isomiR expression studies, which will correct some biases introduced by golden standard analysis, improving the resolution of such assays and the biological significance of their downstream studies.
Semantic representations during language comprehension are affected by context
Authors: Deniz Fatma , Tseng Christine , Wehbe Leila , la Tour Tom Dupré , Gallant Jack L.
Published: December 2021

The meaning of words in natural language depends crucially on context. However, most neuroimaging studies of word meaning use isolated words and isolated sentences with little context. Because the brain may process natural language differently from how it processes simplified stimuli, there is a pressing need to determine whether prior results on word meaning generalize to natural language. fMRI was used to record human brain activity while four subjects (two female) read words in four conditions that vary in context: narratives, isolated sentences, blocks of semantically similar words, and isolated words. We then compared the signal-to-noise ratio (SNR) of evoked brain responses, and we used a voxelwise encoding modeling approach to compare the representation of semantic information across the four conditions. We find four consistent effects of varying context. First, stimuli with more context evoke brain responses with higher SNR across bilateral visual, temporal, parietal, and prefrontal cortices compared to stimuli with little context. Second, increasing context increases the representation of semantic information across bilateral temporal, parietal, and prefrontal cortices at the group level. In individual subjects, only natural language stimuli consistently evoke widespread representation of semantic information. Third, context affects voxel semantic tuning. Finally, models estimated using stimuli with little context do not generalize well to natural language. These results show that context has large effects on the quality of neuroimaging data and on the representation of meaning in the brain. Thus, neuroimaging studies that use stimuli with little context may not generalize well to the natural regime.

Significance Statement

Context is an important part of understanding the meaning of natural language, but most neuroimaging studies of meaning use isolated words and isolated sentences with little context. Here we examined whether the results of neuroimaging studies that use out-of-context stimuli generalize to natural language. We find that increasing context improves the quality of neuroimaging data and changes where and how semantic information is represented in the brain. These results suggest that findings from studies using out-of-context stimuli may not generalize to natural language used in daily life.
A recurring YYDRxG pattern in broadly neutralizing antibodies to a conserved site on SARS-CoV-2, variants of concern, and related viruses
Authors: Liu Hejun , Kaku Chengzi I. , Song Ge , Yuan Meng , Andrabi Raiees , Burton Dennis R. , Walker Laura M. , Wilson Ian A.
Published: December 2021

Studying the antibody response to SARS-CoV-2 informs on how the human immune system can respond to antigenic variants as well as other SARS-related viruses. Here, we structurally and functionally characterized a potent human antibody ADI-62113 that also neutralizes SARS-CoV- 2 variants of concern and cross-reacts with many other sarbecoviruses. A YYDRxG motif encoded by IGHD3-22 in CDR H3 facilitates targeting to a highly conserved epitope on the SARS-CoV-2 receptor binding domain. A computational search for a YYDRxG pattern in publicly available sequences identified many antibodies with broad neutralization activity against SARS-CoV-2 variants and SARS-CoV. Thus, the YYDRxG motif represents a common convergent solution for the human humoral immune system to counteract sarbecoviruses. These findings also suggest an epitope targeting strategy to identify potent and broadly neutralizing antibodies that can aid in the design of pan-sarbecovirus vaccines and antibody therapeutics.

Short Summary

Decryption of a recurrent sequence feature in anti-SARS-CoV-2 antibodies identifies how potent pan-sarbecovirus antibodies target a conserved epitope on the receptor binding domain.
Distinguishing COVID-19 infection and vaccination history by T cell reactivity
Authors: Yu Esther Dawen , Wang Eric , Garrigan Emily , Goodwin Benjamin , Sutherland Aaron , Chang James , Gálvez Rosa Isela , Mateus Jose , Rawlings Stephen A. , Smith Davey M. , Frazier April , Weiskopf Daniela , Dan Jennifer M. , Crotty Shane , Grifoni Alba , da Silva Antunes Ricardo , Sette Alessandro
Published: December 2021

