bluuebunny/crossref_metadata_2025 huggingface dataset:
Implications of a Field-Based Police Leadership Development Programme
Authors: Davies Amanda , Heysmand Matt
Published: September 2019

Evolving demands of the global police community to provide authentic, impactful leadership education and training programmes remain unabated. At the centre of this article is the evaluation of the impact of a unique simulation-based learning for leadership development for police officers. A mixed-method approach including field-based interviews 6 months post programme participation was applied to capture the officers’ perspective of their experience and the potential short- and long-term implications. The evaluation included the officers’ supervisors providing an important contribution in understanding the perception of the influence of the programme on the officers’ development and contribution to their professional practice. The key learning initiative discussed in the article is the influence of the unique mobile simulation-based learning approach for transfer of leadership learning to application in the field. The findings indicate that the learning experience is influential in supporting the development of the officers’ leadership capability and application in their operational duties and their approach to leadership and decision-making beyond the professional to their personal lives. Furthermore, the programme content and delivery design offer an efficient and effective leadership development strategy that is realizing tangible benefits for the officers, the organization, and the community they serve.
Measuring Aggregate Price Indices with Taste Shocks: Theory and Evidence for CES Preferences*
Authors: Redding Stephen J , Weinstein David E
Published: September 2019

We develop an approach to measuring the cost of living for CES preferences that treats demand shocks as taste shocks that are equivalent to price shocks. In the presence of relative taste shocks, the Sato-Vartia price index is upward biased because an increase in the relative consumer taste for a variety lowers its taste-adjusted price and raises its expenditure share. By failing to allow for this association, the Sato-Vartia index underweights drops in taste-adjusted prices and overweights increases in taste-adjusted prices, leading to what we call a “taste-shock bias.” We show that this bias generalizes to other invertible demand systems.
SIMULATION OF THE RESPONSE OF A LaBr3(Ce) DETECTOR IN AN ATMOSPHERE CONTAMINATED WITH RADIONUCLIDES AFTER A NUCLEAR POWER PLANT ACCIDENT
Authors: Urban Tomáš , Vágner Petr
Published: September 2019

The aim of this paper is to investigate the possibility of using detectors based on LaBr3(Ce) scintillation crystal as part of gamma spectrometry systems for field use and possibly as part of a monitoring network around nuclear power plants, i.e. whether LaBr3(Ce) detectors can follow the classical scintillation detectors based on NaI (Tl). For this purpose, the Monte Carlo simulation of the IPROL-1 probe response was performed in the simplified geometry of the radionuclides-contaminated atmosphere. A study shows that a LaBr3(Ce)-based probe is usable for this purpose and results are at least comparable to those with a conventional NaI (Tl)-based probe.
Plaster cast treatment for distal forearm fractures in children: which index best predicts the loss of reduction?
Authors: Ravier Domenico , Morelli Ilaria , Buscarino Valentina , Mattiuz Chiara , Sconfienza Luca M. , Spreafico Andrea A. , Peretti Giuseppe M. , Curci Domenico
Published: September 2019

Several radiological indices were introduced to evaluate cast adequacy for paediatric distal forearm fractures: cast, gap, padding, Canterbury (reflecting the cast shape and the amount of padding) and three-point indices, and second metacarpal-radius angle (measuring cast ulnar-moulding). The aim of this study is to define which index is most reliable in assessing cast adequacy and predicting redisplacements. Hundred twenty-four consecutive patients (age 5–18) affected by distal both-bone forearm or radius fractures treated with casting were included. These indices and the displacement angles were calculated on the initial radiograph after reduction. Radiographs at 7 and 30 days were taken to assess if the loss of reduction occurred, and measure the displacement deltas (displacement angle at day 30 – displacement angle at day 0). Student’s t-test, Chi-square test and Pearson’s correlation were used for the statistical analysis. High padding (P = 0.034), Canterbury (P = 0.002) and Cast (P < 0.001) indices showed an association with redisplacements in distal forearm fractures. Both-bone forearm fractures have a higher risk of loss of reduction than radius fractures [odds ratio (OR = 4.99, 95% confidence interval (CI) = 2.21–11.3, P < 0.001]. A higher displacement delta in antero-posterior (Pearson’s r = 0.418, P = 0.037) and lateral (P = 0.045) views for both-bone fractures showed an association with a high gap Index. Regarding radius fractures, a high cast index is associated with a higher displacement delta in antero-posterior (P = 0.035). The three-point index and the second metacarpal-radius angle did not show any association with the redisplacement risk. Cast oval moulding without excessive padding may prevent redisplacements in paediatric distal forearm fractures, while casts ulnar-moulding does not.
How Wide Should the Excision Margins for Facial Small Aggressive Basal Cell Carcinoma Be? Experience With 306 Cases
Authors: Ariza Santiago A. , Calderón Diana C. , Aristizábal Juan C. , Parra-Medina Rafael
Published: September 2019

BACKGROUND

Subclinical extension (SCE) of basal cell carcinomas (BCCs) may be responsible for incomplete resection of the tumor. The aggressive histological patterns (micronodular, infiltrative, and morpheaform) have greater tendencies toward invading surrounding tissues in an irregular pattern.

OBJECTIVE

To determine the SCE of small facial aggressive BCCs excised using Mohs micrographic surgery (MMS).

