bluuebunny/crossref_metadata_2025 huggingface dataset:
Genetic susceptibility to fungal infection in children
Authors: Ochoa Sebastian , Constantine Gregory M. , Lionakis Michail S.
Published: October 2020

Purpose of review

Fungal infections have steadily increased in incidence, emerging as a significant cause of morbidity and mortality in patients with iatrogenic immunosuppression. Simultaneously, we have witnessed a growing population of newly described inherited immune disorders that have enhanced our understanding of the human immune response against fungi. In the present review, we provide an overview and diagnostic roadmap to inherited disorders which confer susceptibility to superficial and invasive fungal infections.

Recent findings

Inborn errors of fungal immunity encompass a heterogeneous group of disorders, some of which confer fungal infection-specific susceptibility, whereas others also feature broader infection vulnerability and/or noninfectious manifestations. Infections by Candida, Aspergillus, endemic dimorphic fungi, Pneumocystis, and dermatophytes along with their organ-specific presentations provide clinicians with important clues in the assessment of patients with suspected immune defects.

The absence of iatrogenic risk factors should raise suspicion for inborn errors of immunity in children and young adults with recurrent or severe fungal diseases. Expeditious diagnosis and prompt initiation of antifungal therapy and management of complications are paramount to achieve remission of fungal disease in the setting of primary immunodeficiency disorders.
Changing the Paradigm: Lymphovenous Anastomosis in Advanced Stage Lower Extremity Lymphedema
Authors: Cha Han Gyu , Oh Tea Min , Cho Min-Jeong , Pak Chang Sik John , Suh Hyunsuk Peter , Jeon Jae Yong , Hong Joon Pio
Published: October 2020

Background:

Traditionally, lymphovenous anastomosis is not routinely performed in patients with advanced stage lymphedema because of difficulty with identifying functioning lymphatics. This study presents the use of duplex ultrasound and magnetic resonance lymphangiography to identify functional lymphatics and reports the clinical outcome of lymphovenous anastomosis in advanced stage lower extremity lymphedema patients.

Methods:

This was a retrospective study of 42 patients (50 lower limbs) with advanced lymphedema (late stage 2 or 3) that underwent functional lymphovenous anastomoses. Functional lymphatic vessels were identified preoperatively using magnetic resonance lymphangiography and duplex ultrasound.

Results:

An average of 4.64 lymphovenous anastomoses were performed per limb using the lymphatics located in the deep fat underneath the superficial fascia. The average diameter of lymphatic vessels was 0.61 mm (range, 0.35 to 1 mm). The average limb volume was reduced 14.0 percent postoperatively, followed by 15.2 percent after 3 months, and 15.5 percent after 6 months and 1 year (p< 0.001). For patients with unilateral lymphedema, 32.4 percent had less than 10 percent volume excess compared to the contralateral side postoperatively, whereas 20.5 percent had more than 20 percent volume excess. The incidence of cellulitis decreased from 0.84 per year to 0.07 per year after surgery (p< 0.001).

Conclusion:

This study shows that functioning lymphatic vessels can be identified preoperatively using ultrasound and magnetic resonance lymphangiography; thus, lymphovenous anastomoses can effectively reduce the volume of the limb and improve subjective symptoms in patients with advanced stage lymphedema of the lower extremity.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, IV.
Evaluation of Automated Video Monitoring to Decrease the Risk of Unattended Bed Exits in Small Rural Hospitals
Authors: Jones Katherine J. , Haynatzki Gleb , Sabalka Lucas
Published: October 2020

Objectives

This study aimed to evaluate the effectiveness of using 1 to 4 mobile or fixed automated video monitoring systems (AVMSs) to decrease the risk of unattended bed exits (UBEs) as antecedents to unassisted falls among patients at high risk for falls and fall-related injuries in 15 small rural hospitals.

Methods

We compared UBE rates and fall rates during baseline (5 months in which patient movement was recorded but nurses did not receive alerts) and intervention phases (2 months in which nurses received alerts). We determined lead time (seconds elapsed from the first alert because of patient movement until 3 seconds after an UBE) during baseline and positive predictive value and sensitivity during intervention.

Results

Age and fall risk were negatively associated with the baseline patient rate of UBEs/day. From baseline to intervention: in 9 hospitals primarily using mobile systems, UBEs/day decreased from 0.84 to 0.09 (89%); in 5 hospitals primarily using fixed systems, UBEs/day increased from 0.43 to 3.18 (649%) as patients at low risk for falls were observed safely exiting the bed; and among 13 hospitals with complete data, total falls/1000 admissions decreased from 8.83 to 5.53 (37%), and injurious falls/1000 admissions decreased from 2.52 to 0.55 (78%). The median lead time of the AVMS was 28.5 seconds, positive predictive value was nearly 60%, and sensitivity was 97.4%.

Conclusions

Use of relatively few AVMSs may allow nurses to adaptively manage UBEs as antecedents to unassisted falls and fall-related injuries in small rural hospitals. Additional research is needed in larger hospitals to better understand the effectiveness of AVMSs.
Prolonged infusion of beta-lactam antibiotics for Gram-negative infections: rationale and evidence base
Authors: Abdul-Aziz Mohd H. , Portunato Federica , Roberts Jason A.
Published: October 2020

Purpose of review

The aim of this review is to discuss the rationale of and current evidence for prolonged beta-lactam infusion in the management of Gram-negative infections.

