bluuebunny/crossref_metadata_2025 huggingface dataset:
Inheritance of mitochondrial DNA in humans: implications for rare and common diseases
Authors: Wei W. , Chinnery P. F.
Published: March 2020

The first draft human mitochondrial DNA (mtDNA) sequence was published in 1981, paving the way for two decades of discovery linking mtDNA variation with human disease. Severe pathogenic mutations cause sporadic and inherited rare disorders that often involve the nervous system. However, some mutations cause mild organ‐specific phenotypes that have a reduced clinical penetrance, and polymorphic variation of mtDNA is associated with an altered risk of developing several late‐onset common human diseases including Parkinson’s disease. mtDNA mutations also accumulate during human life and are enriched in affected organs in a number of age‐related diseases. Thus, mtDNA contributes to a wide range of human pathologies. For many decades, it has generally been accepted that mtDNA is inherited exclusively down the maternal line in humans. Although recent evidence has challenged this dogma, whole‐genome sequencing has identified nuclear‐encoded mitochondrial sequences (NUMTs) that can give the false impression of paternally inherited mtDNA. This provides a more likely explanation for recent reports of ‘bi‐parental inheritance’, where the paternal alleles are actually transmitted through the nuclear genome. The presence of both mutated and wild‐type variant alleles within the same individual (heteroplasmy) and rapid shifts in allele frequency can lead to offspring with variable severity of disease. In addition, there is emerging evidence that selection can act for and against specific mtDNA variants within the developing germ line, and possibly within developing tissues. Thus, understanding how mtDNA is inherited has far‐reaching implications across medicine. There is emerging evidence that this highly dynamic system is amenable to therapeutic manipulation, raising the possibility that we can harness new understanding to prevent and treat rare and common human diseases where mtDNA mutations play a key role.
Digital Workflow for Implant Rehabilitation with Double Full‐Arch Monolithic Zirconia Prostheses
Authors: Papaspyridakos Panos , Chochlidakis Konstantinos , Kang Kiho , Chen Yo‐wei , Alghfeli Abdulla , Kudara Yukio , Weber Hans‐Peter
Published: March 2020

The purpose of the present report is to illustrate a proof‐of‐concept protocol with the double digital scanning (DDS) technique for complete digital workflow in double full‐arch implant rehabilitation. Two patients (4 restored arches) presented with hopeless dentitions and they were treated with a 4‐appointment prosthodontic protocol and monolithic zirconia prostheses implementing a complete digital workflow. The outcomes are presented after clinical and radiographic observation for 2 years.
The impact of SVR from direct‐acting antiviral‐ and interferon‐based treatments for HCV on hepatocellular carcinoma risk
Authors: Janjua Naveed Z. , Wong Stanley , Darvishian Maryam , Butt Zahid A. , Yu Amanda , Binka Mawuena , Alvarez Maria , Woods Ryan , Yoshida Eric M. , Ramji Alnoor , Feld Jordan , Krajden Mel
Published: March 2020

We evaluated the effect of sustained virologic response (SVR) from direct‐acting antiviral (DAA)‐ and interferon‐based treatments on hepatocellular carcinoma (HCC) risk in a large population‐based cohort in Canada. We used data from the BC Hepatitis Testers Cohort, which includes ~1.3 million individuals tested for HCV since 1990, linked with healthcare administrative and registry datasets. Patients were followed from the end of HCV treatment to HCC, death or 31 December 2016. We assessed HCC risk among those who did and did not achieve SVR by treatment type using proportional hazard models. Of 12 776 eligible individuals, 3905 received DAAs while 8871 received interferon‐based treatments, followed for a median of 1.0 [range: 0.6‐2.7] and 7.9 [range: 4.4‐17.1] years, respectively. A total of 3613 and 6575 achieved SVR with DAAs‐ and interferon‐based treatments, respectively. Among DAAs‐treated patients, HCC incidence rate was 6.9 (95%CI: 4.7‐10.1)/1000 person yr (PY) in SVR group (HCC cases: 26) and 38.2 (95%CI: 20.6‐71.0) in the no‐SVR group (HCC cases: 10, P < .001). Among interferon‐treated individuals, HCC incidence rate was 1.8 (95%CI: 1.5‐2.2) in the SVR (HCC cases: 99) and 13.9 (95%CI: 12.3‐15.8) in the no‐SVR group (HCC cases: 239, P < .001). Compared with no‐SVR from interferon, SVR from DAA‐ and interferon‐based treatments resulted in significant reduction in HCC risk (adjusted subdistribution hazard ratio (adjSHR) DAA = 0.30, 95%CI: 0.19‐0.48 and adjSHR interferon = 0.2, 95%CI: 0.16‐0.26). Among those with SVR, treatment with DAAs compared to interferon was not associated with HCC risk (adjSHR = 0.93, 95%CI: 0.51‐1.71). In conclusion, similar to interferon era, DAA‐related SVR is associated with 70% reduction in HCC risk.
HBV promotes the recruitment of IL‐17 secreting T cells via chemokines CCL22 and CCL17
Authors: Zhang Ka , Liu Yanqiong , Yang Xiaoan , Sun Haixia , Shu Xin , Zhang Yeqiong , Cao Hong , Wu Mengdi , Liu Nan , Zou Yong , Xu Qihuan , Li Gang
Published: March 2020

Background and Aims

Little is known about the mechanisms of IL‐17 secreting T cells accumulation in HBV‐transfected livers. Here, we investigated the role of the chemokines CCL17, CCL20 and CCL22 in this process.

