bluuebunny/crossref_metadata_2025 huggingface dataset:
Serum Anti-PGL-1 IgG, IgM, and IgA in a 3-Year Follow-up Study of 4–15-Year-old Leprosy Contacts
Authors: TiemiNagao-Dias Aparecida , Casimiro de Macedo Alexandre , Rodrigues Raphael Oliveira , Pedroza Fernando Henrique De Castro , Albuquerque Andressa Almeida , Moreira Francisca Aniele , Santos Mateus Camilla dos , Tavares Clódis Maria , Prata de Almeida Thereza Lúcia
Published: June 2019

Background:

In 2015, the detection rate of leprosy in Santana do Ipanema municipality, Alagoas state, Brazil, was 39.3 cases per 100,000 inhabitants, and among young people below 15 years of age, it was 32.8 cases per 100,000 inhabitants.

Material and methods:

A prospective study was carried out from 2015 to 2017, in Santana do Ipanema city, with 69 leprosy contacts in the age group of 4–15 years. Measurement of serum IgM, IgG, and IgA against phenolic glycolipid antigen-1 (PGL-1) was done by an indirect enzyme-linked immunosorbent assay.

Results:

A high frequency of positive anti-PGL-1 IgM was found in both paucibacillary and multibacillary contacts. Twenty-three participants presented suspected lesions and 45 did not. In both groups a high frequency of positive IgM was found. In regard to anti-PGL-1 IgG, it was found a strong association between its positivity and the presence of lesions (relative risk of 3.25). Eight new cases of leprosy were diagnosed, five of which were seropositive for anti-PGL-1. Again, a striking association was found between positive IgG and leprosy (relative risk of 8.5). No significant association was found between IgM isotype and disease, nor between IgA and disease.

Conclusions:

The present study reinforces the importance of measuring the three anti-PGL-1 isotypes in follow-up studies of leprosy contacts. Moreover, positive anti-PGL-1 IgG is associated with a high associated risk of disease.
Investigating Outcomes of Adolescents and Young Adults (10–24 Years of Age) Lost to Follow-up from Tuberculosis Treatment in Gaborone, Botswana
Authors: Enane Leslie A. , Lowenthal Elizabeth D. , Arscott-Mills Tonya , Eby Jessica , Caiphus Cynthia , Kgwaadira Botshelo , Coffin Susan E. , Steenhoff Andrew P.
Published: June 2019

This retrospective study investigated outcomes among lost to follow-up (LTFU) adolescents and young adults (AYAs: 10–24 years of age) with tuberculosis (TB) registered from 2008 to 2014 in Gaborone, using surveillance data. Of 68 LTFU AYAs, 16 repeated treatment; 8 completed and 6 were again LTFU. Of 4 confirmed deaths, 3 had TB/HIV coinfection. Approaches to improve AYA retention in TB care are needed.
Recurrent Acute Septic Arthritis Caused by Kingella kingae in a 16-Month-Old Boy
Authors: Chosidow Anais , Bonacorsi Stéphane , Moissenet Didier , Bidet Philippe , Schnuriger Aurélie , Grimprel Emmanuel , Vialle Raphael , Lorrot Mathie
Published: June 2019

We describe the first case of 2 consecutive acute septic arthritis infections of both knees caused by the same virulent strain of Kingella kingae belonging to the virulent sequence type complex 14, in a 16-month-old boy. Both infections occurred after viral upper respiratory tract infections.
Isolated Langerhans Cell Histiocytosis of the Lacrimal Gland in Conjunction With Mucosa-Associated Lymphoid Tissue Lymphoma and Elevated IgG4 Plasma Cells
Authors: Peck Travis , Bagg Adam , Zhang Xiaoming , Armstrong Blair , Eagle Ralph C. , Milman Tatyana
Published: June 2019

Langerhans cell histiocytosis (LCH) is a clonal neoplastic proliferation of Langerhans-type cells. Orbital LCH is infrequent, typically manifesting as an isolated lytic bony lesion with an adjacent soft tissue mass in a child. Isolated lacrimal gland involvement by LCH is extremely rare, with only 2 previously reported cases. The authors describe a 37-year-old woman with a 6-month history of painless right upper eyelid swelling and diffuse right lacrimal gland enlargement without bony changes on computed tomography scan. Excisional biopsy of the lacrimal gland demonstrated concurrent LCH, extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue, and increased IgG4-expressing plasma cells. Work-up was negative for systemic hematolymphoid malignancy and IgG4-related disease. This case illustrates the association between LCH, mucosa-associated lymphoid tissue lymphoma, and elevated IgG4 plasma cells in the lacrimal gland, and we review the emerging theories proposed to explain this phenomenon.
Methylglyoxal causes pain and hyperalgesia in human through C-fiber activation
Authors: Düll Miriam M. , Riegel Kathrin , Tappenbeck Julia , Ries Vivien , Strupf Marion , Fleming Thomas , Sauer Susanne K. , Namer Barbara
Published: June 2019