Recent findings

Pharmacokinetic/pharmacodynamic (PK/PD) data from various in-vitro and in-vivo experimental studies conclusively support prolonged infusion over intermittent infusion in terms of achieving effective beta-lactam exposure for maximal bacterial killing. Superior PK/PD target attainment has been demonstrated with prolonged beta-lactam infusion in patient populations that are more likely to have less susceptible Gram-negative infections. These populations include critically ill patients, cystic fibrosis patients and patients with malignant diseases. The clinical impact of prolonged beta-lactam infusion is likely to be the greatest in these patient groups: critically ill patients with a high level of illness severity who are not receiving renal replacement therapy; patients with nonfermenting Gram-negative bacilli infection and patients with respiratory infection. Critically ill patients with augmented renal clearance may not achieve effective beta-lactam exposure even with the use of prolonged infusion. Maximizing the effectiveness of prolonged beta-lactam infusion via therapeutic drug monitoring is becoming a more common strategy in the management of critically ill patients with Gram-negative infection.

Prolonged beta-lactam infusion may not benefit all patients but only for those who are critically ill and/or immunocompromised, who are also more likely to have less susceptible Gram-negative infections.
Prospective Evaluation of Daily and Weekly Urine pH Variations Along With Diet Intake in Postmenopausal Women With Recurrent Urinary Tract Infections
Authors: Chavez Jacqueline A. , Chavez Juliann M. , Kuprasertkul Amy , Carroll Timothy F. , Fuentes Jorge L. , Christie Alana L. , Alhalabi Feras , Zimmern Philippe E.
Published: October 2020

Objectives

Acidic urine pH may be protective against recurrent urinary tract infections (RUTIs). After reviewing the literature, we primarily analyzed urine pH fluctuations and secondarily compared them with diet in older women with RUTIs.

Methods

After IRB approval, postmenopausal women with documented RUTIs were enrolled. Participants were given preformatted charts to record urinalysis reagent strips (Medimpex) findings 4 times per day and concomitant food/beverage intake (food diary). Urine cultures at baseline ensured no infection during measurement period. Nutrient content reported in food diaries was analyzed by an experienced registered dietitian and compared with parallel fluctuations in urine pH.

Results

Of 26 women with median age of 72 years (55–86 years), the first 3 days of diet and urine pH recordings found that 17 (65%) of 26 exhibited urine pH variation greater than 1 unit, with an overall median of 6 (5–9). Comparing dietary analysis and urine pH changes, beta-carotene (P = 0.017) and total dietary sugar intake (P = 0.036) were associated with a decrease in urine pH, whereas monounsaturated fatty acids (MFA, 22:1, P = 0.023) and protein (P = 0.028) were associated with an increase in urine pH.

Conclusions

In this real-life, observational study, 65% of older women with RUTIs exhibited notable changes in urine pH, with decreased urine pH associated with nutrients found in orange and yellow vegetables and several major food groups. A longitudinal study is needed to determine if changing an individual’s diet and/or adding supplements could decrease the urine pH, thus affecting the rate of RUTIs.
A high fat anti-inflammatory diet improves widespread allodynia despite worsening metabolic outcomes in adult mice exposed to neonatal maternal separation
Authors: Eller Olivia C. , Foright Rebecca M. , Brake Aaron D. , Winter Michelle K. , Bantis Leonidas E. , Morris E. Matthew , Thyfault John P. , Christianson Julie A.
Published: October 2020

Inflammation plays a key role in the progression and maintenance of chronic pain, which impacts the lives of millions of Americans. Despite growing evidence that chronic pain can be improved by treating underlying inflammation, successful treatments are lacking and pharmaceutical interventions are limited due to drug side effects. Here we are testing whether an anti-inflammatory diet (AID) containing a combination of key anti-inflammatory compounds, at clinically relevant doses, improves pain-like behaviors in a preclinical model of chronic widespread hypersensitivity induced by neonatal maternal separation (NMS). Our results demonstrate a benefit of the AID on pain-like behaviors, despite the diet being high in fat, which led to increased caloric intake, adiposity, and weight gain. The AID specifically increased measures of metabolic syndrome and inflammation in female mice, compared to an isocaloric, macronutrient-matched diet lacking the anti-inflammatory compounds. Male mice, especially those exposed to NMS, were equally susceptible to both diets worsening metabolic measures. This work highlights important sexual dimorphic outcomes related to early life stress exposure and dietary interventions, as well as a potential disconnect between improvements in pain-like behaviors and metabolic measures.
Adult spiny mice (Acomys) exhibit endogenous cardiac recovery in response to myocardial infarction
Authors: Peng Hsuan , Shindo Kazuhiro , Donahue Renée R. , Gao Erhe , Ahern Brooke M. , Levitan Bryana M. , Tripathi Himi , Powell David , Noor Ahmed , Satin Jonathan , Seifert Ashley W. , Abdel-Latif Ahmed
Published: October 2020

Complex tissue regeneration is extremely rare among adult mammals. An exception, however, is the superior tissue healing of multiple organs in spiny mice (Acomys). WhileAcomysspecies exhibit the remarkable ability to heal complex tissue with minimal scarring, little is known about their cardiac structure and response to cardiac injury. In this study, we first examined baselineAcomyscardiac anatomy and function in comparison with the commonly used laboratoryMusstrains (C57BL6 and SWR). Our results demonstrated comparable cardiac anatomy and function betweenAcomysandMus, butAcomysexhibited a higher percentage of cardiomyocytes exhibiting immature characteristics. In response to myocardial infarction, all animals experienced a comparable level of initial cardiac damage. However,Acomysdemonstrated superior ischemic tolerance and cytoprotection in response to injury as evidenced by cardiac functional stabilization, higher survival rate and smaller scar size 50 days after injury compared to the inbred and outbred mouse strains. Overall, these findings demonstrate augmented myocardial preservation in spiny mice post-MI and establishAcomysas a new adult mammalian model for cardiac research.
A Convolutional Auto-Encoder for Haplotype Assembly and Viral Quasispecies Reconstruction
Authors: Ke Ziqi , Vikalo Haris
Published: October 2020

