bluuebunny/crossref_metadata_2025 huggingface dataset:
SER-109, an Investigational Microbiome Drug to Reduce Recurrence After Clostridioides difficile Infection: Lessons Learned From a Phase 2 Trial
Authors: McGovern Barbara H , Ford Christopher B , Henn Matthew R , Pardi Darrell S , Khanna Sahil , Hohmann Elizabeth L , O’Brien Edward J , Desjardins Christopher A , Bernardo Patricia , Wortman Jennifer R , Lombardo Mary-Jane , Litcofsky Kevin D , Winkler Jonathan A , McChalicher Christopher W J , Li Sunny S , Tomlinson Amelia D , Nandakumar Madhumitha , Cook David N , Pomerantz Roger J , Auninš John G , Trucksis Michele
Published: April 2020

Background

Recurrent Clostridioides difficile infection (rCDI) is associated with loss of microbial diversity and microbe-derived secondary bile acids, which inhibit C. difficile germination and growth. SER-109, an investigational microbiome drug of donor-derived, purified spores, reduced recurrence in a dose-ranging, phase (P) 1 study in subjects with multiple rCDIs.

Methods

In a P2 double-blind trial, subjects with clinical resolution on standard-of-care antibiotics were stratified by age (< or ≥65 years) and randomized 2:1 to single-dose SER-109 or placebo. Subjects were diagnosed at study entry by PCR or toxin testing. Safety, C. difficile–positive diarrhea through week 8, SER-109 engraftment, and bile acid changes were assessed.

Results

89 subjects enrolled (67% female; 80.9% diagnosed by PCR). rCDI rates were lower in the SER-109 arm than placebo (44.1% vs 53.3%) but did not meet statistical significance. In a preplanned analysis, rates were reduced among subjects ≥65 years (45.2% vs 80%, respectively; RR, 1.77; 95% CI, 1.11–2.81), while the <65 group showed no benefit. Early engraftment of SER-109 was associated with nonrecurrence (P < .05) and increased secondary bile acid concentrations (P < .0001). Whole-metagenomic sequencing from this study and the P1 study revealed previously unappreciated dose-dependent engraftment kinetics and confirmed an association between early engraftment and nonrecurrence. Engraftment kinetics suggest that P2 dosing was suboptimal. Adverse events were generally mild to moderate in severity.

Conclusions

Early SER-109 engraftment was associated with reduced CDI recurrence and favorable safety was observed. A higher dose of SER-109 and requirements for toxin testing were implemented in the current P3 trial.

Clinical Trials Registration

NCT02437487, https://clinicaltrials.gov/ct2/show/NCT02437487?term=SER-109&draw= 2&rank=4.
Encoder–Decoder Couplet Generation Model Based on ‘Trapezoidal Context’ Character Vector
Authors: Gao Rui , Zhu Yuanyuan , Li Mingye , Li Shoufeng , Shi Xiaohu
Published: April 2020

This paper studies the couplet generation model which automatically generates the second line of a couplet by giving the first line. Unlike other sequence generation problems, couplet generation not only considers the sequential context within a sentence line but also emphasizes the relationships between the corresponding words of first and second lines. Therefore, a trapezoidal context character embedding the vector model has been developed firstly, which considers the ‘sequence context’ and the ‘corresponding word context’ simultaneously. Afterwards, we chose the typical encoder–decoder framework to solve the sequence–sequence problems, of which the encoder and decoder are used by bi-directional GRU and GRU, respectively. In order to further increase the semantic consistency of the first and second lines of couplets, the pre-trained sentence vector of the first line is added to the attention mechanism in the model. To verify the effectiveness of the method, it is applied to the real data set. Experimental results show that our proposed model can compete with the up-to-date methods, and both adding sentence vectors to attention and using trapezoidal context character vectors can improve the effectiveness of the algorithm.
Integrated in silico and 3D in vitro model of macrophage migration in response to physical and chemical factors in the tumor microenvironment
Authors: Lee Sharon Wei Ling , Seager R J , Litvak Felix , Spill Fabian , Sieow Je Lin , Leong Penny Hweixian , Kumar Dillip , Tan Alrina Shin Min , Wong Siew Cheng , Adriani Giulia , Zaman Muhammad Hamid , Kamm and Roger D
Published: April 2020

