bluuebunny/crossref_metadata_2025 huggingface dataset:
The Partnership for Accelerating Cancer Therapies
Authors: Baker Rebecca G. , Hoos Axel X. , Adam Stacey J. , Wholley David , Doroshow James H. , Lowy Douglas R. , Tabak Lawrence A. , Collins Francis S.
Published: August 2018

As a part of the Cancer Moonshot, the National Cancer Institute, part of the National Institutes of Health, the Foundation for National Institutes of Health, the US Food and Drug Administration, and 12 pharmaceutical companies have formed a 5-year, $220 million precompetitive public-private research collaboration called the Partnership for Accelerating Cancer Therapies. A systematic cross-sector effort to identify and develop robust, standardized biomarkers and related clinical data, Partnership for Accelerating Cancer Therapies will support the selection and testing of promising immunotherapies for the treatment of cancer, with the goal of bringing effective therapy to more patients.
Impact of a Comprehensive Adolescent-Focused Case Finding Intervention on Uptake of HIV Testing and Linkage to Care Among Adolescents in Western Kenya
Authors: Kose Judith , Tiam Appolinaire , Ochuka Bernard , Okoth Elizabeth , Sunguti Joram , Waweru Michael , Mwangi Eliud , Wolters Theresa , Rakhmanina Natella
Published: August 2018

Background:

Low HIV testing uptake prevents identification of adolescents living with HIV and linkage to care and treatment. We implemented an innovative service package at health care facilities to improve HIV testing uptake and linkage to care among adolescents aged 10–19 years in Western Kenya.

Methods:

This quasi-experimental study used preintervention and postintervention data at 139 health care facilities (hospitals, health centers, and dispensaries). The package included health worker capacity building, program performance monitoring tools, adolescent-focused HIV risk screening tool, and adolescent-friendly hours.

The study population was divided into early (10–14 years) and late (15–19 years) age cohorts. Implementation began in July 2016, with preintervention data collected during January–March 2016 and postintervention data collected during January–March 2017. Descriptive statistics were used to analyze the numbers of adolescents tested for HIV, testing HIV-positive, and linked to care services. Preintervention and postintervention demographic and testing data were compared using the Poisson mean test. χ2 testing was used to compare the linkage to care rates.

Results:

During the preintervention period, 25,520 adolescents were tested, 198 testing HIV-positive (0.8%) compared with 77,644 adolescents tested with 534 testing HIV-positive (0.7%) during the postintervention period (both P-values <0.001). The proportion of HIV-positive adolescents linked to care increased from 61.6% to 94.0% (P < 0.001). The increase in linkage to care was observed among both age cohorts and within each facility type (both P-values <0.001).

Conclusions:

The adolescent-focused case finding intervention package led to a significant increase in both HIV testing uptake and linkage to care services among adolescents in Western Kenya.
Medial Arm Flap
Authors: de la Parra Marquez Miguel , Fernandez-Riera Ricardo
Published: August 2018

Currently, deep inferior epigastric perforator flap is undoubtedly the first choice for autologous breast reconstruction for most surgeons; however, there are instances where lower abdominal tissue is unavailable for microvascular transfer. In these cases, most surgeons choose gluteal or lower-extremity territories as donor sites.

In the setting of morbid obesity, there is an increased risk of flap and donor site complications, as well as increased blood loss, surgical time, and risk of deep venous thrombosis, not to mention a more challenging surgical technique. Added to these problems, Tamoxifen intake and delayed or limited ambulation due to pain or surgical wounds increases deep venous thrombosis risk even further.

The use of the upper arm as donor site for microvascular transfer avoids most of these problems and allows for immediate, comfortable ambulation. On the other hand, upper arm flaps have smaller caliber vessels for microanastomosis, shorter pedicles, and a limited amount of skin which makes them a viable option for only a select group of patients with redundant upper arm skin. We provide a previously undocumented proof-of-concept case report of a delayed breast reconstruction using the medial arm free flap that resulted in an uneventful postoperatory follow-up with a naturally textured and shaped reconstructed breast.
Early Hyperoxia in The Intensive Care Unit is Significantly Associated With Unfavorable Neurological Outcomes in Patients With Mild-to-Moderate Aneurysmal Subarachnoid Hemorrhage
Authors: Yokoyama Shota , Hifumi Toru , Kawakita Kenya , Tamiya Takashi , Minamino Tetsuo , Kuroda Yasuhiro
Published: August 2018

Introduction:

Although oxygen administration is fundamental in the management of aneurysmal subarachnoid hemorrhage (SAH) patients in the acute stage, hyperoxia has harmful effects. The effects of hyperoxia on neurological outcomes in SAH patients are unclear. We aimed to examine the association of hyperoxia during the first 24 h in the intensive care unit (ICU) with unfavorable neurological outcomes in SAH patients.

Methods:

We retrospectively selected consecutive adult patients admitted to ICU for SAH between January 2009 and April 2018. We defined normoxia during the first 24 h in ICU as PaO2 of 60 mm Hg to 120 mm Hg, mild hyperoxia as PaO2 of 121 mm Hg to 200 mm Hg, moderate hyperoxia as PaO2 of 201 mm Hg to 300 mm Hg, and severe hyperoxia as PaO2 of >300 mm Hg. Univariate and multivariate analyses were performed to examine the association between hyperoxia during the first 24 h in ICU and unfavorable neurological outcomes (i.e., modified Rankin scale score of 3–6 at hospital discharge).