Methods

Peripheral blood and liver tissues were obtained from 30 chronic hepatitis B (CHB) patients and 15 healthy volunteers and were evaluated by flow cytometric analysis and immunohistochemistry. Chemokine production by monocyte‐derived dendritic cells (MoDCs) cocultured with HBV‐transfected or untransfected Huh7 cells was measured by quantitative real‐time PCR and enzyme‐linked immunosorbent assay. The chemotactic activity of the culture supernatants was also tested.

Results

The proportions of IL‐17 secreting CD4 (Th17) and CD8 (Tc17) T cells were both increased in liver and peripheral blood mononuclear cells of CHB patients compared to those in HVs. CHB patients showed higher intrahepatic levels of CCL17 mRNA, CCL22 mRNA, CCR6 mRNA and CCR4 mRNA than HVs. The expression of CCR6 and CCR4 on the surface of Th17 and Tc17 cells in CHB patients was also significantly higher than that in HVs. Significant correlations existed between the CCR4/CCR6 levels and both the alanine transaminase levels and HBV DNA loads. Contact between MoDCs and pBlue‐HBV‐transfected Huh7 cells induced the expression of CCL17 and CCL22 dependent on the dose of HBV DNA. However, CCL20 expression was lower in CHB patients than in HVs. Transwell experiments showed that upregulation of CCL17 and CCL22 enhanced the migration of IL‐17 secreting T cells.

Conclusions

Contact of HBV‐transfected cells with MoDCs induces CCL17 and CCL22 chemokine production, which may favour the recruitment of Th17 and Tc17 cells to liver tissue in CHB. Our results reveal the mechanism of IL‐17 secreting T cells recruitment to liver tissue and thus provide new immunotherapy targets for CHB patients.
When I say … emotional intelligence
Authors: Tiffin Paul A. , Paton Lewis W.
Published: March 2020

Throughout its history, the concept of ‘emotional intelligence’ has elicited controversy. Here Tiffin, Paton explore the definition of the term to highlight how EI has been applied to medical education, how it might be used to guide future research.
Ecogenetics of antibiotic resistance in Listeria monocytogenes
Authors: Baquero Fernando , F. Lanza Val , Duval Mélodie , Coque Teresa M.
Published: March 2020

The acquisition process of antibiotic resistance in an otherwise susceptible organism is shaped by the ecology of the species. Unlike other relevant human pathogens, Listeria monocytogenes has maintained a high rate of susceptibility to the antibiotics used for decades to treat human and animal infections. However, L. monocytogenes can acquire antibiotic resistance genes from other organisms’ plasmids and conjugative transposons. Ecological factors could account for its susceptibility. L. monocytogenes is ubiquitous in nature, most frequently including reservoirs unexposed to antibiotics, including intracellular sanctuaries. L. monocytogenes has a remarkably closed genome, reflecting limited community interactions, small population sizes and high niche specialization. The L. monocytogenes species is divided into variants that are specialized in small specific niches, which reduces the possibility of coexistence with potential donors of antibiotic resistance. Interactions with potential donors are also hampered by interspecies antagonism. However, occasional increases in population sizes (and thus the possibility of acquiring antibiotic resistance) can derive from selection of the species based on intrinsic or acquired resistance to antibiotics, biocides, heavy metals or by a natural tolerance to extreme conditions. High‐quality surveillance of the emergence of resistance to the key drugs used in primary therapy is mandatory.
Clinical, pathological, and proteomic characteristics of newly diagnosed amyloidosis patients: Experience from a single referral center in Japan
Authors: Ando Yukio , Yamashita Taro , Misumi Yohei , Nomura Toshiya , Sasada Keiko , Okada Masamitsu , Inoue Yasuteru , Masuda Teruaki , Ueda Akihiko , Takamatsu Kotaro , Obayashi Konen , Matsui Hirotaka , Naiki Hironobu , Ueda Mitsuharu
Published: March 2020

Novel therapies have recently been used for different amyloidoses including hereditary transthyretin (ATTR, ATTRv) amyloidosis, wild‐type ATTR (ATTRwt) amyloidosis, immunoglobulin light chain (AL)amyloidosis, and amyloid A (AA) amyloidosis. Early, accurate diagnosis is important for improved prognosis and cure. However, early intervention with early diagnosis is often difficult, because these diseases are frequently difficult to identify given their phenotypic heterogeneity. This study aimed to analyze characteristics of patients with amyloidosis that was diagnosed at the Amyloidosis Medical Practice Center, Kumamoto University Hospital, which, as an amyloidosis center in Japan, conducts histopathological, proteomic, and genetic analyses of amyloidosis. We analyzed diagnostic results and disease manifestations of patients diagnosed during April 2012 and March 2019. This study reviewed 1937 consecutive consultations that provided clinical information. The patients’ average age was 65.9 (median 69) years. Of all patients, 66.6% were male. Diagnoses included ATTRv: 13.4%, ATTRwt: 14.3%, ATTR (no genetic analysis consultation requested): 4.6%, ALλ: 19.7%, ALκ: 8.8%, AA: 3.0%, β2‐microglobulin (dialysis‐related): 0.8%, and others: 1.9%, no TTR gene mutation (no histopathological analysis consultation requested): 23.2% (including duplicate consultations). ATTRv amyloidosis cases included V30M in endemic areas: 7.4%, V30M in non‐endemic areas: 51.2%, and non‐V30M: 41.4%. Sixty‐six cases required laser microdissection and liquid chromatography‐tandem mass spectrometry. Initial manifestations included polyneuropathy: 13.2%, carpal tunnel syndrome: 5.6%, autonomic dysfunction: 2.7%, heart failure: 28.4%, cardiac hypertrophy: 2.2%, arrhythmia: 5.0%, renal impairment: 11.1%, and stroke: 1.8%. Amyloidosis types and manifestations were diverse. For early diagnosis and appropriate interventions, improved diagnostic systems are needed.
Ischemic stroke associated with adenomyosis with marked elevation of serum CA125 level
Authors: Takahashi Sunao , Kobayashi Zen , Kijima Emi , Ishihara Shoichiro , Tomimitsu Hiroyuki , Shintani Shuzo
Published: March 2020