Macrophages are abundant in the tumor microenvironment (TME), serving as accomplices to cancer cells for their invasion. Studies have explored the biochemical mechanisms that drive pro-tumor macrophage functions; however the role of TME interstitial flow (IF) is often disregarded. Therefore, we developed a three-dimensional microfluidic-based model with tumor cells and macrophages to study how IF affects macrophage migration and its potential contribution to cancer invasion. The presence of either tumor cells or IF individually increased macrophage migration directedness and speed. Interestingly, there was no additive effect on macrophage migration directedness and speed under the simultaneous presence of tumor cells and IF. Further, we present an in silico model that couples chemokine-mediated signaling with mechanosensing networks to explain our in vitro observations. In our model design, we propose IL-8, CCL2, and β-integrin as key pathways that commonly regulate various Rho GTPases. In agreement, in vitro macrophage migration remained elevated when exposed to a saturating concentration of recombinant IL-8 or CCL2 or to the co-addition of a sub-saturating concentration of both cytokines. Moreover, antibody blockade against IL-8 and/or CCL2 inhibited migration that could be restored by IF, indicating cytokine-independent mechanisms of migration induction. Importantly, we demonstrate the utility of an integrated in silico and 3D in vitro approach to aid the design of tumor-associated macrophage-based immunotherapeutic strategies.
Factors Associated with Poor Quality of Life in a Canadian Cohort of Patients with Inflammatory Bowel Disease: A Cross-sectional Study
Authors: Nazarian Amir , Bishay Kirles , Gholami Reza , Scaffidi Michael A , Khan Rishad , Cohen-Lyons Daniel , Griller Nadia , Satchwell Joshua B , Baker Jeffrey P , Grover Samir C , Irvine Elizabeth Jan
Published: April 2020

Background

Health-related quality of life (QoL) is often adversely affected in patients with inflammatory bowel disease (IBD). We aimed to identify factors associated with poor QoL among Canadian patients with IBD in clinical remission.

Methods

We enrolled patients at a single academic tertiary care center with inactive IBD. All eligible patients completed a series of questionnaires that included questions on demographics, disease activity, anxiety, depression and the presence of irritable bowel syndrome (IBS) symptoms. Stool sample for fecal calprotectin (FC) was also collected to assess for subclinical inflammation. The primary outcome measure was QoL assessed by the short inflammatory bowel disease questionnaire (SIBDQ), with planned subgroup comparisons for fatigue, anxiety, depression and IBS symptoms.

Results

Ninety-three patients were eligible for inclusion in this study. The median SIBDQ scores were lower in patients with anxiety (P < 0.001), depression (P = 0.004), IBS symptoms (P < 0.001) and fatigue (P = 0.018). Elevated FC in patients in clinical remission did not impact QoL. These findings were consistent on multivariate linear regression.

Conclusions

Anxiety, depression, fatigue and IBS symptoms are all independently associated with lower QoL in patients with inactive IBD. Clinicians are encouraged to screen for these important factors as they may detrimentally impact QoL in IBD patients even in clinical remission.
Manipulation of long-shaft stapler in robotic-assisted thoracoscopic surgery lung resection
Authors: Mitsuboshi Shota , Ogihara Akira , Katagiri Sayaka , Maeda Hideyuki , Aoshima Hiroe , Matsumoto Takako , Isaka Tamami , Kanzaki Masato
Published: April 2020

The number of robotic surgical procedures for thoracic disease is increasing. The automatic linear stapler has become a necessary device in endoscopic surgery. A 67-year-old man with a history of smoking was referred to our hospital for an abnormal finding on chest x-ray. Computer tomography of the chest revealed a ground glass nodule in the right middle lobe. We performed right middle wedge resection through the assistant port using a long-shaft stapler (LSS). Because the nodule was diagnosed as an adenocarcinoma on the intraoperative frozen section, the patient underwent robotic-assisted thoracoscopic surgery (RATS) right middle lobectomy using the da Vinci® Xi system. The pulmonary arteries, veins, right middle bronchus and minor fissure were divided using the LSS through the utility thoracotomy or assistant port. The postoperative course was uncomplicated. This case suggests that the LSS can be used in RATS lung resection for cancer.
The effects of knee arthroplasty on plasma vitamin C concentrations and cognitive function: a case study
Authors: Travica Nikolaj , Ried Karin , Pipingas Andrew , Hudson Irene , Young David , Scholey Andrew , Sali Avni
Published: April 2020

Post-operative neurocognitive disorders are becoming well-documented conditions, with their pathogenesis remaining unclear. Vitamin C is a molecule that has recently demonstrated both a potential link with cognitive function and a significant post-operative decline. Here, we present a case study of a 72-year-old male who underwent total knee replacement surgery. The patient demonstrated a substantial decline in plasma vitamin C concentrations, indicative of a severe deficiency, during the first post-operative week (post-operative Days 3 and 7). Similarly, at these time points, a number of validated paper and pen tests revealed a substantial decline in cognition on tasks relating to total recall, delayed recall, motor speed, recognition and motor speed, with no signs of delirium. These results provide the justification for larger, cohort studies to determine whether post-operative plasma vitamin C depletions could contribute to cognitive deficits post-operatively.
Electrical Stimulation Therapies for Active Duty Military with Patellofemoral Pain Syndrome: A Randomized Trial
Authors: Talbot Laura A , Solomon Zack , Webb Lee , Morrell Christopher , Metter E Jeffrey
Published: April 2020

Introduction

Patellofemoral pain syndrome (PFPS) is a common musculoskeletal disorder among military service members that causes knee pain, quadriceps strength loss, and impaired motor performance in otherwise healthy individuals. PFPS poses a threat to the health, fitness, and subsequent readiness of the total force. The goal of rehabilitation for military service members with PFPS is to regain physical capacity of strength and function and to reduce pain, in order to restore readiness in this population. The randomized controlled trial reported here compared an active home exercise program (HEP) alone with three different electrical stimulation treatment regimens implemented concurrently with HEP postulated improvements in lower extremity strength and physical functional performance while also reducing pain in active duty military diagnosed with PFPS.