SARS-CoV-2 infection and COVID-19 vaccines elicit memory T cell responses. Here, we report the development of two new pools of Experimentally-defined T cell epitopes derived from the non-spike Remainder of the SARS-CoV-2 proteome (CD4RE and CD8RE). The combination of T cell responses to these new pools and Spike (S) were used to discriminate four groups of subjects with different SARS-CoV-2 infection and COVID-19 vaccine status: non-infected, non-vaccinated (I−V−); infected and non-vaccinated (I+V−); infected and then vaccinated (I+V+); and non-infected and vaccinated (I−V+). The overall classification accuracy based on 30 subjects/group was 89.2% in the original cohort and 88.5% in a validation cohort of 96 subjects. The T cell classification scheme was applicable to different mRNA vaccines, and different lengths of time post-infection/post-vaccination. T cell responses from breakthrough infections (infected vaccinees, V+I+) were also effectively segregated from the responses of vaccinated subjects using the same classification tool system. When all five groups where combined, for a total of 239 different subjects, the classification scheme performance was 86.6%. We anticipate that a T cell-based immunodiagnostic scheme able to classify subjects based on their vaccination and natural infection history will be an important tool for longitudinal monitoring of vaccination and aid in establishing SARS-CoV−2 correlates of protection.
Commercially-available heart rate monitor repurposed into a 9-gram standalone device for automatic arrhythmia detection with snapshot electrocardiographic capability: a pilot validation
Authors: Gaibazzi Nicola , Reverberi Claudio , Tuttolomondo Domenico , Di Maria Bernardo
Published: December 2021

Background

The usefulness of opportunistic arrhythmia screening strategies, using an electrocardiogram (ECG) or other methods for random “snapshot” assessments is limited by the unexpected and occasional nature of arrhythmias, leading to a high rate of missed-diagnosis.

We have previously validated a cardiac monitoring system for AF detection pairing simple consumer-grade Bluetooth low-energy (BLE) heart rate (HR) sensors with a smartphone application (RITMIAtm, Heart Sentinel srl, Italy). In the current study we test a significant upgrade to the abovementioned system, thanks to the technical capability of new HR sensors to run algorithms on the sensor itself and to acquire (and store on-board) single-lead ECG strips, if asked to do so.

Methods and Result

We have reprogrammed a HR monitor intended for sports use (Movensense HR+) to run our proprietary RITMIA algorithm code in real-time, based on RR analysis, so that if any type of arrhythmia is detected it triggers a brief retrospective recording of a single-lead ECG, providing tracings of the specific arrhythmia for later consultation.

We report the initial data on the behavior, feasibility and high diagnostic accuracy of this ultra-low weight customized device for standalone automatic arrhythmia detection and ECG recording, when several types of arrhythmias were simulated, under different baseline conditions.

Conclusions

The customized device was capable to detect all types of simulated arrhythmias and correctly triggered an visually interpretable ECG tracing. Future human studies are needed to address real-life accuracy of this device.
Pathogenic CD8 T cells defined by longitudinal liver sampling in chronic hepatitis B patients starting antiviral therapy
Authors: Nkongolo Shirin , Mahamed Deeqa , Kuipery Adrian , Sanchez Vasquez Juan D. , Kim Samuel C. , Mehrotra Aman , Patel Anjali , Hu Christine , McGilvray Ian , Feld Jordan J. , Fung Scott , Chen Diana , Wallin Jeffrey J. , Gaggar Anuj , Janssen Harry L. A. , Gehring Adam J.
Published: December 2021

Accumulation of activated immune cells results in non-specific hepatocyte killing in chronic hepatitis B (CHB), leading to fibrosis and cirrhosis. We enrolled 15 CHB patients with active liver damage to receive antiviral therapy, and performed longitudinal liver sampling using fine-needle aspiration to investigate mechanisms of CHB pathogenesis in the human liver. Single-cell sequencing of total liver cells revealed a distinct liver-resident, polyclonal CD8 T cell population that was enriched at baseline and displayed a highly activated immune signature during liver damage. Cytokine combinations, identified by in silico prediction of ligand-receptor interaction, induced the activated phenotype in healthy liver CD8 T cells, resulting in non-specific Fas ligand-mediated killing of target cells. These results define a CD8 T cell population in the human liver that can drive pathogenesis, and a key pathway involved in their function in CHB patients.
Genome-wide association meta-analysis identifies novel ancestry-specific primary open-angle glaucoma loci and shared biology with vascular mechanisms and cell proliferation
Authors: Faro Valeria Lo , Bhattacharya Arjun , Zhou Wei , Zhou Dan , Wang Ying , Läll Kristi , Kanai Masahiro , Lopera-Maya Esteban , Straub Peter , Pawar Priyanka , Tao Ran , Zhong Xue , Namba Shinichi ,   the Global Biobank Meta-analysis Initiative, Sanna Serena , Nolte Ilja M. , Okada Yukinori , Ingold Nathan , MacGregor Stuart , Snieder Harold , Surakka Ida , Willer Cristen , Martin Alicia R. , Brantley Milam A. , Gamazon Eric R. , Jansonius Nomdo M. , Joos Karen , Cox Nancy J. , Hirbo Jibril
Published: December 2021