A 51‐year‐old woman with adenomyosis developed vertigo during menstruation. Brain MRI demonstrated acute multiple infarcts. Blood tests showed marked elevation of fibrin degradation products (428.8 μg/mL, reference range: <5.0 μg/mL) and CA125 (4276.7 U/mL, reference range: <35.0 U/mL). Whole‐body CT using contrast medium demonstrated a uterine mass, which was not accompanied by deep vein thrombosis, pulmonary thromboembolism, cardioaortic abnormalities, or cancer. Pelvic MRI demonstrated thickening of the posterior myometrium, consistent with the finding of adenomyosis. Anticoagulation therapy and hormonal therapy for adenomyosis prevented recurrence of ischemic stroke. Our case suggests that serum CA125 level can exceed 100 times the upper reference limit even in patients with adenomyosis and that adenomyosis with marked elevation of serum CA125 causes ischemic stroke.
CD209+ monocyte‐derived myeloid dendritic cells were increased in patients with leukemic cutaneous T‐cell lymphoma undergoing extracorporeal photopheresis via the CELLEXTM system
Authors: Ni Xiao , Austin Michael , Langridge Timothy , Bojaxhi Pierr , Bijani Pedram , Wang Xiaohong , Duvic Madeleine
Published: March 2020

Background/Purpose

We previously reported that myeloid dendritic cells (mDC) were increased in patients with leukemic cutaneous T‐cell lymphoma (L‐CTCL) following extracorporeal photopheresis (ECP) using the Therakos UVAR XTS™ system. We now assessed monocyte‐derived mDCs (Mo‐DCs) in L‐CTCL patients treated with the CELLEXTM photopheresis system. CD209, a transmembrane receptor, was used to define Mo‐DCs.

Methods

Peripheral blood samples from baseline pre‐ECP and at Day 2, 1 month, 3 months, and 6 months post‐ECP were analyzed by flow cytometry for Lin−HLA‐DR+CD123+ plasmacytoid dendritic cells (pDCs), Lin−HLA‐DR+CD11c+ mDCs, and CD209+ mDCs. The expression of CD209 mRNA was assessed by real‐time PCR.

Results

At baseline, 7 of 19 patients had lower than normal mDCs, and all patients had lower than normal CD209+ mDCs in peripheral blood mononuclear cells (0.005% in patients, n = 19, vs 0.50% in healthy donors, n = 7, P < .0001). The CD209+ mDC numbers only accounted for 3.28% out of total mDCs in patients compared with 66.51% in healthy donors. After treatment, the CD209+ mDC numbers showed increasing trends in patients. The average absolute numbers of CD209+ mDCs went up by 4.8‐fold at 3 months (n = 10, P = .103) and by 6.4‐fold at 6 months (n = 9, P = .100). CD209 mRNA expression went up in two patients responsive to therapy, parallel to CD209+ mDC numbers. L‐CTCL patients achieved 70% overall clinical response rate (7/10) following ECP therapy with the CELLEXTM system.

Conclusions

Our results suggest that the CELLEXTM photopheresis system is effective for treating L‐CTCL patients like the UVAR XTS™ system, and in vivo‐generated Mo‐DCs increase following ECP.
Pupils' use of school outdoor play settings across seasons and its relation to sun exposure and physical activity
Authors: Pagels Peter , Wester Ulf , Mårtensson Fredrika , Guban Peter , Raustorp Anders , Fröberg Andreas , Söderström Margareta , Boldemann Cecilia
Published: March 2020

Background

Long outdoor stay may cause hazardous exposure to ultraviolet radiation (UVR) from the sun even at high latitudes as in Sweden (Spring to Autumn). On the other hand, long outdoor stay is a strong predictor of primary school children´s free mobility involving moderate to vigorous physical activity (MVPA). UV‐protective outdoor environments enable long outdoor stay. We investigated the concurrent impact of different school outdoor play settings upon pupils´ sun exposure and levels of physical activity across different ages, genders, and seasons.

Method

During 1 week each in September, March, and May, UVR exposure and MVPA were measured in pupils aged 7‐11 years. Erythemally effective UVR exposure was measured by polysulphone film dosimeters and MVPA by accelerometers. Schoolyard play was recorded on maps, and used areas defined as four play settings (fixed play equipment, paved surfaces, sport fields, and green settings), categorized by season and gender.

Results

During the academic year, sport fields yielded the highest UVR exposures and generated most time in MVPA. In March, time outdoors and minutes in MVPA dropped and UVR exposures were suberythemal at all play settings. In May, green settings and fixed play equipment close to greenery promoted MVPA and protected from solar overexposure during long outdoor stays.