The endogenous metabolite methylglyoxal (MG) accumulates in diabetic patients with neuropathic pain. Methylglyoxal could be a mediator of diabetes-induced neuropathic pain through TRPA1 activation and sensitization of the voltage-gated sodium channel subtype 1.8. In this study, we tested the algogenic and sensitizing effect of MG in healthy human subjects using intracutaneous microinjections. The involvement of C fibers was assessed through selective A-fiber nerve block, axon-reflex-erythema, and through single nerve fiber recordings in humans (microneurography). Involvement of the transduction channels TRPA1 and TRPV1 in MG-induced pain sensation was investigated with specific ion channel blockers. We showed for the first time in healthy humans that MG induces pain, axon-reflex-erythema, and long-lasting hyperalgesia through the activation of C nociceptors. Predominantly, the subclass of mechano-insensitive C fibers is activated by MG. A fibers contribute only negligibly to the burning pain sensation. Selective pharmacological blockade of TRPA1 or TRPV1 showed that TRPA1 is crucially involved in MG-induced chemical pain sensation and heat hyperalgesia. In conclusion, the actions of MG through TRPA1 activation on predominantly mechano-insensitive C fibers might be involved in spontaneously perceived pain in diabetic neuropathy and hyperalgesia as well as allodynia.
Clinical Engineering and Disposables
Authors: Hyman William A.
Published: June 2019

The scope of clinical engineering generally includes the selection, use, maintenance, and repair of multiuse medical devices. This may also include active participation in the selection of devices for purchase and incident investigations. Increasingly clinical engineering has also played a role in connectivity of medical devices and in the exercise of cybersecurity. Clinical engineering has less often been actively engaged in the selection and use of disposable and single-use medical devices, but some of the same skills that support reusable assets can and should be applied to the selection and use of disposables.
Three Ways Telemedicine Is Mitigating (What Can Be) the Perilous Effects of the Flu
Authors: Ide Lisa
Published: June 2019

During the height of flu season last year, 49 states had widespread influenza, schools in Oklahoma and Texas had to close, and governors in New York and Alabama directed state resources toward the epidemic. In fact, last year was one of the worst flu seasons in history—with more than 80,000 flu-related deaths and 900,000 hospitalizations in the United States alone. The flu continues to be a major epidemic that threatens the health of millions around the world each year. The good news is that virtual care solutions can help prevent the spread of this awful illness.
Risk Factors for Vestibular and Oculomotor Outcomes After Sport-Related Concussion
Authors: Womble Melissa N. , McAllister-Deitrick Jamie , Marchetti Gregory F. , Reynolds Erin , Collins Michael W. , Elbin R.J. , Kontos Anthony P.
Published: June 2019

Objective:

To investigate the association between risk factors and vestibular–oculomotor outcomes after sport-related concussion (SRC).

Study Design:

Cross-sectional study of patients seen 5.7 ± 5.4 days (range 0-30 days) after injury.

Setting:

Specialty clinic.

Participants:

Eighty-five athletes (50 male athletes and 35 female athletes) aged 14.1 ± 2.8 years (range 9-24 years) seeking clinical care for SRC.

Interventions:

Participants completed a clinical interview, history questionnaire, symptom inventory, and vestibular/ocularmotor screening (VOMS). Chi-square tests with odds ratios and diagnostic accuracy were used to examine the association between risk factors and VOMS outcomes.

Main Outcome Measures:

The VOMS.

Results:

Female sex (χ2 = 4.9, P = 0.03), on-field dizziness (χ2 = 7.1, P = 0.008), fogginess (χ2 = 10.3, P = 0.001), and post-traumatic migraine (PTM) symptoms including headache (χ2 = 16.7, P = 0.001), nausea (χ2 = 10.9, P = 0.001), light sensitivity (χ2 = 14.9, P = 0.001), and noise sensitivity (χ2 = 8.7, P = 0.003) were associated with presence of one or more postconcussion VOMS score above clinical cutoff. On-field dizziness (χ2 = 3.8, P = 0.05), fogginess (χ2 = 7.9, P = 0.005), and PTM-like symptoms including nausea (χ2 = 9.0, P = 0.003) and noise sensitivity (χ2 = 7.2, P = 0.007) were associated with obtaining a postconcussion near-point convergence (NPC) distance cutoff >5 cm. The likelihood ratios were 5.93 and 5.14 for VOMS symptoms and NPC distance, respectively.

Conclusions:

Female sex, on-field dizziness, fogginess, and PTM symptoms were predictive of experiencing vestibular–oculomotor symptoms/impairment after SRC.
Management of the protuberant premaxilla: where does it fit in?
Authors: Morris Lisa
Published: June 2019

Purpose of review

To discuss multidisciplinary treatment options for the protuberant premaxilla associated with bilateral cleft lip and palate. Lessons have been learned throughout the years regarding the effect of growth restriction after early and aggressive therapy. Multiple surgical and orthodontic interventions are discussed. Recent literature will be highlighted and discussed.

Recent findings

A paucity of long-term studies was noted. Recent literature revealed numerous studies introducing innovative presurgical orthopedic devices as less expensive and easier to use alternatives to nasoalveolar molding. Multiple approaches to premaxillary setback were presented, offering multiple approaches to improve success rates and minimize burden to the patient. Novel orthodontic and advanced microvascular procedures were discussed as additional tools for treatment of the malpositioned premaxilla once skeletal maturity is reached.