Materials and Methods

After baseline testing, 130 active duty military members with PFPS were randomized to 1 of 4 treatment groups: (1) neuromuscular electrical stimulation (NMES) with HEP; (2) transcutaneous electrical nerve stimulation (TENS) with HEP; (3) combined NMES/TENS with HEP; (4) active HEP only. The primary outcome measure was degree of change in knee flexion and extension strength over 9 weeks. Secondary outcomes were physical functional performance and knee pain. The primary analyses used repeated measures, linear mixed-effects models with a random effect for subject, time as a continuous variable, group as a categorical variable, and a group and time interaction to test for differences in change over time among the groups.

Results

All three electrical stimulation treatment groups improved in knee extension strength in the PFPS limb to a greater extent than the HEP alone group over the 9-week treatment period. The NMES and NMES/TENS groups improved to a greater extent than the HEP alone group in knee flexion strength in the PFPS limb. The reported pain improved over time for all treatment groups with no significant group differences. All three stimulation groups performed better on the 6-min walk test than the HEP alone group.

Conclusion

The findings from this study showed that all three electrical stimulation with HEP treatment groups showed greater improvement in strength compared to the HEP alone group. These findings could offer alternative forms of rehabilitation for AD military with PFPS as these treatment regimens can be easily implemented at home station or during deployment.
Physiological Factors of Importance for Load Carriage in Experienced and Inexperienced Men and Women
Authors: Godhe Manne , Helge Torbjörn , Mattsson C Mikael , Ekblom Örjan , Ekblom Björn
Published: April 2020

Introduction

The ability to carry heavy loads is an important and necessary task during numerous outdoor activities and especially in military operations. The aim of this study was to investigate factors associated with load-carrying ability in men and women with and without extensive load-carrying experience.

Materials and Methods

The energy expenditure during carrying no load, 20, 35, and 50 kg at 2 walking speeds, 3 and 5 km h−1, was studied in 36 healthy participants, 19 men (30 ± 6 years, 82.5 ± 7.0 kg) and 17 women (29 ± 6 years, 66.1 ± 8.9 kg), experienced (>5 years) in carrying heavy loads (n = 16, 8 women) or with minor or no such experience (n = 20, 9 women). A standard backpack filled with weights to according carry load was used during the walks. Anthropometric data, leg muscle strength, as well as trunk muscle endurance and muscle fiber distribution of the thigh, were also obtained. Extra Load Index (ELI)—the oxygen uptake (VO2) during total load over unloaded walking—was used as a proxy for load-carrying ability at 20, 35, and 50 kg (ELI20, ELI35, and ELI50, respectively). In addition to analyzing factors of importance for the ELI values, we also conducted mediator analyses using sex and long-term carrying experience as causal variables for ELI as the outcome value. The study was approved by the Regional Ethics Committee in Stockholm, Sweden.

Results

For the lowest load (20 kg), ELI20, was correlated with body mass but no other factors. Walking with 35 and 50 kg load at 5 km h−1 body mass, body height, leg muscle strength, and absolute VO2max were correlated, while relative VO2max, trunk muscle endurance, and leg muscle fiber distribution were not correlated to ELI35 and ELI50.

ELI50 at 5 km h−1 differed between the sexes. This difference was only mediated by the difference in body mass. Neither muscle fiber distribution, leg muscle strength, trunk muscle endurance, and body height nor did absolute or relative VO2max explain the difference.

Participants with long-term experience of heavy load carrying had significant lower ELI20 and ELI50 values than those with minor or no experience, but none of the above studied factors could explain this difference.

Conclusion

The study showed that body mass, without sex differences, and experience of carrying heavy loads are the dominant factors for the ability to carry heavy loads. Even though the effect of experience alludes to the need for extensive carrying training, no causality can be proven. Load carry training intervention studies is suggested for future investigations.
Post-Traumatic Stress Disorder Symptoms Contribute to Worse Pain and Health Outcomes in Veterans With PTSD Compared to Those Without: A Systematic Review With Meta-Analysis
Authors: Benedict Timothy M , Keenan Patrick G , Nitz Arthur J , Moeller-Bertram Tobias
Published: April 2020

Introduction

Post-traumatic stress disorder (PTSD) and chronic pain are frequently co-morbid conditions in the U.S. veteran population. Although several theories about the cause of increased pain prevalence in individuals with PTSD have been presented, no synthesis of primary data informing the impact of co-morbid PTSD and pain has been completed. The purpose of this study was to systematically review the literature and quantify disability, function, and pain-related beliefs and outcomes in veterans with PTSD compared to veterans without PTSD.

Materials and Methods

A systematic search of three electronic databases was conducted. Inclusion criteria required pain-related comparison of veterans with PTSD to those without PTSD. Primary outcome measures and standardized mean differences (SMDs) were assessed for pain, function, disability, pain beliefs, and healthcare utilization using a random effects model.