Conclusion

More outdoor activities in early spring are recommended. In May, greenery attractive for play could protect against overexposure to UVR and stimulate both girls and boys to vigorous play.
Political Candidates and the Energy Issue: Nuclear Power Position and Electoral Success
Authors: Dermont Clau , Kammermann Lorenz
Published: March 2020

Members of parliament are key actors for the implementation of energy transitions, such as phasing out nuclear power. Before legislators can cast their maybe decisive vote in parliament, they need to run for office and actively strive for election. This paper assesses what political candidates oppose renewable energy transitions and questions whether the energy issue matters in national elections, and thus has consequences for the implementation of new sustainable energy sources. We analyze these questions by first describing the specific characteristics of political candidates. The paper then evaluates the relevance of the energy issue for electoral success in three national elections in Switzerland (2007, 2012, and 2015). Based on candidate data from the voting advice application smartvote.ch, we find that female candidates support ETs more than men do; that especially the French‐speaking part of the country is more in favor of a nuclear phase‐out, and that younger candidates are also more open toward restructuring the energy system than older candidates are. Our models further show that the energy issue does not matter in elections, independently from its salience in the respective election campaigns. Candidates are thus relatively free to choose their position on the issue and do not have to fear consequences at the ballot. However, candidates of center parties, in contrast to the pole parties, are sensitive to the energy issue and reflect public mood in their positions.
Exploring the Effects of North–South and South–South Research Collaboration in Emerging Economies, the Colombian Case
Authors: Ordóñez‐Matamoros Gonzalo , Vernot‐López Michelle , Moreno‐Mattar Ornella , Orozco Luis Antonio
Published: March 2020

International research collaboration (IRC) is associated with both positive and negative effects on the performance of research in emerging economies. While some authors claim that North–South collaborations improve scientific quality and visibility for Southern countries, others claim that it may entail the reorientation of research to comply with Northern agendas. South–South collaborations are thought to increase the focus on local affairs, therefore leading to a relatively small number of scientific international publications appearing in “high quality” journals. Research on the impact of IRC beyond publications in international journals has been neglected despite the importance of other products in knowledge creation. This research uses a broad range of scientific outputs to empirically assess such assumptions and explore the outcomes of IRC in Colombia. Results from multivariate regressions and nonparametric analyses show that, contrary to common assumptions, Colombian research teams collaborating with partners from the global South report higher scientific production, while those collaborating with Northern countries seem to contribute to local knowledge the most.
Flow path system of ultraviolet C irradiation from xenon flash to reduce bacteria survival in platelet products containing a platelet additive solution
Authors: Abe Hideki , Endo Kimika , Shiba Masayuki , Niibe Yoshiyuki , Miyata Shigeki , Satake Masahiro
Published: March 2020

BACKGROUND

Our previous study showed that ultraviolet C (UVC) from xenon (Xe) flash without any photoreactive compounds inactivated bacteria in platelet concentrates (PCs) with less damage to platelets (PLTs) as compared with Xe flash containing ultraviolet A, ultraviolet B, and visible light. Here, we report a UVC irradiation system for PCs under flow conditions consisting of a flow path–irradiation sheet, a peristaltic pump, and a collection bag.

STUDY DESIGN AND METHODS

Platelet concentrates containing Ringerʼs solution (R‐PCs) inoculated with bacteria were injected into a flow path sheet using a peristaltic pump, being irradiated with UVC from Xe flash. The quality of the irradiated PCs containing platelet additive solution (PAS‐PCs) was assessed based on PC variables, PLT surface markers, and aggregation ability.

RESULTS

Streptococcus dysgalactiae (12 tests) and Escherichia coli (11) were all negative on bacterial culture, while Staphylococcus aureus (12) and Klebsiella pneumoniae (14) grew in one and two R‐PCs, respectively. Bacillus cereus spores were inactivated in 7 of 12 R‐PCs. PC variables became significantly different between irradiated and nonirradiated PAS‐PCs. P‐selectin, first procaspase‐activating compound (PAC‐1) binding, and phosphatidylserine increased by irradiation. Aggregability stimulated by adenosine diphosphate, collagen, or thromboxane A2 increased in the irradiated PAS‐PCs, while that by thrombin became smaller compared with nonirradiated controls.

CONCLUSION

This newly developed system inactivated bacteria including spores in R‐PCs. PAS‐PCs irradiated by this system retained acceptable in vitro quality and aggregability. Usage of a peristaltic pump instead of agitator during irradiation may enable this system to be directly combined with an apheresis blood cell separator.
Inhibition of ice recrystallization during cryopreservation of cord blood grafts improves platelet engraftment
Authors: Jahan Suria , Adam Madeleine K. , Manesia Javed K. , Doxtator Emily , Ben Robert N. , Pineault Nicolas
Published: March 2020

BACKGROUND

Platelet engraftment following cord blood (CB) transplantation remains a significant hurdle to this day. The uncontrolled growth of ice, a process referred to as ice recrystallization, is one of several mechanisms that lead to cell loss and decreased potency during freezing and thawing. We hypothesized that reducing cell damage induced by ice recrystallization in CB units (CBUs) would reduce losses of stem and progenitor cells and therefore improve engraftment. We previously demonstrated that the ice recrystallization inhibitor (IRI) N‐(2‐fluorophenyl)‐D‐gluconamide (IRI 2) increases the postthaw recovery of CB progenitors. Herein, we set out to ascertain whether IRI 2 can enhance platelet and bone marrow engraftment activity of hematopoietic stem cells (HSCs) in cryopreserved CBUs using a serial transplantation model.

STUDY DESIGN AND METHODS

CBUs were processed following standard volume/red blood cell reduction procedure and portions frozen with dimethyl sulfoxide (DMSO) supplemented or not with IRI 2. Thawed CB samples were serially transplanted into immunodeficient mice.

RESULTS

Our results show that supplementation of DMSO with IRI 2 had several beneficial effects. Specifically, higher levels of human platelets were observed in the peripheral blood (p < 0.05; n = 4) upon transplant of CBUs preserved with the IRIs. In addition, human BM chimerism and the number of human CFU progenitors in the bone marrow were superior in IRI 2 recipients compared to DMSO recipients. Moreover, IRI 2 had no negative impact on the multilineage differentiation and self‐renewal activities of HSCs.

