bluuebunny/crossref_metadata_2025 huggingface dataset:
Ecological Transitions and the Shape of the Decapod Tree of Life
Authors: Davis Katie E , De Grave Sammy , Delmer Cyrille , Payne Alexander R D , Mitchell Steve , Wills Matthew A
Published: May 2022

Synopsis

Understanding the processes that shaped the distribution of species richness across the Tree of Life is a central macroevolutionary research agenda. Major ecological innovations, including transitions between habitats, may help to explain the striking asymmetries of diversity that are often observed between sister clades. Here, we test the impact of such transitions on speciation rates across decapod crustaceans, modeling diversification dynamics within a phylogenetic framework. Our results show that, while terrestrial lineages have higher speciation rates than either marine or freshwater lineages, there is no difference between mean speciation rates in marine and freshwater lineages across Decapoda. Partitioning our data by infraorder reveals that those clades with habitat heterogeneity have higher speciation rates in freshwater and terrestrial lineages, with freshwater rates up to 1.5 times faster than marine rates, and terrestrial rates approximately four times faster. This averaging out of marine and freshwater speciation rates results from the varying contributions of different clades to average speciation rates. However, with the exception of Caridea, we find no evidence for any causal relationship between habitat and speciation rate. Our results demonstrate that while statistical generalizations about ecological traits and evolutionary rates are valuable, there are many exceptions. Hence, while freshwater and terrestrial lineages typically speciate faster than their marine relatives, there are many atypically slow freshwater lineages and fast marine lineages across Decapoda. Future work on diversification patterns will benefit from the inclusion of fossil data, as well as additional ecological factors.
Firm Expectations and Economic Activity
Authors: Enders Zeno , Hünnekes Franziska , Müller Gernot
Published: May 2022

We assess how firm expectations about future production impact current production and pricing decisions. Our analysis is based on a large survey of firms in the German manufacturing sector. To identify the causal effect of expectations, we rely on the timing of survey responses and match firms with the same fundamentals but different views about the future. Firms that expect their production to increase (decrease) in the future are 15 percentage points more (less) likely to raise current production and prices, compared to firms that expect no change in production. In a second step, we show that expectations also matter even if they turn out to be incorrect. Lastly, we aggregate expectation errors across firms and find that they account for about 15% of aggregate fluctuations.
Dynamic permeability in porous media and identification of pore fluids by using borehole Stoneley wave
Authors: Peng Fan , Zhang Xiumei , Wang Xiuming , Chen Hao
Published: May 2022

The sound field in porous media is affected by fluid flow governed by dynamic permeability. This macroscopic quantity is frequency dependent and can be connected with a relevant pore-scale estimation called the stochastic dynamic permeability (SDP) model. To further investigate the characteristics of the SDP model with different variables related to Biot relaxation frequency and envisage its potential applications in borehole acoustics, the influence of microstructures from a pore-scale image on dynamic permeability is studied. Then, the characteristics of dynamic permeability and a borehole Stoneley wave with different parameters are explored by sensitivity analysis. According to the influences of pore fluid parameters including density and viscosity, the velocity dispersion and attenuation of Stoneley waves in oil, gas and water-bearing formations are calculated. The results show that the dynamic permeability is affected by the microstructure of pores and the Biot relaxation frequency parameters have a crucial influence on the attenuation of the borehole Stoneley wave. Meanwhile, the attenuation coefficient can be used to identify the type of pore fluids. This is verified by an application to in situ acoustic logging data. The work provides a relatively comprehensive understanding of the features of the SDP dynamic permeability and indicates an approach to identify pore fluid by using a borehole Stoneley wave.
“The pedigree of Honey”
Authors: Nashar Claire
Published: May 2022

This essay provides a national and local context for understanding how Emily Dickinson used, rejected, or ignored the contemporary symbolic associations of bees, which during her lifetime were both extremely popular metaphors in American social and political discourse at large and prominent in the social language and geography of Amherst. Drawing on newspaper coverage of the Amherst “Bee Hive” (1850s–64), a tenement building home to low-income Irish and Black families that stood a few houses down from Dickinson’s childhood home, as well as other local news stories and advertisements, the essay establishes the function of bee rhetoric in national and local explorations of class, gender, and race. It argues that, in reflection of this broader rhetorical context, Dickinson’s bee poems experiment with different guises of agency, manifesting it in relation to different classes, types of privilege, and aspects of American history, including colonialism and immigration. Especially in the context of her own relatively retiring life, the ambition of Dickinson’s bees suggests that the broader social world was in fact of distinct interest to her. Among other things, the bee poems clarify that Dickinson’s social environment gave her a multitude of ways to define herself—both against others, whom she considered to be unlike herself, and with others, whose experiences built up and exceeded her own.
Standardization of Screening Methodology for Assessing the Susceptibility of Sweet Basil Cultivars and Lines to Fusarium oxysporum f. sp. basilici
Authors: Homa Kathryn , Barney William P. , Wyenandt Christian A. , Ward Daniel L. , Simon James E.
Published: May 2022

