bluuebunny/crossref_metadata_2025 huggingface dataset:
Correlation of Macular Sparing and Homonymous Paracentral Scotomas With MRI Lesions in Posterior Cerebral Artery Infarction
Authors: Cho Juno , Liao Eric , Trobe Jonathan D.
Published: June 2022

Background:

The concepts of the representation of visual field in primary visual cortex are based on studies of war wounds and correlations with brain imaging in small cohorts. Because of the difficulty of judging brain lesion extent and the small number of studied patients, there is lingering controversy as to whether the central 15° of visual field are mapped onto the posterior 25% of primary visual cortex or onto a larger area. To improve the delineation of MRI lesion extent, we have studied only patients with posterior cerebral artery (PCA) ischemic strokes.

Methods:

We accrued a cohort of 92 patients with PCA strokes from an electronic medical records search between 2009 and 2020 at a single tertiary care academic institution. Patients had reliable static perimetry demonstrating homonymous hemianopias and high-definition reviewable brain imaging. We divided the primary visual cortex on the MRI T1 sagittal sequence into 8 equal segments in right and left cerebral hemispheres and located lesions according to the segments they occupied. We correlated lesion locations with 3 visual field defects (VFDs): macular-sparing homonymous quadrantanopias, macular-splitting homonymous quadrantanopias, and homonymous paracentral scotomas.

Results:

Among 25 cases with macular sparing, 13 had lesion-sparing confined to the posterior 25% of visual cortex. Among 6 cases with homonymous paracentral scotomas, 2 had lesions confined to the posterior 25% of visual cortex. Macular-splitting quadrantanopia did not occur in any patients with lesions confined to the posterior 25% of visual cortex, but did occur in 3 patients with lesions confined to the posterior 50% of visual cortex. These phenomena would not be expected if the central 15° of visual field were mapped onto a region extending beyond the posterior 25% of visual cortex. In patients with PCA strokes that involved the retrogeniculate visual pathway proximal to visual cortex, the visual cortex lesions were often less extensive than predicted by the VFDs, perhaps because of widespread damage to axons before they reached their destination in visual cortex.

Conclusions:

These results support the concept that the central 15° of the visual field are represented in the posterior 25% of visual cortex. Although this study contributes a larger cohort of patients with better-defined lesion borders than in past reports, its conclusions must be tempered by the variability of patient attention during visual field testing, the subjectivity in the interpretation of the defect patterns, and the difficulty in judging MRI lesion extent even on diffusion-weighted and precontrast T1 sagittal sequences.
Stapled Full-Thickness Diaphragm Resection: A Novel Approach to Diaphragmatic Resection in Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemotherapy
Authors: Hanna David N , Schlegel Cameron , Ghani Muhammad O , Hermina Andrew , S Mina Alexander , McKay Katlyn , Bailey Christina E , Magge Deepa , Idrees Kamran
Published: June 2022

Full-thickness diaphragm resection (FT-DR) during cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) is sometimes required to achieve a complete cytoreduction. It is conventionally performed with electrocautery with primary repair or mesh repair. FT-DR using a linear cutting stapler is a novel technique that avoids entry to the chest cavity and minimizes the use of electrocautery on the diaphragm. We performed an institutional retrospective review of a prospectively maintained database of 145 patients who underwent CRS-HIPEC between 2013 and 2019. Patients were divided into the Conventional or Stapled group based on the FT-DR approach indicated in the operative report. Of the 145 patients who underwent CRS-HIPEC, 27 underwent FT-DR, with 63% (n = 17) in the Stapled group. There were no significant demographic or oncologic differences between the 2 groups. Patients in the Stapled group underwent tube thoracostomy (13.3% vs 60%; p = 0.008), were diagnosed with pneumonia (12% vs 50%; p = 0.04), required reintubation (6% vs 40%; p = 0.03), and required mechanical ventilation more than 48 hours (6% vs 50%; p = 0.02) less frequently than the Conventional group. There was no difference in pleural recurrence between the 2 groups (Conventional 20% vs Stapled 12%, p = 0.56). Stapled full-thickness diaphragm resection is a novel approach to achieving a complete cytoreduction that excludes the pleural cavity, minimizes diaphragm manipulation, and is associated with improved postoperative pulmonary outcomes in patients undergoing CRS-HIPEC.
Proxy Detection of Resident Burnout by Program Directors and Domestic Partners
Authors: Esposito Andrew C , White Erin M , Coppersmith Nathan A , Huot Stephen J , Asnes Andrea G , Yoo Peter S , Solomon Daniel G
Published: June 2022

BACKGROUND:

Resident burnout is associated with increased incidence of depression, suicide, and poor patient outcomes, yet identification of it is difficult. This study was designed to compare how well program directors (directors) and a resident’s spouse or domestic partner (partner) can serve as a proxy to identify burnout in the resident.

STUDY DESIGN:

An electronic survey, including the Maslach Burnout Inventory, was distributed to residents, their partners, and directors of all ACGME-accredited residencies at a single university-affiliated hospital. Burnout rates were compared with McNemar’s test. Emotional exhaustion and depersonalization rates were compared with Spearman’s correlation.

