bluuebunny/crossref_metadata_2025 huggingface dataset:
Activated protein C in neuroprotection and malaria
Authors: Mosnier Laurent O.
Published: July 2019

Purpose of review

Activated protein C (APC) is a homeostatic coagulation protease with anticoagulant and cytoprotective activities. Focusing on APC's effects in the brain, this review discusses three different scenarios that illustrate how APC functions are intimately affecting the physiology and pathophysiology of the brain.

Recent findings

Cytoprotective APC therapy holds promise for the treatment of ischemic stroke, and a recently completed trial suggested that cytoprotective-selective 3K3A-APC reduced bleeding in ischemic stroke patients. In contrast, APC's anticoagulant activity contributes to brain bleeding as shown by the disproportional upregulation of APC generation in cerebral cavernous malformations lesions in mice. However, too little APC generation also contributes to maladies of the brain, such as in case of cerebral malaria where the binding of infected erythrocytes to the endothelial protein C receptor (EPCR) may interfere with the EPCR-dependent functions of the protein C pathway. Furthermore, discoveries of new activities of APC such as the inhibition of the NLRP3-mediated inflammasome and of new applications of APC therapy such as in Alzheimer's disease and graft-versus-host disease continue to advance our knowledge of this important proteolytic regulatory system.

APC's many activities or lack thereof are intimately involved in multiple neuropathologies, providing abundant opportunities for translational research.
Neointimal hyperplasia: are fatty acid transport proteins a new therapeutic target?
Authors: Rekhi Umar , Piche Julia E. , Immaraj Linnet , Febbraio Maria
Published: July 2019

Purpose of review

High-fat diets contribute to hyperlipidemia and dysregulated metabolism underlying insulin resistant states and cardiovascular diseases. Neointimal hyperplasia is a significant resulting morbidity. Increased fatty acid (FA) levels lead to dysfunctional endothelium, defined as activated, proinflammatory and prothrombotic. The purpose of this review is to assess the recent literature on the emerging concept that uptake of FA into many tissues is regulated at the endothelial level, and this in turn contributes to endothelial dysfunction, an initiating factor in insulin resistant states, atherosclerosis and neointimal hyperplasia.

Recent findings

Studies support the role of endothelial FA uptake proteins as an additional level of regulation in tissue FA uptake. These proteins include CD36, FA transport proteins, FA-binding proteins and caveolin-1. In many cases, inappropriate expression of these proteins can result in a change in FA and glucose uptake, storage and utilization. Accumulation of plasma FA is one mechanism by which alterations in expression of FA uptake proteins can lead to endothelial dysfunction; changes in tissue substrate metabolism leading to inflammation are also implicated.

Identification of the critical players and regulators can lead to therapeutic targeting to reduce endothelial dysfunction and sequela such as insulin resistance and neointimal hyperplasia.
The pathology of solid organ xenotransplantation
Authors: Rosales Ivy A. , Colvin Robert B.
Published: July 2019

Purpose of review

The use of genetically modified pigs has resulted in prolonged xenograft organ survival, overcoming the initial barriers that lead to hyperacute rejection and immediate loss of the graft. The purpose of the present review is to revisit the xenogeneic response and the pathologic changes in the xenograft organ in the context of recent publications of large animal studies that highlight existing challenges.

Recent findings

Transgenic modifications that have included complement regulatory proteins and coagulation regulatory proteins have prolonged xenograft survival in pig to nonhuman primate kidneys, livers, and hearts. Modifications of immunosuppressive regimens such as the addition of mTOR inhibition and costimulatory blockade have also led to better outcomes. Antibody-mediated rejection and thrombotic microangiopathy persist as primary challenges to the field and require further systematic exploration.

The efforts to overcome the natural antibody response to xenoantigens are largely sufficient. There is great opportunity for designing immunosuppression protocols and for detecting early coagulopathies, complement activation, and donor-specific antibody response. With graft survival prolongation, there is also a greater need to understand mechanisms and to enhance diagnostic tools for pathologic evaluation.
Fake Nutrition/Health News, Part 3
Authors: Rowe Sylvia , Alexander Nick
Published: July 2019

The third in a 3-part series of articles on so-called “fake news” regarding health and nutrition science focuses specifically on false scientific news—exaggerated or misleading reporting of research, reporting of fabricated or fraudulent research, misleading press releases, and communication of Web-based scientific fantasies. The authors explore the origins of such misinformation and its context within the current proliferation of similar unhelpful “news” throughout the broader society. They call for educational efforts at helping the public better recognize scientific misinformation, and they offer suggestions on how nutrition and other health communicators might make consumers more aware and more skeptical of such claims as nutritional “cures,” medical “breakthroughs,” “miracle foods,” and alarming health scares in news reports.
Integrating Financial Incentives for Viral Load Suppression into HIV Care Coordination Programs: Considerations for Development and Implementation
Authors: Gambone Gina F. , Feldman Matthew B. , Thomas-Ferraioli Anna Y. , Shubert Virginia , Ghose Toorjo
Published: July 2019

Context:

Interventions that support durable viral load suppression (VLS) among people living with HIV (PLWH) who face barriers to treatment adherence are needed to maintain optimal individual health, prevent new HIV infections, and advance health equity. Efficacy trials indicate that financial incentives (FIs) are a promising strategy for promoting VLS, although less is known about their implementation in “real-world” settings. This article describes considerations for the development and implementation of FI interventions identified in existing literature, and how they informed the scale-up of a multilevel treatment adherence support program designed to increase VLS among PLWH in New York City.