Results:

Among 196 SAH patients, 90 had unfavorable neurological outcomes. Hyperoxia was observed in 93.4% of patients. No significant association was observed between unfavorable neurological outcomes and hyperoxia in overall patients. However, we found that early hyperoxia in ICU was significantly associated with unfavorable neurological outcomes in SAH patients with Hunt and Kosnik (H&K) grades I to III (Relative risk, 1.84; 95% confidence interval, 1.10–2.94; P = 0.02).

Conclusions:

Early hyperoxia was not associated with unfavorable neurological outcomes in overall SAH patients, but it was associated with unfavorable neurological outcomes in those with H&K grades I to III.
The Impact of Hospital Volume and Charlson Score on Postoperative Mortality of Proctectomy for Rectal Cancer
Authors: El Amrani Mehdi , Clement Guillaume , Lenne Xavier , Rogosnitzky Moshe , Theis Didier , Pruvot François-René , Zerbib Philippe
Published: August 2018

Objective:

To identify the impact of hospital volume according to Charlson Comorbidity Index (ChCI) on postoperative mortality (POM) after rectal cancer surgery.

Background:

A volume–outcome relationship has been established in complex surgical procedures. However, little is known regarding the impact of hospital volume on POM according to patients’ comorbidities after rectal cancer surgery.

Methods:

All patients undergoing proctectomy for cancer from 2012 to 2016 were identified in the French nationwide database. Patient condition was assessed on the basis of the validated ChCl and was stratified into 3 groups according to the score (0–2, 3, and ≥4). Chi-square automatic interaction detector (CHAID) was used to identify the cut-off values of the annual proctectomy caseload affecting the 90-day POM. The 90-day POM was analyzed according to hospital volume (low: <10, intermediate: 10–40, and high: ≥41 cases/yr) and ChCI.

Results:

Among 45,569 rectal cancer resections, the 90-day POM was 3.5% and correlated to ChCI (ChCI 0–2: 1.9%, ChCI 3: 4.9%, ChCI ≥4: 5.8%; P < 0.001). There was a linear decrease in POM with increasing hospital volume (low: 5.6%, intermediate: 3.5%, high: 1.9%; P < 0.001). For low-risk patients (ChCl 0–2), 90-day POM was significantly higher in low and intermediate hospital volume compared with high hospital volume centers (3.2% and 1.8% vs 1.1%; P < 0.001). A significant decrease in postoperative hemorrhage complication rates was observed with increasing center volume (low: 13.3%, intermediate: 11.9%, and high: 9.4%; P < 0.001). After multivariable analysis, proctectomy in low [odds ratio (OR) 2.1, 95% confidence interval (CI) 1.71–2.58, P < 0.001] and intermediate (OR 1.45, 95% CI 1.2–1.75, P < 0.001) hospital volume centers were independently associated with higher risk of mortality.

Conclusion:

The POM after proctectomy for rectal cancer is strongly associated with hospital volume independent of patients’ comorbidities. To improve postoperative outcomes, rectal surgery should be centralized.
Establishing a Regional Trauma Preventable/Potentially Preventable Death Rate
Authors: Drake Stacy A. , Holcomb John B. , Yang Yijiong , Thetford Caitlin , Myers Lauren , Brock Morgan , Wolf Dwayne A. , Cron Stanley , Persse David , McCarthy James , Kao Lillian , Todd S. Rob , Naik-Mathuria Bindi J. , Cox Charles , Kitagawa Ryan , Sandberg Glenn , Wade Charles E.
Published: August 2018

Objective:

To establish a trauma preventable/potentially preventable death rate (PPPDR) within a heavily populated county in Texas.

The National Academies of Sciences estimated the trauma preventable death rate in the United States to be 20%, issued a call for zero preventable deaths, while acknowledging that an accurate preventable death rate was lacking. In this absence, effective strategies to improve quality of care across trauma systems will remain difficult.

Methods:

A retrospective review of death-related records that occurred during 2014 in Harris County, TX, a diverse population of 4.4 million. Patient demographics, mechanism of injury, cause, timing, and location of deaths were assessed. Deaths were categorized using uniform criteria and recorded as preventable, potentially preventable or nonpreventable.

Results:

Of 1848 deaths, 85% had an autopsy and 99.7% were assigned a level of preventability, resulting in a trauma PPPDR of 36.2%. Sex, age, and race/ethnicity varied across preventability categories (P < 0.01). Of 847 prehospital deaths, 758 (89.5%) were nonpreventable. Among 89 prehospital preventable/potentially preventable (P/PP) deaths, hemorrhage accounted for 55.1%. Of the 657 initial acute care setting deaths, 292 (44.4%) were P/PP; of these, hemorrhage, sepsis, and traumatic brain injury accounted for 73.3%. Of 339 deaths occurring after initial hospitalization, 287 (84.7%) were P/PP, of these 117 resulted from sepsis and 31 from pulmonary thromboembolism, accounted for 51.6%.

Conclusions:

The trauma PPPDR was almost double that estimated by the National Academies of Sciences. Data regarding P/PP deaths offers opportunity to target research, prevention, intervention, and treatment corresponding to all phases of the trauma system.
The Impact of Corporate Payments on Robotic Surgery Research
Authors: Criss Cory N. , MacEachern Mark P. , Matusko Niki , Dimick Justin B. , Maggard-Gibbons Melinda , Gadepalli Samir K.
Published: August 2018

Objective:

To quantify the influence of financial conflict of interest (COI) payments on the reporting of clinical results for robotic surgery.