DISCUSSION

Taken together, these results demonstrate that supplementation of a hematopoietic graft with IRI can improve the postthaw engraftment activities of HSCs.
Histopathologic changes associated with Meibomian Gland dropout in a dog
Authors: Kitamura Yasunari , Arita Reiko , Miwa Yukihiro , Iwashita Hiroko , Saito Akihiko
Published: March 2020

Purpose

To perform histopathologic analysis of tissue manifesting meibomian gland dropout on noncontact infrared meibography in a dog.

Methods

A 14‐year‐old intact male Cairn terrier was evaluated at Triangle Animal Eye Clinic for dense corneal opacity of the right eye. A complete ocular examination was performed, including slit‐lamp biomicroscopy, tonometry, and noncontact meibography. Pigmentary glaucoma with elevation of intraocular pressure was diagnosed, and meibography revealed morphological changes suggestive of gland dropout in the middle of the upper right eyelid.

Results

The globe was enucleated by the transpalpebral method, and palpebral tissue was subjected to histopathologic analysis. The analysis revealed an almost complete loss of meibomian gland structure accompanied by slight enlargement and proliferation of fibroblasts as well as by infiltration of plasma cells and lymphocytes.

Conclusions

Meibomian gland dropout as detected by meibography can be associated with chronic inflammation.
Divergent response of low‐ versus high‐threshold motor units to experimental muscle pain
Authors: Martinez‐Valdes Eduardo , Negro Francesco , Farina Dario , Falla Deborah
Published: March 2020

Key points

The neural strategies behind the control of force during muscle pain are not well understood as previous research has been limited in assessing pain responses only during low‐force contractions.

Here we compared, for the first time, the behaviour of motor units recruited at low and high forces in response to pain.

The results showed that motor units activated at low forces were inhibited while those recruited at higher forces increased their activity in response to pain.

When analysing lower‐ and higher‐threshold motor unit behaviour at high forces we observed differential changes in discharge rate and recruitment threshold across the motor unit pool.

These adjustments allow the exertion of high forces in acutely painful conditions but could eventually lead to greater fatigue and stress of the muscle tissue.

During low‐force contractions, motor unit discharge rates decrease when muscle pain is induced by injecting nociceptive substances into the muscle. Despite this consistent observation, it is currently unknown how the central nervous system regulates motor unit behaviour in the presence of muscle pain at high forces. For this reason, we analysed the tibialis anterior motor unit behaviour at low and high forces. Surface EMG signals were recorded from 15 healthy participants (mean age (SD) 26 (3) years, six females) using a 64‐electrode grid while performing isometric ankle dorsiflexion contractions at 20% and 70% of the maximum voluntary force (MVC). Signals were decomposed and the same motor units were tracked across painful (intramuscular hypertonic saline injection) and non‐painful (baseline, isotonic saline, post‐pain) contractions. At 20% MVC, discharge rates decreased significantly in the painful condition (baseline vs. pain: 12.7 (1.1) Hz to 11.5 (0.9) Hz, P < 0.001). Conversely, at 70% MVC, discharge rates increased significantly during pain (baseline vs. pain: 19.7 (2.8) Hz to 21.3 (3.5) Hz, p = 0.029) and recruitment thresholds decreased (baseline vs. pain: 59.0 (3.9) %MVC to 55.9 (3.2) %MVC, p = 0.02). These results show that there is a differential adjustment between low‐ and high‐threshold motor units during painful conditions. An increase in excitatory drive to high‐threshold motor units is likely required to compensate for the inhibitory influence of nociceptive afferent inputs on low‐threshold motor units. These differential mechanisms allow the force output to be maintained during acute pain but this strategy could lead to increased muscle fatigue and symptom aggravation in the long term.
Bidirectional LSTM Recurrent Neural Network Plus Hidden Markov Model for Wearable Sensor-Based Dynamic State Estimation
Authors: Sibal Ritika , Zhang Ding , Rocho-Levine Julie , Shorter K. Alex , Barton Kira
Published: March 2020

Behavior of animals living in the wild is often studied using visual observations made by trained experts. However, these observations tend to be used to classify behavior during discrete time periods and become more difficult when used to monitor multiple individuals for days or weeks. In this work, we present automatic tools to enable efficient behavior and dynamic state estimation/classification from data collected with animal borne bio-logging tags, without the need for statistical feature engineering. A combined framework of an long short-term memory (LSTM) network and a hidden Markov model (HMM) was developed to exploit sequential temporal information in raw motion data at two levels: within and between windows. Taking a moving window data segmentation approach, LSTM estimates the dynamic state corresponding to each window by parsing the contiguous raw data points within the window. HMM then links all of the individual window estimations and further improves the overall estimation. A case study with bottlenose dolphins was conducted to demonstrate the approach. The combined LSTM–HMM method achieved a 6% improvement over conventional methods such as K-nearest neighbor (KNN) and support vector machine (SVM), pushing the accuracy above 90%. In addition to performance improvements, the proposed method requires a similar amount of training data to traditional machine learning methods, making the method easily adaptable to new tasks.
Metamaterial Vibration of Tensioned Circular Few-Layer Graphene Sheets
Authors: Lu Lu , Ru C.Q. , Guo Xingming
Published: March 2020