Primary open-angle glaucoma (POAG) is a leading cause of irreversible blindness globally. There is disparity in POAG prevalence and manifestations across ancestries. We identify novel and unique genetics that underlie POAG risk in different ancestries by performing meta-analysis across 15 biobanks (of the Global Biobank Meta-analysis Initiative) with previously multi-ancestry studies. 18 novel significant loci, three of which were ancestry-specific, and five sex-specific were identified. We performed gene-enrichment and transcriptome-wide association studies (TWAS), implicating vascular and cancer genes. A fifth of these genes are primary ciliary genes. Extensive statistical analysis of genes in theSIX6andCDKN2B-AS1loci (implicated in POAG, cardiovascular diseases and cancers) found interaction betweenSIX6and causal variants in chr9p21.3, with expression effect onCDKN2A/B. We infer that some POAG risk variants may be ancestry-specific, sex-specific, or both. Our results further support the contribution of vascular, cancer, and primary cilia genes in POAG pathogenesis.
A one health approach to investigating an outbreak of alimentary tick-borne encephalitis in a non-endemic area in France (Ain, Eastern France): a longitudinal serological study in livestock, detection in ticks, and the first TBE virus isolation and molecular characterization
Authors: Gonzalez Gaëlle , Bournez Laure , Moraes Rayane Amaral , Dumarest Marine , Galon Clémence , Vorimore Fabien , Cochin Maxime , Nougairède Antoine , Hennechart-Collette Catherine , Perelle Sylvie , Leparc-Goffart Isabelle , Durand Guillaume André , Grard Gilda , Bénet Thomas , Danjou Nathalie , Blanchin Martine , Lacour Sandrine A , Boué Franck , Chenut Guillaume , Mainguet Catherine , Simon Catherine , Brémont Laurence , Zientara Stephan , Moutailler Sara , Martin-Latil Sandra , Dheilly Nolwenn M , Beck Cécile , Lecollinet Sylvie
Published: December 2021

Tick borne encephalitis virus geographic range and human incidence is increasing throughout Europe, putting a number of non-endemic regions and countries at risk of outbreaks. In spring 2020, there was an outbreak of TBE in Ain, Eastern France, where the virus had never been detected before. All patients but one had consumed traditional unpasteurized raw goat cheese from a local producer. We conducted an investigation in the suspected farm using an integrative One Health approach. Our methodology included (i) the detection of virus in cheese and milk products, (ii) serological testing of all animals in the suspected farm and surrounding farms, (iii) an analysis of the landscape and localisation of wooded area, (iv) the capture of questing ticks and small mammals for virus detection and estimating enzootic hazard, and (v) virus isolation and genome sequencing. This approach allowed us to confirm the alimentary origin of the TBE outbreak and to witness in real time the seroconversion of recently exposed individuals and the excretion of virus in goat milk. In addition, we identified a wooded focus area where and around which there is a risk of TBEV exposure. We provide the first TBEV isolate responsible for as a source of dietary contamination in France, obtained its full-length genome sequence, and found that it does not cluster very closely neither with the isolate circulating in Alsace nor with any other isolate within the European lineage. TBEV is now a notifiable human disease in France, which should facilitate surveillance of TBEV incidence and distribution throughout France.
Partial recovery of amblyopia following fellow eye ischemic optic neuropathy
Authors: Resnick Hannah H. , Bear Mark F. , Gaier Eric D.
Published: December 2021

Background

Recovery from amblyopia in adulthood following fellow eye (FE) vision loss is a well-known phenomenon. Incidence of recovery varies widely following different FE pathologies and rate of recovery following FE ischemic optic neuropathy (ION) has not been examined. We aimed to determine frequency and degree of improvement in amblyopic eye (AE) visual function following ION in the FE.

Methods

We performed a retrospective chart review of patients between 2007-2021 confirmed to have amblyopia and ischemic optic neuropathy in different eyes. Patients with unstable ocular pathology potentially limiting vision were excluded. We compared best-corrected visual acuity (VA) in each eye before and after FE ION over time. For patients with available data, we examined change in perimetric performance over time.