Program:

The UndetectablesSM VLS Program comprises a social marketing campaign and a “tool kit” of evidence-based HIV treatment adherence strategies, including quarterly FIs ($100) that patients receive for achieving or maintaining an undetectable viral load (<200 copies/mL; also referred to as VLS). The intervention was developed and pilot tested by Housing Works Community Healthcare and the University of Pennsylvania from 2014 to 2016. Initial findings from the pilot evaluation showed a statistically significant positive effect on VLS.

Implementation:

The New York City Department of Health and Mental Hygiene contracted with 7 agencies across New York City to scale up The Undetectables Program over a 3-year period (2016-2019) by integrating the program into existing services for PLWH.

Evaluation Plans:

Quality indicators (eg, percentage of clients who received an FI each quarter; percentage of clients who were virally suppressed at 90 days postenrollment) will be used to measure program performance and impact over time.

Discussion:

Recommendations for implementing FIs for PLWH include packaging FIs with client-centered, evidence-based adherence strategies, incorporating FIs into existing service delivery systems, and obtaining organization-wide buy-in to facilitate their implementation. Implementation science research is needed to identify strategies to effectively implement and sustain evidence-based FI interventions.
An Innovative Tribal-State Partnership: The Development of the Healthy Alaskans 2020 Statewide Health Improvement Plan
Authors: Mohelsky Romy , Redwood Diana , Fenaughty Andrea , Provost Ellen , Dalena Cheryl , McGuire Lisa
Published: July 2019

This article details the development of Healthy Alaskans 2020, Alaska's statewide health improvement plan. Healthy Alaskans 2020 is a framework that supports collaborative efforts among many agencies and communities working toward the common goals of improving health and ensuring health equity for all Alaskans. The initiative was created through a unique tribal-state partnership between the Alaska Native Tribal Health Consortium and the Alaska Department of Health and Social Services. Through an iterative process using the best available epidemiologic data and extensive community input, Alaskan's health priorities were identified, with 25 leading health indicators and accompanying targets to be met by 2020. Two indicator scorecards, one for all Alaskans and one specifically for Alaska Native people, are updated annually and used for continual monitoring. The collaborative and iterative nature of Healthy Alaskans provides a model for others interested in creating multisector health improvement initiatives that align goals across systems and partners.
Survival and Disease Recurrence Rates among Breast Cancer Patients following Mastectomy with or without Breast Reconstruction
Authors: Siotos Charalampos , Naska Androniki , Bello Ricardo J. , Uzosike Akachimere , Orfanos Philippos , Euhus David M. , Manahan Michele A. , Cooney Carisa M. , Lagiou Pagona , Rosson Gedge D.
Published: July 2019

Background:

Concerns have been expressed about the oncologic safety of breast reconstruction following mastectomy for breast cancer. This study aimed to evaluate the association of breast reconstruction with breast cancer recurrence, and 5-year survival among breast cancer patients.

Methods:

The authors analyzed data from The Johns Hopkins Hospital comprehensive cancer registry, comparing mastectomy-only to postmastectomy breast reconstruction in breast cancer patients to evaluate differences in breast cancer recurrence and 5-year survival. Kaplan-Meier curves were used to compare unadjusted estimates of survival or disease recurrence. Data were modeled through Cox proportional hazards regression, using as outcomes time to death from any cause or time to cancer recurrence.

Results:

The authors analyzed data on 1517 women who underwent mastectomy for breast cancer at The Johns Hopkins hospital between 2003 and 2015. Of these, 504 (33.2 percent) underwent mastectomy only and 1013 (66.8 percent) underwent mastectomy plus immediate breast reconstruction. Women were followed up for a median of 5.1 years after diagnosis. There were 132 deaths and 100 breast cancer recurrences. A comparison of Kaplan-Meier survival estimates demonstrated a survival benefit among patients undergoing mastectomy plus reconstruction. After adjusting for various clinical and socioeconomic variables, there was still an overall survival benefit associated with breast reconstruction which, however, was not statistically significant (hazard ratio, 0.78; 95 percent CI, 0.53 to 1.13). Patients who underwent reconstruction had a similar rate of recurrence compared to mastectomy-only patients (hazard ratio, 1.08; 95 percent CI, 0.69 to 1.69).

Conclusion:

This study suggests that breast reconstruction does not have a negative impact on either overall survival or breast cancer recurrence rates.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, III.
Patterns and Correlates of Knowledge, Communication, and Receipt of Breast Reconstruction in a Modern Population-Based Cohort of Patients with Breast Cancer
Authors: Momoh Adeyiza O. , Griffith Kent A. , Hawley Sarah T. , Morrow Monica , Ward Kevin C. , Hamilton Ann S. , Shumway Dean , Katz Steven J. , Jagsi Reshma
Published: July 2019

Background:

Disparities persist in the receipt of breast reconstruction after mastectomy, and little is known about the nature of communication received by patients and potential variations that may exist.