The present work aims to examine the metamaterial vibrational behavior of circular few-layer graphene sheets under layerwise tension forces. For this objective, a simplified three-membrane model is developed to simulate flexural vibration of tensioned circular few-layer graphene sheets, in which tensioned top and bottom layers are modeled as two elastic membranes while all less-tensioned or tension-free inner layers together are treated as a single membrane, and the three membranes are coupled through the van der Waals interaction between adjacent layers. Our results show that when the two outermost layers are highly tensioned but the inner layers are free of tension, circular few-layer graphene sheets exhibit negative effective mass within a certain terahertz frequency range. Moreover, such few-layer graphene sheets with negative effective mass demonstrate remarkable vibration isolation and vibration suppression. This research broadens our perspectives for designing and analyzing graphene-based metamaterials and resonators and could find potential application in nanoelectromechanical systems.
Low-density patterned InAs quantum dot arrays
Authors: McCabe Lauren N. , Wang Yuejing , Doty Matthew F. , Zide Joshua M. O.
Published: March 2020

The authors present work on patterned InAs quantum dot (QD) arrays using periodicities between 0.25 and 10 μm, with tailored molecular beam epitaxy growth conditions to promote high QD occupancy in the 10 μm array for further device implementation. The gallium-deoxidation method was used to maintain the pattern integrity. At high growth temperatures and reduced arsenic overpressure conditions, the authors have shown increasing QD occupancy as the patterned spacing increases. The 10 μm array was found to have 89% single QD occupancy. A low density of QDs in known locations enables the QDs to be patterned singly into quantum device applications.
Nitrogen addition increased CO
2
uptake more than non-CO
2
greenhouse gases emissions in a Moso bamboo forest
Authors: Song Xinzhang , Peng Changhui , Ciais Philippe , Li Quan , Xiang Wenhua , Xiao Wenfa , Zhou Guomo , Deng Lei
Published: March 2020

Moso bamboo forests have greater net carbon uptake benefits with increasing nitrogen deposition in the coming decades.
Platelets trigger perivascular mast cell degranulation to cause inflammatory responses and tissue injury
Authors: Karhausen Jörn , Choi Hae Woong , Maddipati Krishna Rao , Mathew Joseph P. , Ma Qing , Boulaftali Yacine , Lee Robert Hugh , Bergmeier Wolfgang , Abraham Soman N.
Published: March 2020

Activated platelets cause microvascular inflammation via direct activation of perivascular mast cells.
Highly bioactive zeolitic imidazolate framework-8–capped nanotherapeutics for efficient reversal of reperfusion-induced injury in ischemic stroke
Authors: He Lizhen , Huang Guanning , Liu Hongxing , Sang Chengcheng , Liu Xinxin , Chen Tianfeng
Published: March 2020

Nanotherapeutics reverses reperfusion-induced injury in ischemic stroke.
Universal interferometric signatures of a black hole’s photon ring
Authors: Johnson Michael D. , Lupsasca Alexandru , Strominger Andrew , Wong George N. , Hadar Shahar , Kapec Daniel , Narayan Ramesh , Chael Andrew , Gammie Charles F. , Galison Peter , Palumbo Daniel C. M. , Doeleman Sheperd S. , Blackburn Lindy , Wielgus Maciek , Pesce Dominic W. , Farah Joseph R. , Moran James M.
Published: March 2020

A black hole image contains a series of increasingly narrow rings measurable with progressively longer interferometers.
Platelets from HIV-infected individuals on antiretroviral drug therapy with poor CD4
+
T cell recovery can harbor replication-competent HIV despite viral suppression
Authors: Real Fernando , Capron Claude , Sennepin Alexis , Arrigucci Riccardo , Zhu Aiwei , Sannier Gérémy , Zheng Jonathan , Xu Lin , Massé Jean-Marc , Greffe Ségolène , Cazabat Michelle , Donoso Maribel , Delobel Pierre , Izopet Jacques , Eugenin Eliseo , Gennaro Maria Laura , Rouveix Elisabeth , Cramer Bordé Elisabeth , Bomsel Morgane
Published: March 2020

In virally suppressed HIV-infected individuals on antiretroviral drug therapy, platelets harboring HIV correlate with poor immunological recovery.
Design of anti-inflammatory heparan sulfate to protect against acetaminophen-induced acute liver failure
Authors: Arnold Katelyn , Xu Yongmei , Sparkenbaugh Erica M. , Li Miaomiao , Han Xiaorui , Zhang Xing , Xia Ke , Piegore Mark , Zhang Fuming , Zhang Xiaoxiao , Henderson Mike , Pagadala Vijayakanth , Su Guowei , Tan Lisi , Park Pyong Woo , Stravitz Richard T. , Key Nigel S. , Linhardt Robert J. , Pawlinski Rafal , Xu Ding , Liu Jian
Published: March 2020

Synthetic heparan sulfate protects against drug-induced acute liver failure by inhibiting the proinflammatory activity of HMGB1/RAGE axis.
Trivalent Glycoprotein Subunit Vaccine Prevents Neonatal Herpes Simplex Virus Mortality and Morbidity
Authors: Patel Chaya D. , Taylor Sean A. , Mehrbach Jesse , Awasthi Sita , Friedman Harvey M. , Leib David A.
Published: March 2020

Herpes simplex virus is among the most serious infections of newborns. Current antiviral therapies can prevent mortality if infection is recognized early and treated promptly. Most children who survive nHSV develop lifelong neurological and behavioral deficits, despite aggressive antiviral treatment. We propose that maternal immunization could provide protection against HSV for both mother and baby. To this end, we used a trivalent glycoprotein vaccine candidate to demonstrate that offspring are protected from nHSV following maternal immunization. Significantly, this approach protected offspring from long-term behavioral morbidity. Our results emphasize the importance of providing protective immunity to neonates during this window of vulnerability.
Coding-Complete RNA Virus Genomes Assembled from Murine Cecal Metatranscriptomes
Authors: Stough Joshua M. A. , Beaudoin Andrew J. , Schloss Patrick D.
Published: March 2020