MATERIALS AND METHODS

An observational case series study. Data of patients with facial BCCs with aggressive histological patterns, less than or equal to 6 mm in diameter in high risk site (H zone), and 10 mm in intermediate risk site (M zone), treated with MMS between January 2008 and December 2016, were included.

RESULTS

This study included 306 histologically confirmed lesions retrieved from 1,196 clinical records reviewed. Median size of tumors was 5.7 mm (interquartile range: 5–6 mm). Resection of the tumors using 2, 3, and 4 mm margins achieves complete excision of the lesion including the subclinical extension area in 73.9%, 94.4%, and 99% of cases, respectively.

CONCLUSION

The present study demonstrated that a 4-mm resection margin was enough to eradicate the lesion completely in 99% of cases of primary small facial BCCs with aggressive histological patterns.
Assessment of the Safety and Efficacy of Prolapsed Orbital Fat Resection During Involutional Entropion Repair
Authors: Prendes Mark A. , Geng June , Ediriwickrema Lilangi S. , Areephanthu Christopher , Burchell Patrick , Kikkawa Don O. , Nunery William R. , Korn Bobby , Harold Lee H. B.
Published: September 2019

The authors propose that orbital fat prolapse contributes to the mechanics of involutional entropion and that conservative orbital fat resection during surgical repair of entropion can be done safely, resulting in low recurrence rates.

Purpose:

To assess the recurrence rate of involutional entropion in patients treated with a combined approach including a modified Bick procedure, excision of preseptal orbicularis muscle, and conservative resection of prolapsed orbital fat.

Methods:

A retrospective chart review of patients undergoing repair of involutional entropion with the combined procedure including orbital fat resection and a second group with standard entropion repair without orbital fat resection was performed. Only patients with follow-up greater than 6 months were included in the study.

Results:

Seventy eyelids of 54 patients met all inclusion criteria for the combined procedure group over a 9-year period from 2008 to 2016. Average follow-up was 46.9 months. There was a documented recurrence of entropion in 1 eyelid during the follow-up period (1.4%). The remaining 69 cases had successful subjective and objective results without need for any additional procedures. In the group undergoing entropion repair without fat resection, 22 eyelids of 19 patients had the required follow-up period with a recurrence rate of 4.5% (p > 0.05).

Conclusions:

The authors demonstrate good surgical success with a combined approach of a modified Bick procedure, preseptal orbicularis excision, and conservative orbital fat resection. Conservative fat resection during entropion repair was found to be safe, and the combined procedure was found to be effective with a rate of recurrent entropion of 1.4% on extended follow-up.
Validation of Transtek TMB-1776 according to European Society of Hypertension International Protocol revision 2010 in adults
Authors: Liu Zhonghua , Chen Liyi
Published: September 2019

In the present study, accuracy of Transtek TMB-1776 upper-arm blood pressure monitor in adult subjects was determined by comparing with a non-invasive (auscultatory) reference mercury sphygmomanometer, following the European Society of Hypertension International Protocol revision 2010 (ESH-IP 2010). All the validation requirement were reached: 74, 93, and 98 of systolic blood pressure measurements and 86, 97, and 99 of diastolic blood pressure measurements were within 5, 10, and 15 mmHg of absolute difference, respectively. The mean ± SD device-observer difference was −1.2 ± 4.9 mmHg for systolic blood pressure and −0.7 ± 3.5 mmHg for diastolic blood pressure. For systolic blood pressure and diastolic blood pressure, respectively, 25 and 30 of subjects had at least two of their three difference within 5 mmHg, and three and zero subject showed no difference within 5 mmHg. In conclusion, Transtek TMB-1776 has passed all phases of ESH-IP 2010 and is suitable for self/home blood pressure measurement of adults.
Practical Approaches on CD30 Detection and Reporting in Lymphoma Diagnosis
Authors: Xu Mina L. , Gabali Ali , Hsi Eric D. , Fedoriw Yuri , Vij Kiran , Salama Mohamed E. , Ramchandren Radhakrishnan , O’Malley Dennis , Wick Mark R. , Battistella Maxime , Gru Alejandro A.
Published: September 2019

While our understanding of the biology of CD30 in lymphoma continues to evolve, our need to detect and measure its expression at the protein level remains critically important for diagnosis and patient care. In addition to its diagnostic and prognostic utility, CD30 has emerged as a vehicle for drug targeting through the antibody-drug conjugate brentuximab-vedotin (BV). Given the numerous ways that CD30 is utilized and its emergence as a predictive/prognostic biomarker, pathologists must come to a general consensus on the best reporting structure and methodology to ensure appropriate patient care. In this manuscript, we review the indications for testing, various modalities for testing, technical challenges, pitfalls, and potential standards of reporting. The following questions will try to be addressed in the current review article: What defines a “POSITIVE” level of CD30 expression?; How do we evaluate and report CD30 expression?; What are the caveats in the evaluation of CD30 expression?
Integrative Medicine Therapies for Pain Management in Cancer Patients
Authors: Deng Gary
Published: September 2019

Pain management for cancer patients should include pharmacologic and nonpharmacologic interventions. Integrative medicine therapies, such as mind-body practice, acupuncture, massage therapy, and music therapy, have been studied for their roles in pain management. Data from randomized controlled trials support the effect of hypnosis, acupuncture, and music therapy in reduction of pain. Mindfulness meditation, yoga, qigong, and massage therapy, although may not reduce pain per se, can relieve anxiety and mood changes, which are commonly associated with pain. In clinical practice, one should also consider burdens and risks to patients, patient preference, and the presence or absence of better alternatives when making decisions on whether an integrative medicine therapy is of clinical value.
Evaluation of Traditional Chinese Medicine Herbs in Oncology Clinical Trials
Authors: Liu Jie , Mao Jun J. , Wang Xin Shelley , Lin Hongsheng
Published: September 2019