Fusarium wilt (FOB), caused by Fusarium oxysporum f. sp. basilici, remains an important disease of basil because of its persistence in the soil and seed transmission. Standardization of the methodology for investigating FOB resistance of basil cultivars is necessary for meaningful results. In a seed source experiment, six commercial seed sources of the sweet basil cultivar Nufar were tested in the greenhouse for their response to a single isolate of FOB at four inoculum concentrations (0, 102, 104, 106) at the six-leaf stage of growth. Differential susceptibility of the Nufar seed source lines was only revealed at a concentration of 104, but not at the lowest (102) or highest (106) concentrations. To understand the effects of inoculum concentration (0, 104, 105, 106), cultivar (Caesar, Nufar, RU172), and leaf stage (two, four, six) on FOB incidence and severity, a split-split plot experiment was conducted. There was a highly significant ( P < 0.0001) cultivar with inoculum concentration interaction effect on AUDPC, final plant height, and mortality. There were significant leaf stage with inoculum concentration interaction effects on AUDPC values ( P = 0.0093) and percentage of live plants ( P < 0.0001). There was a significant cultivar by leaf stage interaction effect ( P = 0.0006) on the final plant height. These results demonstrate that inoculum concentration and leaf stage interact to influence FOB incidence and severity. Based on our results, we recommend (i) screening at an intermediate inoculum concentration of 104 and a range of leaf stages; and (ii) culturing stem tissue from asymptomatic plants to detect latent infections.
Development and Pilot Testing of a Data-Rich Clinical Reasoning Training and Assessment Tool
Authors: Waechter Jason , Allen Jon , Lee Chel Hee , Zwaan Laura
Published: May 2022

Problem

Clinical reasoning is a core competency for physicians and also a common source of errors, driving high rates of misdiagnoses and patient harm. Efforts to provide training in and assessment of clinical reasoning skills have proven challenging because they are either labor- and resource-prohibitive or lack important data relevant to clinical reasoning. The authors report on the creation and use of online simulation cases to train and assess clinical reasoning skills among medical students.

Approach

Using an online library of simulation cases, they collected data relevant to the creation of the differential diagnosis, analysis of the history and physical exam, diagnostic justification, ordering tests; interpreting tests, and ranking of the most probable diagnosis. These data were compared with an expert-created scorecard, and detailed quantitative and qualitative feedback were generated and provided to the learners and instructors.

Outcomes

Following an initial pilot study to troubleshoot the software, the authors conducted a second pilot study in which 2 instructors developed and provided 6 cases to 75 second-year medical students. The students completed 376 cases (average 5.0 cases per student), generating more than 40,200 data points that the software analyzed to inform individual learner formative feedback relevant to clinical reasoning skills. The instructors reported that the workload was acceptable and sustainable.

Next Steps

The authors are actively expanding the library of clinical cases and providing more students and schools with formative feedback in clinical reasoning using our tool. Further, they have upgraded the software to identify and provide feedback on behaviors consistent with premature closure, anchoring, and confirmation biases. They are currently collecting and analyzing additional data using the same software to inform validation and psychometric outcomes for future publications.
Chronic exertional compartment syndrome: a review of the literature
Authors: Bouck Trevor T. , Ravi Sreeram , Stokey Phillip J. , Sawyer Ethan R. , Ebraheim Nabil A.
Published: May 2022

Chronic exertional compartment syndrome (CECS) is a serious, yet underdiagnosed condition that can cause severe lower-extremity pain in running athletes. CECS is a transient increase in compartment pressure that can lead to severe pain, paresthesia, and vascular compromise. Understanding the detailed anatomy is paramount to proper diagnosis and treatment. Diagnosis is made with measuring compartment pressures before and after exercise at certain time intervals. When properly diagnosed and treated, CECS can be appropriately managed and patients can return to their previous level of activity. The aim of this review is to familiarize providers with CECS to increase proper diagnosis and treatment with elective fasciotomy. Proper diagnosis and treatment allow patients to return to their previous level of activity without pain.
Knee joint osteoarthritis in obese subjects, effects of diet and exercise on knee joint loading: a review of literature
Authors: Karimi Mohammad Taghi , Hemati Fatemeh
Published: May 2022

The incidence of osteoarthritis (OA) is greater in the knee than in other joints and is increasing. This could be because of an increase in the applied loads on this joint or because of a change in the alignment of the knee joint. The aim of this review was to determine the effects of being overweight on knee joint OA. Moreover, it aimed to determine whether a change in body weight by diet or exercise influenced the loads applied on the knee joint and decreased the incidence of knee OA. A systematic literature search was carried out to find the literature published on the effects of joint loading and being overweight on knee OA in databases such as Medline, PubMed, Embase, Web of Sciences, Scopus, and Google Scholar. The key words such as knee OA and loading, knee OA and joint contact forces, knee OA and body weight were used to determine the effects of joint loading on knee OA. The quality of the studies was evaluated by use of Downs and Black tool. There were 15 studies on the effects of joint loading, overweight, and obesity on joint contact force and knee OA symptoms and three studies on the effects of weight loss, exercise, and intensive diet intervention on joint loading. The quality of these papers varied between 9 and 20. The results of this review showed that obese subjects are at high risk of knee OA because of change in alignment of the knee joint and also overloading of the joint. Use of approaches such as diet and exercise may decrease the loads applied on the joint and decrease the incidence of knee OA.
The shock team: a multidisciplinary approach to early patient phenotyping and appropriate care escalation in cardiogenic shock
Authors: Brusca Samuel B. , Caughron Hope , Njoroge Joyce N. , Cheng Richard , O’Brien Connor G. , Barnett Christopher F.
Published: May 2022

Purpose of review

Cardiogenic shock (CS) is a highly morbid condition with mortality remaining greater than 30% despite improved pathophysiologic understanding and access to mechanical circulatory support (MCS). In response, shock teams modeled on successful multidisciplinary care structures for other diseases are being implemented nationwide.