Haplotype assembly and viral quasispecies reconstruction are challenging tasks concerned with analysis of genomic mixtures using sequencing data. High-throughput sequencing technologies generate enormous amounts of short fragments (reads) which essentially oversample components of a mixture; the representation redundancy enables reconstruction of the components (haplotypes, viral strains). The reconstruction problem, known to be NP-hard, boils down to grouping together reads originating from the same component in a mixture. Existing methods struggle to solve this problem with required level of accuracy and low runtimes; the problem is becoming increasingly more challenging as the number and length of the components increase. This paper proposes a read clustering method based on a convolutional auto-encoder designed to first project sequenced fragments to a low-dimensional space and then estimate the probability of the read origin using learned embedded features. The components are reconstructed by finding consensus sequences that agglomerate reads from the same origin. Mini-batch stochastic gradient descent and dimension reduction of reads allow the proposed method to efficiently deal with massive numbers of long reads. Experiments on simulated, semi-experimental and experimental data demonstrate the ability of the proposed method to accurately reconstruct haplotypes and viral quasispecies, often demonstrating superior performance compared to state-of-the-art methods.
Role of intercellular coupling and delay on the synchronization of genetic oscillators
Authors: Dey Supravat , Tracey Lee , Singh Abhyudai
Published: October 2020

Living cells encode diverse biological clocks for circadian timekeeping and formation of rhythmic structures during embryonic development. A key open question is how these clocks synchronize across cells through intercellular coupling mechanisms. To address this question, we leverage the classical motif for genetic clocks the Goodwin oscillator where a gene product inhibits its own synthesis via time-delayed negative feedback. More specifically, we consider an interconnected system of two identical Goodwin oscillators (each operating in a single cell), where state information is conveyed between cells via a signaling pathway whose dynamics is modeled as a first-order system. In essence, the interaction between oscillators is characterized by an intercellular coupling strength and an intercellular time delay that represents the signaling response time. Systematic stability analysis characterizes the parameter regimes that lead to oscillatory dynamics, with high coupling strength found to destroy sustained oscillations. Within the oscillatory parameter regime we find both in-phase and anti-phase oscillations with the former more likely to occur for small intercellular time delays. Finally, we consider the stochastic formulation of the model with low-copy number fluctuations in biomolecular components. Interestingly, stochasticity leads to qualitatively different behaviors where in-phase oscillations are susceptible to the inherent fluctuations but not the anti-phase oscillations. In the context of the segmentation clock, such synchronized in-phase oscillations between cells are critical for the proper generation of repetitive segments during embryo development that eventually leads to the formation of the vertebral column.
Leptin receptor expression in the dorsomedial hypothalamus stimulates breathing during NREM sleep indb/dbmice
Authors: Pho Huy , Berger Slava , Freire Carla , Kim Lenise J , Shin Mi-Kyung , Streeter Stone R , Hosamane Nishitha , Cabassa Meaghan E , Anokye-Danso Frederick , Dergacheva Olga , Amorim Mateus , Fleury-Curado Thomaz , Jun Jonathan J , Schwartz Alan R , Ahima Rexford S , Mendelowitz David , Polotsky Vsevolod Y
Published: October 2020

Obesity can lead to recurrent upper airway obstruction (obstructive sleep apnea, OSA) during sleep as well as alveolar hypoventilation. We have previously shown that leptin stimulates breathing and treats OSA in leptin-deficientob/obmice and leptin-resistant diet-induced obese mice. Our previous data also suggest that leptin’s respiratory effects may occur in the dorsomedial hypothalamus (DMH). We selectively expressed leptin receptorLepRbin the DMH neurons of obeseLepRb-deficientdb/dbmice (LepRb-DMH mice), which hypoventilate at baseline, and showed that intracerebroventricular injection of leptin in these animals increased inspiratory flow, tidal volume and minute ventilation during NREM sleep without any effect on the quality of NREM sleep or CO2production. Leptin had no effect on upper airway obstruction inLepRb-DMHanimals. We conclude that leptin stimulates breathing and treats obesity related hypoventilation acting on LepRb-positive neurons in the DMH.
Syncmers are more sensitive than minimizers for selecting conservedk-mers in biological sequences
Authors: Edgar Robert C.
Published: October 2020

Minimizers are widely used to select subsets of fixed-length substrings (k-mers) from biological sequences in applications ranging from read mapping to taxonomy prediction and indexing of large datasets. The minimizer of a string ofwconsecutivek-mers is thek-mer with smallest value according to an ordering of allk-mers. Syncmers are a family of alternative methods which selectk-mers by inspecting the position of the smallest-valued substring of lengths<kwithin thek-mer. For example, a closed syncmer selected if its smallests-mer is at the start of end of thek-mer. At least one closed syncmer must be found in every window of length (k–s)k-mers. Unlike a minimizer, a syncmer is identified by its sequence alone, and is therefore synchronized in the following sense: if a givenk-mer is selected from one sequence, it will also be selected from any other sequence. Also, minimizers can be deleted by mutations in flanking sequence, which cannot happen with syncmers. Experiments on minimizers with parameters used in the minimap2 read mapper and Kraken taxonomy prediction algorithm respectively show that syncmers can simultaneously achieve both lower density and higher conservation compared to minimizers.
Identification and transcriptional regulation of the mir-218-1 alternative promoter
Authors: Rheinheimer Brenna A. , Vrba Lukas , Futscher Bernard W , Heimark Ronald L
Published: October 2020