Methods:

Women with early-stage breast cancer (stages 0 to II) diagnosed between July of 2013 and September of 2014 were identified through the Georgia and Los Angeles Surveillance, Epidemiology, and End Results registries and surveyed to collect additional data on demographics, treatment, and decision-making experiences. Treating general/oncologic surgeons were also surveyed. Primary outcomes measures included self-reported communication-related measures on receipt of information on breast reconstruction and on the receipt of breast reconstruction.

Results:

The authors analyzed 936 women who underwent mastectomy for unilateral breast cancer. Four hundred eighty-four (51.7 percent) underwent mastectomy with reconstruction. Women who were older and for whom English was not their primary spoken language had lower odds of being informed by a doctor about breast reconstruction. Ultimately, women who were older, were Asian, had invasive disease, had bronchitis/emphysema, and had lower income were less likely to undergo breast reconstruction. Breast reconstruction was performed more often in patients undergoing bilateral mastectomies (OR, 3.27; 95 percent CI, 2.26 to 4.75). Women cared for by surgeons with higher volumes of breast cancer patients (≥51 patients per year) were more likely to undergo breast reconstruction (OR, 2.43; 95 percent CI, 1.40 to 4.20).

Conclusion:

To eliminate existing disparities, increased efforts should be made in consultations for surgical management of breast cancer to provide information to all patients regarding the option of breast reconstruction, the possibility of immediate reconstruction, and insurance coverage of all stages of reconstruction.
The Relationship between Hand Therapy and Long-Term Outcomes after Distal Radius Fracture in Older Adults: Evidence from the Randomized Wrist and Radius Injury Surgical Trial
Authors: Chung Kevin C. , Malay Sunitha , Shauver Melissa J.
Published: July 2019

Background:

Older patients are frequently referred to hand therapy after distal radius fracture. Supervised therapy sessions place a transportation burden on patients and are costly on both the individual and systematic levels. Furthermore, there is little evidence that supervised therapy or home exercises improve long-term outcomes.

Methods:

Data were collected for the Wrist and Radius Injury Surgical Trial, a multicenter, international, pragmatic, randomized trial of distal radius fracture treatment in patients aged 60 years and older. Referral to therapy and therapy protocol were at the discretion of the treating surgeon and therapist. The authors examined outcomes between participants who underwent therapy and those who did not and assessed the duration of therapy. The authors also analyzed the effect of therapy on subgroups at risk for poor outcomes: older participants and those who had more comorbidities or lower baseline activity.

Results:

Eighty percent of participants underwent therapy; 70 percent participated in both supervised therapy and home exercises. Participants had a mean 9.2 supervised sessions over 14.2 weeks. There were no differences in patient-reported outcomes between participants who underwent therapy and those who did not. Participants who did not have therapy recovered more grip strength. Participants who engaged in therapy for a shorter time reported greater function, ability to work, and satisfaction. There were no relationships revealed in subgroup analyses.

Conclusions:

Hand therapy after distal radius fracture may not be necessary for older patients. Encouraging participants to resume activities of daily living as soon as possible may be as effective as formal therapy.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, II.
Caprine Models of the Agonist-Antagonist Myoneural Interface Implemented at the Above- and Below-Knee Amputation Levels
Authors: Clites Tyler R. , Carty Matthew J. , Srinivasan Shriya S. , Talbot Simon G. , Brånemark Rickard , Herr Hugh M.
Published: July 2019

Background:

Traditional approaches to amputation are not capable of reproducing the dynamic muscle relationships that are essential for proprioceptive sensation and joint control. In this study, the authors present two caprine models of the agonist-antagonist myoneural interface (AMI), a surgical approach designed to improve bidirectional neural control of a bionic limb. The key advancement of the AMI is the surgical coaptation of natively innervated agonist-antagonist muscle pairs within the residual limb.

Methods:

One AMI was surgically created in the hindlimb of each of two African Pygmy goats at the time of primary transtibial amputation. Each animal was also implanted with muscle electrodes and sonomicrometer crystals to enable measurement of muscle activation and muscle state, respectively. Coupled agonist-antagonist excursion in the agonist-antagonist myoneural interface muscles was measured longitudinally for each animal. Fibrosis in the residual limb was evaluated grossly in each animal as part of a planned terminal procedure.

Results:

Electromyographic and muscle state measurements showed coupled agonist-antagonist motion within the AMI in the presence of both neural activation and artificial muscle stimulation. Gross observation of the residual limb during a planned terminal procedure revealed a thin fibrotic encapsulation of the AMI constructs, which was not sufficient to preclude coupled muscle excursion.

Conclusions:

These findings highlight the AMI’s potential to provide coupled motion of distal agonist-antagonist muscle pairs preserved during below- or above-knee amputation at nearly human scale. Guided by these findings, it is the authors’ expectation that further development of the AMI architecture will improve neural control of advanced limb prostheses through incorporation of physiologically relevant muscle-tendon proprioception.
In the Eye of the Beholder: Changes in Perceived Emotion Expression after Smile Reanimation
Authors: Dusseldorp Joseph R. , Guarin Diego L. , van Veen Martinus M. , Jowett Nate , Hadlock Tessa A.
Published: July 2019

Background:

Tools to quantify layperson assessments of facial palsy are lacking. In this study, artificial intelligence was applied to develop a proxy for layperson assessments, and compare sensitivity to existing outcome measures.