Recent findings

Primary data supporting a benefit of shock team implementation on patient outcomes are relatively limited and entirely observational. Four single-center before-and-after studies and one multicenter registry study have demonstrated improved outcomes in patients with CS, potentially driven by increased pulmonary artery catheter (PAC) utilization and earlier (and more appropriate) initiation of MCS. Shock teams are also supported by a growing body of literature recognizing the independent benefit of the interventions they seek to implement, including patient phenotyping with PAC use and an algorithmic approach to CS care. Though debated, MCS is also highly likely to improve CS outcomes when applied appropriately, which further supports a multidisciplinary shock team approach to patient and device selection.

Shock teams likely improve patient outcomes by facilitating early patient phenotyping and appropriate intervention. Institutions should strongly consider adopting a multidisciplinary shock team approach to CS care, though additional data supporting these interventions are needed.
Observational Trends in Publicly Reported Quality Measures of Hospital Outpatient Quality Reporting Program, 2013-2019
Authors: Hamadi Hanadi , Zhao Mei , Haley D. Rob , Xu Jing , Paryani Shyam , Spaulding Aaron
Published: May 2022

In 2011, the Centers for Medicare & Medicaid Services (CMS) implemented the Hospital Outpatient Quality Reporting Program to assess the quality of outpatient imaging efficiency (OIE). In this study, trends in hospital performance on these national hospital OIE measures a year after inception and public reporting were described. An observational trend analysis was conducted using 2013-2019 data from CMS 6 OIE measures. The trend analysis of metric scores indicates year-to-year variability in all 6 OIE variables. The reporting of these measures appears to have effectively improved the efficiency of most of the measures since the inception of the program.
Key Patient Experience Drivers That Result in Exemplary Overall Provider Performance Ratings in the Ambulatory Environment
Authors: Jurdi Zahi R. , Crosby Joseph F.
Published: May 2022

This study highlights the key drivers that form particular patient impressions resulting in exemplary overall provider performance ratings across service lines in the ambulatory environment. Two national samples of CG-CAHPS data were analyzed. Results indicate variance of impact among all CG-CAHPS questions on “top-box” scores for overall rating of provider among specialties. Interestingly, the same 5 explanatory variables—provider listened carefully, provider spent enough time, provider showed respect, provider knew important information about medical history, and provider explained things clearly—had the greatest explanatory power across the primary and specialty care samples when analyzed via multiple logistic regression analysis.
Transforming Clinical Practice Initiative Boosted Participation in Medicare Alternative Payment Models
Authors: Zurovac Jelena , Barna Michael , Merrill Angela , Zickafoose Joseph S. , Felt-Lisk Sue , Vollmer Forrow Lauren , Gallegos Karen Frederick , Everhart Damian , Flemming Robert
Published: May 2022

The Centers for Medicare & Medicaid Services' (CMS's) Transforming Clinical Practice Initiative (TCPi) was the largest national-scale practice transformation model. We analyzed the effect of TCPi on new enrollment into Medicare Alternative Payment Models (APMs) through January 2020 (3 months after program end), using 6958 physician practices enrolled in TCPi and a closely matched comparison group of 6958 practices. More TCPi practices enrolled in Medicare APMs and Medicare Advanced APMs relative to comparison practices overall and in subgroups, including rural, small, and specialty practices. Results suggest that large-scale technical assistance can boost participation in Medicare APMs for a diverse set of practices.
The Role of Community Health Workers in Developing Multidimensional Organizational Relationships
Authors: Gronowski Benjamin , Roth Sarah E. , Woodson Tanisha Tate , Cohen-Cline Hannah , Kenton Natalie
Published: May 2022

Effective care coordination relies on organizations working collaboratively to meet medically and socially complex participants' needs. This study examines community health workers' (CHWs') roles in developing the organizational relationships on which care coordination efforts depend. Semistructured interviews (n = 13) were conducted with CHWs, CHWs' supervisors, and executive staff at organizations participating in a Washington State care coordination program. Interviewees described how CHWs developed and furthered multidimensional relationships in service of participants between and within participating organizations, as well as external organizations. Relationship-building challenges included COVID-19, geographic context, and staffing. The study concludes with considerations for care coordination efforts to support CHWs.
Secondary Alveolar Bone Grafting in Patients with Unilateral and Bilateral Complete Cleft Lip and Palate: A Single-Institution Outcomes Evaluation Using Three-Dimensional Cone Beam Computed Tomography
Authors: Kimia Rotem , Scott Michelle , Magee Leanne , Jackson Oksana A.
Published: May 2022

Background:

Secondary alveolar bone grafting of autologous bone from the iliac crest is a widely accepted modality for repair of residual alveolar cleft in patients with mixed dentition with previously repaired complete cleft lip and palate. There remains debate regarding surgical timing and preoperative, perioperative, and postoperative management of these cases.

Methods:

This retrospective study reviewed patient demographic information in addition to preoperative, perioperative, and postoperative course to evaluate how patient and practice factors impact graft outcomes as assessed by three-dimensional cone beam computed tomographic evaluation at the 6-month postoperative visit.