RESULTS:

The response rate by respondent type was 33% (292 of 876) for residents, 48% (55 of 114) for partners, and 57% (13 of 23) for directors. Residents’ self-reported burnout rate was 51% (148 of 292), while partners’ proxy predicted burnout rate was 25% (14 of 55), and directors’ was 5% (9 of 174). There was moderate correlation of partners’ prediction of resident emotional exhaustion (ρ = 0.537, p < 0.01), depersonalization (ρ = 0.501, p < 0.01), and personal accomplishment (ρ = 0.416, p < 0.01). There was poor correlation of directors’ prediction of residents’ emotional exhaustion (ρ = 0.361, p < 0.01) and depersonalization (ρ = 0.223, p < 0.01). Partners had a 50% sensitivity, 94% specificity, 86% positive predictive value, and 71% negative predictive value in predicting resident burnout. Directors had a 6% sensitivity, 96% specificity, 56% positive predictive value, and 54% negative predictive value in predicting resident burnout.

CONCLUSIONS:

Directors are not skilled in detecting burnout in their trainees. Partners are an underused group for detecting burnout and may represent an important target audience for awareness of available resources to benefit residents.
Have Factors Influencing Female Medical Students’ Intention to Pursue a Career in Surgery Changed over the Last 10 Years? A Systematic Review
Authors: Mauiliu-Wallis Melbourne C , Park Brittany , Hill Andrew G , Jin James Z , Unasa Hanson , Locke Michelle
Published: June 2022

In 2012, a systematic review reported on factors influencing female medical students, career intentions for surgery. This current review is a direct follow-up of that article with the aim of assessing whether factors affecting female medical student career choices have changed over the last decade. This review has identified access to research opportunities as a new factor that can be used to promote female medical student and trainee interest in surgery. Other factors have largely remained unchanged over the last 10 years, such as lack of access to leave, part-time work, and same-gender role models.
Round Ligament Management in Female Patients Undergoing Inguinal Hernia Repair: Should We Divide or Preserve?
Authors: Renshaw Savannah , Collins Courtney , Gupta Anand , Poulose Benjamin , Haisley Kelly R
Published: June 2022

BACKGROUND:

Although inguinal hernia repair in female patients is less common than in male patients, it remains a frequent procedure. The decision to divide or preserve the round ligament has largely been left to surgeon preference, but little data exists about its impact on outcomes. This study aimed to describe current practices for round ligament management and identify the impact of division on surgical and patient-reported outcomes.

STUDY DESIGN:

The 2013 to 2021 Abdominal Core Health Quality Collaborative database was queried for all female patients undergoing inguinal hernia repair with 30-day patient-reported outcome data available. Comparison groups were created based on round ligament management: round ligament division (RLD) or round ligament preservation (RLP).

RESULTS:

We identified 1365 female patients who underwent open (36.3%), laparoscopic (34.5%), or robotic (28.2%) repair. Most were non-recurrent (93%) and unilateral (82.6%). The round ligament was divided in 868 (63.6%) and preserved in 497 (36.4%) cases. There were no significant differences in overall complications (RLD 7.1%, RLP 5.2%, p = 0.17), reoperation (RLD 0.5%, RLP 0.2%, p = 0.4), or recurrence (RLD 0.1%, RLP 0.4%, p = 0.28). Mean European Registry for Abdominal Wall Hernias quality of life summary scores were not significantly different at 30 days (RLD 27.2, RLP 27.8) or 6 months (RLD 12.8, RLP 17.1). However, a significant difference was found in terms of mean pain-specific scores at 6 months, with lower pain scores in the RLD group (3 vs 4.7, p < 0.01), which persisted on multivariable analysis (p = 0.02).

CONCLUSIONS:

RLD is a common practice and is not associated with increased complications or recurrence. Although there is some evidence that RLD may result in decreased pain at 6 months, this must be balanced with potential functional complications of division that are not fully studied in this paper.
Colorectal Liver Micrometastases: Association with RAS/TP53 Co-Mutation and Prognosis after Surgery
Authors: Chun Yun Shin , Passot Guillaume , Nishioka Yujiro , Katkhuda Riham , Arvide Elsa M , Benzerdjeb Nazim , Lopez Jonathan , Kopetz Scott E , Maru Dipen M , Vauthey Jean-Nicolas
Published: June 2022

BACKGROUND:

Micrometastases, defined as microscopic cancer cells spatially separated from the macroscopically evident metastasis, are identified in 24% to 56% of resected colorectal liver metastases (CLMs). Somatic gene mutations have emerged as independent prognostic factors in CLM. This study aimed to determine the prognostic impact and risk factors for the presence of micrometastases, including somatic gene mutations.

STUDY DESIGN:

Prospective evaluation for micrometastases was performed at 2 centers in the US and France from 2015 to 2019. CLM specimens were cut radially from the tumor margin to surrounding grossly normal liver for a distance of 2 cm. Depending on CLM size, 3 to 8 specimens per patient were submitted for microscopic analysis. Somatic gene mutations were detected by next-generation sequencing.

RESULTS:

Among 140 patients undergoing CLM resection in the US (n = 84) and France (n = 56), 36 (26%) patients were found to have micrometastases. Five-year overall and recurrence-free survival rates with micrometastases were 39% and 0%, respectively, compared with 61% and 20% without micrometastases (both p < 0.05). In multivariable analyses, the presence of micrometastases was an independent risk factor for worse overall survival (hazard ratio 2.88, 95% CI 1.46 to 5.70, p = 0.002) and recurrence-free survival (hazard ratio 1.56, 95% CI 1.01 to 2.41, p = 0.046). In binary logistic regression analysis, RAS/TP53 co-mutation was found to significantly increase the risk of micrometastases (odds ratio 2.77, 95% CI 1.15 to 6.71, p = 0.024).

