Distinct information conveyed to the olfactory bulb by feedforward input from the nose and feedback from the cortex.

Sensory systems are organized hierarchically, but feedback projections frequently disrupt this order. In the olfactory bulb (OB), cortical feedback projections numerically match sensory inputs. To unravel information carried by these two streams, we imaged the activity of olfactory sensory neurons (OSNs) and cortical axons in the mouse OB using calcium indicators, multiphoton microscopy, and diverse olfactory stimuli. Here, we show that odorant mixtures of increasing complexity evoke progressively denser OSN activity, yet cortical feedback activity is of similar sparsity for all stimuli. Also, representations of complex mixtures are similar in OSNs but are decorrelated in cortical axons. While OSN responses to increasing odorant concentrations exhibit a sigmoidal relationship, cortical axonal responses are complex and nonmonotonic, which can be explained by a model with activity-dependent feedback inhibition in the cortex. Our study indicates that early-stage olfactory circuits have access to local feedforward signals and global, efficiently formatted information about odor scenes through cortical feedback.

Sticky issues in turbulent transport.

We investigate the role of partial stickiness among particles or with a surface for turbulent transport. For the former case, we re-derive known results for the case of the compressible Kraichnan model by using a method based on bi-orthogonality for the expansion of the propagator in terms of left and right eigenvectors. In particular, we show that enforcing the constraints of orthogonality and normalization yields results that were previously obtained by a rigorous, yet possibly less intuitive method. For the latter case, we introduce a general model of transport within the atmospheric boundary layer. As suggested by experimental observations on the transport of atmospheric tracers, both drift and diffusivity scale with the height to the ground. The strength of the drift is parameterized by a velocity V. We use the bi-orthogonality method to show that for V in the range -1 < V < 0 and 0 < V < 1 there is a one-parameter family of boundary conditions that are a priori admissible. Outside of that range, there is a single boundary condition that is admissible. In physical terms, the one-parameter family is parametrized by the degree to which particles stick to the ground.

Adaptive algorithms for shaping behavior.

Dogs and laboratory mice are commonly trained to perform complex tasks by guiding them through a curriculum of simpler tasks ('shaping'). What are the principles behind effective shaping strategies? Here, we propose a machine learning framework for shaping animal behavior, where an autonomous teacher agent decides its student's task based on the student's transcript of successes and failures on previously assigned tasks. Using autonomous teachers that plan a curriculum in a common sequence learning task, we show that near-optimal shaping algorithms adaptively alternate between simpler and harder tasks to carefully balance reinforcement and extinction. Based on this intuition, we derive an adaptive shaping heuristic with minimal parameters, which we show is near-optimal on the sequence learning task and robustly trains deep reinforcement learning agents on navigation tasks that involve sparse, delayed rewards. Extensions to continuous curricula are explored. Our work provides a starting point towards a general computational framework for shaping animal behavior.

Inferring sparse structure in genotype-phenotype maps.

Correlation among multiple phenotypes across related individuals may reflect some pattern of shared genetic architecture: individual genetic loci affect multiple phenotypes (an effect known as pleiotropy), creating observable relationships between phenotypes. A natural hypothesis is that pleiotropic effects reflect a relatively small set of common "core" cellular processes: each genetic locus affects one or a few core processes, and these core processes in turn determine the observed phenotypes. Here, we propose a method to infer such structure in genotype-phenotype data. Our approach, sparse structure discovery (SSD) is based on a penalized matrix decomposition designed to identify latent structure that is low-dimensional (many fewer core processes than phenotypes and genetic loci), locus-sparse (each locus affects few core processes), and/or phenotype-sparse (each phenotype is influenced by few core processes). Our use of sparsity as a guide in the matrix decomposition is motivated by the results of a novel empirical test indicating evidence of sparse structure in several recent genotype-phenotype datasets. First, we use synthetic data to show that our SSD approach can accurately recover core processes if each genetic locus affects few core processes or if each phenotype is affected by few core processes. Next, we apply the method to three datasets spanning adaptive mutations in yeast, genotoxin robustness assay in human cell lines, and genetic loci identified from a yeast cross, and evaluate the biological plausibility of the core process identified. More generally, we propose sparsity as a guiding prior for resolving latent structure in empirical genotype-phenotype maps.