Despite wide empirical use and demand for traditional Chinese medicine (TCM) herbs worldwide, high-quality clinical trials of TCM herbs in oncology are limited. We developed recommendations for rigorous clinical trials to evaluate their safety and efficacy for oncology patients. To accomplish this goal, the TCM & Cancer Research Committee of the Chinese Pharmaceutical Association convened a working group of oncologists, TCM experts, clinical researchers, biostatisticians, and industry/government representatives to develop principles and approaches for TCM cancer drug clinical trials. They identified 2 categories of herbal drugs based on therapeutic intent: survival improvement and symptom management. The working group also emphasized the need to adopt international standards when appropriate for TCM herbal drug approval and to develop methodology to standardize diagnostic criteria, treatment approaches, and outcome measures according to defining TCM characteristics. These recommendations aim to improve study design and methods to inform rigorous investigation of TCM herbs in patients with cancer.
Polymorphisms in FGF3, FGF10, and FGF13 May Contribute to the Presence of Temporomandibular Disorders in Patients Who Required Orthognathic Surgery
Authors: Horta Karla Carpio , Weiss Suyany Gabriely , Miranda Katheleen , Sebastiani Aline Monise , Costa Delson João da , Matsumoto Mírian Aiko Nakane , Marañón-Vásquez Guido Artemio , Vieira Alexandre Rezende , Scariot Rafaela , Küchler Erika Calvano
Published: September 2019

Background:

To evaluate whether genetic polymorphisms in FGF3, FGF10, and FGF13 are associated with temporomandibular disorders (TMD) in patients that presented dentofacial deformities requiring orthognathic surgery.

Material and Methods:

The sample comprised a total of 113 patients of both sexes. The diagnosis of TMD was performed before orthognathic surgery between Research Diagnostic Criteria for Temporomandibular Disorders (RDC-TMD). According to the TMD assessment, the patients were divided into 3 major groups: myofascial pain, articular disc displacements and other TMD conditions (arthralgia, arthritis, and arthrosis). Genomic DNA was collected from saliva samples and genetic polymorphisms in FGF3 (rs1893047 and rs7932320), FGF10 (rs900379) and FGF13 (rs5931572 and rs5974804) were analyzed by real-time polymerase chain reactions. The association between the TMD conditions and the genetic polymorphisms assessed were analyzed by Poisson Regression. The model was calculated on bivariate and adjusted by sex. The established alpha was 5%. Data were analyzed by using SPSS software (IBM, Armonk, NY).

Results:

The genetic polymorphisms rs7932320 in FGF3 (P < 0.001) and rs900379 in FGF10 (P < 0.05) were associated with the presence of muscle disorder. The genetic polymorphisms rs1893047 in FGF3, rs900379 in FGF10, and rs5974804 and rs5931572 in FGF13, were associated with the presence of disk displacement (P < 0.05). The genetic polymorphisms rs1893047 and rs7932320 in FGF3, rs900379 in FGF10, and rs900379 in FGF10 were associated with other TMD conditions (P < 0.05).

Conclusion:

Genetic polymorphisms in FGF3, FGF10, and FGF13 genes were associated with temporomandibular disorders in a population with dentofacial deformities.
Antithymocyte Globulin Antibody Titer Congruent With Kidney Transplantation: Analysis of Incidence, Outcomes, Cost, and Alternative Targets
Authors: Lattimore Sherene , Skill Nicholas J. , Maluccio Mary A. , Elliott Holly , Dobben Elizabeth , Shafuddin Asif , Goggins William C.
Published: September 2019

Background.

Rabbit antithymocyte globulin (rATG) use for immunosuppression induction is widespread but is contraindicated by the presence of anti-rATG antibodies. This study reports the incidence of positive anti-rATG antibody titers in patients before and after renal transplant and evaluates associated outcomes and costs. In addition, it will correlate CD40L and interleukin (IL)-21 with anti-rATG antibody titers.

Methods.

Clinical and billing records from the Indiana University Transplant Laboratory were reviewed for positive versus negative anti-rATG antibody titers, graft survival, and 7-day readmission costs between 2004 and 2018. Serum from patients with positive and negative rATG antibody titers were quantitated for CD40L and IL-21 by enzyme-linked immunosorbent assay.

Results.

On average, between 2004 and May 2018, 163 kidney transplants per year were performed. Anti-rATG antibody titers were ordered for 17 patients/year, of which 18.2% were positive at 1:100 titer either pre- or post-transplant. Time to graft loss correlated with a positive rATG titer at time of readmission. Moreover, second kidney transplant increased the anti-rATG positive rate. A weak correlation was observed between anti-rATG titer and recipient age. Seven-day readmission treatment costs were significantly lower in patients with positive anti-rATG titer. IL-21 and CD40L were significantly greater in patients with positive anti-rATG titers after transplant when compared with negative anti rATG patients.

Conclusions.