Background

miRNAs are small, endogenous non-coding RNAs approximately 22 nucleotides in length that account for approximately 1% of the genome and play key regulatory roles in multiple signaling pathways. mir-218-1 is an intronic miRNA located within intron 15 of theSLIT2gene. Public datasets showed enrichment of H3K4me3 within intron 4 of the SLIT2 gene. Therefore, we sought to determine the genomic location and transcriptional regulatory elements of the mir-218-1 candidate alternative promoter in pancreatic ductal adenocarcinoma.

Methods

Expression of mir-218 was evaluated in a panel of pancreatic ductal adenocarcinoma cell lines. The mir-218-1 candidate alternative promoter was characterized by chromatin immunoprecipitation, Sequenom, and luciferase assays. Transcriptional regulation of the mir-218-1 candidate alternative promoter was assessed using chromatin immunoprecipitation and an inhibitor to NF-kB.

Results

We found that expression of mir-218-1 does not correlate with SLIT2 expression and that mir-218-1 has a novel transcriptional start site separate from the SLIT2 promoter. This novel transcriptional start site showed transcriptional activity and was regulated by NF-kB.

Conclusions

mir-218-1 is transcribed from an independent and novel transcriptional start site located within intron 4 of the SLIT2 gene in pancreatic ductal adenocarcinoma. Additionally, mir-218-1 expression is regulated by Nf-kB at this alternative transcriptional start site in pancreatic cancer.
Continuous Rate Modelling of bacterial stochastic size dynamics
Authors: Nieto Cesar , Vargas-Garcia Cesar , Pedraza Juan
Published: October 2020

Bacterial division is an inherently stochastic process. However, theoretical tools to simulate and study the stochastic transient dynamics of cell-size are scarce. Here, we present a general theoretical approach based on the Chapman-Kolmogorov formalism to describe these stochastic dynamics including continuous growth and division events as jump processes. Using this approach, we analyze the effect of different sources of noise on the dynamics of the size distribution. Oscillations in the distribution central moments were found as consequence of the discrete translation invariance of the system with period of one doubling time, these oscillations are found in both the central moments of the size distribution and the auto-correlation function and do not disappear including stochasticity on division times or size heterogeneity on the population but only after include noise in either growth rate or septum position.
A preferential role for ventromedial prefrontal cortex in assessing “the value of the whole” in multi-attribute object evaluation
Authors: Pelletier Gabriel , Aridan Nadav , Fellows Lesley K. , Schonberg Tom
Published: October 2020

Everyday decision-making commonly involves assigning values to complex objects with multiple value-relevant attributes. Drawing on object recognition theories, we hypothesized two routes to multi-attribute evaluation: assessing the value of the whole object based on holistic attribute configuration or summing individual attribute-values. In two samples of healthy human participants undergoing eye-tracking and fMRI while evaluating novel pseudo-objects, we found evidence for both forms of evaluation. Fixations to, and transitions between attributes differed systematically when value of pseudo-objects was associated with individual attributes or attribute configurations. Ventromedial prefrontal cortex (vmPFC) and perirhinal cortex were engaged when configural processing was required. These results converge with our recent findings that individuals with vmPFC lesions were impaired in decisions requiring configural evaluation, but not when evaluating “the sum of the parts”. This suggests that multi-attribute decision-making engages distinct evaluation mechanisms relying on partially dissociable neural substrates, depending on the relationship between attributes and value.

SIGNIFICANCE STATEMENT

Decision neuroscience has only recently begun to address how multiple choice-relevant attributes are brought together during evaluation and choice among complex options. Object recognition research makes a crucial distinction between individual attribute and holistic/configural object processing, but how the brain evaluates attributes and whole objects remains unclear. Using fMRI and eye-tracking, we found that the vmPFC and the perirhinal cortex contribute to value estimation specifically when it emerged from the whole objects i.e. predicted by the unique configuration of attributes, and not when value was predicted by the sum of individual attributes. This novel perspective on the interactions between subjective value and object processing mechanisms bridges an important gap between the fields of object recognition and reward-guided decision-making.
Experimental Estimate of Soil Nutrient Exchange in an Afrotropical Forest: The Role of Dung Beetle Community Complexity
Authors: Stanbrook Roisin
Published: October 2020

Despite recognition of its importance, little is known about functional aspects of soil fauna. Here, we investigate the effect that different dung beetle functional groups have on macronutrient movement (N, P, K, and C) from dung into soil over 112-day period. We report a large overall effect where more macronutrients are moved into soil over time when beetles are present compared to a control treatment. We also report a large effect of beetle functional groupings on the amount of macronutrient movement, with larger dung beetles moving more nutrients over time. We provide the first experimental evidence that dung beetle body size directly influences macronutrient recycling and discuss the importance of dung beetle functional characteristics in maintaining soil fertility.
Epigenetic clock and DNA methylation analysis of porcine models of aging and obesity
Authors: Schachtschneider Kyle M. , Schook Lawrence B , Meudt Jennifer J. , Shanmuganayagam Dhanansayan , Zoller Joseph A. , Haghani Amin , Li Caesar Z. , Zhang Joshua , Yang Andrew , Raj Ken , Horvath Steve
Published: October 2020