Data Sources and Study Selection:

A systematic search (Ovid MEDLINE databases) was conducted (May 2017) to identify randomized controlled trials (RCTs) and observational studies comparing the efficacy of the da Vinci robot on clinical outcomes. Financial COI data for authors (per study) were determined using open payments database.

Main Outcomes and Measures:

Primary outcomes assessed were receipt of financial COI payments and overall conclusion reported between robotic versus comparative approach. Quality/risk of bias was assessed using Newcastle-Ottawa Scale (NOS)/Cochrane risk of bias tool. Disclosure discrepancies were also analyzed.

Data Extraction and Synthesis:

Study characteristics, surgical subspecialty, methodological assessment, reporting of disclosure statements, and study findings dual abstracted. The association of the amount of financial support received as a predictor of reporting positive findings associated robotic surgery was assessed at various cut-offs of dollar amount received by receiver operating curve (ROC).

Results:

Thirty-three studies were included, 9 RCTs and 24 observational studies. There was a median, 111 patients (range 10 to 6420) across studies. A little more than half (17/33) had a conclusion statement reporting positive results in support of robotic surgery, with 48% (16/33) reporting results not in favor [equivocal: 12/33 (36%), negative: 4/33 (12%)]. Nearly all (91%) studies had authors who received financial COI payments, with a median of $3364.46 per study (range $9 to $1,775,378.03). ROC curve demonstrated that studies receiving greater than $9557.31 (cutpoint) were more likely to report positive robotic surgery results (sensitivity: 0.65, specificity: 0.81, area under the curve: 0.73). Studies with financial COI payment greater than this amount were more likely to report beneficial outcomes with robotic surgery [(78.57% vs 31.58%, P = 0.013) with an odds ratio of 2.07 (confidence interval: 0.47–3.67; P = 0.011)]. Overall, studies were high quality/low risk of bias [median NOS: 8 (range 5 to 9)]; Cochrane risk: “low risk” (9/9, 100%)].

Conclusion and Relevance:

Financial COI sponsorship appears to be associated with a higher likelihood of studies reporting a benefit of robotic surgery. Our findings suggest a dollar amount where financial payments influence reported clinical results, a concept that challenges the current guidelines, which do not account for the amount of COI funding received.
Laparoscopic Ileocolic Pexy as Preventive Treatment Alternative for Ileocolic Intussusception With Multiple Recurrences in Children
Authors: Li Bing , Sun Chun-Xia , Chen Wei-Bing , Zhang Feng-Nian
Published: August 2018

Purpose:

Idiopathic intussusception is one of the most common causes of small bowel obstruction in children. To decrease subsequent recurrence and to detect a lead point, an early laparoscopy was performed for children with multiple recurrent ileocolic intussusception.

Materials and Methods:

Between January 2014 and July 2017, a total of 2561 consecutive children with intussusception were treated and followed. There were 110 patients with multiple recurrences, 61 were treated with ileocolic pexy and 49 were not and the results were compared. Using a 5-mm laparoscope and 2 additional transabdominal wall stab incisions, an appendectomy and an ileocolic pexy with nonabsorbable sutures were performed simultaneously for the children after the last successful enema reduction.

Results:

The mean operative time was 59.4±13.1 minutes (range, 45 to 85 min). No cases required conversion to an open surgery, blood loss was minimal. There was no operative morbidity. Two patients were found with a Meckel’s diverticulum, and were removed by slightly enlarged transumbilical incision. The 61 cases were followed up for 4 to 42 months (mean, 19.3±1.1 mo). In the ileocolic pexy group, 2 of 61 (3.2%) got 2 episodes of recurrences. Among the 25 patients with 3 recurrences without undergoing ileocolic pexy, 18 (72%) had 22 episodes of recurrence. Of the 16 patients with 4 recurrences and without ileocolic pexy, 14 (87.5%) had 17 episodes of recurrence. There was statistical difference in recurrent rate among the 3 groups (ileocolonic pexy group vs. 3 recurrences group, P<0.01; ileocolic pexy group vs. 4 recurrences group, P<0.01).

Conclusions:

Early preventive laparoscopic ileocolic pexy should be undertaken for the patients with multiple recurrences after the last nonsurgical reduction had been attempted successfully.
Laparoscopic Curative Resection for Rectal Cancer: A Cohort Study on Long-term Outcome
Authors: Portale Giuseppe , Valdegamberi Alessandro , Cavallin Francesco , Morabito Alberto , Frigo Flavio , Fiscon Valentino
Published: August 2018

The aim of the present study was to evaluate the long-term results of laparoscopic curative resection for rectal cancer. We included all patients who underwent laparoscopic curative resection for rectal cancer from June 2005 to September 2015. A total of 159 patients were included; 33.9% received neoadjuvant chemoradiotherapy. Thirty-day mortality and morbidity rates were 0.6% and 26.4%, respectively. Pathologic stage was 0 in 12%, I in 39%, II in 24.5%, and III in 24.5%. The median number of lymph nodes harvested was 16. In 5% of patients, mesorectal excision was incomplete. Median follow-up was 59 months. Overall 5-year survival was 80%. Multivariable analysis identified older age, higher Charlson Comorbidity Index, advanced tumor stage, and postoperative morbidity as independent risk factors for overall/disease-free survival. Local/distant recurrence rate was 4.4%/17.6%. Deaths during follow-up were 33/159 (20.8%): cancer related 54.6% and non cancer related 45.4% of patients. Laparoscopic curative resection for rectal cancer can yield prolonged survival and low recurrence.
Exercise and movement in musculoskeletal pain: a double-edged problem
Authors: Casale Roberto , Chimento Pierluigi L. , Bartolo Michelangelo , Taveggia Giovanni
Published: August 2018

Purpose of review

Exercise and movement are increasingly used in pain management and in palliative care, outside the traditional context of physical medicine and rehabilitation. This critical review aims to provide specialists in pain and palliative medicine with recent insights into the use of exercise and movement in the approach to musculoskeletal disorders when pain and disability are the major complaints.