Results

20 original research studies met inclusion criteria and were assessed for quality and outcomes of interest. The majority of studies were cross-sectional. Veterans with PTSD and pain demonstrated higher pain (SMD = 0.58, 95% CI 0.28–0.89), disability (SMD = 0.52, 95%CI 0.33–0.71), depression (SMD = 1.40, 95%CI 1.2–1.6), catastrophizing beliefs (SMD = 0.95, 95% CI 0.69–1.2), sleep disturbance (SMD = 0.80, 95% CI 0.57–1.02), and healthcare utilization; they had lower function (SMD = 0.41, 95% CI 0.25–0.56) and pain self-efficacy (SMD = 0.77, 95% CI 0.55–0.99) compared to veterans without PTSD.

Conclusion

In veterans with chronic pain, PTSD symptomology has a large effect for many negative health-related outcomes. This review supports the need for clinicians to screen and understand the effects of PTSD symptoms on patients with pain. Clinicians should recognize that veterans with PTSD and pain likely have elevated pain catastrophizing beliefs and decreased self-efficacy that should be targeted for intervention.
The imprint of the protoplanetary disc in the accretion of super-Earth envelopes
Authors: Ali-Dib Mohamad , Cumming Andrew , Lin Douglas N C
Published: April 2020

Super-Earths are by far the most dominant type of exoplanet, yet their formation is still not well understood. In particular, planet formation models predict that many of them should have accreted enough gas to become gas giants. Here, we examine the role of the protoplanetary disc in the cooling and contraction of the protoplanetary envelope. In particular, we investigate the effects of (1) the thermal state of the disc as set by the relative size of heating by accretion or irradiation, and whether its energy is transported by radiation or convection, and (2) advection of entropy into the outer envelope by disc flows that penetrate the Hill sphere, as found in 3D global simulations. We find that, at 5 and 1 au, this flow at the level reported in the non-isothermal simulations where it penetrates only to ∼0.3 times the Hill radius has little effect on the cooling rate since most of the envelope mass is concentrated close to the core, and far from the flow. On the other hand, at 0.1 au, the envelope quickly becomes fully radiative, nearly isothermal, and thus cannot cool down, stalling gas accretion. This effect is significantly more pronounced in convective discs, leading to envelope mass orders of magnitude lower. Entropy advection at 0.1 au in either radiative or convective discs could therefore explain why super-Earths failed to undergo runaway accretion. These results highlight the importance of the conditions and energy transport in the protoplanetary disc for the accretion of planetary envelopes.
Midkine and chronic kidney disease-associated multisystem organ dysfunctions
Authors: Campbell Victoria K , Gately Ryan P , Krishnasamy Rathika , Burg Dominic , Robertson Graham R , Gray Nicholas A
Published: April 2020

Chronic kidney disease (CKD) is a progressive multisystem condition with yet undefined mechanistic drivers and multiple implicated soluble factors. If identified, these factors could be targeted for therapeutic intervention for a disease that currently lacks specific treatment. There is increasing preclinical evidence that the heparin/endothelial glycocalyx-binding molecule midkine (MK) has a pathological role in multiple CKD-related, organ-specific disease processes, including CKD progression, hypertension, vascular and cardiac disease, bone disease and CKD-related cancers. Concurrent with this are studies documenting increases in circulating and urine MK proportional to glomerular filtration rate (GFR) loss in CKD patients and evidence that administering soluble MK reverses the protective effects of MK deficiency in experimental kidney disease. This review summarizes the growing body of evidence supporting MK’s potential role in driving CKD-related multisystem disease, including MK’s relationship with the endothelial glycocalyx, the deranged MK levels and glycocalyx profile in CKD patients and a proposed model of MK organ interplay in CKD disease processes and highlights the importance of ongoing research into MK’s potential as a therapeutic target.
Hypoxia in chronic kidney disease: towards a paradigm shift?
Authors: Faivre Anna , Scholz Carsten C. , de Seigneux Sophie
Published: April 2020

Chronic kidney disease (CKD) is defined as an alteration of kidney structure and/or function lasting for >3 months [1]. CKD affects 10% of the general adult population and is responsible for large healthcare costs [2]. Since the end of the last century, the role of hypoxia in CKD progression has controversially been discussed. To date, there is evidence of the presence of hypoxia in late-stage renal disease, but we lack time-course evidence, stage correlation and also spatial co-localization with fibrotic lesions to ensure its causative role. The classical view of hypoxia in CKD progression is that it is caused by peritubular capillary alterations, renal anaemia and increased oxygen consumption regardless of the primary injury. In this classical view, hypoxia is assumed to further induce pro-fibrotic and pro-inflammatory responses, as well as oxidative stress, leading to CKD worsening as part of a vicious circle. However, recent investigations tend to question this paradigm, and both the presence of hypoxia and its role in CKD progression are still not clearly demonstrated. Hypoxia-inducible factor (HIF) is the main transcriptional regulator of the hypoxia response. Genetic HIF modulation leads to variable effects on CKD progression in different murine models. In contrast, pharmacological modulation of the HIF pathway [i.e. by HIF hydroxylase inhibitors (HIs)] appears to be generally protective against fibrosis progression experimentally. We here review the existing literature on the role of hypoxia, the HIF pathway and HIF HIs in CKD progression and summarize the evidence that supports or rejects the hypoxia hypothesis, respectively.
Occupational exposure to cytostatic fumes during hyperthermic intraperitoneal chemotherapy
Authors: Wiszniewska M , Książek A , Lipińska-Ojrzanowska A , Walusiak-Skorupa J
Published: April 2020