Results:

On univariate analysis, age at operation older than 9 years, history of oronasal fistula, history of cleft lip or palate revision, and history of international adoption were all found to significantly increase likelihood of graft failure (p < 0.05). On multivariate analysis, age older than 9 years was found to be the single most significant predictor of graft failure (p < 0.05). There was no significant difference in graft outcomes between patients with unilateral or bilateral cleft lip and palate, and no single variable was found to significantly correlate to increased complication rates. The graft success rate overall of the authors’ practice was 86.2 percent, with a complication rate of 7.7 percent.

Conclusions:

Secondary alveolar bone grafting is an integral part of the cleft lip and palate surgical treatment series; this study identified several outcome predictors for both graft failure and adverse events, the most significant of which was age at operation. Although the mixed dentition phase often extends to 12 years of age, it is recommended that bone grafting be performed before 9 years of age to optimize outcomes.

CLINICAL QUESTIONS/LEVEL OF EVIDENCE:

Risk, III.
Elastic anisotropy in the reduced Landau–de Gennes model
Authors: Han Yucen , Harris Joseph , Majumdar Apala , Zhang Lei
Published: May 2022

We study the effects of elastic anisotropy on Landau–de Gennes critical points, for nematic liquid crystals, on a square domain. The elastic anisotropy is captured by a parameter,

L
2

, and the critical points are described by 3 d.f. We analytically construct a symmetric critical point for all admissible values of

L
2

, which is necessarily globally stable for small domains, i.e. when the square edge length,

λ

, is small enough. We perform asymptotic analyses and numerical studies to discover at least five classes of these symmetric critical points—the

WORS

,

Ring

±

,

C
o
n
s
t
a
n
t

and

p
W
O
R
S

solutions, of which the

WORS

,

Ring

+

and

C
o
n
s
t
a
n
t

solutions can be stable. Furthermore, we demonstrate that the novel

C
o
n
s
t
a
n
t

solution is energetically preferable for large

λ

and large

L
2

, and prove associated stability results that corroborate the stabilizing effects of

L
2

for reduced Landau–de Gennes critical points. We complement our analysis with numerically computed bifurcation diagrams for different values of

L
2

, which illustrate the interplay of elastic anisotropy and geometry for nematic solution landscapes, at low temperatures.
The time course of metabolic plasticity and its consequences for growth performance under variable food supply in the northern pike
Authors: Nilsson-Örtman Viktor , Brönmark Christer
Published: May 2022

Many species up- or downregulate their resting metabolic rate (RMR) when they encounter favourable or unfavourable feeding conditions, respectively. This is thought to promote faster growth when food is abundant and conserve energy reserves when food is scarce. The time it takes to express metabolic plasticity remain little studied. Here, we develop a conceptual model showing how rapid or slow metabolic plasticity alter growth trajectories in response to changes in food supply. We test predictions from the model in a food manipulation experiment with young-of-the-year northern pike,
Esox lucius
, a species that experience drastic changes in food supply in nature. We find that metabolic plasticity is expressed gradually over several weeks in this species. Rapid changes in food supply thus caused apparent trait-environment mismatches that persisted for at least five weeks. Contrary to predictions, pike grew faster at high food levels when they had previously experienced low food levels and downregulated their RMR. This was not owing to increases in food intake but probably reflected that low RMRs increased the energetic scope for growth when feeding conditions improved. This highlights the important but complex effects of metabolic plasticity on growth dynamics under variable resource levels on ecologically relevant time scales.
Endothelial Brg1 fine-tunes Notch signaling during zebrafish heart regeneration
Authors: Xiao Chenglu , Hou Junjie , Wang Fang , Song Yabing , Zheng Jiyuan , Luo Lingfei , Wang Jianbin , Ding Wanqiu , Zhu Xiaojun , Xiong Jing-Wei
Published: May 2022

Myocardial Brg1 is essential for heart regeneration in zebrafish, but it remains unknown whether and how endothelial Brg1 plays a role in heart regeneration. Here, we found that both brg1 mRNA and protein were induced in cardiac endothelial cells after ventricular resection, and endothelium-specific over-expression of dominant-negative Xenopus Brg1 (DN-xBrg1) inhibited myocardial proliferation and heart regeneration and increased cardiac fibrosis. RNA-seq and ChIP-seq analysis revealed that the endothelium-specific over-expression of DN-xBrg1 changed the levels of H3K4me3 modifications in the promoter regions of the zebrafish genome and induced abnormal activation of Notch family genes upon injury. Mechanistically, Brg1 interacted with lysine demethylase 7aa (Kdm7aa) to fine-tune the level of H3K4me3 within the promoter regions of Notch family genes and thus regulated Notch gene transcription. Together, this work demonstrates that the Brg1-Kdm7aa-Notch axis in cardiac endothelial cells, including the endocardium, regulates myocardial proliferation and regeneration via modulating the H3K4me3 of the Notch promoters in zebrafish.
Bayesian Inference of Dependent Population Dynamics in Coalescent Models
Authors: Cappello Lorenzo , Kim Jaehee , Palacios Julia
Published: May 2022