DNA-methylation profiles have been used successfully to develop highly accurate biomarkers of age, epigenetic clocks, for many species. Using a custom methylation array, we generated DNA methylation data from n=238 porcine tissues including blood, bladder, frontal cortex, kidney, liver and lung, from domestic pigs (Sus scrofa domesticus) and minipigs (Wisconsin Miniature Swine™). We present 4 epigenetic clocks for pigs that are distinguished by their compatibility with tissue type (pan-tissue and blood clock) and species (pig and human). Two dual-species human-pig pan-tissue clocks accurately measure chronological age and relative age, respectively. We also characterized CpGs that differ between minipigs and domestic pigs. Strikingly, several genes implicated by our epigenetic studies of minipig status overlap with genes (ADCY3, TFAP2B, SKOR1, andGPR61) implicated bygeneticstudies of body mass index in humans. In addition, CpGs with different levels of methylation between the two pig breeds were identified proximal to genes involved in blood LDL levels and cholesterol synthesis, of particular interest given the minipig’s increased susceptibility to cardiovascular disease compared to domestic pigs. Thus, inbred differences of domestic and minipigs may potentially help to identify biological mechanisms underlying weight gain and aging-associated diseases. Our porcine clocks are expected to be useful for elucidating the role of epigenetics in aging and obesity, and the testing of anti-aging interventions.
Single molecule dynamics of DNA receptor ComEA, membrane permease ComEC and taken up DNA in competentBacillus subtiliscells
Authors: Burghard-Schrod Marie , Kilb Alexandra , Krämer Kai , Graumann Peter L.
Published: October 2020

In competent gram-negative and gram-positive bacteria, double stranded DNA is taken up through the outer cell membrane and/or the cell wall, and is bound by ComEA, which inBacillus subtilisis a membrane protein. DNA is converted to single stranded DNA, and transported through the cell membrane via ComEC. We show that inBacillus subtilis, the C-terminus of ComEC, thought to act as a nuclease, is not only important for DNA uptake, as judged from a loss of transformability, but also for the localization of ComEC to the cell pole and its mobility within the cell membrane. Using single molecule tracking, we show that only 13% of ComEC molecules are statically localised at the pole, while 87% move throughout the cell membrane. These experiments suggest that recruitment of ComEC to the cell pole is mediated by a diffusion/capture mechanism. Mutation of a conserved aspartate residue in the C-terminus, likely affecting metal binding, strongly impairs transformation efficiency, suggesting that this periplasmic domain of ComEC could indeed serve a catalytic function as nuclease. By tracking fluorescently labeled DNA, we show that taken up DNA has a similar mobility within the periplasm as ComEA, suggesting that most taken up molecules are bound to ComEA. We show that DNA can be highly mobile within the periplasm, indicating that this subcellular space can act as reservoir for taken up DNA, before its entry into the cytosol.

Importance

Bacteria can take up DNA from the environment and incorporate it into their chromosome in case similarity to the genome exists. This process of “natural competence” can result in the uptake of novel genetic information leading to horizontal gene transfer. We show that fluorescently labelled DNA moves within the periplasm of competentBacillus subtiliscells with similar dynamics as DNA receptor ComEA, and thus takes a detour to get stored before uptake across the cell membrane into the cytosol by DNA permease ComEC. The latter assembles at a single cell pole, likely by a diffusion-capture mechanism, and requires its large C-terminus, including a conserved residue thought to confer nuclease function, for proper localization, function and mobility within the membrane.
The Association of Late-Life Self-Reported Vision and Hearing Impairments with Cognitive Function: A 3-Year Longitudinal Mediation Analysis Through Social Isolation
Authors: Yorgason Jeremy B. , Tanner Corinna Trujillo , Richardson Stephanie , Hill Melanie S. , Stagg Brian , Wettstein Markus , Ehrlich Joshua R.
Published: October 2020

Background and Objectives

Vision impairment (VI), hearing impairment (HI), and dual sensory impairment (DSI), are prevalent among older adults and have been associated with cognitive impairment in later life. Knowledge about mediating pathways that account for the association between sensory impairment and cognitive impairment is scarce. Mediators of this association could serve as possible future intervention targets. We examined longitudinal associations between sensory impairment and cognitive functioning indirectly through social isolation.

Research Design and Methods

Data were taken from a nationally representative panel study, The National Health and Aging Trends Study, an annual survey of Medicare beneficiaries age ≥ 65. Participants (N = 6,286) from Rounds 5, 6, and 7 (2015, 2016, 2017), with complete data on self-reported VI and/or HI status at baseline. Structural equation models were estimated to test longitudinal direct and indirect associations.

Results

Adjusting for covariates, cross-sectional results indicated that all sensory impairments (VI, HI, and DSI) were negatively associated with all cognitive functioning measures through social isolation. Longitudinally, only VI was indirectly associated with word-recall scores across 1 and 2 years through social isolation, as well as across 2 years for orientation.