Hyperthermic intraperitoneal chemotherapy (HIPEC)—heated, intra-abdominal chemotherapy—has become the treatment of choice for treating peritoneal metastases from ovarian, stomach or colorectal cancers. HIPEC has several advantages and disadvantages. The major benefit is minimal systemic toxicity for the patient, but there is a risk of occupational exposure for operating room staff. We have not found any reports of workers with chronic aplastic anaemia as a result of exposure to cytostatic fumes during HIPEC. The aim of this case report is to raise the awareness of potential negative health effects of inhalation exposure to cytostatic drugs. We present a rare case of a 43-year-old woman, suffering from aplastic anaemia as a long-term consequence of exposure to cytostatics. During the HIPEC procedure, surgical revision of the peritoneal cavity was undertaken which resulted in release of cytostatic fumes. Despite awareness of the health effects of occupational exposure to cytostatic drugs and well-developed procedures for safely handling them, unexpected exposure may occur causing serious medical conditions. These may develop in sensitive subjects although accidental high-level exposure may lead to unexpected long-term consequences in all workers. Medical staff need to be informed of the risks of HIPEC and safety guidelines to reduce the risk of exposure.
Memories replayed: reactivating past successes and new dilemmas
Authors: Robertson Edwin M. , Genzel Lisa
Published: April 2020

Our experiences continue to be processed ‘offline’ in the ensuing hours of both wakefulness and sleep. During these different brain states, the memory formed during our experience is replayed or reactivated. Here, we discuss the unique challenges in studying offline reactivation, the growth in both the experimental and analytical techniques available across different animals from rodents to humans to capture these offline events, the important challenges this innovation has brought, our still modest understanding of how reactivation drives diverse synaptic changes across circuits, and how these changes differ (if at all), and perhaps complement, those at memory formation. Together, these discussions highlight critical emerging issues vital for identifying how reactivation affects circuits, and, in turn, behaviour, and provides a broader context for the contributions in this special issue.

This article is part of the Theo Murphy meeting issue ‘Memory reactivation: replaying events past, present and future’.
Memory reactivation in rat medial prefrontal cortex occurs in a subtype of cortical UP state during slow-wave sleep
Authors: Tatsuno Masami , Malek Soroush , Kalvi LeAnna , Ponce-Alvarez Adrian , Ali Karim , Euston David R. , Grün Sonja , McNaughton Bruce L.
Published: April 2020

Interaction between hippocampal sharp-wave ripples (SWRs) and UP states, possibly by coordinated reactivation of memory traces, is conjectured to play an important role in memory consolidation. Recently, it was reported that SWRs were differentiated into multiple subtypes. However, whether cortical UP states can also be classified into subtypes is not known. Here, we analysed neural ensemble activity from the medial prefrontal cortex from rats trained to run a spatial sequence-memory task. Application of the hidden Markov model (HMM) with three states to epochs of UP–DOWN oscillations identified DOWN states and two subtypes of UP state (UP-1 and UP-2). The two UP subtypes were distinguished by differences in duration, with UP-1 having a longer duration than UP-2, as well as differences in the speed of population vector (PV) decorrelation, with UP-1 decorrelating more slowly than UP-2. Reactivation of recent memory sequences predominantly occurred in UP-2. Short-duration reactivating UP states were dominated by UP-2 whereas long-duration ones exhibit transitions from UP-1 to UP-2. Thus, recent memory reactivation, if it occurred within long-duration UP states, typically was preceded by a period of slow PV evolution not related to recent experience, and which we speculate may be related to previously encoded information. If that is the case, then the transition from UP-1 to UP-2 subtypes may help gradual integration of recent experience with pre-existing cortical memories by interleaving the two in the same UP state.

This article is part of the Theo Murphy meeting issue ‘Memory reactivation: replaying events past, present and future'.
Coordinated activities of retrosplenial ensembles during resting-state encode spatial landmarks
Authors: Chang HaoRan , Esteves Ingrid M. , Neumann Adam R. , Sun Jianjun , Mohajerani Majid H. , McNaughton Bruce L.
Published: April 2020

The brain likely uses offline periods to consolidate recent memories. One hypothesis holds that the hippocampal output provides a unique, global linking or ‘index’ code for each memory, and that this code is stored in the cortex in association with locally encoded attributes of each memory. Activation of the index code is hypothesized to evoke coordinated memory trace reactivation thus facilitating consolidation. Retrosplenial cortex (RSC) is a major recipient of hippocampal outflow and we have described populations of neurons there with sparse and orthogonal coding characteristics that resemble hippocampal ‘place’ cells, and whose expression depends on an intact hippocampus. Using two-photon Ca
2+
imaging, we recorded ensembles of neurons in the RSC during periods of immobility before and after active running on a familiar linear treadmill track. Synchronous bursting of distinct groups of neurons occurred during rest both prior to and after running. In the second rest epoch, these patterns were associated with the locations of tactile landmarks and reward. Complementing established views on the functions of the RSC, our findings indicate that the structure is involved with processing landmark information during rest.