Positive anti-rATG antibody titer is associated with a significant negative impact on outcomes. Monitoring of anti-rATG antibody titer is recommended to optimize treatment options in patients, especially in the setting of second transplants. Elucidation of the mechanisms associated with positive anti-rATG antibody is required. IL-21 and CD40L are potential targets for future study.
Sleep Quality and Cognitive Function in Type 1 Diabetes
Authors: Gilsanz Paola , Lacy Mary E. , Beeri Michal Schnaider , Karter Andrew J. , Eng Chloe W. , Whitmer Rachel A.
Published: September 2019

Study Objective:

The objective was to examine the association between sleep quality and global and domain-specific cognitive function among older individuals with type 1 diabetes (T1D).

Methods:

We evaluated 695 individuals with T1D aged 60 years or above who participated in the baseline assessment of the Study of Longevity in Diabetes (SOLID), which captured subjective sleep quality (Pittsburgh Sleep Quality Index) and global and domain-specific (language, executive function, episodic memory, and simple attention) cognitive function. Multivariable linear regressions estimated the associations between sleep quality quartiles and overall and domain-specific cognitive function adjusting for age, sex, race/ethnicity, education, depressive symptoms, and severe hypoglycemic episodes. Sensitivity analyses examined the associations between aspects of sleep quality and global cognitive function.

Results:

The worst sleep quality quartile was associated with lower global cognition (β=−0.08; 95% confidence interval: −0.17, −0.01) and lower executive function (β=−0.17, 95% confidence interval: −0.30, −0.03) compared with the best quartile of sleep quality adjusting for demographics and comorbidities. Sleep quality was not associated with language, episodic memory, or simple attention. Sleep medications and daytime dysfunction were most strongly associated with global cognition.

Conclusion:

Our results suggest that sleep quality may be a modifiable risk factor for global cognitive function and executive function among elderly individuals with T1D.
A metabolite-based machine learning approach to diagnose Alzheimer’s-type dementia in blood: Results from the European Medical Information Framework for Alzheimer’s Disease biomarker discovery cohort
Authors: Stamate Daniel , Kim Min , Proitsi Petroula , Westwood Sarah , Baird Alison , Nevado-Holgado Alejo , Hye Abdul , Bos Isabelle , Vos Stephanie , Vandenberghe Rik , Teunissen Charlotte E. , Kate Mara Ten , Scheltens Philip , Gabel Silvy , Meersmans Karen , Blin Olivier , Richardson Jill , Roeck Ellen De , Engelborghs Sebastiaan , Sleegers Kristel , Bordet Régis , Rami Lorena , Kettunen Petronella , Tsolaki Magda , Verhey Frans , Alcolea Daniel , Lléo Alberto , Peyratout Gwendoline , Tainta Mikel , Johannsen Peter , Freund-Levi Yvonne , Frölich Lutz , Dobricic Valerija , Frisoni Giovanni B , Molinuevo José L , Wallin Anders , Popp Julius , Martinez-Lage Pablo , Bertram Lars , Blennow Kaj , Zetterberg Henrik , Streffer Johannes , Visser Pieter J , Lovestone Simon , Legido-Quigley Cristina
Published: September 2019

INTRODUCTION

Machine learning (ML) may harbor the potential to capture the metabolic complexity in Alzheimer’s Disease (AD). Here we set out to test the performance of metabolites in blood to categorise AD when compared to CSF biomarkers.

METHODS

This study analysed samples from 242 cognitively normal (CN) people and 115 with AD-type dementia utilizing plasma metabolites (n=883). Deep Learning (DL), Extreme Gradient Boosting (XGBoost) and Random Forest (RF) were used to differentiate AD from CN. These models were internally validated using Nested Cross Validation (NCV).

RESULTS

On the test data, DL produced the AUC of 0.85 (0.80-0.89), XGBoost produced 0.88 (0.86-0.89) and RF produced 0.85 (0.83-0.87). By comparison, CSF measures of amyloid, p-tau and t-tau (together with age and gender) produced with XGBoost the AUC values of 0.78, 0.83 and 0.87, respectively.

DISCUSSION

This study showed that plasma metabolites have the potential to match the AUC of well-established AD CSF biomarkers in a relatively small cohort. Further studies in independent cohorts are needed to validate whether this specific panel of blood metabolites can separate AD from controls, and how specific it is for AD as compared with other neurodegenerative disorders
Combinations of antifungals to effectively kill drug-resistant Candida auris
Authors: Jaggavarapu Siddharth , Burd Eileen M. , Weiss David S.
Published: September 2019

Candida auris is an emerging, highly virulent fungal pathogen that is often resistant to multiple classes of antifungals. To overcome this resistance, we investigated the in vitro efficacy of antifungal combinations, finding that amphotericin B/micafungin resulted in drastically reduced survival (~5 logs) of all 10 isolates tested including 2 that were refractory to each individual drug. These findings suggest that combination therapy with micafungin/amphotericin B may have clinical utility against broadly resistant C. auris.
Prospective evaluation of beta-lactamase detection in penicillin susceptibleStaphylococcus aureusby interpretation of the penicillin disc edge
Authors: Henderson Andrew , Whiley David , Francis Fleur , Engler Cathy , Glover Matthew , Douglas Joel , Gore Letitia , Harris Patrick , Paterson David , Nimmo Graeme , Norton Robert
Published: September 2019