Results

Among the 12 patients who met inclusion criteria (mean age 67±8 years), 9 (75%) improved ≥1 line and 2 (17%) improved ≥3 lines. Median time from ION symptom onset to maximal improvement was 6 months (range: 2-101 months). Reliable perimetric data were available for 6 patients. Mean sensitivity improved in the amblyopic eye for all patients, with a mean improvement of 1.9±1.1 dB. There was no correspondence between foci of ION-related field loss and gains in field sensitivity in the AE.

Conclusion

A high proportion of patients with amblyopia and contralateral ION experience improvement in their amblyopic eye. Modest gains in perimetric sensitivity in the AE may accompany FE ION. These findings support the view that residual plasticity in the adult visual cortex can be tapped to support functional improvement in amblyopia.
The quorum sensing com system regulates pneumococcal colonisation and invasive disease in a pseudo-stratified airway tissue model
Authors: Kahlert Christian R. , Nigg Susanne , Onder Lucas , Dijkman Ronald , Diener Liliane , Rodriguez Regulo , Vernazza Pietro , Thiel Volker , Vidal Jorge E. , Albrich Werner C.
Published: December 2021

Streptococcus pneumoniae (Spn) colonises respiratory epithelia but can also invade lung cells causing pneumonia. We developed an ex vivo model with human airway epithelial (HAE) cells harvested from lung biopsies to study Spn colonisation and translocation. Flow-cytometry, confocal imaging and electron microscopy studies identified the epithelial lineage with signs of differentiation (beating cilia, mucus, and tight junctions). HAE cells were challenged with Spn wild-type TIGR4 (wtSpn) or its isogenic ΔcomC quorum sensing-deficient mutant. ΔcomC mutant colonised significantly less than wtSpn at 6 h post-inoculation but at significantly higher levels at 19 h and 30 h. Translocation correlated inversely with colonisation density. Transepithelial electric resistance (TEER) decreased after pneumococcal infection and correlated with increased translocation for both strains.

Confocal imaging illustrated colocalisation of intracellular Spn with both cilia and zonulin-1 and prominent microcolony formation with wtSpn but disintegration of microcolony structures over time with ΔcomC mutant. ΔcomC caused a more pronounced release of both zonulin-1 and lactate dehydrogenase into the supernatant at later time points than wtSpn, suggesting that cytotoxicity is likely not the mechanism leading to translocation. There was a density- and time-dependent increase of inflammatory cytokines from human HAE cells infected with ΔcomC compared with wtSpn, including increased levels of the NLRP3 inflammasome-related IL-18.

In conclusion, our experiments indicate that ComC system allows a higher organisational level of population structure resulting in microcolony formation, increased early colonisation and subsequent translocation. We propose that ComC inactivation unleashes a very different and possibly more virulent phenotype that merits further investigation.
RFX6-mediated dysregulation defines human β cell dysfunction in early type 2 diabetes
Authors: Walker John T. , Saunders Diane C. , Rai Vivek , Dai Chunhua , Orchard Peter , Hopkirk Alexander L. , Reihsmann Conrad V. , Tao Yicheng , Fan Simin , Shrestha Shristi , Varshney Arushi , Wright Jordan J. , Pettway Yasminye D. , Ventresca Christa , Agarwala Samir , Aramandla Radhika , Poffenberger Greg , Jenkins Regina , Hart Nathaniel J. , Greiner Dale L. , Shultz Leonard D. , Bottino Rita ,   Human Pancreas Analysis Program, Liu Jie , Parker Stephen C.J. , Powers Alvin C. , Brissova Marcela
Published: December 2021