Multidisciplinary team management of the protuberant premaxilla and bilateral cleft lip and palate is becoming increasingly embraced worldwide. Numerous surgical procedures and orthodontic treatments are required to optimally reposition the premaxilla; however, these interventions can inhibit growth, resulting in maxillary retrusion. Long-term follow-up studies are needed to determine what protocol is best. Studies should also include ways to overcome barriers to treatment success, such as late intervention, resource disparity, and limited access to care.
Kidney transplantation across minor ABO incompatibility: the use of A2 to B transplants
Authors: Gilbert Alexander J.
Published: June 2019

Purpose of review

On 4 December 2014, the new kidney allocation system (KAS) went into effect. As part of this system, UNOS approved for the first time a national system with a specific mechanism affording priority to allocate kidneys across so-called ‘minor ABO incompatibility’ from blood group A2 donors into blood group B recipients. This significantly increased the number of such transplants done and the opportunities to learn about the specifics of such transplants.

Recent findings

A2 to B transplants have been demonstrated to be well tolerated, effective, and cost-effective ways of addressing disparities in the allocation system. Further data about the use of anti-A titers and the limits to successful transplant have better defined the bounds of who can benefit from such transplants.

The success thus far with A2 to B transplants should increase comfort and acceptance of the allocation policy changes and we should see further increases in centers willing to use such transplants to better address inequalities in the system.
Longitudinal Trend in Emergency Department Reliance for Pain Among Sickle Cell Disease Patients in Wisconsin
Authors: Singh Ashima , Yan Ke , Brandow Amanda M. , Panepinto Julie A.
Published: June 2019

Patients with sickle cell disease frequently visit the emergency department for pain. The metric of emergency department reliance (EDR) describes emergency department utilization in relation to all ambulatory visits and serves as a quality of care indicator. This study uses Wisconsin Medicaid data from 2011 to 2015 to examine trend of EDR for pain over the period of 5 years. We stratified our cohort (N=750) by patient ages into 4 groups: (1) children; (2) transition group; (3) young adults; and (4) adults. Using a linear mixed model, we estimated longitudinal trends adjusting for age group and hydroxyurea possession calculated as medication possession ratio. Results show that EDR for pain has distinct temporal patterns for each group. EDR for pediatrics continually remained less than the established threshold of 0.33. The EDR for transition group significantly increased over time; however, the EDR for young adults has significantly decreased since 2011. There were no significant differences in EDR over time for adults older than 30 years. Overall, increase in medication possession ratio was associated with lower EDR. The low EDR for pain among children and the improvements among adults indicate the success of efforts for sickle cell disease patients. However, further interventions are needed for the transition age group.
Family Caregivers’ Satisfaction With Specialized End-of-Life Care Provided at Home
Authors: Hjörleifsdóttir Elísabet , Einarsdóttir Audur , Óskarsson Gudmundur Kristján , Frímannsson Gudmundur Heidar
Published: June 2019

Several studies have highlighted the significant role of families in end-of-life care. Carers’ well-being may depend on how they experience the care and support provided to their loved ones. This study was conducted to investigate family caregivers’ assessment of specialized end-of-life care in a sample of 119 close family members in Iceland. The response rate was 58.8% (n = 70). Furthermore, the aim was to assess the psychometric characteristics of the Icelandic version of Family Assessment of Treatment at the End of Life (FATE). Descriptive statistics were used to describe the characteristics of the data. Results indicate that good communication and understanding of all parties concerned are the foundation for family caregivers’ satisfaction with end-of-life care. Participants were generally satisfied with the care provided, whereas some important aspects of care were rated as excellent. Evaluation of management of symptoms reported in this study should be given specific attention in future studies considering its unsatisfactory outcomes. Nurses need to be aware of the impact that physical suffering of the patient might have on the family caregivers. The Icelandic version of the Family Assessment of Treatment at the End of Life instrument is a psychometrically sound instrument useful for measuring caregivers’ satisfaction with service provided at the end of life, although modifications would improve the instrument for use on this population.
Accuracy of Intraoperative Frozen Section of Sentinel Lymph Nodes After Neoadjuvant Chemotherapy for Breast Carcinoma
Authors: Grabenstetter Anne , Moo Tracy-Ann , Hajiyeva Sabina , Schüffler Peter J. , Khattar Pallavi , Friedlander Maria A. , McCormack Maura A. , Raiss Monica , Zabor Emily C. , Barrio Andrea , Morrow Monica , Edelweiss Marcia
Published: June 2019

False-negative (FN) intraoperative frozen section (FS) results of sentinel lymph nodes (SLN) have been reported to be more common after neoadjuvant chemotherapy (NAC) in the primary surgical setting. We evaluated SLN FS assessment in breast cancer patients treated with NAC to determine the FN rate and the histomorphologic factors associated with FN results. Patients who had FS SLN assessment following NAC from July 2008 to July 2017 were identified. Of the 711 SLN FS cases, 522 were negative, 181 positive, and 8 deferred. The FN rate was 5.4% (28/522). There were no false-positive results. Of the 8 deferred cases, 5 were positive on permanent section and 3 were negative. There was a higher frequency of micrometastasis and isolated tumor cells in FN cases (P<0.001). There was a significant increase in tissue surface area present on permanent section slides compared with FS slides (P<0.001), highlighting the inherent technical limitations of FS and histologic under-sampling of tissue which leads to most FN results. The majority (25/28, 89%) of FN cases had metastatic foci identified exclusively on permanent sections and were not due to a true diagnostic interpretation error. FN cases were more frequently estrogen receptor positive (P<0.001), progesterone receptor positive (P=0.001), human epidermal growth factor receptor-2 negative (P=0.009) and histologic grade 1 (P=0.015), which most likely reflects the lower rates of pathologic complete response in these tumors. Despite its limitations, FS is a reliable modality to assess the presence of SLN metastases in NAC treated patients.
Invasive Yersiniosis in a Pediatric Patient With β-Thalassemia Major: Acute Decompensation After Rapid Blood Transfusion
Authors: Hsu George , Jones Andrew , Thornton Ben
Published: June 2019