Penicillin susceptibleStaphylococcus aureus(PSSA) may occasionally be encountered as a cause of complicatedS. aureusinfection, such as endocarditis or bloodstream infections. Clinicians may choose to treat these patients with penicillin over a semi-synthetic penicillin derivative, such as flucloxacillin or oxacillin, due to a favourable Pk/Pd profile. In this study, we prospectively evaluated the penicillin disc (1-IU) method for detection ofblaZ, with interpretation of the penicillin edge according to EUCAST recommendations. 472 PSSA isolates were collected between September 2014 to December 2015 from three clinical microbiology laboratories in Queensland, Australia. Initial antimicrobial susceptibility testing was performed by the Vitek 2 system. Real-time PCR forblaZwas performed following phenotypic testing with the 1-IU penicillin disc and the PCR used as the gold standard for detection of penicillinase. The prevalence ofblaZamongst the isolates was 7%. The sensitivity, specificity, positive predictive value and negative predictive value of the penicillin disc method was 97%, 95%, 61% and 100% when compared toblaZPCR. In summary, the penicillin disc zone size and edge interpretation is a reliable method for detection ofblaZinS. aureusisolates that otherwise test susceptible to penicillin by Vitek 2 AST.
D1 and D2 systems converge in the striatum to update goal-directed learning
Authors: Matamales Miriam , McGovern Alice E. , Mi Jia Dai , Mazzone Stuart B. , Balleine Bernard W. , Bertran-Gonzalez Jesus
Published: September 2019

Extinction learning allows animals to withhold voluntary actions that are no longer related to reward and so provides a major source of behavioral control. Although such learning is thought to depend on dopamine signals in the striatum, the way the circuits mediating goal-directed control are reorganized during new learning remains unknown. Here, by mapping a dopamine-dependent transcriptional activation marker in large ensembles of striatal projection neurons (SPNs) expressing dopamine receptor type 1 (D1-SPNs) or 2 (D2-SPNs) in mice, we demonstrate an extensive and dynamic D2- to D1-SPN trans-modulation across the dorsal striatum that is necessary for updating previous goal-directed learning. Our findings suggest that D2-SPNs suppress the influence of outdated D1-SPN plasticity within functionally relevant striatal territories to reshape volitional action.
Recombinant human soluble thrombomodulin is associated with attenuation of sepsis-induced renal impairment by inhibition of extracellular histone release
Authors: Akatsuka Masayuki , Masuda Yoshiki , Tatsumi Hiroomi , Yamakage Michiaki
Published: September 2019

Multiple organ dysfunction induced by sepsis often involves kidney injury. Extracellular histones released in response to damage-associated molecular patterns are known to facilitate sepsis-induced organ dysfunction. Recombinant human soluble thrombomodulin (rhTM) and its lectin-like domain (D1) exert anti-inflammatory effects and neutralize damage-associated molecular patterns. However, the effects of rhTM and D1 on extracellular histone H3 levels and kidney injury remain poorly understood. Our purpose was to investigate the association between extracellular histone H3 levels and kidney injury, and to clarify the effects of rhTM and D1 on extracellular histone H3 levels, kidney injury, and survival in sepsis-induced rats. Rats in whom sepsis was induced via cecal ligation and puncture were used in this study. Histone H3 levels, histopathology of the kidneys, and the survival rate of rats at 24 h after cecal ligation and puncture were investigated. Histone H3 levels increased over time following cecal ligation and puncture. Histopathological analyses indicated that the distribution of degeneration foci among tubular epithelial cells of the kidney and levels of histone H3 increased simultaneously. Administration of rhTM and D1 significantly reduced histone H3 levels compared with that in the vehicle-treated group and improved kidney injury. The survival rates of rats in rhTM- and D1-treated groups were significantly higher than that in the vehicle-treated group. The results of this study indicated that rhTM and its D1 similarly reduce elevated histone H3 levels, thereby reducing acute kidney injury. Our findings also proposed that rhTM and D1 show potential as new treatment strategies for sepsis combined with acute kidney injury.
The Effects of Sex and Strain onPneumocystis murinaFungal Burdens in Mice
Authors: Tisdale Nikeya L. , Ashbaugh Alan , Hendrix Keeley , Collins Margaret S. , Porollo Alexey P. , Cushion Melanie T.
Published: September 2019

Many preclinical studies of infectious diseases have neglected experimental designs that evaluate potential differences related to sex with a concomitant over-reliance on male model systems. Hence, the NIH implemented a monitoring system for sex inclusion in preclinical studies.

Methods

Per this mandate, we examined the lung burdens ofPneumocystis murinainfection in 3 mouse strains in both male and female animals at early, mid and late time points.

Results

Females in each strain had higher infection burdens compared to males at the later time points.

Conclusion

Females should be included in experimental models studying Pneumocystis.
Discovery of a celecoxib binding site on PTGES with a cleavable chelation-assisted biotin probe
Authors: Miyamoto David K. , Flaxman Hope A. , Wu Hung-Yi , Gao Jinxu , Woo Christina M.
Published: September 2019