The coalescent is a powerful statistical framework that allows us to infer past population dynamics leveraging the ancestral relationships reconstructed from sampled molecular sequence data. In many biomedical applications, such as in the study of infectious diseases, cell development, and tumorgenesis, several distinct populations share evolutionary history and therefore become dependent. The inference of such dependence is a highly important, yet a challenging problem. With advances in sequencing technologies, we are well positioned to exploit the wealth of high-resolution biological data for tackling this problem. Here, we present a novel probabilistic model that relies on jointly distributed Markov random fields. We use this model to estimate past population dynamics of dependent populations and to quantify their degree of dependence. An essential feature of our approach is the ability to track the time-varying association between the populations while making minimal assumptions on their functional shapes via Markov random field priors. We provide nonparametric estimators, extensions of our base model that integrate multiple data sources, and fast scalable inference algorithms. We test our method using simulated data under various dependent population histories and demonstrate the utility of our model in shedding light on evolutionary histories of different variants of SARS-CoV-2.
Causal links between inflammatory bowel disease and both psoriasis and psoriatic arthritis: a bidirectional two-sample Mendelian randomization study
Authors: Freuer Dennis , Linseisen Jakob , Meisinger Christa
Published: May 2022

Introduction

Psoriasis (PsO), psoriatic arthritis (PsA) and inflammatory bowel disease (IBD), i.e. Crohn’s disease (CD) and ulcerative colitis (UC) are chronic systemic immune-mediated disorders affecting an increasing proportion of adults and children worldwide. Observational studies suggested an association between IBD and PsO and vice versa. However, so far it remains unclear whether a causal relationship exists.

Methods

To investigate the causal paths, a bidirectional two-sample Mendelian randomization (MR) study was conducted using summary statistics from genome-wide association studies (GWASs) including up to 463,372 Europeans. Total and direct effects were derived performing an iterative radial and robust inverse-variance weighted method within the univariable and multivariable MR setting, respectively. Causal estimates were verified using a validation IBD-sample, a series of pleiotropy-robust MR-methods, and sensitivity analyses based on PhenoScanner search in conjunction with network analysis.

Results

Genetically predicted IBD was associated with higher risk of PsO (pooled OR=1.10; 95% CI: (1.05; 1.15); P=1⋅10−4) and PsA (pooled OR=1.10; 95% CI: (1.04; 1.18); P=3⋅10−3). In contrast to UC, the CD subentity was related to PsO (OR=1.16; 95% CI: (1.12; 1.20); P=1⋅10−14) and PsA (OR=1.13; 95% CI: (1.06; 1.20); P=1⋅10−4). Regarding the reverse directions, no notable associations could be found.

Conclusions

This study supports a causal effect between IBD and PsO as well as PsA, but not vice versa. It seems that mainly CD and not UC is responsible for the causal impact of IBD on both psoriasis outcomes. These findings have implications for the management of IBD and psoriasis in clinical practice.
An Igh novel enhancer modulates antigen receptor diversity by determining locus conformation
Authors: Bhat Khalid H. , Priyardarshi Saurabh , Naiyer Sarah , Qu X. , Farooq Hammad , Kleiman Eden , Xu J. , Lei X. , Cantillo Jose F. , Wuerffel Robert , Baumgarth Nicole , Liang Jie , Feeney Ann J. , Kenter Amy L.
Published: May 2022

The Igh locus is organized into a developmentally regulated topologically associated domain (TAD) that is divided into subTADs. Here we identify a series of novel enhancers (NEs) that collaborate to configure the locus, determine transcriptional potential in over a hundred functional VH genes and their usage in V(D)J recombination. NE1 engages in a network of long-range interactions that interconnect the subTADs and the recombination center at the DHJH gene cluster. Deletion of NE1 alters discrete chromatin loops, higher order locus conformation, locus-wide VH gene transcription and regional V gene utilization that is linked to a greatly reduced splenic B1 B cell compartment. NE1 blocks long-range loop extrusion that in turn contributes to locus contraction and determines the proximity of distant VH genes to the recombination center. NE1 is a critical architectural element that coordinates chromatin conformational states that favor VH gene transcription or V(D)J rearrangement.
Sex-specific transgenerational effects of diet on offspring life history and physiology
Authors: Camilleri Tara-Lyn , Piper Matthew D.W. , Robker Rebecca L. , Dowling Damian K.
Published: May 2022

Dietary variation in males and females can shape the expression of offspring life histories and physiology. However, the relative contributions of maternal and paternal dietary variation to phenotypic expression of latter generations is currently unknown. We provided male and female Drosophila melanogaster diets differing in sucrose concentration prior to reproduction, and similarly subjected grandoffspring to the same treatments. We then investigated the phenotypic consequences of this dietary variation among grandsons and granddaughters. We demonstrate transgenerational effects of dietary sucrose, mediated through the grandmaternal lineage, which mimic the direct effects of sucrose on lifespan, with opposing patterns across sexes; low sucrose increased female, but decreased male, lifespan. Dietary mismatching of grandoffspring-grandparent diets increased lifespan and reproductive success, and moderated triglyceride levels, of grandoffspring, providing insights into the physiological underpinnings of the complex transgenerational effects on life histories.
Design of a systemic small molecule clinical STING agonist using physics-based simulations and artificial intelligence
Authors: Allen Bryce K. , Kulkarni Meghana M. , Chamberlain Brian , Dwight Timothy , Koh Cheryl , Samant Ramya , Jernigan Finith , Rice Jamie , Tan Dazhi , Li Stella , Marino Kristen , Huang Huang , Chiswick Evan , Tesar Bethany , Sparks Sam , Lin Zhixiong , McGee T. Dwight , Kolossváry István , Lin Charles , Shechter Sharon , Soutter Holly , Bastos Cecilia , Taimi Mohammed , Lai Sujen , Petrin Alicia , Kane Tracy , Swann Steven , Gardner Humphrey , Winter Christopher , Sherman Woody
Published: May 2022