Yersinia enterocolitica infection, or yersiniosis, is a common cause of gastroenteritis in developing nations, but the disease is less common in the developed world. Yersiniosis typically presents as a self-limited gastroenteritis in an immunocompetent patient and rarely progresses to the more fulminant disseminated form. Certain patient populations are at greater risk of disseminated disease, and providers caring for these patients should have heightened suspicion for invasive disease. Patients dependent on serial transfusion therapy, such as those with inherited hemoglobinopathies, often have chronically elevated serum iron levels. These patients are at increased risk of fulminant yersiniosis due to the bacteria's siderophilic nature. Yersinia infection can be devastating in these patients, and early intervention with empiric antibiotics combined with targeted resuscitation can be essential in their care. The following case illustrates the utility for heightened surveillance, early intervention, and guided resuscitation in the management of this at-risk population.
Physical Therapy Scoliosis-Specific Exercises May Reduce Curve Progression in Mild Adolescent Idiopathic Scoliosis Curves
Authors: Zapata Karina A. , Sucato Daniel J. , Jo Chan-Hee
Published: June 2019

Purpose:

To evaluate the curve magnitude in participants with mild adolescent idiopathic scoliosis (AIS) at high risk of progression who received outpatient physical therapy scoliosis-specific exercises (PSSEs).

Methods:

Participants with AIS curves 12° to 20° and Risser grade 0 chose either the PSSE or the control group. The PSSE group was instructed in the Barcelona Scoliosis Physical Therapy School. The control group was observed. Cobb angles were measured by one observer masked to group type at baseline, 6-month follow-up, and 1-year follow-up.

Results:

Forty-nine participants were enrolled (26 exercise vs 23 controls). Thirty-three participants (19 exercise vs 14 controls) were seen at 1-year follow-up. At 1-year follow-up, the exercise group had smaller curves than controls (16.3° vs 21.6°, P = .04) and less curve progression (0° vs 5.6°, P = .02). Bracing was performed similarly between groups at 1-year follow-up (37% vs 43%).

Conclusions:

In this small prospective series, PSSE resulted in significantly less curve progression compared with controls.
Apathy is Associated with Reduced Precision of Prior Beliefs about Action Outcomes
Authors: Hezemans Frank H. , Wolpe Noham , Rowe James B.
Published: June 2019

Apathy is a debilitating syndrome that is associated with reduced goal-directed behaviour. Although apathy is common and detrimental to prognosis in many neuropsychiatric diseases, its underlying mechanisms remain controversial. We propose a new model of apathy, in the context of Bayesian theories of brain function, whereby actions require predictions of their outcomes to be held with sufficient precision for ‘explaining away’ differences in sensory inputs. In this active inference model, apathy would result from reduced precision of prior beliefs about action outcomes. Healthy adults (N=47) performed a visuomotor task that independently manipulated physical effort and reward, and served to estimate the precision of priors. Participants’ perception of their performance was biased towards the target, which was accounted for by precise prior beliefs about action outcomes. Crucially, prior precision was negatively associated with apathy. The results support a Bayesian account of apathy, that could inform future studies of clinical populations.
Gene expression-based identification of antigen-responsive CD8+ T cells on a single-cell level
Authors: Fuchs Yannick F. , Sharma Virag , Eugster Anne , Kraus Gloria , Morgenstern Robert , Dahl Andreas , Reinhardt Susanne , Petzold Andreas , Lindner Annett , Löbel Doreen , Bonifacio Ezio
Published: June 2019

CD8+ T cells are important effectors of adaptive immunity against pathogens, tumors and self antigens. Here, we asked how human cognate antigen-responsive CD8+ T cells and their receptors could be identified in unselected single-cell gene expression data. Single-cell RNA sequencing and qPCR of dye-labelled antigen-specific cells identified large gene sets that were congruently up- or downregulated in virus-responsive CD8+ T cells under different antigen presentation conditions. Combined expression of TNFRSF9, XCL1, XCL2, and CRTAM was the most distinct marker of virus-responsive cells on a single-cell level. Using transcriptomic data, we developed a machine learning-based classifier that provides sensitive and specific detection of virus-responsive CD8+ T cells from unselected populations. Gene response profiles of CD8+ T cells specific for the autoantigen islet-specific glucose-6-phosphatase catalytic subunit-related protein differed markedly from virus-specific cells. These findings provide single-cell gene expression parameters for comprehensive identification of rare antigen-responsive cells and T cell receptors.