Recent findings

If there is a common sense linking pain and movement in both directions, that is pain influencing movement – as a withdrawal movement or a reduction of mobility as a defense reaction – or movement evoking pain, not so clear and recognized is the link between exercise and movement in controlling pain.

Conflicting results emerge between absolutely convincing basic science research confirming important effects induced by movement and exercise on pain and substantial poor low evidence level from clinical research as stated by almost all systematic reviews. The need of rigorous clinical trials is mandatory to ascertain a real clinical benefit for the use of movement and exercise for pain control.
Does Islet Size Really Influence Graft Function After Clinical Islet Transplantation?
Authors: Hughes Stephen J. , Bateman Paul A. , Cross Sarah E. , Brandhorst Daniel , Brandhorst Heide , Spiliotis Ioannis , Ballav Chitrabhanu , Rosenthal Miranda , Rutter Martin K. , Shaw James , Gough Stephen , Johnson Paul R.V.
Published: August 2018

Background

It has been proposed that islet transplants comprised primarily of small rather than large islets may provide better graft function, due to their lower susceptibility to hypoxic damage. Our aim was to determine whether islet size correlated with in vivo graft function in islet transplant recipients with C peptide–negative type 1 diabetes when islets have undergone pretransplant islet culture.

Methods

Human pancreatic islets were isolated, cultured for 24 hours and infused by standardized protocols. Ninety-minute stimulated C-peptide concentrations were determined during a standard meal tolerance test 3 months posttransplant. The islet isolation index (IEq/islet number) was determined immediately after isolation and again before transplantation (after tissue culture). This was correlated with patient insulin requirement or stimulated C-peptide.

Results

Changes in insulin requirement did not significantly correlate with islet isolation index. Stimulated C-peptide correlated weakly with IEq at isolation (P = 0.40) and significantly with IEq at transplantation (P = 0.018). Stimulated C-peptide correlated with islet number at isolation (P = 0.013) and more strongly with the islet number at transplantation (P = 0.001). In contrast, the correlation of stimulated C-peptide and islet isolation index was weaker (P = 0.018), and this was poorer at transplantation (P = 0.034). Using linear regression, the strongest association with graft function was islet number (r = 0.722, P = 0.001). Islet size was not related to graft function after adjusting for islet volume or number.

Conclusions

These data show no clear correlation between islet isolation index and graft function; both small and large islets are suitable for transplantation, provided the islets have survived a short culture period postisolation.
Cell polarity: having and making sense of direction—on the evolutionary significance of the primary cilium/centrosome organ in Metazoa
Authors: Bornens Michel
Published: August 2018

Cell-autonomous polarity in Metazoans is evolutionarily conserved. I assume that permanent polarity in unicellular eukaryotes is required for cell motion and sensory reception, integration of these two activities being an evolutionarily constrained function. Metazoans are unique in making cohesive multicellular organisms through complete cell divisions. They evolved a primary cilium/centrosome (PC/C) organ, ensuring similar functions to the basal body/flagellum of unicellular eukaryotes, but in different cells, or in the same cell at different moments. The possibility that this innovation contributed to the evolution of individuality, in being instrumental in the early specification of the germ line during development, is further discussed. Then, using the example of highly regenerative organisms like planarians, which have lost PC/C organ in dividing cells, I discuss the possibility that part of the remodelling necessary to reach a new higher-level unit of selection in multi-cellular organisms has been triggered by conflicts among individual cell polarities to reach an organismic polarity. Finally, I briefly consider organisms with a sensorimotor organ like the brain that requires exceedingly elongated polarized cells for its activity. I conclude that beyond critical consequences for embryo development, the conservation of cell-autonomous polarity in Metazoans had far-reaching implications for the evolution of individuality.
Implications of dimeric activation of PDE6 for rod phototransduction
Authors: Lamb Trevor D. , Heck Martin , Kraft Timothy W.
Published: August 2018

We examine the implications of a recent report providing evidence that two transducins must bind to the rod phosphodiesterase to elicit significant hydrolytic activity. To predict the rod photoreceptor's electrical response, we use numerical simulation of the two-dimensional diffusional contact of interacting molecules at the surface of the disc membrane, and then we use the simulated PDE activity as the driving function for the downstream reaction cascade. The results account for a number of aspects of rod phototransduction that have previously been puzzling. For example, they explain the existence of a greater initial delay in rods than in cones. Furthermore, our analysis suggests that the ‘continuous’ noise recorded in rods in darkness is likely to arise from spontaneous activation of individual molecules of PDE at a rate of a few tens per second per rod, probably as a consequence of spontaneous activation of transducins at a rate of thousands per second per rod. Hence, the dimeric activation of PDE in rods provides immunity against spontaneous transducin activation, thereby reducing the continuous noise. Our analysis also provides a coherent quantitative explanation of the amplification underlying the single photon response. Overall, numerical analysis of the dimeric activation of PDE places rod phototransduction in a new light.
Designing efficient hybrid strategies for information spreading in scale-free networks
Authors: Wang Shuangyan , Cheng Wuyi , Hao Yang
Published: August 2018