Efforts to catalog viral diversity in the gut microbiome have largely focused on DNA viruses, while RNA viruses remain understudied. To address this, we screened assemblies of previously published mouse gut metatranscriptomes for the presence of RNA viruses. We identified the coding-complete genomes of an astrovirus and five mitovirus-like viruses.
Complete Genome Sequence of
Desulfuromonas
sp. Strain AOP6, an Iron(III) Reducer Isolated from Subseafloor Sediment
Authors: Guo Yong , Aoyagi Tomo , Inaba Tomohiro , Sato Yuya , Habe Hiroshi , Hori Tomoyuki
Published: March 2020

Desulfuromonas
sp. strain AOP6, with iron(III)-reducing activity, was isolated from subseafloor sediment in Nankai Trough. We report the complete genome of this strain determined by Illumina MiSeq sequencing and PCR/Sanger sequencing-based gap closing. The genome includes the genes encoding
c
-type cytochromes, type IV pili, and fatty acid degradation enzymes.
Hematite (U-Th)/He thermochronometry detects asperity flash heating during laboratory earthquakes
Authors: Calzolari Gabriele , Ault Alexis K. , Hirth Greg , McDermott Robert G.
Published: March 2020

Evidence for coseismic temperature rise that induces dynamic weakening is challenging to directly observe and quantify in natural and experimental fault rocks. Hematite (U-Th)/He (hematite He) thermochronometry may serve as a fault-slip thermometer, sensitive to transient high temperatures associated with earthquakes. We test this hypothesis with hematite deformation experiments at seismic slip rates, using a rotary-shear geometry with an annular ring of silicon carbide (SiC) sliding against a specular hematite slab. Hematite is characterized before and after sliding via textural and hematite He analyses to quantify He loss over variable experimental conditions. Experiments yield slip surfaces localized in an ∼5–30-µm-thick layer of hematite gouge with <300-µm-diameter fault mirror (FM) zones made of sintered nanoparticles. Hematite He analyses of undeformed starting material are compared with those of FM and gouge run products from high-slip-velocity experiments, showing >71% ± 1% (1σ) and 18% ± 3% He loss, respectively. Documented He loss requires short-duration, high temperatures during slip. The spatial heterogeneity and enhanced He loss from FM zones are consistent with asperity flash heating (AFH). Asperities >200–300 µm in diameter, producing temperatures >900 °C for ∼1 ms, can explain observed He loss. Results provide new empirical evidence describing AFH and the role of coseismic temperature rise in FM formation. Hematite He thermochronometry can detect AFH and thus seismicity on natural FMs and other thin slip surfaces in the upper seismogenic zone of Earth’s crust.
Enveloping calcification of flexor digitorum profundus tendon: a diagnosis easily missed
Authors: Senthilkumaran Sriskandarasa , Ledingham William M
Published: March 2020

Calcific tendonitis of the hand is a rare condition. We present a case where there was extensive calcification along the flexor digitorum profundus tendon of the little finger. The patient’s symptoms resolved with non-operative management.
Management of ANCA associated vasculitis
Authors: Wallace Zachary S , Miloslavsky Eli M
Published: March 2020

Anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV) is a small to medium vessel vasculitis associated with excess morbidity and mortality. This review explores how management of AAV has evolved over the past two decades with pivotal randomized controlled trials shaping the management of induction and maintenance of remission. Contemporary AAV care is characterized by approaches that minimize the cumulative exposure to cyclophosphamide and glucocorticoids, increasingly use rituximab for remission induction and maintenance, and consider therapies with less toxicity (for example, methotrexate, mycophenolate mofetil) for manifestations of AAV that do not threaten organ function or survival. Simultaneously, improvements in outcomes, such as renal and overall survival, have been observed. Additional trials and observational studies evaluating the comparative effectiveness of agents for AAV in various patient subgroups are needed. Prospective studies are necessary to assess the effect of psychosocial interventions on patient reported outcomes in AAV. Despite the expanding array of treatments for AAV, little guidance on how to personalize AAV care is available to physicians.
Vasomodulation of peripheral blood flow by focused ultrasound potentiates improvement of diabetic neuropathy
Authors: Tan Joo-Shin , Lin Chou-Ching , Chen Gin-Shin
Published: March 2020

Objective

Effective treatment methods for diabetic peripheral neuropathy are still lacking. Here, a focused ultrasound (FUS) technique was developed to improve blood flow in diabetic peripheral vessels and potentially treat diabetic peripheral neuropathy.

Research design and methods

Male adult Sprague-Dawley rats at 4 weeks poststreptozotocin injections were adopted as models for diabetic neuropathic rats. For single FUS treatment, blood perfusion in the skin of the pad of the middle toe was measured before, during, and after the medial and lateral plantar arteries were treated by FUS. For multiple FUS treatments, blood perfusion measurements, von Frey and hot plate testing and nerve conduction velocity measurements were performed before ultrasonic treatment on the first day of each week, and the microvascular and neural fiber densities in the pad of the toe were measured on the first day of the last week.