One-sentence summary

Identification of genes, gene sets, and development of a machine learning-based classifier that distinguishes antigen-responsive CD8+ T cells on a single-cell level.
Higher fitness yeast genotypes are less robust to deleterious mutations
Authors: Johnson Milo S. , Martsul Alena , Kryazhimskiy Sergey , Desai Michael M.
Published: June 2019

Natural selection drives populations towards higher fitness, but second-order selection for adaptability and mutational robustness can also influence the dynamics of adaptation. In many microbial systems, diminishing returns epistasis contributes to a tendency for more-fit genotypes to be less adaptable, but no analogous patterns for robustness are known. To understand how robustness varies across genotypes, we measure the fitness effects of hundreds of individual insertion mutations in a panel of yeast strains. We find that more-fit strains are less robust: they have distributions of fitness effects (DFEs) with lower mean and higher variance. These shifts in the DFE arise because many mutations have more strongly deleterious effects in faster-growing strains. This negative correlation between fitness and robustness implies that second-order selection for robustness will tend to conflict with first-order selection for fitness.
Oncoprotein GT198 is a direct target of taxol
Authors: Yang Zheqiong , Gurvich Vadim J. , Gupta Mohan L. , Mivechi Nahid F. , Ko Lan
Published: June 2019

Taxol (paclitaxel) is one of the most successful chemotherapeutic drugs in the treatment of human cancer. It has recently been questioned whether the mechanism of action in mitotic arrest, which is ubiquitously present in all cells, is sufficient to explain the tumor specificity, clinical efficacy, and side effects of taxol. In this report, we have identified a new protein target of taxol as GT198 (gene symbolPSMC3IP, also known as Hop2). GT198 is an oncoprotein and a DNA repair factor involved in human common solid tumors. TheGT198gene carries germline mutations in breast and ovarian cancer families and recurrent somatic mutations in tumor microenvironment. Mutant GT198 was identified in pericyte stem cells on capillary blood vessels inducing tumor angiogenesis. GT198 is a DNA-binding protein dimer, also stimulates DNA repair, regulates meiosis, participates in homologous DNA recombination, and activates nuclear receptor-mediated gene expression. Here we show that taxol directly binds to the DNA-binding domain of GT198in vitro. Taxol serves as an allosteric inhibitor to block DNA binding to GT198 with an IC50 of 8.6 nM. Labeled taxol colocalizes with GT198 in interphase nuclei of cultured cells. Decreased GT198 expression desensitizes taxolinduced cell death, and taxol inhibits GT198 nuclear foci formation during DNA repair. Together, these results demonstrate that GT198 is a previously unrecognized direct protein target of taxol. The finding of taxol target as an oncoprotein GT198 in common solid tumors provides a rationale for the clinical efficacy of taxol. We anticipate that GT198 may serve as a clinical predictive marker of taxol efficacy as well as a new drug target for future anti-cancer therapy.
Stereoscopic Rendering in a Head Mounted Display Elicits Higher Functional Connectivity During Virtual Reality
Authors: Forlim Caroline Garcia , Bittner Lukas , Mostajeran Fariba , Steinicke Frank , Gallinat Jürgen , Kühn Simone
Published: June 2019

Virtual reality (VR) simulates real world scenarios by creating a presence in users. Such immersive scenarios lead to more similar behaviour to that displayed in real world settings, which may facilitate the transfer of knowledge and skills acquired in VR to real world situations. VR has already been used in education, psychotherapy, rehabilitation and it is an appealing choice for training intervention. The aim was to investigate to what extend VR technology can be used in a magnetic resonance imaging scanner(MRI), addressing the question of whether brain connectivity differs between VR and screen via mirror projection presentations. Moreover, we investigate whether stereoscopic goggle stimulation, where eyes receive different input, would elicit more brain connectivity than stimulation where both eyes receive the same input (monoscopic). To our knowledge, there is no previous research addressing this question. Multiple analyses were performed to cover different aspects of brain connectivity: fractional low frequency fluctuation, independent component analysis, seed-based functional connectivity and graph analysis. In goggles (mono and stereoscopic) vs. screen, we found connectivity differences in cerebellum and postcentral gyrus and in visual and frontal inferior cortex in visual/default-mode networks. Considering specific areas, we found higher connectivity between superior frontal cortex and temporal lobe, as well as inferior parietal cortex with calcarine and lingual. Furthermore, superior frontal cortex and insula/putamen were more strongly connected in stereoscopic, in line with our hypothesis. We assume that conditions eliciting most connectivity should be suited for long-term interventions as extended training under these conditions could permanently improve functional/structural connectivity.
Firing rate homeostasis occurs in the absence of neuronal activity-regulated transcription
Authors: Tyssowski Kelsey M. , Letai Katherine C. , Rendall Samuel D. , Nizhnik Anastasia , Gray Jesse M.
Published: June 2019

Despite dynamic inputs, neuronal circuits maintain relatively stable firing rates over long periods. This maintenance of firing rate, or firing rate homeostasis, is likely mediated by homeostatic mechanisms such as synaptic scaling and regulation of intrinsic excitability. Because some of these homeostatic mechanisms depend on transcription of activity-regulated genes, including Arc and Homer1a, we hypothesized that activity-regulated transcription would be required for firing rate homeostasis. Surprisingly, however, we found that cultured mouse cortical neurons grown on multi-electrode arrays homeostatically adapt their firing rates to persistent pharmacological stimulation even when activity-regulated transcription is disrupted. Specifically, we observed firing rate homeostasis Arc knock-out neurons, as well as knock-out neurons lacking activity-regulated transcription factors, AP1 and SRF. Firing rate homeostasis also occurred normally during acute pharmacological blockade of transcription. Thus, firing rate homeostasis in response to increased neuronal activity can occur in the absence of neuronal-activity-regulated transcription.