Designing a spreading strategy is one of the critical issues strongly affecting spreading efficiency in complex networks. In this paper, to improve the efficiency of information spreading in scale-free networks, we propose four hybrid strategies by combining two basic strategies, i.e. (i) the LS (in which information is preferentially spread from the large-degree vertices to the small-degree ones), and (ii) the SL (in which information is preferentially spread from the small-degree vertices to the large-degree ones). The objective in combining the two basic LS and SL strategies is to fully exploit the advantages of both strategies. To evaluate the spreading efficiency of the proposed four hybrid strategies, we first propose an information spreading model. Then, we introduce the details of the proposed hybrid strategies that are formulated by combining LS and SL. Third, we build a set of scale-free network structures by differently configuring the relevant parameters. In addition, finally, we conduct various Monte Carlo experiments to examine the spreading efficiency of the proposed hybrid strategies in different scale-free network structures. Experimental results indicate that the proposed hybrid strategies are effective and efficient for spreading information in scale-free networks.
5′-(CGA)

n

sequence-assisted pH-controlled assembly of supramolecular DNA nanostructure
Authors: Yan Yuting , Cao Yanwei , Xiao Chunsheng , Li Yang , Xiang Xiaoxuan , Guo Xinhua
Published: August 2018

Herein, the DNA strands containing 5′-(CGA)

n

and consecutive guanines are used to construct supramolecular DNA nanostructures that are size-controlled by pH values. Additionally, the introduction of thymine linkers within DNA nanostructures is necessary to maintain the stability of long-sized nanostructures. This work also demonstrates a method for accurately building DNA nanostructures.
Advancing risk assessment: mechanistic dose–response modelling ofListeria monocytogenesinfection in human populations
Authors: Rahman Ashrafur , Munther Daniel , Fazil Aamir , Smith Ben , Wu Jianhong
Published: August 2018

The utility of characterizing the effects of strain variation and individual/subgroup susceptibility on dose–response outcomes has motivated the search for new approaches beyond the popular use of the exponential dose–response model for listeriosis. While descriptive models can account for such variation, they have limited power to extrapolate beyond the details of particular outbreaks. By contrast, this study exhibits dose–response relationships from a mechanistic basis, quantifying key biological factors involved in pathogen–host dynamics. An efficient computational algorithm and geometric interpretation of the infection pathway are developed to connect dose–response relationships with the underlying bistable dynamics of the model. Relying onin vitroexperiments as well as outbreak data, we estimate plausible parameters for the human context. Despite the presence of uncertainty in such parameters, sensitivity analysis reveals that the host response is most influenced by the pathogen–immune system interaction. In particular, we show how variation in this interaction across a subgroup of the population dictates the shape of dose–response curves. Finally, in terms of future experimentation, our model results provide guidelines and highlight vital aspects of the interplay between immune cells and particular strains ofListeria monocytogenesthat should be examined.
Social and endocrine correlates of immune function in meerkats: implications for the immunocompetence handicap hypothesis
Authors: Smyth Kendra N. , Caruso Nicholas M. , Davies Charli S. , Clutton-Brock Tim H. , Drea Christine M.
Published: August 2018

Social status can mediate effects on the immune system, with profound consequences for individual health; nevertheless, most investigators of status-related disparities in free-ranging animals have used faecal parasite burdens to proxy immune function in the males of male-dominant species. We instead use direct measures of innate immune function (complement and natural antibodies) to examine status-related immunocompetence in both sexes of a female-dominant species. The meerkat is a unique model for such a study because it is a cooperatively breeding species in which status-related differences are extreme, evident in reproductive skew, morphology, behaviour, communication and physiology, including that dominant females naturally express the greatest total androgen (androstenedione plus testosterone) concentrations. We found that, relative to subordinates, dominant animals had reduced serum bacteria-killing abilities; also, relative to subordinate females, dominant females had reduced haemolytic complement activities. Irrespective of an individual's sex or social status, androstenedione concentrations (but not body condition, age or reproductive activity) negatively predicted concurrent immunocompetence. Thus, dominant meerkats of both sexes are immunocompromised. Moreover, in female meerkats, androstenedione perhaps acting directly or via local conversion, may exert a double-edged effect of promoting dominance and reproductive success at the cost of increased parasitism and reduced immune function. Given the prominent signalling of dominance in female meerkats, these findings may relate to the immunocompetence handicap hypothesis (ICHH); however, our data would suggest that the endocrine mechanism underlying the ICHH need not be mediated solely by testosterone and might explain trade-offs in females, as well as in males.
The reproductive strategy in aChloris virgatapopulation in response to precipitation regimes
Authors: Ying Wang , Chunxia Wang , Jukui Zhang , Chunqing Wang
Published: August 2018