The protein STING (stimulator of interferon genes) is a central regulator of the innate immune system and plays an important role in antitumor immunity by inducing the production of cytokines such as type I interferon (IFN). Activation of STING stems from the selective recognition of endogenous cyclic dinucleotides (CDNs) by the large, polar, and flexible binding site, thus posing challenges to the design of small molecule agonists with drug-like physicochemical properties. In this work we present the design of SNX281, a small molecule STING agonist that functions through a unique self-dimerizing mechanism in the STING binding site, where the ligand dimer approximates the size and shape of a cyclic dinucleotide while maintaining drug-like small molecule properties. SNX281 exhibits systemic exposure, STING-mediated cytokine release, strong induction of type I IFN, potent in vivo antitumor activity, durable immune memory, and single-dose tumor elimination in mouse models via a Cmax-driven pharmacologic response. Bespoke computational methods – a combination of quantum mechanics, molecular dynamics, binding free energy simulations, and artificial intelligence – were developed during the course of the project to design SNX281 by explicitly accounting for the unique self-dimerization mechanism and the large-scale conformational change of the STING protein upon activation. Over the course of the project, we explored millions of virtual molecules while synthesizing and testing only 208 molecules in the lab. This work highlights the value of a multifaceted computationally-driven approach anchored by methods tailored to address target-specific problems encountered along the project progression from initial hit to the clinic.
TDP-43 oligomerization and RNA binding are codependent but their loss elicits distinct pathologies
Authors: Pérez-Berlanga Manuela , Wiersma Vera I. , Zbinden Aurélie , De Vos Laura , Wagner Ulrich , Foglieni Chiara , Mallona Izaskun , Betz Katharina M. , Cléry Antoine , Weber Julien , Guo Zhongning , Rigort Ruben , de Rossi Pierre , Manglunia Ruchi , Tantardini Elena , Sahadevan Sonu , Stach Oliver , Hruska-Plochan Marian , Allain Frederic H.-T. , Paganetti Paolo , Polymenidou Magdalini
Published: May 2022

Aggregation of the RNA-binding protein TDP-43 is the main common neuropathological feature of TDP-43 proteinopathies. In physiological conditions, TDP-43 is predominantly nuclear and contained in biomolecular condensates formed via liquid-liquid phase separation (LLPS). However, in disease, TDP-43 is depleted from these compartments and forms cytoplasmic or, sometimes, intranuclear inclusions. How TDP-43 transitions from physiological to pathological states remains poorly understood. Here, we show that self-oligomerization and RNA binding cooperatively govern TDP-43 stability, functionality, LLPS and cellular localization. Importantly, our data reveal that TDP-43 oligomerization is connected to, and conformationally modulated by, RNA binding. Mimicking the impaired proteasomal activity observed in patients, we found that TDP-43 forms nuclear aggregates via LLPS and cytoplasmic aggregates via aggresome formation. The favored aggregation pathway depended on the TDP-43 state –monomeric/oligomeric, RNA-bound/-unbound– and the subcellular environment –nucleus/cytoplasm. Our work unravels the origins of heterogeneous pathological species occurring in TDP-43 proteinopathies.
Privacy-preserving integration of multiple institutional data for single-cell type identification with scPrivacy
Authors: Chen Shaoqi , Duan Bin , Zhu Chenyu , Tang Chen , Wang Shuguang , Gao Yicheng , Fu Shaliu , Fan Lixin , Yang Qiang , Liu Qi
Published: May 2022

The rapid accumulation of large-scale single-cell RNA-seq datasets from multiple institutions presents remarkable opportunities for automatically cell annotations through integrative analyses. However, the privacy issue has existed but being ignored, since we are limited to access and utilize all the reference datasets distributed in different institutions globally due to the prohibited data transmission across institutions by data regulation laws. To this end, we presentscPrivacy, which is the first and generalized automatically single-cell type identification prototype to facilitate single cell annotations in a data privacy-preserving collaboration manner. We evaluatedscPrivacyon a comprehensive set of publicly available benchmark datasets for single-cell type identification to stimulate the scenario that the reference datasets are rapidly generated and distributed in multiple institutions, while they are prohibited to be integrated directly or exposed to each other due to the data privacy regulations, demonstrating its effectiveness, time efficiency and robustness for privacy-preserving integration of multiple institutional datasets in single cell annotations.
Striatal µ-Opioid Receptor Activation Triggers Direct-Pathway GABAergic Plasticity to Induce Negative Affect
Authors: Wang Wei , Xie Xueyi , Zhuang Xiaowen , Huang Yufei , Tan Tao , Gangal Himanshu , Huang Zhenbo , Purvines William , Wang Xuehua , Stefanov Alexander , Chen Ruifeng , Yu Emily , Hook Michelle , Huang Yun , Darcq Emmanuel , Wang Jun
Published: May 2022