This article is part of the Theo Murphy meeting issue ‘Memory reactivation: replaying events past, present and future’.
A mechanism for learning with sleep spindles
Authors: Peyrache Adrien , Seibt Julie
Published: April 2020

Spindles are ubiquitous oscillations during non-rapid eye movement (NREM) sleep. A growing body of evidence points to a possible link with learning and memory, and the underlying mechanisms are now starting to be unveiled. Specifically, spindles are associated with increased dendritic activity and high intracellular calcium levels, a situation favourable to plasticity, as well as with control of spiking output by feed-forward inhibition. During spindles, thalamocortical networks become unresponsive to inputs, thus potentially preventing interference between memory-related internal information processing and extrinsic signals. At the system level, spindles are co-modulated with other major NREM oscillations, including hippocampal sharp wave-ripples (SWRs) and neocortical slow waves, both previously shown to be associated with learning and memory. The sequential occurrence of reactivation at the time of SWRs followed by neuronal plasticity-promoting spindles is a possible mechanism to explain NREM sleep-dependent consolidation of memories.

This article is part of the Theo Murphy meeting issue ‘Memory reactivation: replaying events past, present and future'.
On the methods for reactivation and replay analysis
Authors: Tingley David , Peyrache Adrien
Published: April 2020

A major task in the history of neurophysiology has been to relate patterns of neural activity to ongoing external stimuli. More recently, this approach has branched out to relating current neural activity patterns to external stimuli or experiences that occurred in the past or future. Here, we aim to review the large body of methodological approaches used towards this goal, and to assess the assumptions each makes with reference to the statistics of neural data that are commonly observed. These methods primarily fall into two categories, those that quantify zero-lag relationships without examining temporal evolution, termed
reactivation
, and those that quantify the temporal structure of changing activity patterns, termed
replay
. However, no two studies use the exact same approach, which prevents an unbiased comparison between findings. These observations should instead be validated by multiple and, if possible, previously established tests. This will help the community to speak a common language and will eventually provide tools to study, more generally, the organization of neuronal patterns in the brain.

This article is part of the Theo Murphy meeting issue ‘Memory reactivation: replaying events past, present and future’.
A sleep spindle framework for motor memory consolidation
Authors: Boutin Arnaud , Doyon Julien
Published: April 2020

Sleep spindle activity has repeatedly been found to contribute to brain plasticity and consolidation of both declarative and procedural memories. Here we propose a framework for motor memory consolidation that outlines the essential contribution of the hierarchical and multi-scale periodicity of spindle activity, as well as of the synchronization and interaction of brain oscillations during this sleep-dependent process. We posit that the clustering of sleep spindles in ‘trains', together with the temporally organized alternation between spindles and associated refractory periods, is critical for efficient reprocessing and consolidation of motor memories. We further argue that the long-term retention of procedural memories relies on the synchronized (functional connectivity) local reprocessing of new information across segregated, but inter-connected brain regions that are involved in the initial learning process. Finally, we propose that oscillatory synchrony in the spindle frequency band may reflect the cross-structural reactivation, reorganization and consolidation of motor, and potentially declarative, memory traces within broader subcortical–cortical networks during sleep.

This article is part of the Theo Murphy meeting issue ‘Memory reactivation: replaying events past, present and future'.
Patterned activation of action potential patterns during offline states in the neocortex: replay and non-replay
Authors: Liu Tang-Yu , Watson Brendon O.
Published: April 2020

Action potential generation (spiking) in the neocortex is organized into repeating non-random patterns during both awake experiential states and non-engaged states ranging from inattention to sleep to anaesthesia—and even occur in slice preparations. Repeating patterns in a given population of neurons between states may imply a common means by which cortical networks can be engaged despite brain state changes, but super-imposed on this common firing is a variability that is both specific to ongoing inputs and can be re-shaped by experience. This similarity with specifically induced variance may allow for a range of processes including perception, memory consolidation and network homeostasis. Here, we review how patterned activity in neocortical populations has been studied and what it may imply for a cortex that must be both static and plastic.

This article is part of the Theo Murphy meeting issue ‘Memory reactivation: replaying events past, present and future’.
Experience and sleep-dependent synaptic plasticity: from structure to activity
Authors: Sun Linlin , Zhou Hang , Cichon Joseph , Yang Guang
Published: April 2020

Synaptic plasticity is important for learning and memory. With increasing evidence linking sleep states to changes in synaptic strength, an emerging view is that sleep promotes learning and memory by facilitating experience-induced synaptic plasticity. In this review, we summarize the recent progress on the function of sleep in regulating cortical synaptic plasticity. Specifically, we outline the electroencephalogram signatures of sleep states (e.g. slow-wave sleep, rapid eye movement sleep, spindles), sleep state-dependent changes in gene and synaptic protein expression, synaptic morphology, and neuronal and network activity. We highlight studies showing that post-experience sleep potentiates experience-induced synaptic changes and discuss the potential mechanisms that may link sleep-related brain activity to synaptic structural remodelling. We conclude that both synapse formation or strengthening and elimination or weakening occur across sleep. This sleep-dependent synaptic plasticity plays an important role in neuronal circuit refinement during development and after learning, while sleep disorders may contribute to or exacerbate the development of common neurological diseases.