Resource availability influences plant growth and reproduction. Here, a controlled experiment was conducted in order to evaluate the adaptation response ofChloris virgatato different precipitation conditions, and to further predict the reproductive strategy in a population ofC. virgataunder different precipitation regimes. Three regimes (low, typical and high) of water addition were used to simulate current precipitation patterns. In total 20 individuals for each treatment were analysed to compare tiller number, spike traits, seed traits, the relationship between seed size and seed number, and so on. In addition, the effects of different precipitation regimes on offspring vigour ofC. virgatawere also studied. Results indicated that tiller number, spike number, seed yield and seed number were unchanged under different water addition regimes, while seed size was about 0.5 mg at typical and high precipitation levels and was higher than that in the low precipitation level. The higher seed mass per spike and spike mass both occurred at typical and high precipitation levels. Significant positive correlations between seed mass and non-seed mass inC. virgatain response to precipitation regimes were largely allometric (size dependent), as was a significant negative correlation between seed size and seed number at low precipitation. The highest germination rates and seedling weights both occurred at typical and high precipitation levels. These findings showed that different precipitation regimes affected reproductive strategy ofC. virgata. Chloris virgatawill not benefit from low precipitation, while typical and high precipitation will improve seed traits and offspring vigour of this species.
A malaria transmission model with seasonal mosquito life-history traits
Authors: Djidjou-Demasse Ramsès , Abiodun Gbenga J. , Adeola Abiodun M. , Botai Joel O.
Published: August 2018

In this paper we develop and analyse a malaria model with seasonality of mosquito life-history traits: periodic-mosquitoes per capita birth rate, -mosquitoes death rate, -probability of mosquito to human disease transmission, -probability of human to mosquito disease transmission and -mosquitoes biting rate. All these parameters are assumed to be time dependent leading to a nonautonomous differential equation systems. We provide a global analysis of the model depending on two thresholds parametersand(with). When, then the disease-free stationary state is locally asymptotically stable. In the presence of the human disease-induced mortality, the global stability of the disease-free stationary state is guarantied when. On the contrary, if, the disease persists in the host population in the long term and the model admits at least one positive periodic solution. Moreover, by a numerical simulation, we show that a subcritical (backward) bifurcation is possible at. Finally, the simulation results are in accordance with the seasonal variation of the reported cases of a malaria-epidemic region in Mpumalanga province in South Africa.
Benchmarking Time-Series Data Discretization on Inference Methods
Authors: Li Yuezhe , Jann Tiffany , Vera-Licona Paola
Published: August 2018

The rapid development in quantitatively measuring DNA, RNA, and protein has generated a great interest in the development of reverse-engineering methods, that is, data-driven approaches to infer the network structure or dynamical model of the system. Many reverse-engineering methods require discrete quantitative data as input, while many experimental data are continuous. Some studies have started to reveal the impact that the choice of data discretization has on the performance of reverse-engineering methods. However, more comprehensive studies are still greatly needed to systematically and quantitatively understand the impact that discretization methods have on inference methods. Furthermore, there is an urgent need for systematic comparative methods that can help select between discretization methods. In this work, we consider 4 published intracellular networks inferred with their respective time-series datasets. We discretized the data using different discretization methods. Across all datasets, changing the data discretization to a more appropriate one improved the reverse-engineering methods’ performance. We observed no universal best discretization method across different time-series datasets. Thus, we propose DiscreeTest, a two-step evaluation metric for ranking discretization methods for time-series data. The underlying assumption of DiscreeTest is that an optimal discretization method should preserve the dynamic patterns observed in the original data across all variables. We used the same datasets and networks to show that DiscreeTest is able to identify an appropriate discretization among several candidate methods. To our knowledge, this is the first time that a method for benchmarking and selecting an appropriate discretization method for time-series data has been proposed.

Availability

All the datasets, reverse-engineering methods and source code used in this paper are available in Vera-Licona’s lab Github repository: https://github.com/VeraLiconaResearchGroup/Benchmarking_TSDiscretizations
Interspecies malate-pyruvate shuttle drives amino acid exchange in organohalide-respiring microbial communities
Authors: Wang Po-Hsiang , Correia Kevin , Ho Han-Chen , Venayak Naveen , Nemr Kayla , Flick Robert , Mahadevan Radhakrishnan , Edwards Elizabeth A.
Published: August 2018

Most microorganisms in the biosphere live in communities and develop coordinated metabolisms via trading metabolites. In this study, we sought to deconstruct the metabolic interdependency in organohalide-respiring microbial communities enriched withDehalobacter restrictus(Dhb), using a complementary approach of computational metabolic modeling and experimental validation.Dhbpossesses a complete set of genes for amino acid biosynthesis yet requires amino acid supplementation. We reconciled this discrepancy using Flux Balance Analysis with consideration for cofactor availability, enzyme promiscuity, and shared protein expression patterns of severalDhbstrains. Experimentally,13C incorporation assays, growth assays, and metabolite analysis of strain PER-K23 cultures were performed to validate the model predictions. The model resolved thatDhb’s amino acid dependency results from restricted NADPH regeneration and diagnosed that malate supplementation can replenish intracellular NADPH using malic enzyme. Interestingly, we observed unexpected export of glutamate and pyruvate in parallel to malate consumption in the strain PER-K23 cultures. Further experiments onDhb-enriched consortium ACT-3 suggested an interspecies malate-pyruvate shuttle betweenDhband a glutamate-auxotrophicBacteroidessp., reminiscent of the mitochondrial malate shunt pathway in eukaryotic cells. Altogether, this study reveals that redox constraints and metabolic complementarity are important driving forces for amino acid exchange in anaerobic microbial communities.
Synthetic chromosome fusion: effects on genome structure and function
Authors: Luo Jingchuan , Vale-Silva Luis A. , Raghavan Adhithi R. , Mercy Guillaume , Heldrich Jonna , Sun Xiaoji , Li Mingyu , Zhang Weimin , Agmon Neta , Yang Kun , Cai Jitong , Stracquadanio Giovanni , Thierry Agnès , Zhao Yu , Coelho Camila , Lauer Stephanie , Ahn Ju Young , Adoff Greg , D’Avino Andrew , Berger Henri , Chen Yi , Chickering Michael , Fishman Oren , Greeno Rebeca Vergara , Kim Sangmin , Kim Sunghan , Lim Hong Seo , Im Jay , Meyer Lauren , Moyer Allison , Annadanam Surekha , Murphy Natalie A. , Natov Peter , Nimer Maisa , Radley Arthur , Tripathy Arushi , Wang Tony , Wilkerson Nick , Zheng Tony , Zhou Vivian , Zeller Karen , Kaback David B. , Bader Joel S. , Mitchell Leslie A. , Mozziconacci Julien , Koszul Romain , Hochwagen Andreas , Boeke Jef D.
Published: August 2018