SIGNIFICANCE STATEMENT

Neuronal circuits maintain relatively stable firing rates even in the face of dynamic circuit inputs. Understanding the molecular mechanisms that enable this firing rate homeostasis could potentially provide insight into neuronal diseases that present with an imbalance of excitation and inhibition. However, the molecular mechanisms underlying firing rate homeostasis are largely unknown.

It has long been hypothesized that firing rate homeostasis relies upon neuronal activity-regulated transcription. For example, a 2012 review (PMID 22685679) proposed it, and a 2014 modeling approach established that transcription could theoretically both measure and control firing rate (PMID 24853940). Surprisingly, despite this prediction, we found that cortical neurons undergo firing rate homeostasis in the absence of activity-regulated transcription, indicating that firing rate homeostasis is controlled by non-transcriptional mechanisms.
NeuroPAL: A Neuronal Polychromatic Atlas of Landmarks for Whole-Brain Imaging inC. elegans
Authors: Yemini Eviatar , Lin Albert , Nejatbakhsh Amin , Varol Erdem , Sun Ruoxi , Mena Gonzalo E. , Samuel Aravinthan D.T. , Paninski Liam , Venkatachalam Vivek , Hobert Oliver
Published: June 2019

Comprehensively resolving single neurons and their cellular identities from whole-brain fluorescent images is a major challenge. We achieve this inC. elegansthrough the engineering and use of a multicolor transgene called NeuroPAL (aNeuronalPolychromaticAtlas ofLandmarks). NeuroPAL worms share a stereotypical multicolor fluorescence map for the entire hermaphrodite nervous system that allows comprehensive determination of neuronal identities. Neurons labeled with NeuroPAL do not exhibit fluorescence in the green, cyan, or yellow emission channels, allowing the transgene to be used with numerous reporters of gene expression or neuronal dynamics. Here we showcase three studies that leverage NeuroPAL for nervous-system-wide neuronal identification. First, we determine the brainwide expression patterns of all metabotropic receptors for acetylcholine, GABA, and glutamate, completing a map of this communication network. Second, we uncover novel changes in cell fate caused by transcription factor mutations. Third, we record brainwide activity in response to attractive and repulsive chemosensory cues, characterizing multimodal coding and novel neuronal asymmetries for these stimuli. We present a software package that enables semi-automated determination of all neuronal identities based on color and positional information. The NeuroPAL framework and software provide a means to design landmark atlases for other tissues and organisms. In conclusion, we expect NeuroPAL to serve as an invaluable tool for gene expression analysis, neuronal fate studies, and for mapping whole-brain activity patterns.
CD44 inhibits α-SMA gene expression via a novel G-actin/MRTF mediated pathway that requires TGFβR/p38MAPK activity in murine skin fibroblasts
Authors: Wang Yan , Mack Judith A. , Maytin Edward V.
Published: June 2019

Well-regulated differentiation of fibroblasts into myofibroblasts (MF) is critical for skin wound healing. Neoexpression of α-smooth muscle actin (α-SMA), an established marker for MF differentiation, is driven by TGFβ receptor (TGFβR)-mediated signaling. Hyaluronan (HA) and its receptor CD44 may also participate in this process. To further understand this process, primary mouse skin fibroblasts were isolated and treatedin vitrowith recombinant TGF-β1 (rTGF-β1) to induce α-SMA expression. CD44 expression was also increased. Paradoxically, CD44 knockdown by RNA interference (RNAi) led to increased α-SMA expression and α-SMA-containing stress fibers. Removal of extracellular HA or inhibition of HA synthesis had no effect on α-SMA levels, suggesting a dispensable role for HA. Exploration of mechanisms linking CD44 knockdown to α-SMA induction, using RNAi and chemical inhibitors, revealed a requirement for non-canonical TGFβR signaling through p38MAPK. Decreased monomeric G-actin but increased filamentous F-actin following CD44 RNAi suggested a possible role for Myocardin-related Transcription Factor (MRTF), a known regulator of α-SMA transcription and itself being regulated by G-actin binding. CD44 RNAi promoted nuclear accumulation of MRTF and the binding to its transcriptional cofactor, SRF. MRTF knockdown abrogated the increased α-SMA expression caused by CD44 RNAi, suggesting that MRTF is required for CD44-mediated regulation of α-SMA. Finally, chemical inhibition of p38MAPK reversed nuclear MRTF accumulation after rTGF-β1 addition or CD44 RNAi, revealing a central requirement for p38MAPK in both cases. We concluded that CD44 regulates α-SMA gene expression through cooperation between two intersecting signaling pathways, one mediated by G-actin/MRTF and the other via TGFβR/p38MAPK.
Increased task-dependent functional connectivity by stimulation of the hippocampal network predicts memory enhancement
Authors: Warren Kristen N. , Hermiller Molly S. , Nilakantan Aneesha S. , Voss Joel L.
Published: June 2019