Discussion and Implications

As social isolation is both a consequence of sensory impairment and a risk factor for cognitive impairment, it provided a starting point from which to study the process of cognitive decline among those with sensory impairments. Awareness of the association of sensory impairment with social isolation, as well as its longitudinal implications for cognitive health, may enhance our ability to intervene.
Widely used mutants ofeiger, encoding theDrosophilaTumor Necrosis factor, carry additional mutations in the NimrodC1 phagocytosis receptor
Authors: Kodra Albana , de la Cova Claire , Gerhold Abigail R. , Johnston Laura A.
Published: October 2020

The process of apoptosis in epithelia involves activation of caspases, delamination of cells, and degradation of cellular components. Corpses and cellular debris are then rapidly cleared from the tissue by phagocytic blood cells. In studies of theDrosophilaTNF, Eiger (Egr) and cell death in wing imaginal discs, the epithelial primordia of fly wings, we noticed that dying cells persisted longer inegr3mutant wing discs than in wild type discs, raising the possibility that their phagocytic engulfment by hemocytes was impaired. Further investigation revealed that lymph glands and circulating hemocytes fromegr3mutant larvae were completely devoid of NimC1 staining, a marker of phagocytic hemocytes. Genome sequencing uncovered mutations in theNimC1coding region that are predicted to truncate the NimC1 protein before its transmembrane domain, and provide an explanation for the lack of NimC staining. The work that we report here demonstrates the presence of theseNimC1mutations in the widely usedegr3mutant, its sister allele,egr1, and its parental strain,Regg1GS9830. As theegr3andegr1alleles have been used in numerous studies of immunity and cell death, it may be advisable to re-evaluate their associated phenotypes.
Epithelial HVEM promotes basement membrane synthesis and intraepithelial T cell survival and migration
Authors: Takahashi Daisuke , Wang Qingyang , Seo Goo-Young , Shui Jr-wen , Mikulski Zbigniew , Marcovecchio Paola , Takahashi Masumi , Surh Charles D. , Cheroutre Hilde , Kronenberg Mitchell
Published: October 2020

Intraepithelial T cells (IET) provide continuous surveillance of the intestinal epithelium, but little was known about how epithelial-derived signals regulate the IET population. We show that epithelial expression of the herpes virus entry mediator (HVEM), a member of the TNF receptor superfamily (TNFRSF), maintained the survival of small intestine IET, especially innate-like TCRαβ+cells lacking CD4 and CD8β. Patrolling movement of all CD8α+IET also was impaired in the absence of HVEM. HVEM-deficient epithelial cells exhibited downregulation of synthesis of basement membrane components, including collagen IV. Collagen IV supported IET survivalin vitrovia interactions with β1integrins expressed by the IET; absence of β1integrins decreased some IET subsets. Therefore, these data define a circuit whereby epithelial cells regulate intestine resident T lymphocyte populations through basement membrane synthesis.
DDX3X and DDX3Y are redundant in protein synthesis
Authors: Venkataramanan Srivats , Calviello Lorenzo , Wilkins Kevin , Floor Stephen N.
Published: October 2020

DDX3 is a DEAD-box RNA helicase that regulates translation and is encoded by the X- and Y-linked paralogs DDX3X and DDX3Y. While DDX3X is ubiquitously expressed in human tissues and essential for viability, DDX3Y is male-specific and shows lower and more variable expression than DDX3X in somatic tissues. Heterozygous genetic lesions in DDX3X mediate a class of developmental disorders called DDX3X syndrome, while loss of DDX3Y is implicated in male infertility. One possible explanation for female-bias in DDX3X syndrome is that DDX3Y encodes a polypeptide with different biochemical activity. In this study, we use ribosome profiling and in vitro translation to demonstrate that the X- and Y-linked paralogs of DDX3 play functionally redundant roles in translation. We find that transcripts that are sensitive to DDX3X depletion or mutation are rescued by complementation with DDX3Y. Our data indicate that DDX3X and DDX3Y proteins can functionally complement each other in human cells. DDX3Y is not expressed in a large fraction of the central nervous system. These findings suggest that expression differences, not differences in paralog-dependent protein synthesis, underlie the sex-bias of DDX3X-associated diseases.
Phenotypic Differences in Adult and Fetal Dermal Fibroblast Responses to Mechanical Tension
Authors: Short Walker D. , Parikh Umang M. , Templeman Natalie , Olutoye Oluyinka O. , Blum Alexander , Colchado Daniel , Padon Benjamin , Kaul Aditya , Li Hui , Vangapandu Hima V. , Jung Olivia S. , Bommekal Pranav , Kogan Phillip , Fahrenholtz Monica M. , Coarfa Cristian , Balaji Swathi
Published: October 2020

Objective

Fetal regenerative wound healing is characterized by hyaluronan(HA)-rich microenvironment and fibroblasts that produce pericellular matrices(PCM) abundant in high molecular weight HA. Recent studies showed that while small wounds in fetal skin heal regeneratively, large wounds heal with fibrosis. We posit large wounds generate higher mechanical tension which alters HA metabolism in the fetal fibroblasts and lead to a pro-fibrotic phenotype.

Approach

C57BL/6J murine fetal (FFB; E14.5) and adult (AFB; 8wk) dermal fibroblasts were subjected to +/-10% tonic strain. Changes in PCM, HA enzymes and molecular weight, and fibrotic gene expression were measured.

Results

FFB pericellular matrix reduced upon exposure to increased tension, and the HA profile shifted from high to lower molecular weight. Under static conditions, AFB had higher expression of HA synthases (HAS) 1 and 2 and degradation enzymes KIAA1199, HYAL1, and TMEM2 than FFB, suggesting more HA turnover in AFB. Tension resulted in an increase in HAS1, HAS3, KIAA1199, and HYAL2 expression and a decrease in HAS2 and TMEM2 expression in FFB. CD26, a marker associated with scar production, increased in FFB under tension, along with altered fibrotic gene expression profile and reorganized cytoskeletal f-actin and increased α-SMA that resembled AFB.