A hallmark of type 2 diabetes (T2D), a major cause of world-wide morbidity and mortality, is dysfunction of insulin-producing pancreatic islet β cells1–3. T2D genome-wide association studies (GWAS) have identified hundreds of signals, mostly in the non-coding genome and overlapping β cell regulatory elements, but translating these into biological mechanisms has been challenging4–6. To identify early disease-driving events, we performed single cell spatial proteomics, sorted cell transcriptomics, and assessed islet physiology on pancreatic tissue from short-duration T2D and control donors. Here, through integrative analyses of these diverse modalities, we show that multiple gene regulatory modules are associated with early-stage T2D β cell-intrinsic defects. One notable example is the transcription factor RFX6, which we show is a highly connected β cell hub gene that is reduced in T2D and governs a gene regulatory network associated with insulin secretion defects and T2D GWAS variants. We validated the critical role of RFX6 in β cells through direct perturbation in primary human islets followed by physiological and single nucleus multiome profiling, which showed reduced dynamic insulin secretion and large-scale changes in the β cell transcriptome and chromatin accessibility landscape. Understanding the molecular mechanisms of complex, systemic diseases necessitates integration of signals from multiple molecules, cells, organs, and individuals and thus we anticipate this approach will be a useful template to identify and validate key regulatory networks and master hub genes for other diseases or traits with GWAS data.
A new analytical pipeline reveals metatranscriptomic changes upon high-fat diet in a Down syndrome mouse model
Authors: Grabowicz Ilona E. , Herman-Iżycka Julia , Fructuoso Marta , Dierssen Mara , Wilczyński Bartek
Published: December 2021

The existing methods designated for metatranscriptomic studies are still rare and being developed. In this paper we present a new analytical pipeline combining contig assembly, gene selection and functional annotation. This pipeline allowed us to reconstruct contigs with very high unique mappability (83%) and select sequences encoding putative bacterial genes reaching also a very high (66%), unique mappability of the NGS sequencing reads. Then, we have applied our pipeline to study faecal metatranscriptome of a Down syndrome (DS) mouse model, the Ts65Dn mice, in order to identify the differentially expressed transcripts. Recent studies have implicated dysbiosis of gut microbiota in several central nervous system (CNS) disorders, including DS. Given that DS individuals have an increased prevalence of obesity, we also studied the effects of a high-fat diet (HFD) on the transcriptomic changes of mice gut microbiomes, as the complex symbiotic relationship between the gut microbiome and its host is strongly influenced by diet and nutrition. Using our new pipeline we found that compared to wild type (WT), Ts65Dn mice showed an elevated expression levels of genes involved in hypoxanthine metabolism, which contributes to oxidative stress, and a down-regulated expression of genes involved in interactions with host epithelial cells and virulence. Microbiomes of mice fed HFD showed significantly higher expression levels of genes involved in membrane lipopolysaccharides / lipids biosynthesis, and decreased expression of osmoprotection and lysine fermentation genes, among others. We also found evidence that mice microbiota is capable of expressing genes encoding for neuromodulators, which may play a role in development of compulsive overeating and obesity. Our results show a DS-specific metatranscriptome profile and show that a high-fat diet affects the metabolism of mice gut microbiome by changing activity of genes involved in lipids, sugars, proteins and amino acids metabolism and cell membranes turnover. Our new analytical pipeline combining contig assembly, gene selection and functional annotation provides new insights into the metatranscriptomic studies.
Investigation on the changes of Bifidobacterium and lactic acid bacteria in soybean meal fermented feed
Authors: Kang Lingyu , Chen Huayou , Feng Tao , Li Keyi , Ni Zhong , Gao Ebin , Yong Yangchun
Published: December 2021

The main objective of this research was to explore the dynamic changes of Bifidobacterium and lactic acid bacteria (LAB) in the process of feed fermentation under anaerobic condition, so as to increase the number of fermented bacteria of Bifidobacterium from the aspect of strain combination. The results showed that when Bifidobacterium lactis (B. lactis, i.e. Bifidobacterium animalis subsp. lactis) fermented with Bacillus coagulans or Lactobacillus paracasei, the maximum number of B. lactis in those samples was 9.42 times and 4.64 times of that of fermented sample with B. lactis only. The soybean meal was fermented by B. lactis, L. paracasei and B. coagulans, and the number of B. lactis reached the maximum after fermented 10 days, which was 6.13 times of that in unfermented sample. The reducing sugar content and highest activity of α-galactosidase were higher than the control. These results suggest that B. coagulans and L. paracasei can promote the growth of B. lactis. It is inferred that B. coagulans can metabolize normally in aerobic, micro-aerobic and anaerobic environments, consume oxygen, produce digestive enzymes, and cooperate with L. paracasei to produce metabolic products benefit for the growth of B. lactis.
High-affinity nanobodies as tools for structural and functional studies on mammalian Arc
Authors: Markússon Sigurbjörn , Hallin Erik I. , Bustad Helene J. , Raasakka Arne , Xu Ju , Muruganandam Gopinath , Loris Remy , Martinez Aurora , Bramham Clive R. , Kursula Petri
Published: December 2021