This article is part of the Theo Murphy meeting issue ‘Memory reactivation: replaying events past, present and future’.
Effects of sleep and waking on the synaptic ultrastructure
Authors: Cirelli Chiara , Tononi Giulio
Published: April 2020

We summarize here several studies performed in our laboratory, mainly using serial block-face scanning electron microscopy (SBEM), to assess how sleep, spontaneous waking and short sleep deprivation affect the size and number of synapses in the cerebral cortex and hippocampus. With SBEM, we reconstructed thousands of cortical and hippocampal excitatory, axospinous synapses and compared the distribution of their size after several hours of sleep relative to several hours of waking. Because stronger synapses are on average also bigger, the goal was to test a prediction of the synaptic homeostasis hypothesis, according to which overall synaptic strength increases during waking, owing to ongoing learning, and needs to be renormalized during sleep, to avoid saturation and to benefit memory consolidation and integration. Consistent with this hypothesis, we found that the size of the axon–spine interface (ASI), a morphological measure of synaptic strength, was on average smaller after sleep, but with interesting differences between primary cortex and the CA1 region of the hippocampus. In two-week-old mouse pups, the decline in ASI size after sleep was larger, and affected more cortical synapses, compared with one-month-old adolescent mice, suggesting that synaptic renormalization during sleep may be especially important during early development. This work is still in progress and other brain areas need to be tested after sleep, acute sleep loss and chronic sleep restriction. Still, the current results show that a few hours of sleep or waking lead to significant changes in synaptic morphology that can be linked to changes in synaptic efficacy.

This article is part of the Theo Murphy meeting issue ‘Memory reactivation: replaying events past, present and future’.
Potential factors influencing replay across CA1 during sharp-wave ripples
Authors: de la Prida Liset M.
Published: April 2020

Sharp-wave ripples are complex neurophysiological events recorded along the trisynaptic hippocampal circuit (i.e. from CA3 to CA1 and the subiculum) during slow-wave sleep and awake states. They arise locally but scale brain-wide to the hippocampal target regions at cortical and subcortical structures. During these events, neuronal firing sequences are replayed retrospectively or prospectively and in the forward or reverse order as defined by experience. They could reflect either pre-configured firing sequences, learned sequences or an option space to inform subsequent decisions. How can different sequences arise during sharp-wave ripples? Emerging data suggest the hippocampal circuit is organized in different loops across the proximal (close to dentate gyrus) and distal (close to entorhinal cortex) axis. These data also disclose a so-far neglected laminar organization of the hippocampal output during sharp-wave events. Here, I discuss whether by incorporating cell-type-specific mechanisms converging on deep and superficial CA1 sublayers along the proximodistal axis, some novel factors influencing the organization of hippocampal sequences could be unveiled.

This article is part of the Theo Murphy meeting issue ‘Memory reactivation: replaying events past, present and future’.
Mechanisms of neural organization and rhythmogenesis during hippocampal and cortical ripples
Authors: McKenzie Sam , Nitzan Noam , English Daniel F.
Published: April 2020

Neural activity during ripples has attracted great theoretical and experimental attention over the last three decades. Perhaps one reason for such interest is that ripples occur during quiet waking moments and during sleep, times when we reflect and dream about what has just occurred and what we expect to happen next. The hope is that understanding such ‘offline’ activity may yield insights into reflection, planning, and the purposes of sleep. This review focuses on the mechanisms by which neurons organize during these high-frequency events. In studying ripples, broader principles have emerged that relate intrinsic neural properties, network topology and synaptic plasticity in controlling neural activity. Ripples, therefore, serve as an excellent model for studying how properties of a neural network relate to neural dynamics.

This article is part of the Theo Murphy meeting issue ‘Memory reactivation: replaying events past, present and future’.
Progress and issues in second-order analysis of hippocampal replay
Authors: van der Meer Matthijs A. A. , Kemere Caleb , Diba Kamran
Published: April 2020

Patterns of neural activity that occur spontaneously during sharp-wave ripple (SWR) events in the hippocampus are thought to play an important role in memory formation, consolidation and retrieval. Typical studies examining the content of SWRs seek to determine whether the identity and/or temporal order of cell firing is different from chance. Such ‘first-order’ analyses are focused on a single time point and template (map), and have been used to show, for instance, the existence of preplay. The major methodological challenge in first-order analyses is the construction and interpretation of different chance distributions. By contrast, ‘second-order’ analyses involve a comparison of SWR content between different time points, and/or between different templates. Typical second-order questions include tests of experience-dependence (replay) that compare SWR content before and after experience, and comparisons or replay between different arms of a maze. Such questions entail additional methodological challenges that can lead to biases in results and associated interpretations. We provide an inventory of analysis challenges for second-order questions about SWR content, and suggest ways of preventing, identifying and addressing possible analysis biases. Given evolving interest in understanding SWR content in more complex experimental scenarios and across different time scales, we expect these issues to become increasingly pervasive.