Results

The blood perfusion rate significantly increased for 7–10 min in the control and neuropathic rats after a single ultrasound exposure. Multiple ultrasound treatments compared with no treatments significantly increased blood perfusion at the second week and further enhanced perfusion at the third week in the neuropathic rats. Additionally, the paw withdrawal force and latency significantly increased from 34.33±4.55 g and 3.96±0.25 s at the first week to 39.10±5.02 g and 4.77±0.71 s at the second week and to 41.13±2.57 g and 5.24±0.86 s at the third week, respectively. The low nerve conduction velocity in the diabetic rats also improved after the ultrasound treatments. Additionally, ultrasound treatments halted the decrease in microvessel and neural fiber densities in the skin of the diabetic toes. Histologic analysis indicated no damage to the treated arteries or neighboring tissue.

Conclusions

FUS treatment can increase upstream arterial blood flow in diabetic feet, ameliorate the decrease in downstream microvessel perfusion and halt neuropathic progression.
Students’ perceptions of an in-house developed pharmacy serious game for professional skills training
Authors: Yap Kevin Yi-Lwern , Tan Shawn Ignatius Boon Heng , Yap Kai Zhen , Yap John Yin Gwee
Published: March 2020

Background

An in-house three-dimensional (3D) multiplayer online role-playing game was developed for professional skills training of pharmacy students. Students play the game in a post-apocalyptic world to save humankind from zombies. They solve virtual patient encounters through visual and motion-capture technologies. Their gaming perceptions and experiences were investigated.

Method

A self-administered questionnaire obtained participants’ demographics, gaming interests, perceptions of game effectiveness, preferences on gaming elements and gameplay experience through the Game Engagement Questionnaire (GEQ). Pre-gameplay and post-gameplay assessments were tracked to assess student learning. Descriptive statistics and paired sample t-tests were used for analysis.

Results

Fifty-five students were recruited. Two-thirds of the gameplay group (67.9%) liked the post-apocalyptic fantasy settings and heroic storyline (66.0%). Three quarters liked the modern setting (73.1%), authentic plots (73.5%) and plot animations (72.3%). Participants felt the game was effective in training health communication and patient history-taking skills (81.8%). Participants’ test scores for counselling increased from 66.1%±7.6% (pre-gameplay) to 70.3%±8.0% (post-gameplay, p=0.004). The highest scoring GEQ dimension was sensory and imaginative immersion (2.92±0.74).

Conclusion

Students found the game useful for pharmacy professional skills training. With proper implementation, this game can become a useful tool to enhance student learning and gear them towards clinical practices.
Transcriptome complexity in intravascular NK/T-cell lymphoma
Authors: Fujikura Kohei , Yoshida Makoto , Uesaka Kazuma
Published: March 2020

Aims

Intravascular NK/T-cell lymphoma (IVNKTCL) is a rare disease, which is characterised by exclusive growth of large cells within the lumen of small vessels, Epstein–Barr virus infection and somatic mutations in epigenetic regulator genes. Here, we elucidate the transcriptomic complexity of IVNKTCL.

Methods

IVNKTCL cases were retrieved from a single-centre cohort of 25 intravascular lymphomas. RNA-seq and whole exome sequencing (WES) were performed to analyse transcriptomic abnormalities and mutations in splicing factors.

Results

Approximately 88% of the total reads from the RNA-seq were considered exonic, while the remaining reads (12%) were mapped to intronic or intergenic regions. We detected 28,941 alternative splicing events, some of which would produce abnormal proteins rarely found in normal cells. The detected events also included tumour-specific splicing alterations in oncogenes and tumour suppressors (e.g.,HRAS,MDM2andVEGFA). WES identified premature termination mutations or copy number losses in a total of 15 splicing regulator genes, includingSF3B5,SRSF12andTNPO3.

Conclusions

This study raises the possibility that IVNKTCL may be driven by multiple complex regulatory loops, including non-exonic expression and aberrant splicing, in addition to defects in epigenetic regulation.
Simultaneous inhibition of CXCR1/2, TGF-β, and PD-L1 remodels the tumor and its microenvironment to drive antitumor immunity
Authors: Horn Lucas A , Riskin Jeffrey , Hempel Heidi A , Fousek Kristen , Lind Hanne , Hamilton Duane H , McCampbell Kristen K , Maeda Dean Y , Zebala John A , Su Zhen , Schlom Jeffrey , Palena Claudia
Published: March 2020

Background

Despite the success of immune checkpoint blockade therapy in the treatment of certain cancer types, only a small percentage of patients with solid malignancies achieve a durable response. Consequently, there is a need to develop novel approaches that could overcome mechanisms of tumor resistance to checkpoint inhibition. Emerging evidence has implicated the phenomenon of cancer plasticity or acquisition of mesenchymal features by epithelial tumor cells, as an immune resistance mechanism.

Methods

Two soluble factors that mediate tumor cell plasticity in the context of epithelial-mesenchymal transition are interleukin 8 (IL-8) and transforming growth factor beta (TGF-β). In an attempt to overcome escape mechanisms mediated by these cytokines, here we investigated the use of a small molecule inhibitor of the IL-8 receptors CXCR1/2, and a bifunctional agent that simultaneously blocks programmed death ligand 1 (PD-L1) and traps soluble TGF-β.

Results

We demonstrate that simultaneous inhibition of CXCR1/2, TGF-β, and PD-L1 signaling synergizes to reduce mesenchymal tumor features in murine models of breast and lung cancer, and to markedly increase expression of tumor epithelial E-cadherin while reducing infiltration with suppressive granulocytic myeloid-derived suppressor cells, significantly enhancing T-cell infiltration and activation in tumors, and leading to improved antitumor activity.

Conclusions

This study highlights the potential benefit of combined blockade of CXCR1/2 and TGF-β signaling for modulation of tumor plasticity and potential enhancement of tumor responses to PD-L1 blockade. The data provide rationale for the evaluation of this novel approach in the clinic.