Activity-regulated cytoskeleton-associated protein (Arc) is a multidomain protein of retroviral origin with a vital role in the regulation of synaptic plasticity and memory formation in mammals. However, the mechanistic and structural basis of Arc function is little understood. Arc has an NTD involved in membrane binding and a CTD which binds postsynaptic protein ligands. In addition, the NTD and CTD both function in Arc oligomerization, including assembly of retrovirus-like capsid involved in intercellular signaling. We produced and characterised six ultra-high-affinity anti-Arc nanobodies (Nb). The CTD of both rat and human Arc could be crystallised in ternary complexes with two Nbs simultaneously bound (H11 and C11). H11 binding deep into the stargazing-binding pocket of Arc CTD suggested competitive binding with Arc ligand peptides, which was confirmed in vitro. This indicates that the H11 Nb could serve as a genetically-encoded tool for inhibition of endogenous Arc N-lobe interactions in study of neuronal function and plasticity. The crystallisation of the human Arc CTD in two different conformations, accompanied by SAXS data and molecular dynamics simulations, paints a dynamic picture of the mammalian Arc CTD. Dynamics were affected by mutations known to inhibit capsid formation, implying a role for Arc CTD dynamics in oligomerisation. Dimerisation of the NTD, together with structural dynamics of the CTD, suggest a mechanism, by which structural dynamics of the CTD may promote capsomer formation, and dimerisation of the NTD links capsomers, facilitating the formation of capsids. The described recombinant ultrahigh-affinity anti-Arc Nbs are versatile tools that can be further developed for studying mammalian Arc structure and function in vitro and in vivo.
A brain atlas of synapse protein lifetime across the mouse lifespan
Authors: Bulovaite Edita , Qiu Zhen , Kratschke Maximilian , Zgraj Adrianna , Fricker David G. , Tuck Eleanor J. , Gokhale Ragini , Jami Shekib A. , Merino-Serrais Paula , Husi Elodie , O’Dell Thomas J. , DeFelipe Javier , Komiyama Noboru H. , Holtmaat Anthony , Fransén Erik , Grant Seth G.N.
Published: December 2021

Protein turnover is required for synapse maintenance and remodelling and may impact memory duration. We quantified the lifetime of postsynaptic protein PSD95 in individual excitatory synapses across the mouse brain and lifespan, generating the Protein Lifetime Synaptome Atlas. Excitatory synapses have a wide range of protein lifetimes that may extend from a few hours to several months, with distinct spatial distributions in dendrites, neuron types and brain regions. Short protein lifetime (SPL) synapses are enriched in developing animals and in regions controlling innate behaviors, whereas long protein lifetime (LPL) synapses accumulate during development, are enriched in the cortex and CA1 where memories are stored, and are preferentially preserved in old age. The protein lifetime synaptome architecture is disrupted in an autism model, with synapse protein lifetime increased throughout the brain. These findings add a further layer to synapse diversity in the brain and enrich prevailing concepts in behavior, development, ageing and brain repair.
Controlling homology-directed repair outcomes in human stem cells with dCas9
Authors: Skarnes William C. , Ning Gang , Giansiracusa Sofia , Cruz Alexander S. , Blauwendraat Cornelis , Saavedra Brandon , Holden Kevin , Cookson Mark R. , Ward Michael E. , McDonough Justin A.
Published: December 2021

Modeling human disease in human stem cells requires precise, scarless editing of single nucleotide variants (SNV) on one or both chromosomes. Here we describe improved conditions for Cas9 RNP editing of SNVs that yield high rates of biallelic homology-directed repair. To recover both heterozygous and homozygous SNV clones, catalytically inactive ‘dCas9’was added to moderate high activity Cas9 RNPs. dCas9 can also block re-cutting and damage to SNV alleles engineered with non-overlapping guide RNAs.
The zinc-finger transcription factor LSL-1 is a major regulator of the germline transcriptional program in C. elegans
Authors: Rodriguez-Crespo David , Nanchen Magali , Rajopadhye Shweta , Wicky Chantal
Published: December 2021