CONCLUSIONS:

Micrometastases are associated with significantly worse survival after CLM resection. RAS/TP53 co-mutation correlated with increased risk of micrometastases. Further studies are needed to determine strategies to eradicate micrometastases.
A Rising Tide Lifts All Boats: Impact of Combined Volume of Complex Cancer Operations on Surgical Outcomes in a Low-Volume Setting
Authors: de Geus Susanna WL , Papageorge Marianna V , Woods Alison P , Wilson Spencer , Ng Sing Chau , Merrill Andrea , Cassidy Michael , McAneny David , Tseng Jennifer F , Sachs Teviah E
Published: June 2022

BACKGROUND:

Centralization for complex cancer surgery may not always be feasible owing to socioeconomic disparities, geographic constraints, or patient preference. The present study investigates how the combined volume of complex cancer operations impacts postoperative outcomes at hospitals that are low-volume for a specific high-risk cancer operation.

STUDY DESIGN:

Patients who underwent pneumonectomy, esophagectomy, gastrectomy, hepatectomy, pancreatectomy, or proctectomy were identified from the National Cancer Database (2004–2017). For every operation, 3 separate cohorts were created: low-volume hospitals (LVH) for both the individual cancer operation and the total number of those complex operations, mixed-volume hospital (MVH) with low volume for the individual cancer operation but high volume for total number of complex operations, and high-volume hospitals (HVH) for each specific operation.

RESULTS:

LVH was significantly (all p ≤ 0.01) predictive for 30-day mortality compared with HVH across all operations: pneumonectomy (9.5% vs 7.9%), esophagectomy (5.6% vs 3.2%), gastrectomy (6.8% vs 3.6%), hepatectomy (5.9% vs 3.2%), pancreatectomy (4.7% vs 2.3%), and proctectomy (2.4% vs 1.3%). Patients who underwent surgery at MVH and HVH demonstrated similar 30-day mortality: esophagectomy (3.2 vs 3.2%; p = 0.993), gastrectomy (3.2% vs 3.6%; p = 0.637), hepatectomy (3.8% vs 3.2%; p = 0.233), pancreatectomy (2.8% vs 2.3%; p = 0.293), and proctectomy (1.2% vs 1.3%; p = 0.843). Patients who underwent pneumonectomy at MVH demonstrated lower 30-day mortality compared with HVH (5.4% vs 7.9%; p = 0.045).

CONCLUSION:

Patients who underwent complex operations at MVH had similar postoperative outcomes to those at HVH. MVH provide a model for the centralization of complex cancer surgery for patients who do not receive their care at HVH.
Effect of Delay and Disruption in Venous Thromboembolism Prophylaxis in Trauma Patients: Case-Control Study
Authors: Falksen Jessica A , Duby Jeremiah J , Wilson Machelle D , Fine Jeffrey R , Cocanour Christine S
Published: June 2022

BACKGROUND:

Trauma patients are at high risk for venous thromboembolism (VTE) and bleeding. The purpose of this study was to characterize percentage of VTE chemoprophylaxis given to trauma patients with and without a VTE.

STUDY DESIGN:

This retrospective case–control study evaluated trauma patients admitted to a Level I trauma center. Adult patients were included when hospitalized at least 2 days and had a head abbreviated injury score of 1 or less. Non-VTE patients were matched by decade of life and injury severity score (ISS). The primary outcome was percentage of VTE chemoprophylaxis received over the first 14 days of admission. Descriptive statistics, chi-squared test, Student’s t-test, and Cox proportional hazard were used for analysis.

RESULTS:

A total of 44 VTE patients were included with 125 matched non-VTE patients. Baseline demographics included age in years (50.7 ± 19.6 vs 49.6 ± 19.4), ISS (18.9 ± 11.3 vs 19 ± 11.6), and lower extremity fracture (54.5% vs 40%), for VTE and non-VTE groups, respectively. The primary outcome of VTE chemoprophylaxis doses given was significantly lower for VTE patients than non-VTE patients (49.3% vs 59.3%, p = 0.0069). Significant predictors of VTE were percentage of VTE chemoprophylaxis doses given (p < 0.0001) and weight (p = 0.0042) based on regression analysis. Notably, there was a 7% decrease in the hazard for VTE for every 1% increase in VTE chemoprophylaxis given.

CONCLUSIONS:

Patients who developed VTE were more likely to have delays and disruptions in VTE chemoprophylaxis, even after controlling for age, sex, ISS, lower extremity fractures, and number of operations.
Multidomain interventions for risk reduction and prevention of cognitive decline and dementia: current developments
Authors: Röhr Susanne , Kivipelto Miia , Mangialasche Francesca , Ngandu Tiia , Riedel-Heller Steffi G.
Published: June 2022

Purpose of review

The potential for dementia prevention is deemed substantial if modifiable risk factors were addressed. First large-scale multidomain lifestyle interventions aiming at reducing risk of cognitive decline and dementia have yielded mixed but promising evidence.