Epistasis and evolution: recent advances and an outlook for prediction.

As organisms evolve, the effects of mutations change as a result of epistatic interactions with other mutations accumulated along the line of descent. This can lead to shifts in adaptability or robustness that ultimately shape subsequent evolution. Here, we review recent advances in measuring, modeling, and predicting epistasis along evolutionary trajectories, both in microbial cells and single proteins. We focus on simple patterns of global epistasis that emerge in this data, in which the effects of mutations can be predicted by a small number of variables. The emergence of these patterns offers promise for efforts to model epistasis and predict evolution.

A reinforcement-based mechanism for discontinuous learning.

Problem-solving and reasoning involve mental exploration and navigation in sparse relational spaces. A physical analogue is spatial navigation in structured environments such as a network of burrows. Recent experiments with mice navigating a labyrinth show a sharp discontinuity during learning, corresponding to a distinct moment of "sudden insight" when mice figure out long, direct paths to the goal. This discontinuity is seemingly at odds with reinforcement learning (RL), which involves a gradual build-up of a value signal during learning. Here, we show that biologically plausible RL rules combined with persistent exploration generically exhibit discontinuous learning. In tree-like structured environments, positive feedback from learning on behavior generates a "reinforcement wave" with a steep profile. The discontinuity occurs when the wave reaches the starting point. By examining the nonlinear dynamics of reinforcement propagation, we establish a quantitative relationship between the learning rule, the agent's exploration biases, and learning speed. Predictions explain existing data and motivate specific experiments to isolate the phenomenon. Additionally, we characterize the exact learning dynamics of various RL rules for a complex sequential task.

Outcomes of Allograft Medial Patellofemoral Ligament Reconstruction in Children and Adolescents with Hypermobility.

Introduction: Medial patellofemoral ligament (MPFL) reconstruction is used to treat patellofemoral instability either in isolation or in combination with other procedures. Use of allograft can preserve native tissue in children and can be advantageous in patients with connective tissue disorders, including ligamentous laxity. There is limited evidence regarding functional outcomes of allograft MPFL reconstruction in children and adolescents. This study aimed to assess the short to mid-term results of allograft MPFL reconstruction in children with hypermobility at a tertiary pediatric orthopedic center. Materials and Methods: We retrospectively reviewed all children and adolescents who had undergone allograft MPFL reconstruction over 4 years. The primary outcome measure was the validated Kujala score for patellofemoral disorders. The secondary outcome measures included complications such as redislocation of the patella needing revision surgery. Patients with hypermobility were quantified using Beighton criteria. Statistical analysis was performed using Graph Pad Prism (V6). Results: Between 2012 and 2016, the senior author performed 76 allograft MPFL reconstructions in 57 patients. Nineteen patients had bilateral surgery. The mean age was 14 (7-16) years with a female: male ratio of 3:1. The mean Beighton score was 7. Hypermobility was part of a syndrome in ten patients. The mean follow-up was 3 (1-4) years. Nine patients had trochleoplasty and six patients had tibial tubercle osteotomy, in addition to allograft MPFL reconstruction. These fifteen patients, who had additional procedures, were excluded during the analysis of the outcome measures. The mean Kujala score was 89 (80-100). The overall complication rate was 11% (9/76). These included two patella fractures and seven (9%) patients with recurrent instability needing revision surgery. There was no significant difference in complication rates between syndromic and nonsyndromic patients (P = 0.9). Conclusion: Our study shows excellent short to mid-term functional outcomes of allograft MPFL reconstruction in children and adolescents with hypermobility.

Alternation emerges as a multi-modal strategy for turbulent odor navigation.

Foraging mammals exhibit a familiar yet poorly characterized phenomenon, 'alternation', a pause to sniff in the air preceded by the animal rearing on its hind legs or raising its head. Rodents spontaneously alternate in the presence of airflow, suggesting that alternation serves an important role during plume-tracking. To test this hypothesis, we combine fully resolved simulations of turbulent odor transport and Bellman optimization methods for decision-making under partial observability. We show that an agent trained to minimize search time in a realistic odor plume exhibits extensive alternation together with the characteristic cast-and-surge behavior observed in insects. Alternation is linked with casting and occurs more frequently far downwind of the source, where the likelihood of detecting airborne cues is higher relative to ground cues. Casting and alternation emerge as complementary tools for effective exploration with sparse cues. A model based on marginal value theory captures the interplay between casting, surging, and alternation.