The coxibs are a subset of non-steroidal anti-inflammatory drugs (NSAIDs) that primarily target cyclooxygenase-2 (COX-2) to inhibit prostaglandin signaling and reduce inflammation. However, mechanisms to inhibit other members of the prostaglandin signaling pathway may improve selectivity and reduce off-target toxicity. Here, we report a novel binding site for celecoxib on prostaglandin E synthase (PTGES), an enzyme downstream of COX-2 in the prostaglandin signaling pathway, using a cleavable chelation-assisted biotin probe 6. Evaluation of the multi-functional probe 6 revealed significantly improved tagging efficiencies attributable to the embedded picolyl functional group. Application of the probe 6 within the small molecule interactome mapping by photo-affinity labeling (SIM-PAL) platform using photo-celecoxib as a reporter for celecoxib identified PTGES and other membrane proteins in the top eight enriched proteins from A549 cells. Carbonic anhydrase 12, a known protein target of celecoxib, was also enriched. Four binding sites to photo-celecoxib were additionally mapped by the probe 6, including a binding site with PTGES. The binding interaction with PTGES was validated by competitive displacement with celecoxib and known PTGES inhibitor licofelone. The binding site of photo-celecoxib on PTGES enabled the development of a structural model of the interaction and will inform the design of new selective inhibitors of the prostaglandin signaling pathway.
Presynaptic developmental plasticity allows robust sparse wiring of theDrosophilamushroom body
Authors: Elkahlah Najia A. , Rogow Jackson A. , Ahmed Maria , Clowney E. Josephine
Published: September 2019

In order to represent complex stimuli, principle neurons of associative learning regions receive combinatorial sensory inputs. Density of combinatorial innervation is theorized to determine the number of distinct stimuli that can be represented and distinguished from one another, with sparse innervation thought to optimize the complexity of representations in networks of limited size. How the convergence of combinatorial inputs to principle neurons of associative brain regions is established during development is unknown. Here, we explore the developmental patterning of sparse olfactory inputs to Kenyon cells of theDrosophila melanogastermushroom body. By manipulating the ratio between pre- and post-synaptic cells, we find that postsynaptic Kenyon cells set convergence ratio: Kenyon cells produce fixed distributions of dendritic claws while presynaptic processes are plastic. Moreover, we show that sparse odor responses are preserved in mushroom bodies with reduced cellular repertoires, suggesting that developmental specification of convergence ratio allows functional robustness.
A functional cortical network for sensorimotor sequence generation
Authors: Xu Duo , Chen Yuxi , Delgado Angel M. , Hughes Natasha C. , Dong Mingyuan , Zhang Linghua , O’Connor Daniel H.
Published: September 2019

The brain generates complex sequences of movements that can be flexibly reconfigured in real-time based on sensory feedback, but how this occurs is not fully understood. We developed a novel ‘sequence licking’ task in which mice directed their tongue to a target that moved through a series of locations. Mice could rapidly reconfigure the sequence online based on tactile feedback. Closed-loop optogenetics and electrophysiology revealed that tongue/jaw regions of somatosensory (S1TJ) and motor (M1TJ) cortex encoded and controlled tongue kinematics at the level of individual licks. Tongue premotor (anterolateral motor, ALM) cortex encoded intended tongue angle in a smooth manner that spanned individual licks and even whole sequences, and progress toward the reward that marked successful sequence execution. ALM activity regulated sequence initiation, but multiple cortical areas collectively controlled termination of licking. Our results define a functional cortical network for hierarchical control of sensory- and reward-guided orofacial sequence generation.
DrosophilaNeuroblast Selection Gated by Notch, Snail, SoxB and EMT Gene Interplay
Authors: Arefin Badrul , Parvin Farjana , Bahrampour Shahrzad , Stadler Caroline Bivik , Thor Stefan
Published: September 2019

In the developingDrosophilacentral nervous system neural progenitor (neuroblast; NB) selection is gated by lateral inhibition, controlled by Notch signalling and proneural genes. However, proneural mutants only display partial NB reduction, indicating the existence of additional genes with proneural activity. In addition, recent studies reveal involvement of key epithelial-mesenchymal transition (EMT) genes in NB selection, but the regulatory interplay between Notch signalling and the EMT machinery is unclear. We find that the SoxB geneSoxNeuroand the Snail geneworniouare integrated with the Notch pathway, and constitute the missing proneural genes. Notch signalling, the proneural,SoxNeuro, andworniougenes regulate key EMT genes to orchestrate the NB specification process. Hence, we uncover an expanded lateral inhibition network for NB specification, and demonstrate its link to key players in the EMT machinery. Because of the evolutionary conservation of the genes involved, the Notch-SoxB-Snail-EMT network may control neural progenitor selection in many other systems.
Automated Spatially Targeted Optical Micro Proteomics (autoSTOMP) to determine protein complexity of subcellular structures
Authors: Yin Bocheng , Mendez Roberto , Zhao Xiaoyu , Rahkit Rishi , Hsu Ku-Lung , Ewald Sarah E
Published: September 2019