Recent findings

Despite the impact of the COVID-19 pandemic on trials conduction, causing interruptions and delays, the research landscape on multidomain interventions is growing rapidly. The successful Finish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) has led to an adaptation of the FINGER model in trials underway or being planned in over 40 countries. Recent studies identified barriers and facilitators of and adherence to multidomain interventions, showed the suitability of dementia risk scores as surrogate outcomes, and suggested mechanisms. Multidomain interventions are increasingly conducted in the Global South, and study protocols are increasingly testing expanded FINGER models, for example, with pharmacological components, in digital/remote settings and co-designed personalized interventions.

Though results remain mixed, the many ongoing trials will provide more conclusive evidence within the next few years and help to optimize interventions. Continued international collaboration is pivotal to scale and accelerate the development and implementation of effective multidomain interventions as part of larger public health strategies to counteract the global dementia increase.
Electroconvulsive Therapy in Children and Adolescents in Germany—A Case Series From 3 University Hospitals
Authors: Karl Sebastian , Methfessel Isabel , Weirich Steffen , Rothermel Boris , Crozier Jesse , Besse Matthias , Reinhardt Martin , Buchmann Johannes , Dück Alexander , Schulz Jan , Zilles-Wegner David , Häßler Frank , Kölch Michael , Uebel von Sandersleben Henrik , Poustka Luise , Sartorius Alexander
Published: June 2022

Objective

Electroconvulsive therapy (ECT) is a well-established, safe, and efficacious treatment for severe psychiatric disorders. In children and adolescents, it is used much less frequently than in adults, likely because of a lack of knowledge.

Methods

We retrospectively analyzed all patients aged 12 to 17 years who completed a course of ECT at 3 psychiatric university hospitals in Germany between 2010 and 2020. Clinical Global Impression Severity (CGI-S) scores were assessed based on electronic medical records. Changes in CGI-S scores were assessed using a paired samples t test. Predictors for response and remission were assessed using binomial logistic regression.

Results

We included 32 patients. The CGI-S scores improved significantly from before to after ECT treatment (6.9 vs 3.9, t = 10.0, P < 0.01). A total of 40.6% of patients responded (CGI ≤ 3) and 21.9% remitted (CGI ≤ 2). The number of ineffective medication trials in the 6 months before ECT treatment was significantly associated with response (odds ratio, 0.54; P = 0.028) and remission (odds ratio, 0.31; P = 0.048). Five patients reported subjective cognitive adverse effects, 2 patients exhibited a prolonged seizure, 1 patient reported headaches, and 1 patient experienced a mild allergic reaction after anesthesia with etomidate. A total of 65.6% of patients experienced no adverse effects at all.

Conclusions

This retrospective analysis found ECT to be effective and safe in children and adolescents irrespective of their main diagnosis. The reported data point to the importance of an early use of ECT for severe psychiatric diseases in child and adolescent psychiatry.
Multi-functional topology optimization ofVictoria cruzianaveins
Authors: Zhang Hui-Kai , Zhou Jingyi , Fang Wei , Zhao Huichan , Zhao Zi-Long , Chen Xindong , Zhao Hong-Ping , Feng Xi-Qiao
Published: June 2022

The growth and development of biological tissues and organs strongly depend on the requirements of their multiple functions. Plant veins yield efficient nutrient transport and withstand various external loads.Victoria cruziana, a tropical species of the Nymphaeaceae family of water lilies, has evolved a network of three-dimensional and rugged veins, which yields a superior load-bearing capacity. However, it remains elusive how biological and mechanical factors affect their unique vein layout. In this paper, we propose a multi-functional and large-scale topology optimization method to investigate the morphomechanics ofVictoria cruzianaveins, which optimizes both the structural stiffness and nutrient transport efficiency. Our results suggest that increasing the branching order of radial veins improves the efficiency of nutrient delivery, and the gradient variation of circumferential vein sizes significantly contributes to the stiffness of the leaf. In the present method, we also consider the optimization of the wall thickness and the maximum layout distance of circumferential veins. Furthermore, biomimetic leaves are fabricated by using the three-dimensional printing technique to verify our theoretical findings. This work not only gains insights into the morphomechanics ofVictoria cruzianaveins, but also helps the design of, for example, rib-reinforced shells, slabs and dome skeletons.
MicroRNAs: master regulators in host–parasitic protist interactions
Authors: Rojas-Pirela Maura , Andrade-Alviárez Diego , Medina Lisvaneth , Castillo Christian , Liempi Ana , Guerrero-Muñoz Jesús , Ortega Yessica , Maya Juan Diego , Rojas Verónica , Quiñones Wilfredo , Michels Paul A. , Kemmerling Ulrike
Published: June 2022

MicroRNAs (miRNAs) are a group of small non-coding RNAs present in a wide diversity of organisms. MiRNAs regulate gene expression at a post-transcriptional level through their interaction with the 3′ untranslated regions of target mRNAs, inducing translational inhibition or mRNA destabilization and degradation. Thus, miRNAs regulate key biological processes, such as cell death, signal transduction, development, cellular proliferation and differentiation. The dysregulation of miRNAs biogenesis and function is related to the pathogenesis of diseases, including parasite infection. Moreover, during host–parasite interactions, parasites and host miRNAs determine the probability of infection and progression of the disease. The present review is focused on the possible role of miRNAs in the pathogenesis of diseases of clinical interest caused by parasitic protists. In addition, the potential role of miRNAs as targets for the design of drugs and diagnostic and prognostic markers of parasitic diseases is also discussed.
Evidence for active upper mantle flow in the Atlantic and Indo-Australian realms since the Upper Jurassic from hiatus maps and spreading rate changes
Authors: Vilacís Berta , Hayek Jorge N. , Stotz Ingo L. , Bunge Hans-Peter , Friedrich Anke M. , Carena Sara , Clark Stuart
Published: June 2022