Methods:

Artificially intelligent emotion detection software was used to develop the emotionality quotient. The emotionality quotient was defined as the percentage probability of perceived joy over the percentage probability of perceived negative emotions during smiling, as predicted by the software. The emotionality quotient was used to analyze the emotionality of voluntary smiles of normal subjects and unilateral facial palsy patients before and after smile reanimation. The emotionality quotient was compared to oral commissure excursion and layperson assessments of facial palsy patients.

Results:

In voluntary smiles of 10 normal subjects, 100 percent joy and no negative emotion was detected (interquartile ranges, 0/1). Median preoperative emotionality quotient of 30 facial palsy patients was 15/−60 (interquartile range, 73/62). Postoperatively, median emotionality quotient was 84/0 (interquartile range, 28/5). In 134 smile reanimation patients, no correlation was found between postoperative oral commissure excursion and emotionality quotient score. However, in 61 preoperative patients, a moderate correlation was found between layperson-assessed disfigurement and negative emotion perception (correlation coefficient, 0.516; p < 0.001).

Conclusions:

Computer vision artificial intelligence software detected less joy and more negative emotion in smiles of facial palsy patients compared with normal subjects. Following smile reanimation, significantly more joy and less negative emotion were detected. The emotionality quotient was correlated with layperson assessments. The simplicity, sensitivity, and objectivity of the emotionality quotient render it an attractive tool to serve as a potential proxy for layperson assessment, an ideal outcome measure in facial palsy.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Diagnostic, IV.
Paratesticular Paraganglioma
Authors: Gosavi Vikrant , Jadhav Swati , Shah Nalini S. , Shrivastava S. K. , Prakash Gagan , Shah Ravi
Published: July 2019

Paratesticular paragangliomas are a rare occurrence. We present the case of a 43-year-old man who presented with paresthesia and paraparesis and was found to have pathologic fracture involving D1 vertebra as a manifestation of metastasis from a nonsecretory right paratesticular paraganglioma.
Nivolumab-Associated Pulmonary and Bone Sarcoidosis in a Patient With Melanoma of Unknown Primary
Authors: Tulbah Rima I. , Rowe Steven P. , Solnes Lilja B. , Javadi Mehrbod S.
Published: July 2019

A 57-year-old man with stage IIIB malignant melanoma of unknown primary presented for pretherapy FDG PET/CT that demonstrated metastatic left cervical lymph node with no other site of involvement. Following left neck dissection, nivolumab was initiated. Follow-up FDG PET/CT 3 months after initiation of nivolumab demonstrated extensive radiotracer-avid chest lymphadenopathy and multiple bone lesions. Ultrasound-guided endobronchial biopsy of the mediastinal lymph nodes demonstrated sarcoidosis.
Concomitant Prostate Carcinoma and Follicular Lymphoma
Authors: Dhiantravan Nattakorn , Hovey Elizabeth , Bosco Annmarie , Wegner Eva Alina
Published: July 2019

We report a case of a 75-year-old man with concomitant metastatic prostate cancer and progressive follicular lymphoma and the utility of molecular imaging in differentiating these 2 conditions. 18F-FDG PET/CT can offer accurate staging in many cancers, although its role in prostate cancer is limited. The role of 18F-DCFPyL (PSMA) PET/CT in prostate cancer is evolving and has been demonstrated to have a higher sensitivity than conventional bone scan and CT scan. Together, FDG and PSMA PET/CT studies may offer a noninvasive approach to individually characterize concomitant malignancies, aiding optimization of management and follow-up.
Risk of Lymphedema Following Contemporary Treatment for Breast Cancer
Authors: Byun Hwa Kyung , Chang Jee Suk , Im Sang Hee , Kirova Youlia M. , Arsene-Henry Alexandre , Choi Seo Hee , Cho Young Up , Park Hyung Seok , Kim Jee Ye , Suh Chang-Ok , Keum Ki Chang , Sohn Joo Hyuk , Kim Gun Min , Lee Ik Jae , Kim Jun Won , Kim Yong Bae
Published: July 2019

Objective:

The aim of this study was to identify the comprehensive risk factors for lymphedema, thereby enabling a more informed multidisciplinary treatment decision-making.

Summary Background Data:

Lymphedema is a serious long-term complication in breast cancer patients post-surgery; however, the influence of multimodal therapy on its occurrence remains unclear.

Methods:

We retrospectively collected treatment-related data from 5549 breast cancer patients who underwent surgery between 2007 and 2015 at our institution. Individual radiotherapy plans were reviewed for regional nodal irradiation (RNI) field design and fractionation type. We identified lymphedema risk factors and used them to construct nomograms to predict individual risk of lymphedema. Nomograms were validated internally using 100 bootstrap samples and externally using 2 separate datasets of 1877 Asian and 191 Western patients.

Results:

Six hundred thirty-nine patients developed lymphedema during a median follow-up of 60 months. The 3-year lymphedema incidence was 10.5%; this rate increased with larger irradiation volumes (no RNI vs RNI excluding axilla I–II vs RNI including axilla I–II: 5.7% vs 16.8% vs 24.1%) and when using conventional fractionation instead of hypofractionation (13.5% vs 6.8%). On multivariate analysis, higher body mass index, larger number of dissected nodes, taxane-based regimen, total mastectomy, larger irradiation field, and conventional fractionation were strongly associated with lymphedema (all P < 0.001). Nomograms constructed based on these variables showed good calibration and discrimination internally (concordance index: 0.774) and externally (0.832 for Asian and 0.820 for Western patients).