Sector search strategies for odor trail tracking.

Ants, mice, and dogs often use surface-bound scent trails to establish navigation routes or to find food and mates, yet their tracking strategies remain poorly understood. Chemotaxis-based strategies cannot explain casting, a characteristic sequence of wide oscillations with increasing amplitude performed upon sustained loss of contact with the trail. We propose that tracking animals have an intrinsic, geometric notion of continuity, allowing them to exploit past contacts with the trail to form an estimate of where it is headed. This estimate and its uncertainty form an angular sector, and the emergent search patterns resemble a "sector search." Reinforcement learning agents trained to execute a sector search recapitulate the various phases of experimentally observed tracking behavior. We use ideas from polymer physics to formulate a statistical description of trails and show that search geometry imposes basic limits on how quickly animals can track trails. By formulating trail tracking as a Bellman-type sequential optimization problem, we quantify the geometric elements of optimal sector search strategy, effectively explaining why and when casting is necessary. We propose a set of experiments to infer how tracking animals acquire, integrate, and respond to past information on the tracked trail. More generally, we define navigational strategies relevant for animals and biomimetic robots and formulate trail tracking as a behavioral paradigm for learning, memory, and planning.

A lexical approach for identifying behavioural action sequences.

Animals display characteristic behavioural patterns when performing a task, such as the spiraling of a soaring bird or the surge-and-cast of a male moth searching for a female. Identifying such recurring sequences occurring rarely in noisy behavioural data is key to understanding the behavioural response to a distributed stimulus in unrestrained animals. Existing models seek to describe the dynamics of behaviour or segment individual locomotor episodes rather than to identify the rare and transient sequences of locomotor episodes that make up the behavioural response. To fill this gap, we develop a lexical, hierarchical model of behaviour. We designed an unsupervised algorithm called "BASS" to efficiently identify and segment recurring behavioural action sequences transiently occurring in long behavioural recordings. When applied to navigating larval zebrafish, BASS extracts a dictionary of remarkably long, non-Markovian sequences consisting of repeats and mixtures of slow forward and turn bouts. Applied to a novel chemotaxis assay, BASS uncovers chemotactic strategies deployed by zebrafish to avoid aversive cues consisting of sequences of fast large-angle turns and burst swims. In a simulated dataset of soaring gliders climbing thermals, BASS finds the spiraling patterns characteristic of soaring behaviour. In both cases, BASS succeeds in identifying rare action sequences in the behaviour deployed by freely moving animals. BASS can be easily incorporated into the pipelines of existing behavioural analyses across diverse species, and even more broadly used as a generic algorithm for pattern recognition in low-dimensional sequential data.

Global epistasis emerges from a generic model of a complex trait.

Epistasis between mutations can make adaptation contingent on evolutionary history. Yet despite widespread 'microscopic' epistasis between the mutations involved, microbial evolution experiments show consistent patterns of fitness increase between replicate lines. Recent work shows that this consistency is driven in part by global patterns of diminishing-returns and increasing-costs epistasis, which make mutations systematically less beneficial (or more deleterious) on fitter genetic backgrounds. However, the origin of this 'global' epistasis remains unknown. Here, we show that diminishing-returns and increasing-costs epistasis emerge generically as a consequence of pervasive microscopic epistasis. Our model predicts a specific quantitative relationship between the magnitude of global epistasis and the stochastic effects of microscopic epistasis, which we confirm by reanalyzing existing data. We further show that the distribution of fitness effects takes on a universal form when epistasis is widespread and introduce a novel fitness landscape model to show how phenotypic evolution can be repeatable despite sequence-level stochasticity.

Coronavirus infection in hip fractures (CHIP) study.