Histories of large-scale horizontal and vertical lithosphere motion hold important information on mantle convection. Here, we compare continent-scale hiatus maps as a proxy for mantle flow induced dynamic topography and plate motion variations in the Atlantic and Indo-Australian realms since the Upper Jurassic, finding they frequently correlate, except when plate boundary forces may play a significant role. This correlation agrees with descriptions of asthenosphere flow beneath tectonic plates in terms of Poiseuille/Couette flow, as it explicitly relates plate motion changes, induced by evolving basal shear forces, to non-isostatic vertical motion of the lithosphere. Our analysis reveals a timescale, on the order of a geological series, between the occurrence of continent-scale hiatus and plate motion changes. This is consistent with the presence of a weak upper mantle. It also shows a spatial scale for interregional hiatus, on the order of 2000–3000 km in diameter, which can be linked by fluid dynamic analysis to active upper mantle flow regions. Our results suggest future studies should pursue large-scale horizontal and vertical lithosphere motion in combination, to track the expressions of past mantle flow. Such studies would provide powerful constraints for adjoint-based geodynamic inverse models of past mantle convection.
Stability selection enables robust learning of differential equations from limited noisy data
Authors: Maddu Suryanarayana , Cheeseman Bevan L. , Sbalzarini Ivo F. , Müller Christian L.
Published: June 2022

We present a statistical learning framework for robust identification of differential equations from noisy spatio-temporal data. We address two issues that have so far limited the application of such methods, namely their robustness against noise and the need for manual parameter tuning, by proposing stability-based model selection to determine the level of regularization required for reproducible inference. This avoids manual parameter tuning and improves robustness against noise in the data. Our stability selection approach, termed PDE-STRIDE, can be combined with any sparsity-promoting regression method and provides an interpretable criterion for model component importance. We show that the particular combination of stability selection with the iterative hard-thresholding algorithm from compressed sensing provides a fast and robust framework for equation inference that outperforms previous approaches with respect to accuracy, amount of data required, and robustness. We illustrate the performance of PDE-STRIDE on a range of simulated benchmark problems, and we demonstrate the applicability of PDE-STRIDE on real-world data by considering purely data-driven inference of the protein interaction network for embryonic polarization inCaenorhabditis elegans. Using fluorescence microscopy images ofC. eleganszygotes as input data, PDE-STRIDE is able to learn the molecular interactions of the proteins.
Effects of Lorentz symmetry breaking by a tensor field subject to Coulomb-type potential on relativistic quantum oscillator
Authors: Ahmed Faizuddin
Published: June 2022

In this paper, we solve the Klein–Gordon oscillator analytically under Lorentz-violating effects defined by a tensor field subject to a Coulomb-type scalar potential. We obtain the bound-state solutions of the quantum system by choosing various electromagnetic field configurations and discuss the effects on the energy profiles and the wave function of these oscillator fields.
Searching for a source without gradients: how good is infotaxis and how to beat it
Authors: Loisy Aurore , Eloy Christophe
Published: June 2022

Infotaxis is a popular search algorithm designed to track a source of odour in a turbulent environment using information provided by odour detections. To exemplify its capabilities, the source-tracking task was framed as a partially observable Markov decision process consisting in finding, as fast as possible, a stationary target hidden in a two-dimensional grid using stochastic partial observations of the target location. Here, we provide an extended review of infotaxis, together with a toolkit for devising better strategies. We first characterize the performance of infotaxis in domains from one dimension to four dimensions. Our results show that, while being suboptimal, infotaxis is reliable (the probability of not reaching the source approaches zero), efficient (the mean search time scales as expected for the optimal strategy) and safe (the tail of the distribution of search times decays faster than any power law, though subexponentially). We then present three possible ways of beating infotaxis, all inspired by methods used in artificial intelligence: tree search, heuristic approximation of the value function, and deep reinforcement learning. The latter is able to find, without any prior human knowledge, the (near) optimal strategy. Altogether, our results provide evidence that the margin of improvement of infotaxis towards the optimal strategy gets smaller as the dimensionality increases.
Extreme reproductive skew at the dawn of sociality is consistent with inclusive fitness theory but problematic for routes to eusociality
Authors: Hearn Lucas R. , Davies Olivia K. , Schwarz Michael P.
Published: June 2022