Innovation

This study elucidates the differences in how biomechanical tension alters HA metabolism and fibrotic phenotype of FFB vs AFB, providing further understanding of the fetal regenerative wound healing phenotype.

Conclusion

Understanding the intrinsic differences in HA metabolism and fibrotic phenotype among FFB and AFB in response to wound mechanical stimuli may yield new insights to promote regenerative wound healing.
Respiratory depression and analgesia by opioid drugs in freely-behaving larval zebrafish
Authors: Zaig Shenhab , Scarpellini Carolina , Montandon Gaspard
Published: October 2020

An opioid epidemic is spreading in North America with millions of opioid overdoses annually. Opioid drugs, like fentanyl, target the mu opioid receptor system and induce potentially lethal respiratory depression. The challenge in opioid research is to find a safe pain therapy with analgesic properties but no respiratory depression. Current discoveries are limited by lack of amenable animal models to screen candidate drugs. Zebrafish (Danio rerio) is an emerging animal model with high reproduction and fast development, which shares remarkable similarity in their physiology and genome to mammals. However, it is unknown whether zebrafish possesses similar opioid system, respiratory and analgesic responses to opioids than mammals. In freely-behaving larval zebrafish, fentanyl depresses the rate of respiratory mandible movements and induces analgesia, effects reversed by mu-opioid receptor antagonists. Zebrafish presents evolutionary conserved mechanisms of action of opioid drugs, also found in mammals, and constitute amenable models for phenotype-based drug discovery.
Model-guided design of mammalian genetic programs
Authors: Muldoon Joseph J. , Kandula Viswajit , Hong Mihe , Donahue Patrick S. , Boucher Jonathan D. , Bagheri Neda , Leonard Joshua N.
Published: October 2020

Genetically engineering cells to perform customizable functions is an emerging frontier with numerous technological and translational applications. However, it remains challenging to systematically engineer mammalian cells to execute complex functions. To address this need, we developed a method enabling accurate genetic program design using high-performing genetic parts and predictive computational models. We built multi-functional proteins integrating both transcriptional and post-translational control, validated models for describing these mechanisms, implemented digital and analog processing, and effectively linked genetic circuits with sensors for multi-input evaluations. The functional modularity and compositional versatility of these parts enable one to satisfy a given design objective via multiple synonymous programs. Our approach empowers bioengineers to predictively design mammalian cellular functions that perform as expected even at high levels of biological complexity.
The role of cation diffusion facilitator CDF-1 in lipid metabolism inCaenorhabditis elegans
Authors: Hu Ying , Wang Yanli , Wang Xuanjun , Wu Xiaoyun , Fu Lin , Liu Xiayu , Wen Yu , Sheng Jun , Zhang Jingjing
Published: October 2020

Zinc is one of the most important trace elements that plays a vital role in many biological processes, and aberrant zinc metabolism has been implicated in lipid-related metabolic diseases. Previously, we showed that zinc antagonizes iron to regulate sterol regulatory element-binding proteins and stearoyl-CoA desaturase (SREBP-SCD) pathway in lipid metabolism in model organismCaenorhabditis elegans. Here, we further identified another cation diffusion facilitator CDF-1 in addition to SUR-7 in response to zinc to regulate lipid metabolism. Inactivation of SBP-1, the only homolog of SREBPs, leads to increased zinc level but decreased lipid accumulation reversely. However, eithercdf-1(n2527)orsur-7(tm6523)mutation could successfully restore the altered fatty acid profile, fat content and zinc level ofsbp-1(ep79)mutant. Furthermore, we found that CDF-1/SUR-7 may function bypass SBP-1 to directly affect the conversion activity of SCD in the biosynthesis of unsaturated fatty acids and lipid accumulation. Collectively, these results consistently support the link between zinc homeostasis and lipid metabolism via SREBP-SCD axis by cation diffusion facilitators CDF-1 and SUR-7.
Novel genetic tools to model functional enzyme restoration in succinic semialdehyde dehydrogenase deficiency (SSADHD)
Authors: Cheong Lee Henry Hing , Pearl Phillip , Rotenberg Alexander
Published: October 2020

SSADHD is a rare inborn metabolic disorder caused by the functional impairment of SSADH (encoded by the aldh5a1 gene), an enzyme essential for breaking down the inhibitory neurotransmitterγ-aminobutyric acid (GABA). In SSADHD, pathologic accumulation of GABA results in broad spectrum encephalopathy including developmental delay, ataxia, seizures and a risk of sudden unexpected death in epilepsy (SUDEP). Proof-of-concept systemic SSADH restoration via enzyme replacement therapy (ERT) or aldh5a1 gene transfer increased survival of SSADH knockout mice, suggesting that SSADH restoration might be a viable cure for SSADHD. However, before testing SSADH restoration therapy in patients, we must consider its safety and feasibility in context of the unique SSADHD pathophysiology. Specifically, a profound use-dependent down-regulation of GABAAreceptors in SSADHD indicates a risk that sudden SSADH restoration might diminish GABAergic tone and provoke seizures. Such risk may be mitigated by gradual, rather than abrupt, SSADH restoration, or by restoration that is confined to critical cell types and brain regions. We therefore describe early work to construct a novel SSADHD mouse model that allows ‘on-demand’ SSADH restoration for the systematic investigation of the rate, timing and cell-specific parameters of SSADH-restoring therapies. We aim to understand the clinical readiness of specific SSADH restoration protocols on brain physiology for purposes of accelerating the bench to bed-side development of ERT or gene therapy for SSADHD patients.
High-dimensional mass cytometry analysis of NK cell alterations in Acute Myeloid Leukemia identifies a subgroup with adverse clinical outcome
Authors: Chretien Anne-Sophie , Devillier Raynier , Granjeaud Samuel , Cordier Charlotte , Demerle Clemence , Salem Nassim , Wlosik Julia , Orlanducci Florence , Gregori Emilie , Paul Magali , Rochigneux Philippe , Pagliardini Thomas , Morey Mathieu , Fauriat Cyril , Dulphy Nicolas , Toubert Antoine , Luche Herve , Malissen Marie , Blaise Didier , Nunès Jacques A. , Vey Norbert , Olive Daniel
Published: October 2020