Specific gene transcriptional programs are required to ensure proper proliferation and differentiation processes underlying the production of specialized cells during development. Gene activity is mainly regulated by the concerted action of transcription factors and chromatin proteins. In the nematode C. elegans, mechanisms that silence improper transcriptional programs in germline and somatic cells have been well studied, however, how are tissue specific sets of genes turned on is less known. LSL-1 is herein defined as a novel crucial transcriptional regulator of germline genes in C. elegans. LSL-1 is first detected in the P4 blastomere and remains present at all stages of germline development, from primordial germ cell proliferation to the end of meiotic prophase. lsl-1 loss-of-function mutants exhibit many defects including meiotic prophase progression delay, a high level of germline apoptosis, and production of almost no functional gametes. Transcriptomic analysis and ChIP-seq data show that LSL-1 binds to promoters and acts as a transcriptional activator of germline genes involved in various processes, including homologous chromosome pairing, recombination, and genome stability. Furthermore, we show that LSL-1 functions by antagonizing the action of the heterochromatin proteins HPL-2/HP1 and LET-418/Mi2 known to be involved in the repression of germline genes in somatic cells. Based on our results, we propose LSL-1 to be a major regulator of the germline transcriptional program during development.
Isolation disrupts social interactions and destabilizes brain development in bumblebees
Authors: Wang Z Yan , McKenzie-Smith Grace C. , Liu Weijie , Cho Hyo Jin , Pereira Talmo , Dhanerawala Zahra , Shaevitz Joshua W. , Kocher Sarah D.
Published: December 2021

Social isolation, particularly in early life, leads to deleterious physiological and behavioral outcomes. Few studies, if any, have been able to capture the behavioral and neurogenomic consequences of early life social isolation together in a single social animal system. Here, we leverage new high-throughput tools to comprehensively investigate the impact of isolation in the bumblebee (Bombus impatiens) from behavioral, molecular, and neuroanatomical perspectives. We reared newly emerged bumblebees either in complete isolation, small groups, or in their natal colony, and then analyzed their behaviors while alone or paired with another bee. We find that when alone, individuals of each rearing condition show distinct behavioral signatures. When paired with a conspecific, bees reared in small groups or in the natal colony express similar behavioral profiles. Isolated bees, however, showed increased social interactions. To identify the neurobiological correlates of these differences, we quantified brain gene expression and measured the volumes of key brain regions for a subset of individuals from each rearing condition. Overall, we find that isolation increases social interactions and disrupts gene expression and brain development. Limited social experience in small groups is sufficient to preserve typical patterns of brain development and social behavior.
Seed-coat thickness explains contrasting germination responses to smoke and heat by Leucadendron species
Authors: Lamont Byron B. , Barreiro Pablo Gómez , Newton Rosemary J.
Published: December 2021

Fire stimulates germination of most seeds in fire-prone vegetation. Fruits of Leucadendron (Proteaceae) are winged achenes or nutlets that correlate with their requirements for smoke and/or heat in promoting germination. We describe five possible smoke–heat dormancy-release/germination syndromes among plants, of which Leucadendron displays three (no response, smoke only, smoke and heat). As seed-coat thickness varies with seed-storage location (plant or soil) and morphology (winged or wingless), we tested its possible role in water uptake and germination. Species with winged seeds achieved 100% germination in the absence of smoke/heat, seed coats were an order of magnitude thinner, and their permeability greatly exceeded that of nutlets. As seed-coat thickness increased a) imbibitional water uptake declined at a decreasing rate, and b) the response to smoke, and to a lesser extent heat, increased linearly to reach levels of germination approaching those of winged seeds. For species responsive to smoke and heat, there was no additive effect when applied together, suggesting that they may have promoted the same physiological process. By what mechanisms a) the smoke response is greater the thicker the seed coat, and b) smoke chemicals could increase water permeability to explain the non-additive effect of smoke and heat, warrant further investigation.

Highlight

We show Leucadendron seeds are either plant-stored with thin, highly permeable seed-coats that germinate readily; or soil-stored and the thicker their seed-coat, the lower their permeability and greater their need for smoke/heat to promote germination.
SMAD4 and TGFβ are architects of inverse genetic programs during fate-determination of antiviral memory CD8 T cells
Authors: Chandiran K. , Suarez-Ramirez J.E. , Hu Y. , Jellison E.R. , Ugur Z. , Low J.S. , McDonald B. , Kaech S.M. , Cauley L.S.
Published: December 2021