Spatially Targeted Optical Micro Proteomics (STOMP) is a method to study region-specific protein complexity of a biological specimen. STOMP uses a confocal microscope to both visualize structures of interest and to tag the proteins within those structures by a photo-driven crosslinking reaction so that they can be affinity purified and identified by mass spectrometry1. STOMP has the potential to perform discovery proteomics on sub-cellular structures in a wide range of primary cells types and biopsy-scale tissue samples. However, two significant limitations have prevented the broad adoption of this technique by the scientific community. First, STOMP is performed across two software platforms written in different languages, which requires user operation at each field of view. Up to 48 hours of microscope time is necessary to tag sufficient protein (∼1 μg) for mass spectrometry making STOMP prohibitively time and labor-consuming for many researchers. Second, the original STOMP protocol uses a custom photo-crosslinker that limits the accessibility of the technique for some user. To liberate the user, we developed a protocol that automates communication between Zeiss Zen Black imaging software and FIJI image processing software using a customizable code in SikuliX. To fully automate STOMP (autoSTOMP), this protocol includes a tool to make tile array, autofocus and capture images of fields of view across the sample; as well as a method to modify the file that guides photo-tagging so that subsets of the structures of interest can be targeted. To make this protocol broadly accessible, we implemented a commercially available biotin-benzophenone crosslinker as well as a procedure to block endogenous biotin and purify tagged proteins using magnetic streptavidin beads. Here we demonstrate that autoSTOMP can efficiently label, purify and identify proteins that belong to structures measuring 1-2 μm in diameter using human foreskin fibroblasts or mouse bone marrow-derived dendritic cells infected with the protozoan parasiteToxoplasma gondii(Tg). The autoSTOMP platform can easily be adapted to address a range of research questions using Zeiss Zen Black microscopy systems and LC-MS protocols that are standard in many institutional research cores.
P2X1 selective antagonists block HIV-1 infection through inhibition of envelope conformation-dependent fusion
Authors: Soare Alexandra Y. , Malik Hagerah S. , Durham Natasha D. , Freeman Tracey L. , Alvarez Raymond , Patel Foramben , Satija Namita , Upadhyay Chitra , Hioe Catarina E. , Chen Benjamin K. , Swartz Talia H.
Published: September 2019

Purinergic receptors detect extracellular ATP and promote inflammatory processes. Emerging literature has demonstrated that inhibition of these proinflammatory receptors can block HIV-1 productive infection. The specificity of receptor type and mechanism of interaction has not yet been determined. Here we characterize the inhibitory activity of P2X1 receptor antagonists, NF279 and NF449 in cell lines, primary cells, and in a variety of envelope clades. NF279 and NF449 blocked productive infection at the level of viral membrane fusion with a range of inhibitory activities against different HIV-1 envelopes. A mutant virus carrying a truncation deletion of the C-terminal tail of HIV-1 envelope (Env) glycoprotein 41 (gp41) showed reduced sensitivity to P2X1 antagonists, indicating that the sensitivity of inhibition by these molecules is modulated by Env conformation. By contrast, a P2X7 antagonist, A438079, had limited effect on productive infection and fusion. Inhibition with NF449 interfered with the ability of the V1V2 targeted broadly neutralizing antibody PG9 to block productive infection, suggesting that these drugs may antagonize HIV-1 Env at gp120 V1V2 to block viral membrane fusion. Our observations indicate that P2X1 antagonism can inhibit HIV-1 replication at the level of viral membrane fusion through interaction with Env. Future studies will probe the nature of these compounds in inhibiting HIV-1 fusion and in development of a different class of small molecules to block HIV-1 entry.

IMPORTANCE

While effective treatment can lower the severe morbidity and mortality associated with HIV-1 infection, patients infected with HIV-1 suffer from significantly higher rates of non-communicable comorbidities associated with chronic inflammation. Emerging literature suggests a key role for P2X1 receptors in mediating this chronic inflammation but the mechanism is still unknown. Here, we demonstrate that HIV-1 infection is reduced by P2X1 receptor antagonism. This inhibition is mediated by interference with HIV-1 Env and can impact a variety of viral clades. These observations highlight the importance of P2X1 antagonists as potential novel therapeutics that could serve to block a variety of different viral clades with additional benefits for their anti-inflammatory properties.
DRD2 TaqI A polymorphism in Eastern Uttar Pradesh population
Authors: Chaudhary Amrita , Yadav Upendra , Kumar Pradeep , Rai Vandana
Published: September 2019

Dopamine receptor D2 (DRD2) encoded by DRD2 gene, is located on chromosome 11q22-23. Dopamine plays the central role in motivation, cognition, and reward seeking behaviour. Its dysfunction is implicated in numerous neurological and psychiatric disorders including drug abuse, schizophrenia, ADHD etc. The TaqI A polymorphism is localized 9.8 kb downstream from DRD2 gene in exon 8 of protein kinase gene (ANKK1). It is a SNP demonstrated to cause Glutamate to Lysine substitution at 713 amino acid residue in putative binding domain of ANKK1. Due to the central role of dopamine in reward seeking behavior, DRD2 TaqI A loci is a suitable candidate for investigation of molecular basis of addiction. The aim of the present study is to evaluate the frequency of DRD2 TaqI A polymorphism in Eastern Uttar Pradesh population. 3ml blood samples were collected from 50 individuals randomly selected from Eastern UP. Written informed consent along with profile detail was taken from each subject prior to blood sample collection. DRD2 TaqI A polymorphism analysis was done by PCR-RFLP method. Genomic DNA was extracted from each collected blood samples and amplified using DRD2 Taq1 region specific primers. PCR amplification produced 310bp long amplicon which was digested with Taq I enzyme for polymorphism analysis. In case of A2 allele, Taq1 enzyme cleaved 310bp long fragment into two fragments of 180bp and 130bp. In case of A1 allele, a C to T substitution demolished the restriction site of Taq1, so amplicon of A1 allele remained uncut. In total 50 sample analyzed in present study, A2/A2, A2/A1 and A1/A1 genotype were found in 12, 32 and 06 samples respectively. The genotypic frequencies of mutant homozygous (A1/A1) is 0.12, heterozygous (A2/A1) is 0.64 and normal homozygous (A2/A2) is 0.24. The allelic frequency of A1 is 0.44 and of A2 is 0.56. In conclusion, the results of present study suggests that in TaqI A polymorphism of DRD2 gene, the frequency of allele A2 is higher than that of A1 allele in population of Eastern Uttar Pradesh.
Bacteriological Monitoring and Evaluation of Cleaning-disinfection of Computer-related Equipment in an Obstetric and Gynecology Hospital
Authors: Li Meiling , Lu Tingyan , Zhang Hongwei , Chen Shufang , Mao Xueying , Shen Li , Lu Yan , Leng Shufang
Published: September 2019