To understand the earliest stages of social evolution, we need to identify species that are undergoing the initial steps into sociality.
Amphylaeus morosus
is the only unambiguously known social species in the bee family Colletidae and represents an independent origin of sociality within the Apoidea. This allows us to investigate the selective factors promoting the transition from solitary to social nesting. Using genome-wide SNP genotyping, we infer robust pedigree relationships to identify maternity of brood and intracolony relatedness for colonies at the end of the reproductive season. We show that
A. morosus
forms both matrifilial and full-sibling colonies, both involving complete or almost complete monopolization over reproduction. In social colonies, the reproductive primary was also the primary forager with the secondary female remaining in the nest, presumably as a guard. Social nesting provided significant protection against parasitism and increased brood survivorship in general. We show that secondary females gain large indirect fitness benefits from defensive outcomes, enough to satisfy the conditions of inclusive fitness theory, despite an over-production of males in social colonies. These results suggest an avenue to sociality that involves high relatedness and, very surprisingly, extreme reproductive skew in its earliest stages and raises important questions about the evolutionary steps in pathways to eusociality.
Mechanical compensation in the evolution of the early hominin feeding apparatus
Authors: Ledogar Justin A. , Senck Sascha , Villmoare Brian A. , Smith Amanda L. , Weber Gerhard W. , Richmond Brian G. , Dechow Paul C. , Ross Callum F. , Grosse Ian R. , Wright Barth W. , Wang Qian , Byron Craig , Benazzi Stefano , Carlson Kristian J. , Carlson Keely B. , Pryor McIntosh Leslie C. , van Casteren Adam , Strait David S.
Published: June 2022

Australopiths, a group of hominins from the Plio-Pleistocene of Africa, are characterized by derived traits in their crania hypothesized to strengthen the facial skeleton against feeding loads and increase the efficiency of bite force production. The crania of robust australopiths are further thought to be stronger and more efficient than those of gracile australopiths. Results of prior mechanical analyses have been broadly consistent with this hypothesis, but here we show that the predictions of the hypothesis with respect to mechanical strength are not met: some gracile australopith crania are as strong as that of a robust australopith, and the strength of gracile australopith crania overlaps substantially with that of chimpanzee crania. We hypothesize that the evolution of cranial traits that increased the efficiency of bite force production in australopiths may have simultaneously weakened the face, leading to the compensatory evolution of additional traits that reinforced the facial skeleton. The evolution of facial form in early hominins can therefore be thought of as an interplay between the need to increase the efficiency of bite force production and the need to maintain the structural integrity of the face.
Eye-movement replay supports episodic remembering
Authors: Johansson Roger , Nyström Marcus , Dewhurst Richard , Johansson Mikael
Published: June 2022

When we bring to mind something we have seen before, our eyes spontaneously unfold in a sequential pattern strikingly similar to that made during the original encounter, even in the absence of supporting visual input. Oculomotor movements of the eye may then serve the opposite purpose of acquiring new visual information; they may serve as self-generated cues, pointing to stored memories. Over 50 years ago Donald Hebb, the forefather of cognitive neuroscience, posited that such a sequentialreplayof eye movements supports our ability to mentally recreate visuospatial relations during episodic remembering. However, direct evidence for this influential claim is lacking. Here we isolate the sequential properties of spontaneous eye movements during encoding and retrieval in a pure recall memory task and capture their encoding-retrieval overlap. Critically, we show that the fidelity with which a series of consecutive eye movements from initial encoding is sequentially retained during subsequent retrieval predicts the quality of the recalled memory. Our findings provide direct evidence that suchscanpathsare replayed to assemble and reconstruct spatio-temporal relations as we remember and further suggest that distinct scanpath properties differentially contribute depending on the nature of the goal-relevant memory.
Codon optimization, not gene content, predicts XYLose metabolism in budding yeasts
Authors: Nalabothu Rishitha L. , Fisher Kaitlin J. , LaBella Abigail Leavitt , Meyer Taylor A. , Opulente Dana A. , Wolters John F. , Rokas Antonis , Hittinger Chris Todd
Published: June 2022

Xylose is the second most abundant monomeric sugar in plant biomass. Consequently, xylose catabolism is an ecologically important trait for saprotrophic organisms, as well as a fundamentally important trait for industries that hope to convert plant mass to renewable fuels and other bioproducts using microbial metabolism. Although common across fungi, xylose catabolism is rare within Saccharomycotina, the subphylum that contains most industrially relevant fermentative yeast species. Several yeasts unable to consume xylose have been previously reported to possess complete predicted xylolytic metabolic pathways, suggesting the absence of a gene-trait correlation for xylose metabolism. Here, we measured growth on xylose and systematically identify XYL pathway orthologs across the genomes of 332 budding yeast species. We found that most yeast species possess complete predicted xylolytic pathways, but pathway presence did not correlate with xylose catabolism. We then quantified codon usage bias of XYL genes and found that codon optimization was higher in species able to consume xylose. Finally, we showed that codon optimization of XYL2, which encodes xylitol dehydrogenase, positively correlated with growth rates in xylose medium. We conclude that gene content cannot predict xylose metabolism; instead, codon optimization is now the best predictor of xylose metabolism from yeast genome sequence data.

Significance Statement

In the genomic era, strategies are needed for the prediction of metabolic traits from genomic data. Xylose metabolism is an industrially important trait, but it is not found in most yeast species heavily used in industry. Because xylose metabolism appears rare across budding yeasts, we sought to identify a computational means of predicting which species are capable of xylose catabolism. We did not find a relationship between gene content and xylose metabolism traits. Rather, we found that codon optimization of xylolytic genes was higher in species that can metabolize xylose, and that optimization of one specific gene correlated with xylose-specific growth rates. Thus, codon optimization is currently the only means of accurately predicting xylose metabolism from genome sequence data.
Distance-based global analysis of consistentcis-bonds in protein backbones
Authors: Okada Tetsuji , Tomoike Fumiaki
Published: June 2022