Transforming growth factor β (TGFβ) is a morphogenic protein that augments antiviral immunity by altering the functional properties of pathogen-specific memory CD8 T cells. During infection TGFβ inhibits formation of effector (TEFF) and central memory CD8 T cells (TCM), while encouraging tissue-resident memory CD8 T cells (TRM) to settle in peripheral tissues. SMAD proteins are signaling intermediates that are used by members of the TGF cytokine family to modify gene expression. For this study, RNA-sequencing was used to explore how regulation via SMAD4 alters the transcriptional profile of antiviral CTLs during infection. We show that SMAD4 and TGFβ cooperatively regulate a collection of genes that determine whether specialized populations of pathogen-specific CTLs circulate around the body, or settle in peripheral tissue. The target genes include multiple homing receptors (CD103, KLRG1 and CD62L) and transcription factors (Hobit and EOMES) that support memory formation. While TGFβ uses a canonical SMAD-dependent signaling pathway to induce CD103 expression on TRM cells, an alternative SMAD4-dependent mechanism is required for formation of TEFF and TCM cells in the circulation.

Graphical abstract

TGFβ and SMAD4 modulate gene expression in reciprocal directions during differentiation of antiviral CTLs.
IFN-γ-independent control ofM. tuberculosisrequires CD4 T cell-derived GM-CSF and activation of HIF-1α
Authors: Van Dis Erik , Morrison Huntly M , Fines Daniel M , Babirye Janet Peace , McCann Lily H , Rawal Sagar , Cox Jeffery S , Stanley Sarah A
Published: December 2021

The prevailing model of protective immunity to tuberculosis is that CD4 T cells produce the cytokine IFN-γ to activate bactericidal mechanisms in infected macrophages. Recent evidence has expanded this model, and it is now clear that CD4 T cells can controlM. tuberculosisinfection in the absence of IFN-γ production. To identify factors and pathways involved in IFN-γ-independent control, we developed a co-culture model using CD4 T cells isolated from the lungs of infected mice andM. tuberculosis-infectedmurine bone marrow-derived macrophages (BMDMs). We show that IFN-γ-independent control is primarily mediated by CD4 T cell production of the cytokine GM-CSF and requires activation of the macrophage transcription factor HIF-1α. HIF-1α activation drives a metabolic shift toward aerobic glycolysis and leads to the production of lipid droplets, both of which support host defense against infection. Surprisingly, recombinant GM-CSF is insufficient to rescue the absence of control by GM-CSF-deficient CD4 T cells during co-culture with BMDMs. In peritoneal macrophages, GM-CSF is sufficient to control growth, induces lipid droplet biogenesis, and requires HIF-1α expression for control. While HIF-1α-mediated control following IFN-γ stimulation requires nitric oxide, we find that HIF-1α activation by CD4 T cells and recombinant GM-CSF is nitric oxide-independent, implying a distinct pathway of activation. In addition to GM-CSF, CD4 T cells produce a factor that helps maintain phagosome membrane integrity during infection and blocks bacterial access to host lipids, a primary nutrient source. These results advance our understanding of CD4 T cell-mediated immunity toM. tuberculosis, clarify the role of nitric oxide as primarily immunomodulatory duringM. tuberculosisinfection, and reveal a novel mechanism for the activation of HIF-1α. Furthermore, we establish a previously unknown functional link between GM-CSF and HIF-1α and provide evidence that CD4 T cell-derived GM-CSF is a potent bactericidal effector.
Centromere identity is dependent on nuclear spatial organization
Authors: Wu Weifang , McHugh Toni , Kelly David A. , Pidoux Alison L. , Allshire Robin C.
Published: December 2021

The establishment of centromere-specific CENP-A chromatin is influenced by epigenetic and genetic processes. Central domain sequences from fission yeast centromeres are preferred substrates for CENP-ACnp1 incorporation, but their use is context dependent, requiring adjacent heterochromatin. CENP-ACnp1 overexpression bypasses heterochromatin dependency, suggesting heterochromatin ensures exposure to conditions or locations permissive for CENP-ACnp1 assembly. Centromeres cluster around spindle-pole bodies (SPBs). We show that heterochromatin-bearing minichromosomes localize close to SPBs, consistent with this location promoting CENP-ACnp1 incorporation. We demonstrate that heterochromatin-independent de novo CENP-ACnp1 chromatin assembly occurs when central domain DNA is placed near, but not far from, endogenous centromeres or neocentromeres. Moreover, direct tethering of central domain DNA at SPBs permits CENP-ACnp1 assembly, suggesting that the nuclear compartment surrounding SPBs is permissive for CENP-ACnp1 incorporation because target sequences are exposed to high levels of CENP-ACnp1 and associated assembly factors. Thus, nuclear spatial organization is a key epigenetic factor that influences centromere identity.