It is already known that computer keyboards and mouses in hospitals are contaminated with different kinds of bacteria. However, the mouse pad has been neglected with regard to both research and regular cleaning and disinfection in hospitals. In our study, we monitored and evaluated the bacteriology degrees of 74 computers’ keyboards, mouses and mouse pads from six departments. The results showed that before cleaning-disinfection, the contamination rate of the mouse pad ranked second following the keyboards. Enterococcus Faecium was cultured from the mouse pads. The computer-related equipment in the wards and outpatient rooms were much more contaminated than that in the operating rooms. Acinetobacter spp. was only isolated from the doctor’s computers. After cleaning-disinfection, 4 strains of MRSA were isolated from the keyboards and the mouses, one and 3 were cultured at day 3 and day 5 after cleaning-disinfection, respectively. One strain of Pseudomonas Aeruginosa was isolated from the mouses at day 3 after cleaning-disinfection. These demonstrated that the bacterial contamination of the mouse pads must be as emphasized as that of the keyboards and mouses. Furthermore, It is better to clean and disinfect the computer-related equipment(keyboards, mouses, mouse pads) at least once a day.
Humans adapt their anticipatory eye movements to the volatility of visual motion properties
Authors: Pasturel Chloé , Montagnini Anna , Perrinet Laurent Udo
Published: September 2019

Animal behavior constantly adapts to changes, for example when the statistical properties of the environment change unexpectedly. For an agent that interacts with this volatile setting, it is important to react accurately and as quickly as possible. It has already been shown that when a random sequence of motion ramps of a visual target is biased to one direction (e.g. right or left), human observers adapt their eye movements to accurately anticipate the target’s expected direction. Here, we prove that this ability extends to a volatile environment where the probability bias could change at random switching times. In addition, we also recorded the explicit prediction of the next outcome as reported by observers using a rating scale. Both results were compared to the estimates of a probabilistic agent that is optimal in relation to the assumed generative model. Compared to the classical leaky integrator model, we found a better match between our probabilistic agent and the behavioral responses, both for the anticipatory eye movements and the explicit task. Furthermore, by controlling the level of preference between exploitation and exploration in the model, we were able to fit for each individual’s experimental dataset the most likely level of volatility and analyze inter-individual variability across participants. These results prove that in such an unstable environment, human observers can still represent an internal belief about the environmental contingencies, and use this representation both for sensory-motor control and for explicit judgments. This work offers an innovative approach to more generically test the diversity of human cognitive abilities in uncertain and dynamic environments.

Author summary

Understanding how humans adapt to changing environments to make judgments or plan motor responses based on time-varying sensory information is crucial for psychology, neuroscience and artificial intelligence. Current theories for how we deal with the environment’s uncertainty, that is, in response to the introduction of some randomness change, mostly rely on the behavior at equilibrium, long after after a change. Here, we show that in the more ecological case where the context switches at random times all along the experiment, an adaptation to this volatility can be performed online. In particular, we show in two behavioral experiments that humans can adapt to such volatility at the early sensorimotor level, through their anticipatory eye movements, but also at a higher cognitive level, through explicit ratings. Our results suggest that humans (and future artificial systems) can use much richer adaptive strategies than previously assumed.
Evaluating the informativeness of deep learning annotations for human complex diseases
Authors: Dey Kushal K. , Van de Geijn Bryce , Kim Samuel Sungil , Hormozdiari Farhad , Kelley David R. , Price Alkes L.
Published: September 2019

Deep learning models have shown great promise in predicting genome-wide regulatory effects from DNA sequence, but their informativeness for human complex diseases and traits is not fully understood. Here, we evaluate the disease informativeness of allelic-effect annotations (absolute value of the predicted difference between reference and variant alleles) constructed using two previously trained deep learning models, DeepSEA and Basenji. We apply stratified LD score regression (S-LDSC) to 41 independent diseases and complex traits (average N=320K) to evaluate each annotation’s informativeness for disease heritability conditional on a broad set of coding, conserved, regulatory and LD-related annotations from the baseline-LD model and other sources; as a secondary metric, we also evaluate the accuracy of models that incorporate deep learning annotations in predicting disease-associated or fine-mapped SNPs. We aggregated annotations across all tissues (resp. blood cell types or brain tissues) in meta-analyses across all 41 traits (resp. 11 blood-related traits or 8 brain-related traits). These allelic-effect annotations were highly enriched for disease heritability, but produced only limited conditionally significant results – only Basenji-H3K4me3 in meta-analyses across all 41 traits and brain-specific Basenji-H3K4me3 in meta-analyses across 8 brain-related traits. We conclude that deep learning models are yet to achieve their full potential to provide considerable amount of unique information for complex disease, and that the informativeness of deep learning models for disease beyond established functional annotations cannot be inferred from metrics based on their accuracy in predicting regulatory annotations.