Biological polypeptides are known to containcis-linkage in their main chain as a minor but important feature. Such anomalous connection of amino acids has different structural and functional effects on proteins. Experimental evidence ofcis-bonds in proteins is mainly obtained using X-ray crystallography and other methods in the field of structural biology. To date, extensive analyses have been carried out on the experimentally foundcis-bonds using the Protein Data Bank entry bases and/or residue bases; however, their consistency in each protein has not been examined on a global scale. Data accumulation and advances in methodology enable the use of new approaches from a proteomic point of view. Here, we sought to describe a simple procedure for the detection and confirmation ofcis-bonds from a set of experimental coordinates for a protein to discriminate this type of bond from isomerizable and/or misassigned bonds. The resulting set of consistentcisbonds provides unprecedented insights into the trend of “highciscontent” proteins and the upper limit of consistentcisbonds per polypeptide length. Recognizing such limit would not only be important for a practical check of upcoming structures, but also for the design of novel protein folds beyond the evolutionally-acquired repertoire.
Technical Report on Ancient DNA analysis of 27 African Americans from Catoctin Furnace, Maryland
Authors: Harney Éadaoin , Olalde Iñigo , Bruwelheide Kari , Barca Kathryn G. , Curry Roslyn , Comer Elizabeth , Rohland Nadin , Owsley Douglas , Reich David
Published: June 2022

Catoctin Furnace is an industrial site that functioned from 1776–1903 and was operated at least partially by an enslaved workforce until about 1850, when it shifted to paid European laborers. A cemetery including 35 graves from which the remains of 32 individuals identified with African ancestry were excavated in 1979-1980 during construction of a highway that impacted the site. Since then, the human remains have been under the stewardship of the Smithsonian’s National Museum of Natural History (NMNH). The goal of this report is to document the successful generation of ancient DNA from 27 individuals from the cemetery. The analysis of the Catoctin individuals is part of a long-term study dedicated to restoring knowledge of the identity, origins, and legacy of the enslaved and free African Americans who labored and were buried at Catoctin Furnace1.
Generation and Functional Characterization of PLAP CAR-T Cells against Cervical Cancer Cells
Authors: Yekehfallah Vahid , Pahlavanneshan Saghar , Sayadmanesh Ali , Momtahan Zahra , Ma Bin , Basiri Mohsen
Published: June 2022

Chimeric antigen receptor (CAR) T cell therapy is one of the cancer treatment modalities that has recently shown promising results in treating hematopoietic malignancies. However, one of the obstacles that need to be addressed in solid tumors is the on-target/off-tumor cytotoxicity due to the lack of specific tumor antigens with low expression in healthy cells. Placental alkaline phosphatase (PLAP) is a shared placenta/tumor-associated antigen (TAA) that is expressed in ovarian, cervical, colorectal, and prostate cancers and is negligible in normal cells. In this study, we constructed second-generation CAR T cells with a humanized scFv against PLAP antigen, then evaluated the characteristics of PLAP CAR T cells in terms of tonic signaling and differentiation in comparison with ΔPLAP CAR T cells and CD19 CAR T cells. In addition, by coculturing PLAP CAR T cells with HeLa cells, we analyzed the tumor-killing function and secretion of anti-tumor molecules. Results showed that PLAP CAR T cells not only could eliminate the cancer cells but also increase their proliferation in vitro. We also observed increased secretion of IL-2, granzyme A, and IFN-γ by PLAP CAR T cells upon exposure to the target cells. In conclusion, PLAP CAR T cells are potential candidates for further investigation in cervical cancer and potentially other solid tumors.
The cell wall polymer initiates plasma membrane partitioning in mycobacteria
Authors: Kado Takehiro , Akbary Zarina , Motooka Daisuke , Sparks Ian L. , Melzer Emily S. , Nakamura Shota , Rojas Enrique R. , Morita Yasu S. , Siegrist M. Sloan
Published: June 2022

Lateral partitioning of proteins and lipids shapes membrane function. In model membranes, partitioning can be influenced by interactions with other membranes and solid supports. While cellular membranes can departition in response to various perturbations, including disruption of bilayer-extrinsic structures, the mechanisms by which they partitionde novoare largely unknown. The plasma membrane ofMycobacterium smegmatiscan be spatially and biochemically departitioned by the fluidizing agent benzyl alcohol. By screening for mutants that are sensitive to benzyl alcohol, we show that the bifunctional cell wall synthase PonA2 promotes membrane partitioning and cell growth upon fluidizer washout. PonA2’s role in membrane repartitioning and regrowth depends solely on its conserved transglycosylase domain. We find that the cell wall polymer, but not active cell wall polymerization, is critical for membrane partitioning. Our work highlights a key initiating role for bilayer-extrinsic structures in patterning cellular membranes.
Aberrant splicing prediction across human tissues
Authors: Çelik Muhammed H. , Wagner Nils , Hölzlwimmer Florian R. , Yépez Vicente A. , Mertes Christian , Prokisch Holger , Gagneur Julien
Published: June 2022