AIMS: Despite the COVID-19 pandemic, incidence of hip fracture has not changed. Evidence has shown increased mortality rates associated with COVID-19 infection. However, little is known about the outcomes of COVID-19 negative patients in a pandemic environment. In addition, the impact of vitamin D levels on mortality in COVID-19 hip fracture patients has yet to be determined. METHODS: This multicentre observational study included 1,633 patients who sustained a hip fracture across nine hospital trusts in North West England. Data were collected for three months from March 2020 and for the same period in 2019. Patients were matched by Nottingham Hip Fracture Score (NHFS), hospital, and fracture type. We looked at the mortality outcomes of COVID-19 positive and COVID-19 negative patients sustaining a hip fracture. We also looked to see if vitamin D levels had an impact on mortality. RESULTS: The demographics of the 2019 and 2020 groups were similar, with a slight increase in proportion of male patients in the 2020 group. The 30-day mortality was 35.6% in COVID-19 positive patients and 7.8% in the COVID-19 negative patients. There was a potential association of decreasing vitamin D levels and increasing mortality rates for COVID-19 positive patients although our findings did not reach statistical significance. CONCLUSION: In 2020 there was a significant increase in 30-day mortality rates of patients who were COVID-19 positive but not of patients who were COVID-19 negative. Low levels of vitamin D may be associated with high mortality rates in COVID-19 positive patients. Cite this article: Bone Joint J 2021;103-B(4):782-787.

Antagonistic odor interactions in olfactory sensory neurons are widespread in freely breathing mice.

Odor landscapes contain complex blends of molecules that each activate unique, overlapping populations of olfactory sensory neurons (OSNs). Despite the presence of hundreds of OSN subtypes in many animals, the overlapping nature of odor inputs may lead to saturation of neural responses at the early stages of stimulus encoding. Information loss due to saturation could be mitigated by normalizing mechanisms such as antagonism at the level of receptor-ligand interactions, whose existence and prevalence remains uncertain. By imaging OSN axon terminals in olfactory bulb glomeruli as well as OSN cell bodies within the olfactory epithelium in freely breathing mice, we find widespread antagonistic interactions in binary odor mixtures. In complex mixtures of up to 12 odorants, antagonistic interactions are stronger and more prevalent with increasing mixture complexity. Therefore, antagonism is a common feature of odor mixture encoding in OSNs and helps in normalizing activity to reduce saturation and increase information transfer.

Odorant Receptor Inhibition Is Fundamental to Odor Encoding.

Most natural odors are complex mixtures of volatile components, competing to bind odorant receptors (ORs) expressed in olfactory sensory neurons (OSNs) of the nose. To date, surprisingly little is known about how OR antagonism shapes neuronal representations in the detection layer of the olfactory system. Here, we investigated its prevalence, the degree to which it disrupts OR ensemble activity, and its conservation across phylogenetically related ORs. Calcium imaging microscopy of dissociated OSNs revealed significant inhibition, often complete attenuation, of responses to indole-a commonly occurring volatile associated with both floral and fecal odors-by a set of 36 tested odorants. To confirm an OR mechanism for the observed inhibition, we performed single-cell transcriptomics on OSNs exhibiting specific response profiles to a diagnostic panel of odorants and identified three paralogous receptors-Olfr740, Olfr741, and Olfr743-which, when tested in vitro, recapitulated OSN responses. We screened ten ORs from the Olfr740 gene family with ∼800 perfumery-related odorants spanning a range of chemical scaffolds and functional groups. Over half of these compounds (430) antagonized at least one of the ten ORs. OR activity fitted a mathematical model of competitive receptor binding and suggests normalization of OSN ensemble responses to odorant mixtures is the rule rather than the exception. In summary, we observed OR antagonism occurred frequently and in a combinatorial manner. Thus, extensive receptor-mediated computation of mixture information appears to occur in the olfactory epithelium prior to transmission of odor information to the olfactory bulb.

Can the Surgical Approach to Total Knee Arthroplasty Influence Early Postoperative Outcomes? - A Comparative Study between Trivector and Medial Parapatellar Approaches.