This article is part of the Theo Murphy meeting issue ‘Memory reactivation: replaying events past, present and future’.
Electrophysiological signatures of memory reactivation in humans
Authors: Schreiner Thomas , Staudigl Tobias
Published: April 2020

The reactivation of neural activity that was present during the encoding of an event is assumed to be essential for human episodic memory retrieval and the consolidation of memories during sleep. Pioneering animal work has already established a crucial role of memory reactivation to prepare and guide behaviour. Research in humans is now delineating the neural processes involved in memory reactivation during both wakefulness and sleep as well as their functional significance. Focusing on the electrophysiological signatures of memory reactivation in humans during both memory retrieval and sleep-related consolidation, this review provides an overview of the state of the art in the field. We outline recent advances, methodological developments and open questions and specifically highlight commonalities and differences in the neuronal signatures of memory reactivation during the states of wakefulness and sleep.

This article is part of the Theo Murphy meeting issue ‘Memory reactivation: replaying events past, present and future’.
Binocular disparity-based learning is retinotopically specific and independent of sleep
Authors: Klinzing Jens G. , Herbrik Lena , Nienborg Hendrikje , Rauss Karsten
Published: April 2020

Sleep supports the consolidation of recently encoded declarative and procedural memories. An important component of this effect is the repeated reactivation of neuronal ensemble activity elicited during memory encoding. For perceptual learning, however, sleep benefits have only been reported for specific tasks and it is not clear whether sleep targets low-level perceptual, higher-order temporal or attentional aspects of performance. Here, we employed a coarse binocular disparity discrimination task, known to rely on low-level stereoscopic vision. We show that human subjects improve over training and retain the same performance level across a 12-h retention period. Improvements do not generalize to other parts of the visual field and are unaffected by whether the retention period contains sleep or not. These results are compatible with the notion that behavioural improvements in binocular disparity discrimination do not additionally benefit from sleep when compared with the same time spent awake. We hypothesize that this might generalize to other strictly low-level perceptual tasks.

This article is part of the Theo Murphy meeting issue ‘Memory reactivation: replaying events past, present and future'.
Integration of new information in memory: new insights from a complementary learning systems perspective
Authors: McClelland James L. , McNaughton Bruce L. , Lampinen Andrew K.
Published: April 2020

According to complementary learning systems theory, integrating new memories into the neocortex of the brain without interfering with what is already known depends on a gradual learning process, interleaving new items with previously learned items. However, empirical studies show that information consistent with prior knowledge can sometimes be integrated very quickly. We use artificial neural networks with properties like those we attribute to the neocortex to develop an understanding of the role of consistency with prior knowledge in putatively neocortex-like learning systems, providing new insights into when integration will be fast or slow and how integration might be made more efficient when the items to be learned are hierarchically structured. The work relies on deep linear networks that capture the qualitative aspects of the learning dynamics of the more complex nonlinear networks used in previous work. The time course of learning in these networks can be linked to the hierarchical structure in the training data, captured mathematically as a set of dimensions that correspond to the branches in the hierarchy. In this context, a new item to be learned can be characterized as having aspects that project onto previously known dimensions, and others that require adding a new branch/dimension. The projection onto the known dimensions can be learned rapidly without interleaving, but learning the new dimension requires gradual interleaved learning. When a new item only overlaps with items within one branch of a hierarchy, interleaving can focus on the previously known items within this branch, resulting in faster integration with less interleaving overall. The discussion considers how the brain might exploit these facts to make learning more efficient and highlights predictions about what aspects of new information might be hard or easy to learn.

This article is part of the Theo Murphy meeting issue ‘Memory reactivation: replaying events past, present and future’.
Neural ensemble reactivation in rapid eye movement and slow-wave sleep coordinate with muscle activity to promote rapid motor skill learning
Authors: Eckert M. J. , McNaughton B. L. , Tatsuno M.
Published: April 2020

Neural activity patterns of recent experiences are reactivated during sleep in structures critical for memory storage, including hippocampus and neocortex. This reactivation process is thought to aid memory consolidation. Although synaptic rearrangement dynamics following learning involve an interplay between slow-wave sleep (SWS) and rapid eye movement (REM) sleep, most physiological evidence implicates SWS directly following experience as a preferred window for reactivation. Here, we show that reactivation occurs in both REM and SWS and that coordination of REM and SWS activation on the same day is associated with rapid learning of a motor skill. We performed 6 h recordings from cells in rats' motor cortex as they were trained daily on a skilled reaching task. In addition to SWS following training, reactivation occurred in REM, primarily during the pre-task rest period, and REM and SWS reactivation occurred on the same day in rats that acquired the skill rapidly. Both pre-task REM and post-task SWS activation were coordinated with muscle activity during sleep, suggesting a functional role for reactivation in skill learning. Our results provide the first demonstration that reactivation in REM sleep occurs during motor skill learning and that coordinated reactivation in both sleep states on the same day, although at different times, is beneficial for skill learning.

This article is part of the Theo Murphy meeting issue ‘Memory reactivation: replaying events past, present and future’.