Aberrant splicing is a major cause of genetic disorders but its direct detection in transcriptomes is limited to clinically accessible tissues such as skin or body fluids. While DNA-based machine learning models allow prioritizing rare variants for affecting splicing, their performance on predicting tissue-specific aberrant splicing remains unassessed. Here, we generated the first aberrant splicing benchmark dataset, spanning over 8.8 million rare variants in 49 human tissues. At 20% recall, state-of-the-art DNA-based models cap at 10% precision. By mapping and quantifying tissue-specific splice site usage transcriptome-wide and modeling isoform competition, we increased precision by three-fold at the same recall. Integrating RNA-sequencing data of clinically accessible tissues brought precision to 60%. These results, replicated in two independent cohorts, substantially contribute to non-coding loss-of-function variant identification and to genetic diagnostics design and analytics.
Crowd-sourced benchmarking of single-sample tumour subclonal reconstruction
Authors: Salcedo Adriana , Tarabichi Maxime , Buchanan Alex , Espiritu Shadrielle M.G. , Zhang Hongjiu , Zhu Kaiyi , Yang Tai-Hsien Ou , Leshchiner Ignaty , Anastassiou Dimitris , Guan Yuanfang , Jang Gun Ho , Haase Kerstin , Deshwar Amit G. , Zou William , Umar Imaad , Dentro Stefan , Wintersinger Jeff A. , Chiotti Kami , Demeulemeester Jonas , Jolly Clemency , Sycza Lesia , Ko Minjeong ,   PCAWG-11 Working Group,   SMC-Het Participants, Wedge David C. , Morris Quaid D. , Ellrott Kyle , Van Loo Peter , Boutros Paul C.
Published: June 2022

Tumours are dynamically evolving populations of cells. Subclonal reconstruction algorithms use bulk DNA sequencing data to quantify parameters of tumour evolution, allowing assessment of how cancers initiate, progress and respond to selective pressures. A plethora of subclonal reconstruction algorithms have been created, but their relative performance across the varying biological and technical features of real-world cancer genomic data is unclear. We therefore launched the ICGC-TCGA DREAM Somatic Mutation Calling -- Tumour Heterogeneity and Evolution Challenge. This seven-year community effort used cloud-computing to benchmark 31 containerized subclonal reconstruction algorithms on 51 simulated tumours. Each algorithm was scored for accuracy on seven independent tasks, leading to 12,061 total runs. Algorithm choice influenced performance significantly more than tumour features, but purity-adjusted read-depth, copy number state and read mappability were associated with performance of most algorithms on most tasks. No single algorithm was a top performer for all seven tasks and existing ensemble strategies were surprisingly unable to outperform the best individual methods, highlighting a key research need. All containerized methods, evaluation code and datasets are available to support further assessment of the determinants of subclonal reconstruction accuracy and development of improved methods to understand tumour evolution.
Effector target-guided engineering of an integrated domain expands the disease resistance profile of a rice NLR immune receptor
Authors: Maidment JHR , Shimizu M , Vera S , Franceschetti M , Longya A , Stevenson CEM , De la Concepcion JC , Białas A , Kamoun S , Terauchi R , Banfield MJ
Published: June 2022

A subset of plant intracellular NLR immune receptors detect effector proteins, secreted by phytopathogens to promote infection, through unconventional integrated domains which resemble the effector’s host targets. Direct binding of effectors to these integrated domains activates plant defences. The rice NLR receptor Pik-1 binds theMagnaporthe oryzaeeffector AVR-Pik through an integrated heavy metal-associated (HMA) domain. However, the stealthy alleles AVR-PikC and AVR-PikF avoid interaction with Pik-HMA and evade host defences. Here, we exploited knowledge of the biochemical interactions between AVR-Pik and its host target, OsHIPP19, to engineer novel Pik-1 variants that respond to AVR-PikC/F. First, we exchanged the HMA domain of Pikp-1 for OsHIPP19-HMA, demonstrating that effector targets can be incorporated into NLR receptors to provide novel recognition profiles. Second, we used the structure of OsHIPP19-HMA to guide mutagenesis of Pikp-HMA to expand its recognition profile. We demonstrate that the extended recognition profiles of engineered Pikp-1 variants correlate with effector binding in planta and in vitro, and with the gain of new contacts across the effector/HMA interface. Crucially, transgenic rice producing the engineered Pikp-1 variants were resistant to blast fungus isolates carrying AVR-PikC or AVR-PikF. These results demonstrate that effector target-guided engineering of NLR receptors can provide new-to- nature disease resistance in crops.

Graphical abstract
The Mediator complex regulates enhancer-promoter interactions
Authors: Ramasamy Shyam , Aljahani Abrar , Karpinska Magdalena A. , Cao T. B. Ngoc , Cruz J. Neos , Oudelaar A. Marieke
Published: June 2022

Enhancer-mediated gene activation generally requires physical proximity between enhancers and their target gene promoters. However, the molecular mechanisms by which interactions between enhancers and promoters are formed are not well understood. Here, we investigate the function of the Mediator complex in the regulation of enhancer-promoter interactions, by combining rapid protein depletion and high-resolution MNase-based chromosome conformation capture approaches. We show that depletion of Mediator leads to reduced enhancer-promoter interaction frequencies, which are associated with a strong decrease in gene expression. In addition, we find increased interactions between CTCF-binding sites upon Mediator depletion. These changes in chromatin architecture are associated with a re-distribution of the Cohesin complex on chromatin and a reduction in Cohesin occupancy specifically at enhancers. Our results indicate that enhancer-promoter interactions are dependent on an interplay between the Mediator and Cohesin complexes and provide new insights into the molecular mechanisms by which communication between enhancers and promoters is regulated.