As part of the Synthetic Yeast 2.0 (Sc2.0) project, we designed and synthesized synthetic chromosome I. The total length of synI is ∼21.4% shorter than wild-type chromosome I, the smallest chromosome inSaccharomyces cerevisiae. SynI was designed for attachment to another synthetic chromosome due to concerns of potential instability and karyotype imbalance. We used a variation of a previously developed, robust CRISPR-Cas9 method to fuse chromosome I to other chromosome arms of varying length: chrIXR (84kb), chrIIIR (202kb) and chrIVR (1Mb). All fusion chromosome strains grew like wild-type so we decided to attach synI to synIII. Through the investigation of three-dimensional structures of fusion chromosome strains, unexpected loops and twisted structures were formed in chrIII-I and chrIX-III-I fusion chromosomes, which depend on silencing protein Sir3. These results suggest a previously unappreciated 3D interaction betweenHMRand the adjacent telomere. We used these fusion chromosomes to show that axial element Red1 binding in meiosis is not strictly chromosome size dependent even though Red1 binding is enriched on the three smallest chromosomes in wild-type yeast, and we discovered an unexpected role for centromeres in Red1 binding patterns.
Comparing sequence and structure of falcipains and human homologs at prodomain and catalytic active site for malarial peptide-based inhibitor design
Authors: Musyoka Thommas M. , Njuguna Joyce N. , Bishop Özlem Tastan
Published: August 2018

Falcipains are major cysteine proteases ofPlasmodium falciparumessential in hemoglobin digestion. Several inhibitors blocking their activity have been identified, yet none of them has been approved for malaria treatment. For selective therapeutic targeting of these plasmodial proteases, identification of sequence and structure differences with homologous human cathepsins is necessary. The protein substrate processing activity of these proteases is tightly controlled in space and time via a prodomain segment occluding the active site making it inaccessible. Here, we utilisedin silicoapproaches to determine sequence and structure variations between the prodomain regions of plasmodial proteins and human cathepsins. Hot spot residues, key for maintaining structural integrity of the prodomains as well as conferring their inhibitory activity, were identified via residue interaction analysis. Information gathered was used to design short peptides able to mimic the prodomain activity on plasmodial proteases whilst showing selectivity on human cathepsins. Inhibitory potency was highly dependent on peptide amino acid composition and length. Our current results show that despite the conserved structural and catalytic mechanism of human cathepsins and plasmodial proteases, significant differences between the two groups exist and may be valuable in the development of novel antimalarial peptide inhibitors.
Functional Genomics Screen with Pooled shRNA Library and Gene Expression Profiling with Extracts of Azadirachta indica Identify Potential Pathways for Therapeutic Targets in Head and Neck Squamous Cell Carcinoma
Authors: Krishnan Neeraja M , Katoh Hiroto , Palve Vinayak , Pareek Manisha , Sato Reiko , Ishikawa Shumpei , Panda Binay
Published: August 2018

Tumor suppression by the extracts of Azadirachta indica (neem) works via anti-proliferation, cell cycle arrest, and apoptosis, demonstrated previously using cancer cell lines and live animal models. However, very little is known about the molecular targets and pathways that the neem extracts and the associated compounds act through. Here, we address this using a genome-wide functional pooled shRNA screen on head and neck squamous cell carcinoma cell line treated with crude neem leaf extracts, known for their anti-tumorigenic activity. By analyzing differences in global clonal sizes of the shRNA-infected cells cultured under no treatment and treatment with neem leaf extract conditions, assayed using next-generation sequencing, we found 225 genes affected the cancer cell growth in the shRNA-infected cells treated with neem extract. Pathway enrichment analyses of whole-genome gene expression data from cells temporally treated with neem extract revealed important roles played by the TGF-β pathway and HSF-1-related gene network. Our results indicate that neem extract simultaneously affects various important molecular signaling pathways in head and neck cancer cells, some of which may be therapeutic targets for this devastating tumor.
Rho-mediated gene transcription promotes BRAF inhibitor resistance in de-differentiated melanoma cells
Authors: Misek SA , Appleton KM , Dexheimer TS , Lisabeth EM , Lo RS , Larsen SD , Gallo KA , Neubig RR
Published: August 2018