Withdrawal from chronic opioid use often causes hypodopaminergic states and negative affect, which drives relapse. Direct-pathway medium spiny neurons (dMSNs) in the striatal patch compartment contain high levels of µ-opioid receptors (MORs). It remains unclear how chronic opioid exposure affects these MOR-expressing dMSNs and their striatopallidal and striatonigral outputs to induce negative emotions and relapse. Here, we report that MOR activation acutely suppressed GABAergic striatopallidal transmission in habenula-projecting globus pallidus neurons. Notably, repeated administrations of a MOR agonist (morphine or fentanyl) potentiated this GABAergic transmission. We also discovered that intravenous self-administration of fentanyl enhanced GABAergic striatonigral transmission and reduced the firing activity of midbrain dopaminergic neurons. Importantly, fentanyl withdrawal caused depression-like behaviors and promoted the reinstatement of fentanyl-seeking behaviors. These data suggest that chronic opioid use triggers GABAergic striatopallidal and striatonigral plasticity to induce a hypodopaminergic state, promoting negative emotions and leading to relapse.

Highlights

Repeated administration of morphine potentiates IPSCdMSN◊GPhneurotransmission.

Repeated administration of fentanyl potentiates IPSCdMSN◊SNcneurotransmission.

Fentanyl withdrawal induces negative emotional states, which drive relapse.
The effects of combined action observation and motor imagery on corticospinal excitability and movement outcomes: Two meta-analyses
Authors: Chye Samantha , Valappil Ashika Chembila , Wright David J. , Frank Cornelia , Shearer David A. , Tyler Christopher J. , Diss Ceri E. , Mian Omar S. , Tillin Neale A. , Bruton Adam M.
Published: May 2022

Motor simulation interventions involving motor imagery (MI) and action observation (AO) have received considerable interest in the behavioral sciences. A growing body of research has focused on using AO and MI simultaneously, termed ‘combined action observation and motor imagery’ (AOMI). The current paper includes two meta-analyses that quantify changes in corticospinal excitability and motor skill performance for AOMI compared to AO, MI and control conditions. Specifically, the first meta-analysis collated and synthesized existing motor evoked potential (MEP) amplitude data from transcranial magnetic stimulation studies and the second meta-analysis collated and synthesized existing movement outcome data from behavioral studies. AOMI had a positive effect compared to control and AO but not MI conditions for both MEP amplitudes and movement outcomes. No methodological factors moderated the effects of AOMI, indicating a robust effect of AOMI across the two outcome variables. The results of the meta-analyses are discussed in relation to existing literature on motor simulation and skill acquisition, before providing viable directions for future research on this topic.

Highlights

Motor imagery (MI) and action observation (AO) can be combined (AOMI)

This paper synthesizes neurophysiological and behavioral evidence for AOMI

AOMI had increased corticospinal excitability compared to AO and control but not MI

AOMI led to improved movement outcomes compared to AO and control but not MI

The reported effects of AOMI were maintained across all moderators
Connecting human voice profiling to genomics: A predictive algorithm for linking speech phenotypes to genetic microdeletion syndromes
Authors: Singh Rita
Published: May 2022

Changes in vocal acoustic patterns are known to correlate with the occurrence of several diseases and syndromes, many of which do not directly affect the structures or processes that control voice production. In such cases, it is difficult to support the existence of correlated changes in voice. This paper presents a methodology for identifying potential genomic bases for such correlations, by finding links between specific genes involved in the conditions under study, and those involved in voice, speech or language generation. Syndromes associated with chromosomal microdeletions are examined as an illustrative case, with focus on their linkage to the FOXP2 gene which has been strongly implicated in speech and language disorders. A novel path-finding graph algorithm to detect pathway chains that connect the the former to the latter is proposed. Statistical analysis of ensembles of “voice” chains detected by this algorithm indicates that they are predictive of speech phenotypes for the syndromes. Algorithmic findings are validated against clinical findings in the literature pertaining to the actual speech phenotypes that have been found to be associated with these syndromes. This methodology may also potentially be used to predict the existence of voice biomarkers in naїve cases where the existence of voice biomarkers has not already been established.
Reconstitution of the SARS-CoV-2 ribonucleosome provides insights into genomic RNA packaging and regulation by phosphorylation
Authors: Carlson Christopher R. , Adly Armin N. , Bi Maxine , Cheng Yifan , Morgan David O.
Published: May 2022

The nucleocapsid (N) protein of coronaviruses is responsible for compaction of the ∼30-kb RNA genome in the ∼100-nm virion. Cryo-electron tomography suggests that each virion contains 35-40 viral ribonucleoprotein (vRNP) complexes, or ribonucleosomes, arrayed along the genome. There is, however, little mechanistic understanding of the vRNP complex. Here, we show that N protein, when combined with viral RNA fragments in vitro, forms cylindrical 15-nm particles similar to the vRNP structures observed within coronavirus virions. These vRNPs form in the presence of stem-loop-containing RNA and depend on regions of N protein that promote protein-RNA and protein-protein interactions. Phosphorylation of N protein in its disordered serine/arginine (SR) region weakens these interactions and disrupts vRNP assembly. We propose that unmodified N binds stem-loop-rich regions in genomic RNA to form compact vRNP complexes within the nucleocapsid, while phosphorylated N maintains uncompacted viral RNA to promote the protein’s transcriptional function.
SALMA: Scalable ALignment using MAFFT-Add
Authors: Shen Chengze , Liu Baqiao , Williams Kelly P. , Warnow Tandy
Published: May 2022