Conclusions:

Trimodality breast cancer treatment factors interact to promote lymphedema. Lymphedema risk can be decreased by deintensifying node dissection, chemotherapy regimen, and field and dose of radiotherapy. Deescalation strategies on a multidisciplinary basis might minimize lymphedema risk.
Frequency of Electrodiagnostically Measurable Berrettini Anastomosis
Authors: Seidel Geoffrey K. , Seidel Madeleine E. , Hakopian David , Alabdulkarim Moayad , Rahman Abir , Andary Michael T. , Millis Scott R.
Published: July 2019

Purpose:

Ulnar sensory palmar crossover to digit three (D3), the Berrettini anastomosis, is measurable in routine electrodiagnostic nerve conduction studies. The crossover is reported as occurring in 60% of anatomic dissections, but the frequency of measurable ulnar crossover to D3 and its potential as a nerve conduction pitfall is not established. The purpose of this article was to present descriptive statistics regarding the frequency of measurable Berrettini anastomosis in nerve conduction studies.

Methods:

A retrospective chart review and data analysis was completed on 248 patients representing 411 extremities with a main outcome measure of ulnar sensory stimulated nerve conduction simultaneous waveform recording on D3 and digit four (D4). Consistent electrodiagnostic technique with waveform recording data analysis in a private practice and independent university waveform verification was completed on sequential patients referred for upper extremity electrodiagnostic testing.

Results:

Measurable ulnar stimulated D3 sensory nerve action potentials were demonstrated in 34% of patients with amplitudes of 27%, the simultaneously recorded corresponding ulnar D4 amplitudes representing electrophysiological evidence of ulnar sensory crossover.

Conclusions:

The Berrettini anastomosis can frequently be seen as a small amplitude sensory nerve action potential response, but at times can be observed with an amplitude greater than 10 μV. It is possible that patients with an absent or significantly delayed median nerve response may have simultaneous inadvertent spread of stimulus to ulnar axons measurable on D3 that may be interpreted as a falsely normal response. All electromyographers need to be aware of this potential pitfall.
Lactobacillus paracasei endocarditis of bioprosthetic aortic valve presenting with recurrent embolic strokes
Authors: Osman Abdulfatah , Taipale Michael , Najjar Mazen , Osman Baraa
Published: July 2019

Introduction.

Lactobacillus

prosthetic valve endocarditis is a rare infection caused by

Lactobacillus

bacteria. This bacterium is found in the normal flora of the human mouth, gastrointestinal tract and female genital tract. While there have been isolated cases of

Lactobacillus

bacteraemia and endocarditis, the infections are associated with comorbidities, immune deficiency, dental manipulation procedures and other medical history. This case of bioprosthetic valve endocarditis caused by

Lactobacillus paracasei

is unusual, as the patient was immune-competent and treated with pre-procedural antibiotics.

Case. We present a case of a 65-year-old male who underwent a dental extraction. He presented after 3 months of fever, chills and fatigue. On initial presentation, blood cultures were positive for alpha-haemolytic streptococcus bacteraemia. He was treated with IV penicillin and underwent aortic valve replacement with a bioprosthetic valve and excision of the mitral vegetation with repair of the mitral valve. Two years later, he had a tooth extraction after being treated properly with antibiotics. Three months later he presented with difficulty speaking, left leg weakness and increased drooling. All testing was normal. Three months later he presented with left side lower extremity weakness and expressive aphasia. He was diagnosed with bioprosthetic aortic valve endocarditis and was treated with IV penicillin and gentamicin for 6 weeks and then switched to oral penicillin. He remained stable.

Conclusions.

L. paracasei

can potentially be a cause of complicated endocarditis in patients with prosthetic heart valves undergoing dental procedures. Timely culture-guided antibiotic therapy is critical and may obviate the need for valve surgery.
Immune landscapes predict chemotherapy resistance and immunotherapy response in acute myeloid leukemia
Authors: Vadakekolathu Jayakumar , Minden Mark D. , Hood Tressa , Church Sarah E. , Reeder Stephen , Altmann Heidi , Sullivan Amy H. , Viboch Elena , Patel Tasleema , Ibrahimova Narmin , Warren Sarah E. , Arruda Andrea , Liang Yan , Muth John , Schmitz Marc , Cesano Alessandra , Pockley A. Graham , Valk Peter J.M. , Löwenberg Bob , Bornhäuser Martin , Tasian Sarah K. , Rettig Michael P. , Davidson-Moncada Jan , DiPersio John F. , Rutella Sergio
Published: July 2019