Over half of cutaneous melanoma tumors have BRAFV600E/Kmutations. Acquired resistance to BRAF inhibitors (BRAFi) remains a major hurdle in attaining durable therapeutic responses. In this study we demonstrate that approximately 50-60% of melanoma cell lines with vemurafenib resistance acquiredin vitroshow activation of RhoA family GTPases. In BRAFi-resistant melanoma cell lines and tumors, activation of RhoA is correlated with decreased expression of melanocyte lineage genes. Using a machine learning approach, we built gene expression-based models to predict drug sensitivity for 265 common anti-cancer compounds. We then projected these signatures onto the collection of TCGA cutaneous melanoma and found that poorly differentiated tumors were predicted to have increased sensitivity to multiple Rho kinase (ROCK) inhibitors. Two transcriptional effectors downstream of Rho, MRTF and YAP1, are activated in the RhoHighBRAFi-resistant cell lines, and resistant cells are more sensitive to inhibition of these transcriptional mechanisms. Taken together, these results support the concept of targeting Rho-regulated gene transcription pathways as a promising therapy approach to restore sensitivity to BRAFi-resistant tumors or as a combination therapy to prevent the onset of drug resistance.
Mechanism of replication-coupled DNA-protein crosslink proteolysis by SPRTN and the proteasome
Authors: Gao Alan , Larsen Nicolai B. , Sparks Justin L. , Gallina Irene , Mann Matthias , Räschle Markus , Walter Johannes C. , Duxin Julien P.
Published: August 2018

DNA-protein crosslinks (DPCs) are bulky DNA lesions that interfere with DNA metabolism and therefore threaten genomic integrity. Recent studies implicate the metalloprotease SPRTN in S-phase removal of DPCs, but how SPRTN activity is coupled to DNA replication is unknown. Using Xenopus egg extracts that recapitulate replication-coupled DPC proteolysis, we show that DPCs can be degraded by SPRTN or the proteasome, which act as independent DPC proteases. Proteasome recruitment requires DPC polyubiquitylation, which is triggered by single-stranded DNA, a byproduct of DNA replication. In contrast, SPRTN-mediated DPC degradation is independent of DPC polyubiquitylation but requires polymerase extension of a nascent strand to the lesion. Thus, SPRTN and proteasome activities are coupled to DNA replication by distinct mechanisms and together promote replication across immovable protein barriers.

Highlights

The proteasome, in addition to SPRTN, degrades DPCs during DNA replication

Proteasome-dependent DPC degradation requires DPC ubiquitylation

DPC ubiquitylation is triggered by ssDNA and does not require the replisome

SPRTN-dependent DPC degradation is a post-replicative process
Increased influence of periphery on central visual processing in humans during walking
Authors: Cao Liyu , Händel Barbara
Published: August 2018

Cognitive processes are almost exclusively investigated under highly controlled settings while voluntary body movements are suppressed. However, recent animal work suggests differences in sensory processing between movement states by showing drastically changed neural responses in early visual areas between locomotion and stillness. Does locomotion also modulate visual cortical activity in humans and what are its perceptual consequences? Here, we present converging neurophysiological and behavioural evidence that walking leads to an increased influence of peripheral stimuli on central visual input. This modulation of visual processing due to walking is encompassed by a change in alpha oscillations, which is suggestive of an attentional shift to the periphery during walking. Overall, our study shows that strategies of sensory information processing can differ between movement states. This finding further demonstrates that a comprehensive understanding of human perception and cognition critically depends on the consideration of natural behaviour.
Carbon monoxide, a retrograde messenger generated in post-synaptic mushroom body neurons evokes non-canonical dopamine release
Authors: Ueno Kohei , Morstein Johannes , Ofusa Kyoko , Naganos Shintaro , Suzuki-Sawano Ema , Minegishi Saika , Rezgui Samir P. , Kitagishi Hiroaki , Michel Brian W. , Chang Christopher J. , Horiuchi Junjiro , Saitoe Minoru
Published: August 2018

Dopaminergic neurons innervate extensive areas of the brain and release dopamine (DA) onto a wide range of target neurons. However, DA release is also precisely regulated, and inDrosophila,DA is released specifically onto mushroom body (MB) neurons, which have been coincidentally activated by cholinergic and glutamatergic inputs. The mechanism for this precise release has been unclear. Here we found that coincidentally activated MB neurons generate carbon monoxide (CO) which functions as a retrograde signal evoking local DA release from presynaptic terminals. CO production depends on activity of heme oxygenase in post-synaptic MB neurons, and CO-evoked DA release requires Ca2+efflux through ryanodine receptors in DA terminals. CO is only produced in MB areas receiving coincident activation, and removal of CO using scavengers blocks DA release. We propose that DA neurons utilize two distinct modes of transmission to produce global and local DA signaling.

SIGNIFICANCE STATEMENT

Dopamine (DA) is needed for various higher brain functions including memory formation. However, DA neurons form extensive synaptic connections, while memory formation requires highly specific and localized DA release. Here we identify a mechanism through which DA release from presynaptic terminals is controlled by postsynaptic activity. Postsynaptic neurons activated by cholinergic and glutamatergic inputs generate carbon monoxide, which acts as a retrograde messenger inducing presynaptic DA release. Released DA is required for memory-associated plasticity. Our work identifies a novel mechanism that restricts DA release to the specific postsynaptic sites that require DA during memory formation.