Multiple sequence alignment is essential for many biological downstream analyses, but accurate alignment of large datasets, especially those exhibiting high rates of evolution or sequence length heterogeneity, is still unsolved. We present SALMA, a new multiple sequence alignment that provides high accuracy and scalability, even for datasets exhibiting high rates of evolution and great sequence length heterogeneity that arises from evolutionary processes. Like some prior methods (e.g., UPP, WITCH, and MAFFT-sparsecore), SALMA operates in two distinct stages: the first stage computes a “backbone alignment” for a subset of the sequences, and the second stage adds the remaining sequences into the backbone alignment. The main novelty in SALMA is how it adds the remaining (“query”) sequences into the backbone alignment. For this step, which we refer to as SALMA-add, we use divide-and-conquer to scale MAFFT-linsi--add to enable it to add sequences into large backbone alignments. We show that SALMA-add has an advantage over other sequence-adding techniques for many realistic conditions and can scale to very large datasets with high accuracy (hundreds of thousands of sequences). We also show that SALMA is one of the most accurate compared to standard alignment methods. Our open source software for SALMA is available at https://github.com/c5shen/SALMA.
Targeting Pulmonary Fibrosis by SLC1A5 dependent Glutamine Transport Blockade
Authors: Choudhury Malay , Schaefbauer Kyle J. , Kottom Theodore J. , Yi Eunhee S. , Tschumperlin Daniel J. , Limper Andrew H.
Published: May 2022

The neutral amino acid glutamine plays a central role in TGF-β-induced myofibroblast activation and differentiation. Cells take up glutamine mainly through a transporter expressed on the cell surface known as solute carrier SLC1A5. In this current work, we demonstrated that profibrotic actions of TGF-β are mediated, at least in part, through a metabolic maladaptation of SLC1A5 and targeting SLC1A5 abrogates multiple facets of fibroblast activation. This approach could thus represent a novel therapeutic strategy to treat fibroproliferative diseases. We found that SLC1A5 was highly expressed in fibrotic lung fibroblasts and fibroblasts isolated from IPF lungs. The expression of profibrotic targets, cell migration, and anchorage independent growth by TGF-β required the activity of SLC1A5. Loss or inhibition of SLC1A5 function enhanced fibroblast susceptibility to autophagy, suppressed mTOR, HIF, Myc signaling, and impaired mitochondrial function, ATP production and glycolysis. Pharmacological inhibition of SLC1A5 by small molecule inhibitor V-9302 shifted fibroblast transcriptional profiles from profibrotic to fibrosis resolving, and attenuated fibrosis in a bleomycin treated mouse model of lung fibrosis. This is the first study, to our knowledge, to demonstrate the utility of a pharmacological inhibitor of glutamine transport in fibrosis, laying a framework for new paradigm-shifting therapies targeting cellular metabolism for this devastating disease.
Clinical heterogeneity based on race and sex within a large cohort of inclusion body myositis patients
Authors: Michelle E. Harlan , Pinal-Fernandez Iago , Casal-Dominguez Maria , Albayda Jemima , Paik Julie J. , Tiniakou Eleni , Adler Brittany , Mecoli Christopher A. , Danoff Sonye K. , Christopher-Stine Lisa , Mammen Andrew L , Lloyd Thomas E.
Published: May 2022

Background and Objectives

Sporadic inclusion body myositis (IBM) is the most common acquired myopathy in individuals over age 50. The disorder is slowly progressive and while many therapies have been investigated, response has generally been poor. Clinical heterogeneity may influence treatment responsiveness; however, data regarding heterogeneity in IBM is limited and often conflicting. We aim to identify clinically distinct subgroups within a large IBM cohort, as well as prognostic factors for disease progression.

Methods

Clinical, histologic, radiologic, and electrophysiologic data were analyzed for all patients with IBM and other forms of myositis enrolled in a longitudinal cohort from The Johns Hopkins Myositis Center from 2003-2018. Univariate, multivariate, and graphical analyses were used to identify prognostic factors in IBM patients.

Results

Among the 335 IBM patients meeting inclusion criteria, 64% were male with an average age of disease onset of 58.7 years and a delay to diagnosis of 5.2 years. Initial misdiagnosis (52%) and immunosuppressant treatment (42%) were common. Less than half (43%) of muscle biopsies demonstrated all three pathologic hallmarks: endomysial inflammation, mononuclear cell invasion, and rimmed vacuoles. Black patients had significantly weaker arm abductors, hip flexors, and knee flexors compared to non-Black patients but were less likely to develop dysphagia. Female patients had stronger finger flexors and knee extensors compared to their male counterparts but were more likely to develop dysphagia. A significant number (20%) of patients had an age of onset less than 50 years. This group of younger patients was weaker at their first visit; however, this may be accounted for by a longer disease duration at first visit.

Discussion

Although IBM has long been considered a disorder predominately of older, White men, female, and non-White patients comprise a significant proportion of the IBM population. Our study demonstrates that female and Black patients have distinct clinical phenotypes within the overarching IBM clinical phenotype.