Natural killer (NK) cells are major anti-leukemic immune effectors. Leukemic blasts have a negative impact on NK cell function and promote the emergence of phenotypically and functionally impaired NK cells. In the present work, we highlight an accumulation of CD56-CD16+unconventional NK cells in acute myeloid leukemia (AML), an aberrant subset initially described as being elevated in patients chronically infected with HIV-1. Deep phenotyping of NK cells was performed using peripheral blood from patients with newly-diagnosed AML (N=48, HEMATOBIO cohort,NCT02320656) and healthy subjects (N=18) by mass cytometry. We evidenced a moderate to drastic accumulation of CD56-CD16+unconventional NK cells in 27% of patients. These NK cells displayed decreased expression of NKG2A as well as the triggering receptors NKp30, and NKp46, in line with previous observations in HIV-infected patients. High-dimensional characterization of these NK cells highlighted a decreased expression of three additional major triggering receptors required for NK cell activation, NKG2D, DNAM-1, and CD96. A high proportion of CD56-CD16+NK cells at diagnosis was associated with an adverse clinical outcome, with decreased overall survival (HR=0.13; P=.0002) and event-free survival (HR=0.33; P=.018), and retained statistical significance in multivariate analysis. Pseudo-time analysis of the NK cell compartment highlighted a disruption of the maturation process, with a bifurcation from conventional NK cells toward CD56-CD16+NK cells. Overall, our data suggest that the accumulation of CD56-CD16+NK cells may be the consequence of immune escape from innate immunity during AML progression.

Significance

This work provides the first report of accumulation of unconventional CD56-CD16+ NK cells in non-virally induced malignancies. Pseudotime analysis highlights a bifurcation point occurring during the course of NK cell maturation, providing elements regarding the possible origin of CD56-CD16+ NK cells. Increased frequency of CD56-CD16+ NK cells is associated with adverse clinical outcome in AML and might contribute, as well as other maturation defects, to a defective control of AML progression. Overall, accumulation of CD56-CD16+ NK cells could be an important feature of immune escape from innate immunity.

Graphical abstract

Key points

A disruption in the maturation process of NK cells leads to accumulation of unconventional CD56-CD16+NK cells in patients with AML

High frequency of CD56-CD16+NK cells is associated with adverse clinical outcome
Single Cell Analysis Reveals Multi-faceted miR-375 Regulation of the Intestinal Crypt
Authors: Shanahan Michael T. , Kanke Matt , Singh Ajeet P. , Villanueva Jonathan W. , McNairn Adrian J. , Oyesola Oyebola O. , Bonfini Alessandro , Hung Yu-Han , Sheahan Breanna , Bloom Jordana C. , Cubitt Rebecca L. , Curry Ennessa G. , Pitman Wendy A. , Rinaldi Vera D. , Dekaney Christopher M. , Ding Shengli , Peck Bailey C.E. , Schimenti John C. , Dow Lukas E. , Buchon Nicolas , Tait-Wojno Elia D. , Sethupathy Praveen
Published: October 2020

The role of individual miRNAs in small intestinal (SI) epithelial homeostasis is under-explored. In this study, we discovered that miR-375 is among the most enriched miRNAs in intestinal crypts and stem cells (ISCs), especially facultative ISCs. We then showed by multiple manipulations, including CRISPR/Cas9 editing, that miR-375 is strongly suppressed by Wnt-signaling. Single-cell RNA-seq analysis of SI crypt-enriched cells from miR-375 knockout (375-KO) mice revealed elevated numbers of tuft cells and increased expression of pro-proliferative genes in ISCs. Accordingly, the genetic loss of miR-375 promoted resistance to helminth infection and enhanced the regenerative response to irradiation. The conserved effects of miR-375 were confirmed by gain-of-function studies in Drosophila midgut stem cellsin vivo.Moreover, functional experiments in enteroids uncovered a regulatory relationship between miR-375 and Yap1 that controls cell survival. Finally, analysis of mouse model and clinical data revealed an inverse association between miR-375 levels and intestinal tumor development.

Highlights

miR-375 is one of the most enriched miRNAs in ISCs, especially facultative ISCs.

miR-375 modifies tuft cell abundance and pro-proliferative gene expression in ISCs.

Loss of miR-375 in mice enhances the host response to helminth infection and crypt regeneration.

Mouse and human intestinal cancer are associated with reduced miR-375 expression.

eTOC Blurb

Sethupathy and colleagues show that miR-375 is a Wnt-responsive, ISC-enriched miRNA that serves as a break on intestinal crypt proliferation. They also show that miR-375 modulates tuft cell abundance and pro-proliferative gene expression in ISCs, that miR-375 loss enhances the host response to helminth infection as well as crypt regeneration post-irradiation, and its reduced expression is associated with intestinal cancer.