This study dissected the complexity of the immune architecture of acute myeloid leukemia (AML) at high resolution and assessed its influence on therapeutic response. Using 387 primary bone marrow samples from three discovery cohorts of children and adults with AML, we defined immune-infiltrated and immune-depleted disease subtypes and unraveled critical differences in immune gene expression across age groups and disease stages. Importantly, interferon (IFN)-γ-related mRNA profiles were predictive for both chemotherapy resistance and response of primary refractory/relapsed AML to flotetuzumab immunotherapy. Our compendium of microenvironmental gene and protein profiles sheds novel insights into the immuno-biology of AML and will inform the delivery of personalized immunotherapies to IFN-γ-dominant AML subtypes.
Regional Differences Following Partial Salivary Gland Resection
Authors: O’Keefe Kevin J. , DeSantis Kara A. , Altrieth Amber L. , Nelson Deirdre A. , Taroc Ed Zandro M. , Stabell Adam R. , Pham Mary T. , Larsen Melinda
Published: July 2019

Regenerative medicine aims to repair, replace, or restore function to tissues damaged by aging, disease, or injury. Partial organ resection is not only a common clinical approach in cancer therapy, it is also an experimental injury model used to examine mechanisms of regeneration and repair in organs. We performed a partial resection, or partial sialodenectomy, in the murine submandibular salivary gland (SMG) to establish a model for investigation of repair mechanisms in salivary glands (SGs). After partial sialoadenectomy we performed whole gland measurements over a period of 56 days and found that the gland reached its maximum size 14 days after injury. We used microarray analysis and immunohistochemistry to examine mRNA and protein changes in glands over time. Microarray analysis identified dynamic changes in the transcriptome three days after injury that were largely resolved by day 14. At the 3 day time point, we detected gene signatures for cell cycle regulation, inflammatory/repair response, and extracellular matrix remodeling in the partially resected glands. Using quantitative immunohistochemistry, we identified a transient proliferative response throughout the gland, in which both secretory epithelial and stromal cells expressed Ki67 that was detectable at day 3 and largely resolved by day 14. IHC also revealed that while most of the gland underwent a wound healing response that resolved by day 14, a small region of the gland showed an aberrant sustained fibrotic response characterized by increased levels of ECM deposition and sustained Ki67 levels in stromal cells. The partial submandibular salivary gland resection model provides an opportunity to examine a normal healing response and an aberrant fibrotic response within the same gland to uncover mechanisms that prevent wound healing and regeneration in mammals. Understanding regional differences in the wound healing responses may ultimately impact regenerative therapies for patients.
Streptococcus pyogenes infects human endometrium by limiting its immune response
Authors: Weckel Antonin , Guilbert Thomas , Lambert Clara , Plainvert Céline , Goffinet François , Poyart Claire , Méhats Céline , Fouet Agnès
Published: July 2019

Group A Streptococcus (GAS), a Gram-positive human-specific pathogen yields 517,000 deaths annually worldwide, including 163,000 due to invasive infections and among them puerperal fever. GAS is their most feared etiologic agent. Puerperal fever still accounts for more than 75,000 maternal deaths annually and before the introduction of efficient prophylactic measures 10% childbirths were followed by the mother’s death. Yet little is known regarding GAS invasive infection establishment or GAS efficiency in causing postpartum infection. To characterize its early steps, we set up coordinated analyses of ex vivo infection of the human decidua, the puerperal fever portal of entry. We analyzed GAS behavior and the immune response triggered. We demonstrate that GAS (i) benefits from tissue secreted products to multiply; (ii) invades the tissue and leads to the death of half the cells within two hours via SpeB protease and Streptolysin O activities, respectively; (iii) impairs the tissue immune response. Immune impairment occurs both at the RNA level, with the induction of only a restricted immediate innate immune response, and at the protein level, in a SLO- and SpeB-dependent manner. Our study indicates that GAS efficient decidua invasion and immune response restraint favor its propensity to develop rapid invasive infections in a gynecological-obstetrical context.
Biosynthesis of alkylcitric acids inAspergillus nigerinvolves both co-localized and unlinked genes
Authors: Palys Sylvester , Pham Thi Thanh My , Tsang Adrian
Published: July 2019

Filamentous fungi are an abundant source of bioactive secondary metabolites (SMs). In many cases, the biosynthetic processes of SMs are not well understood. This work focuses on a group of SMs, the alkylcitric acids, each of which contains a saturated alkyl “tail” and a citrate-derived “head”. We initially identified their biosynthetic gene cluster and the transcriptional regulator (akcR) involved in the biosynthesis of alkylcitrates in the filamentous fungusAspergillus nigerby examining the functional annotation of SM gene clusters predicted from genomic data. We overexpressed the transcription regulator geneakcRand obtained from a litre of culture filtrate 8.5 grams of extract containing seven alkylcitric acids as determined by NMR. Hexylaconitic acid A comprised ~ 95% of the total production, and four of the seven identified alkylcitrates have not been reported previously. Analysis of orthologous alkylcitrate gene clusters in the Aspergilli revealed an in-cluster cis-aconitate decarboxylase gene (cadA) inA. oryzaeandA. flavus, which inA. nigeris located on a different chromosome. Overexpression of theA. niger cadAandakcRgenes together shifted the profile of alkylcitrates production from primarily hexylaconitic acids to mainly hexylitaconic acids. We also detected two additional, previously unreported, alkylcitric acids in the double overexpression strain. This study shows that phylogenomic analysis together with experimental manipulations can be used to reconstruct a more complete biosynthetic pathway in generating a broader spectrum of alkylcitric compounds. The approach adopted here has the potential of elucidating the complexity of other SM biosynthetic pathways in fungi.
Matrix-Assisted Laser Desorption-Ionization Time-of-Flight mass spectrometry using a custom-made database, biomarker assignment, or mathematical classifiers does not differentiate Shigella spp. and Escherichia coli
Authors: van den Beld Maaike J.C. , Rossen John W.A. , Evers Arie , Kooistra-Smid A.M.D. (Mirjam) , Reubsaet Frans A.G.
Published: July 2019

Purpose

Shigella spp. and E. coli are closely related and cannot be distinguished using Matrix-Assisted Laser Desorption-Ionization Time-of-Flight mass spectrometry (MALDI-TOF MS) with commercially available databases. Here, three alternative approaches using MALDI-TOF MS to identify and distinguish Shigella spp., E. coli, and its pathotype EIEC were explored.