BACKGROUND: Trivector approach to total knee arthroplasty (TKA) is a quadriceps tendon sparing approach, whereas the medial parapatellar (MPP) approach involves making a longitudinal incision in quadriceps tendon. We postulated that quadriceps-sparing approach such as trivector should make postoperative rehabilitation easier and ultimately reduce the length of hospital stay. OBJECTIVES: The aim of the study is to compare the early postoperative outcomes of the TKA performed through the trivector and the MPP approaches. METHODOLOGY: We prospectively reviewed the results of 56 consecutive patients operated on by two knee surgeons: one routinely performs trivector and the other an MPP approach. Both the groups consisted of 28 patients each. We looked at operative times, the time taken to perform straight leg raise (SLR), range of movements achieved before discharge, and length of the hospital stay. RESULTS: The mean time taken for performing the surgery through the MPP approach was 56 min, whereas, for the trivector approach, it was 54 min (P = 0.31). The mean time taken to perform SLR in the MPP approach group was 3.5 days, whereas in the trivector group, the meantime taken for SLR was 2.5 days (P = 0.003). The average extension at the time of discharge in the MPP group was 3.8°, and in the trivector group, it was 0.86° (P = 0.007). The average knee flexion at the time of discharge in the MPP group was 84.2°, whereas in the trivector group, it was 86.5° (P = 0.199). The average hospital stay in the MPP group was 5.96 days, whereas in the trivector group, it was 4.84 days (P = 0.11). CONCLUSIONS: The trivector approach patients took significantly less time to do SLR and achieved a better range of extension before discharge from the hospital. The patients with trivector approach were discharged early by one day, although it is not statistically significant, it is clinically significant.

Novel Antegrade Approach to Transcatheter Aortic Valve Paravalvular Leak Closure.

Aortic paravalvular leak (PVL) is a known complication of TAVR. PVL closure using vascular occluder devices can be used, particularly in cases with annular calcification preventing adequate seal; however, delivery of equipment can be challenging in TAVR patients due to interaction with the valve stent. We describe a novel antegrade closure approach to treat transcatheter aortic PVL.

Receptor crosstalk improves concentration sensing of multiple ligands.

Cells need to reliably sense external ligand concentrations to achieve various biological functions such as chemotaxis or signaling. The molecular recognition of ligands by surface receptors is degenerate in many systems, leading to crosstalk between ligand-receptor pairs. Crosstalk is often thought of as a deviation from optimal specific recognition, as the binding of noncognate ligands can interfere with the detection of the receptor's cognate ligand, possibly leading to a false triggering of a downstream signaling pathway. Here we quantify the optimal precision of sensing the concentrations of multiple ligands by a collection of promiscuous receptors. We demonstrate that crosstalk can improve precision in concentration sensing and discrimination tasks. To achieve superior precision, the additional information about ligand concentrations contained in short binding events of the noncognate ligand should be exploited. We present a proofreading scheme to realize an approximate estimation of multiple ligand concentrations that reaches a precision close to the derived optimal bounds. Our results help rationalize the observed ubiquity of receptor crosstalk in molecular sensing.

Outcomes of Intramedullary Nailing with Cerclage Wiring in Subtrochanteric Femoral Fractures.

AIMS: The aim of this study was to compare the outcomes of closed reduction against open reduction with cerclage wires in patients with subtrochanteric fractures treated with intramedullary nailing (IMN). MATERIALS AND METHODS: We identified 141 patients who had an IMN over a 4-year period. They were classified into three groups based on fracture pattern and whether open or closed reduction was performed. Type I was a transverse fracture, type II, a spiral fracture with an intact posterior and medial wall in the proximal fragment, and a type III fracture without intact posterior or medial walls. The primary outcome measure was a revision surgery for implant failure. Secondary outcome measures were related to fracture reduction and radiological union scores of the hip (RUSH). RESULTS: There were 35 patients who had a type I fracture, 26 patients with a type II fracture, and 80 patients with a type III fracture. The mean follow-up was 7 months. Closed reduction in type III fractures was associated with a significantly increased risk of mechanical complications (p = 0.005) and unplanned returns to theatre for implant failure (p = 0.04) as compared to open reduction. Open reduction in type III fractures was associated with a significantly higher mean RUSH scores (p = 0.0006). There was no significant difference in mean operative time between open and closed reduction in type III fractures (p = 0.12). CONCLUSION: We recommend open reduction with cerclage wiring in type III subtrochanteric fractures in order to reduce the risk of implant failure, nonunion, and need for further surgery. HOW TO CITE THIS ARTICLE: Mehta NJ, Goldsmith T, Lacey A, et al. Outcomes of Intramedullary Nailing with Cerclage Wiring in Subtrochanteric Femoral Fractures. Strategies Trauma Limb Reconstr 2019;14(1):29-33.