Successful episodic memory involves dynamic increases in the coordination of activity across distributed hippocampal networks, including the posterior-medial network (PMN) and the anterior-temporal network (ATN). We tested whether this up-regulation of functional connectivity during memory processing can be enhanced within hippocampal networks by noninvasive stimulation, and whether such task-dependent connectivity enhancement predicts episodic memory improvement. Participants received stimulation targeting either the PMN or an out-of-network control location. We compared the effects of stimulation on fMRI connectivity measured during an autobiographical memory retrieval task versus during rest within the PMN and the ATN. PMN-targeted stimulation significantly increased connectivity during memory retrieval versus rest within the PMN. This effect was not observed in the ATN, or in either network due to control out-of-network stimulation. Task-dependent increases in connectivity due to PMN-targeted stimulation within the medial temporal lobe predicted improved performance of a separate episodic memory test. It is therefore possible to enhance the task-dependent regulation of hippocampal network connectivity that supports memory processing using noninvasive stimulation.
Enabling stable coexistence by modifying the environment
Authors: Pastor Alejandro , Nuño Juan Carlos , Olarrea José , de Vicente Javier
Published: June 2019

In this work coexistence is studied using a model based on two classical population models: the quasispecies of Eigen [1] and the daisyworld presented by Watson and Lovelock [2]. It is assumed that species are able to modify the environment. We show that this ability enables the coexistence between, at most, two species in equilibrium. Given an initial population, the problem arises as to determine which of the many equilibrium populations, i.e. extinction, only one species or coexistence of two species, will be reached as a function of the species characteristics, specifically their capacity to modify the environment and the optimal growth rate. These results are obtained under general assumptions, which broadens its applicability to other fields as evolutionary biology and social sciences.
Unique PKD like protein kinase inEntamoeba histolyticaregulates vital actin mediated processes
Authors: Baidya Mithu , Nayak Santoshi , Das Amit K. , Ghosh Sudip Kumar
Published: June 2019

Entamoeba histolyticacauses widespread amoebiasis in humans. Multiple lines of emerging evidence have identified a repertoire of proteins involved in the process of erythrophagocytosis. However, the early initiation of the erythrophagosome at the site of erythrocyte’s attachment is not well understood. Here in our study we have identified and characterized a small Protein kinase D like protein (EhPKDL) inEh, which nucleates actin polymerization and thus mediates many vital processes inEhincluding erythrophagocytosis. Following multiple biochemical and biophysical approaches, we have characterized EhPKDL and have shown that EhPKDL can indeed interact and prime the nucleation of monomeric actin for polymerization. Furthermore, we went on to demonstrate the vitality of the EhPKDL in major actin-mediated processes like capping, motility, and erythrophagocytosis following knockdown of EhPKDL in the cellular context. Our study thus provides novel insights into the early actin nucleation inEhand thus bridges the gap with our previous understanding of the assembly of erythrophagosomes.
Restricted and non-essential redundancy of RNAi and piRNA pathways in mouse oocytes
Authors: Taborska Eliska , Pasulka Josef , Malik Radek , Horvat Filip , Jenickova Irena , Jelić Matošević Zoe , Svoboda Petr
Published: June 2019

Germline genome defense evolves to recognize and suppress retrotransposons. One of defensive mechanisms is the PIWI-associated RNA (piRNA) pathway, which employs small RNAs for sequence-specific post-transcriptional and transcriptional repression. The loss of the piRNA pathway in mice causes male sterility while females remain fertile. Unlike spermatogenic cells, mouse oocytes have also RNA interference (RNAi), another small RNA pathway capable of retrotransposon suppression. To examine whether RNAi compensates the loss of the piRNA pathway in mouse oocytes, we produced a new RNAi pathway mutantDicerSOMand crossed it with a catalytically-dead mutant ofMili, an essential piRNA gene. Normal follicular and oocyte in double mutants showed that RNAi does not suppress a strong piRNA knock-out phenotype. However, we observed redundant and non-redundant targeting of specific retrotransposons. Intracisternal A Particle retrotransposon was mainly targeted by the piRNA pathway, MT and RLTR10 retrotransposons were targeted mainly by RNAi. Importantly, only double mutants showed increased background levels of transcripts potentially originating from intact LINE-1 elements. Our results thus show that while both small RNA pathways are simultaneously expendable defense pathways for ovarian oocyte development, yet another transcriptional silencing mechanism must mediate LINE-1 repression in female germ cells.

Author summary

Retrotransposons are mobile genomic parasites causing mutations. Germ cells need protection against retrotransposons to prevent heritable transmission of their new insertions. The piRNA pathway is an ancient germline defense system analogous to acquired immunity: once a retrotransposons jumps into a specific “genomic checkpoint”, it is recognized and suppressed. Remarkably, the murine piRNA pathway is essential for spermatogenesis but not oocyte development. In contrast, zebrafish lacking the piRNA pathway do not develop any germ cells. It was hypothesized that RNA interference pathway could rescue oocyte development in mice lacking the piRNA pathway. RNA interference also targets retrotransposons and is particularly enhanced in mouse oocytes. To test this hypothesis, we engineered mice lacking both pathways and observed that oocytes in these mice develop normally, which argues against the hypothesis. Furthermore, analysis of individual retrotransposon groups revealed that in specific cases the two pathways can mutually compensate each other. However, this ability is restricted to specific retrotransposon groups and seems to evolve stochastically. Finally, our results also indicate that there must be yet another layer of retrotransposon silencing in mouse oocytes, which prevents high retrotransposon activity in the absence of piRNA and RNA interference pathways.
Three-dimensional visualization of fibrous tissues in cirrhotic rats via X-ray phase-contrast computed tomography with iodine staining
Authors: Jian Jianbo , Zhao Xinyan , Qin Lili , Zhao Yuqing , Sun Mengyu , Lv Wenjuan , Hu Chunhong
Published: June 2019