Methods

A custom-made database was developed, biomarkers were assigned, and classification models using machine learning were designed and evaluated using spectra of 456 Shigella spp., 42 E. coli, and 61 EIEC isolates, obtained by the direct smear method and the ethanol-formic acid extraction method. The isolates were identified using ipaH PCR and phenotypic and serological typing.

Results

Identification with a custom-made database resulted in >94% Shigella identified at the genus level and >91% S. sonnei and S. flexneri at the species level, but distinction of S. dysenteriae, S. boydii, and E. coli was poor. Moreover, 10-15% of duplicates rendered discrepant results. With biomarker assignment, 98% S. sonnei isolates were correctly identified, although the S. sonnei biomarkers were not specific as other species, for instance S. boydii and E. coli were also identified as S. sonnei. Discriminating markers for S. dysenteriae, S. boydii, and E. coli were not assigned at all. Classifiers identified Shigella in 96% of isolates correctly, but most E. coli isolates were also assigned to Shigella.

Conclusion

None of the proposed alternative approaches is suitable for use in clinical diagnostics for the identification of Shigella spp., E. coli, and EIEC, reflecting their relatedness and problematic taxonomical classification. We suggest the use of MALDI-TOF MS for the identification of the Shigella spp./E. coli complex, but other tests should be used for distinction.
Drifting codes within a stable coding scheme for working memory
Authors: Wolff M. J. , Jochim J. , Akyürek E. G. , Buschman T. J. , Stokes M. G.
Published: July 2019

Working memory (WM) is important to maintain information over short time periods to provide some stability in a constantly changing environment. However, brain activity is inherently dynamic, raising a challenge for maintaining stable mental states. To investigate the relationship between WM stability and neural dynamics, we used electroencephalography to measure the neural response to impulse stimuli during a WM delay. Multivariate pattern analysis revealed representations were both stable and dynamic: there was a clear difference in neural states between time-specific impulse responses, reflecting dynamic changes, yet the coding scheme for memorized orientations was stable. This suggests that a stable subcomponent in WM enables stable maintenance within a dynamic system. A stable coding scheme simplifies readout for WM-guided behaviour, whereas the low-dimensional dynamic component could provide additional temporal information. Despite having a stable subspace, WM is clearly not perfect – memory performance still degrades over time. Indeed, we find that even within the stable coding scheme, memories drift during maintenance. When averaged across trials, such drift contributes to the width of the error distribution.
Better tired than lost: turtle ant trail networks favor coherence over short edges
Authors: Chandrasekhar Arjun , Marshall James A. R. , Austin Cortnea , Navlakha Saket , Gordon Deborah M.
Published: July 2019

Creating a routing backbone is a fundamental problem in both biology and engineering. The routing backbone of the trail networks of arboreal turtle ants (Cephalotes goniodontus) connects many nests and food sources using trail pheromone deposited by ants as they walk. Unlike species that forage on the ground, the trail networks of arboreal ants are constrained by the vegetation. We examined what objectives the trail networks meet by comparing the observed ant trail networks with networks of random, hypothetical trail networks in the same surrounding vegetation and with trails optimized for four objectives: minimizing path length, minimizing average edge length, minimizing number of nodes, and minimizing opportunities to get lost. The ants’ trails minimized path length by minimizing the number of nodes traversed rather than choosing short edges. In addition, the ants’ trails reduced the opportunity for ants to get lost at each node, favoring nodes with 3D configurations most likely to be reinforced by pheromone. Thus, rather than finding the shortest edges, turtle ant trail networks take advantage of natural variation in the environment to favor coherence, keeping the ants together on the trails.

Author Summary

We investigated the trail networks of arboreal turtle ants in the canopy of the tropical forest, to ask what characterizes the colony’s choice of foraging paths within the vegetation. We monitored day to day changes in the junctions and edges of trail networks of colonies in the dry forest of western Mexico. We compared the paths used by the ants to simulated random paths in the surrounding vegetation. We found that the paths of turtle ants prioritize coherence, keeping ants together on the trail, over minimizing the average edge length. The choice of paths reduces the number of junctions in the trail where ants could get lost, and favors junctions with a physical configuration that makes it likely that successive ants will reinforce the same path. Our work suggests that design principles that emphasize keeping information flow constrained to streamlined, coherent trails may be useful in human-designed distributed routing and transport networks or robot swarms.
Reconstructing the Evolutionary History of Nitrogenases: Evidence for Ancestral Molybdenum-Cofactor Utilization
Authors: Garcia Amanda K. , McShea Hanon , Kolaczkowski Bryan , Kaçar Betül
Published: July 2019