To accurately characterize cirrhosis, knowledge of the 3D fibrous structures is essential. Histology is the gold standard in cirrhosis screening, but it mainly provides structural information in 2D planes and destroys the 3D samples in the process. The aim of this study was to evaluate the potential of X-ray phase-contrast computed tomography (PCCT) with iodine staining for the 3D nondestructive visualization of internal structural details in entire cirrhotic livers with histopathologic correlation. In this study, cirrhotic livers induced by carbon tetrachloride (CCl4) in rats were imaged via PCCT and then histopathologically processed. Characteristics of the cirrhosis, i.e. abnormal nodules surrounded by annular fibrosis, were established and a 3D reconstruction of these structures was also performed via PCCT. Fibrosis area, septal width and nodular size were measured and the correlation for these quantitative measurements between PCCT and histopathologic findings was analyzed. The results showed that fibrous bands, small nodules and angio-architecture in cirrhosis were clearly presented in the PCCT images, with histopathologic findings as standard reference. In comparison with histopathology, PCCT was associated with a very close value for fibrosis area, septal width and nodular size. The quantitative measurements showed a strong correlation between PCCT and histopathology. Additionally, the 3D structures of fibrous bands and microvasculature were presented simultaneously. PCCT provides excellent results in the assessment of cirrhosis characteristics and 3D presentation of these feature structures compared with histopathology. Thus, the technique may serve as an adjunct nondestructive 3D modality for cirrhosis characterization.
Consumer Fad Dynamic: the consumer behavior and the Gin case
Authors: Quental de Almeida Rui Miguel , Meneses Raquel
Published: June 2019

Purpose

The purpose of this paper is to characterize the consumption of an international consumer product fad.

Design/methodology/approach

A literature review of the concepts that can be related to an international fad was conducted, which included the study of the product life cycle, CAGE distances, the herd behavior, the consumer behavior in social media, the conformism and perceived newness. To know more about the subject, the Gin case was studied. The quantitative study began to define an initial model with the variables that can have impact on the consumption of the Gin. Based on the initial model, a survey was built and conducted, obtaining 143 valid responses. The data were analyzed on the basis of the structural equation modeling.

Findings

The results verified the positive impact of need for group differentiation on the consumption Gin. The perceived newness had a direct impact on its consumption. An international fad lasts while it is differentiator for the consumer, so the herd behavior influence was not validated.

Research limitations/implications

This study had a limitation in terms of responses. This study was made using a practical case of beverage, so its applicability to other types of products is limited.

Originality/value

This study is about consumer fads. It characterizes the key concepts in various moments of a fad: the implementation, the evolution of its consumption and its end. The study identifies the variables that have a positive impact on the consumption of a real fad. Data from sales geography diffusion in time are also analyzed.
Enhancing supply chain resilience: an empirical investigation
Authors: Naghshineh Bardia , Lotfi Maryam
Published: June 2019

Purpose

Supply chain resilience (SCR) has recently become an important issue for organizations all around the world. In order to decrease the risk of failures, managers and decision makers are constantly looking for practices to enhance SCR. The purpose of this paper is to propose a research model that mainly focuses on the effect of information sharing (IS) to enhance SCR.

Design/methodology/approach

Survey method is used in this research. Data were collected from the supply chain, procurement, executive and IT managers of 82 of Tehran’s stock exchange production companies. Structural equation modeling with SmartPLS3 software is used to analyze the collected data.

Findings

Research results show that IS significantly enhances SCR.

Research limitations/implications

Data were collected at one point in time, and therefore a longitudinal study can further investigate the results of this study. The research was carried out in production companies in Iran. Future research can examine the research model in other industry sectors, e.g. services, in other countries to validate the accuracy of the findings.

Practical implications

The findings of this research should help managers, and decision makers create more resilient supply chains for their own and partners’ organizations.

Originality/value

The research model provides insightful results regarding the significance of IS in the SCR context.
Numerical modelling of granular column collapse using coupled Eulerian–Lagrangian technique with critical state soil model
Authors: Wu Ze-Xiang , Ji Hui , Han Jian , Yu Chuang
Published: June 2019

Purpose

Current modellings of granular collapse are lack of considering the effect of soil density. This paper aims to present a numerical method to analyse the collapse of granular column based on the critical-state soil mechanics.

Design/methodology/approach

In the proposed method, a simple critical-state based constitutive model is first adopted and implemented into a finite element code using the coupled Eulerian–Lagrangian technique for large deformation analysis. Simulations of column collapse with various aspect ratios are then conducted for a given initial soil density. The effect of aspect ratio on the final size of deposit morphology, dynamical collapse profiles and the stable region is discussed comparing to experimental results. Moreover, complementary simulations with various initial soil densities on each aspect ratio are conducted.

Findings

Simulations show that a lower value of initial density leads to a lower final deposit height and a longer run-out distance. The simulated evolutions of kinetic energy and collapsing profile with time by the proposed numerical approach also show clearly a soil density-dependent collapse process.

Practical implications

To the end, this study can improve the understanding of column collapse in different aspect ratios and soil densities, and provide a computational tool for the analysis of real scale granular flow.

Originality/value

The originality of this paper is proposed in a numerical approach to model granular column collapse considering the influences of aspect ratio and initial void ratio. The proposed approach is based on the finite element platform with coupled Eulerian–Lagrangian technique for large deformation analysis and implementing the critical-state based model accounting for the effect of soil density.