The nitrogenase metalloenzyme family, essential for supplying fixed nitrogen to the biosphere, is one of life’s key biogeochemical innovations. The three isozymes of nitrogenase differ in their metal dependence, each binding either a FeMo-, FeV-, or FeFe-cofactor where the reduction of dinitrogen takes place. The history of nitrogenase metal dependence has been of particular interest due to the possible implication that ancient marine metal availabilities have significantly constrained nitrogenase evolution over geologic time. Here, we reconstructed the evolutionary history of nitrogenases, and combined phylogenetic reconstruction, ancestral sequence inference, and structural homology modeling to evaluate the potential metal dependence of ancient nitrogenases. We find that active-site sequence features can reliably distinguish extant Mo-nitrogenases from V- and Fe-nitrogenases, and that inferred ancestral sequences at the deepest nodes of the phylogeny suggest these ancient proteins most resemble modern Mo-nitrogenases. Taxa representing early-branching nitrogenase lineages lack one or more biosyntheticnifEandnifNgenes that both contribute to the assembly of the FeMo-cofactor in studied organisms, suggesting that early Mo-nitrogenases may have utilized an alternate and/or simplified pathway for cofactor biosynthesis. Our results underscore the profound impacts that protein-level innovations likely had on shaping global biogeochemical cycles throughout the Precambrian, in contrast to organism-level innovations that characterize the Phanerozoic Eon.
Control strategies for the timing of intracellular events
Authors: Cao Mengfang , Qiu Baohua , Zhang Jiajun , Zhou Tianshou
Published: July 2019

While the timing of intracellular events is essential for many cellular processes, gene expression inside a cell can exhibit substantial cell-to-cell variability, raising the question of how cells ensure precision in the event timing despite such stochasticity. We address this question by analyzing a biologically reasonable model of gene expression in the context of first passage time (FPT), focusing on two experimentally measurable statistics: mean FPT (MFPT) and timing variability (TV). We show that: (1) transcriptional burst size (BS) and burst frequency (BF) can minimize the TV; (2) translational BS monotonically reduces the MFPT to a nonzero low bound and can minimize the TV; (3) the timescale of promoter kinetics can minimize both the MFPT and the TV, depending on the ratio of the off-switching rate over the on-switching rate; and (4) positive feedback regulation of any form can all minimize the TV, whereas negative feedback regulation of transcriptional BF or BS always enhances the TV. These control strategies can have broad implications for diverse cellular processes relying on precise temporal triggering of events.
Limited intra-host diversity and background evolution accompany 40 years of canine parvovirus host adaptation and spread
Authors: Voorhees Ian E.H. , Lee Hyunwook , Allison Andrew B. , Lopez-Astacio Robert , Goodman Laura B. , Oyesola Oyebola O. , Omobowale Olutayo , Fagbohun Olusegun , Dubovi Edward J. , Hafenstein Susan L. , Holmes Edward C. , Parrish Colin R.
Published: July 2019

Canine parvovirus (CPV) is a highly successful pathogen that has sustained pandemic circulation in dogs for more than 40 years. Here, integrating full-genome and deep sequencing analyses, structural information, andin vitroexperimentation, we describe the macro- and micro-scale features that have accompanied CPV’s evolutionary success. Despite 40 years of viral evolution, all CPV variants are >∼99% identical in nucleotide sequence, with only a limited number (<40) of mutations becoming fixed or widespread during this time. Notably, most changes in the major capsid protein (VP2) are nonsynonymous and fall within, or adjacent to, the overlapping receptor footprint or antigenic regions, suggesting competitive selective pressures have played a key role in CPV evolution and likely constrained its evolutionary trajectory. Moreover, among the limited number of variable sites, CPV genomes exhibit complex patterns of variation that likely include parallel evolution, reversion, and recombination, making phylogenetic inference difficult. Additionally, deep sequencing of viral DNA in original clinical samples collected from dogs and other host species sampled between 1978 and 2018 revealed few sub-consensus single nucleotide variants (SNVs) above ∼0.5%, and experimental passages demonstrate that substantial pre-existing genetic variation is not necessarily required for rapid host receptor driven adaptation. Together, these findings suggest that although CPV is capable of rapid host adaptation, relatively low mutation rate, pleiotropy, and/or a lack of selective challenges since its initial emergence have reduced the long-term genetic diversity accumulation and evolutionary rate. Hence, continuously high levels of inter- and intra-host diversity are not intrinsic to highly adaptable viruses.

IMPORTANCE

Rapid mutation rates and correspondingly high levels of standing intra-host diversity and accumulated inter-host diversity over epidemic scales are often cited as key features of viruses with the capacity for emergence and sustained transmission in a new host species. However, most of this information comes from studies of RNA viruses, with relatively little being known about that evolutionary processes that occur for viruses with DNA genomes. Here we provide a unique model of virus evolution, integrating both long-term global-scale and short-term intra-host evolutionary processes of a virus in a new host animal. Our analysis reveals that successful host jumping and sustained onward transmission does not necessarily depend on a high level of intra-host diversity or result in the continued accumulation of high levels of long-term evolution change. These findings indicate that all aspects of a virus’s biology and ecology are relevant when considering their adaptability.