Active engagement improves learning and memory, and self- vs. externally generated stimuli are processed differently: perceptual intensity and neural responses are attenuated. Whether the attenuation is linked to memory formation remains to be understood. This study investigates whether active oculomotor control over auditory stimuli – controlling for movement and stimulus predictability – benefits associative learning, and studies the underlying neural mechanisms. Using EEG and eyetracking we explored the impact of control during learning on the processing and memory recall of arbitrary oculomotor-auditory associations. Participants (N=23) learned associations through active exploration or passive observation, using a gaze-controlled interface to generate sounds. Our results show faster learning progress in the active condition. ERPs time-locked to the onset of sound stimuli showed that learning progress was linked to an attenuation of the P3a component. The detection of matching movement-sound pairs triggered a target-matching P3b response. There was no general modulation of ERPs through active learning. However, participants could be divided into different learner types: those who benefited strongly from active control during learning and those who did not. The strength of the N1 attenuation effect for self-generated stimuli was correlated with memory gain in active learning. Our results show that control helps learning and memory and modulates sensory responses. Individual differences during sensory processing predict the strength of the memory benefit. Taken together, these results help to disentangle the effects of agency, unspecific motor-based neuromodulation, and stimulus predictability on ERP components and establish a link between self-generation effects and active learning memory gain.

There is no standardized procedure for solid pseudopapillary neoplasm (SPN) of the pancreatic body and tail in children. Recently, an international consensus on precision anatomy for minimally invasive distal pancreatectomy in adults was established. This is the first report of a 12-year-old girl with an incidentally found SPN measuring 7.5 cm in diameter located in the pancreatic tail who successfully underwent an R0 resection by laparoscopic spleen-preserving distal pancreatectomy under the concept of precision anatomy. The implementation of this concept in the pediatric population should facilitate the safe diffusion of MIDP for SPN and other benign or low-malignant tumors in children.

Leaf fall in the autumn opens the forest canopy, allowing more solar radiation to be transmitted to the forest floor. Those understorey species that remain physiologically active may benefit from the sunlight received by assimilating additional carbon while conditions remain favourable. We monitored water and leaf pigment content, as well as photosynthetic capacity in six understorey species growing in three adjacent stands differing in their canopy tree species. Leaf fall, transmitted light and microclimate were followed in each stand. We found that leaf fall started earlier in the Betula pendula, than in the Quercus robur stand, and light transmission changed accordingly. Concurrently, understorey leaf senescence was generally earlier in the birch than in the oak stand, itself earlier than in the evergreen Picea abies stand. Neither atmospheric CO 2, humidity, nor temperature differed between stands. A change in light quality and/or increase in quantity following leaf fall drove the difference in the timing of senescence in the understorey. Species with later senescence were more able to use the increased light after leaf fall. Together these findings help provides a mechanistic foundation to predict how ecosystem functioning and carbon balance will be impacted by phenological shifts in response to global changes.

Background and purpose In Asian traditional medicine, ginseng has been referred to as the “King of Herbs” because to its extensive therapeutic and pharmacologic characteristics, particularly in the treatment of type 2 diabetes mellitus and illnesses connected to diabetes. Experimental approach The 80% ethanol extracts of cultivated, red, and mountain-cultivated ginseng were liquid partitioned with hexane, chloroform, ethyl acetate, and n-butanol, respectively. The residues produced were processed with enzyme-assisted extraction by different enzymes. Cardiomyocytes, skeletal myoblasts, wild-type AB line zebrafish and Tg (kdrl:EGFP) zebrafish were used to screen and verify the protective effect of extracts. Key results APMCG-1 is precipitated by alkaline protease-assisted extract from mountain-cultivated ginseng with 30% ethanol, which has a strong scavenging effect on hydroxyl radicals. In palmitic acid-induced H9c2 cells, APMCG-1 greatly enhanced cell viability while reducing reactive oxygen species generation and lactate dehydrogenase levels. Additionally, it reduced endoplasmic reticulum and mitochondrial dysfunction by increasing the Ca2+ level and membrane potential of mitochondria in H9c2(2-1) cells. In C2C12 cells that had been exposed to palmitic acid, APMCG-1 boosted glucose uptake while lowering creatine kinase levels. More significantly, 5 days after fertilization Tg (kdrl:EGFP) zebrafish and 1-month-old wild-type zebrafish with type 2 diabetic symptoms both had lower blood sugar and lipid levels attributed to APMCG-1. Further, APMCG-1 was identified as a glycopeptide containing O-linked glycopeptide bonds. Conclusions and implications As a PI3K/AKT activator, APMCG-1 protects the dysfunction of oxidant induced cardiomyocytes and skeletal myoblasts in type 2 diabetes, and is a potential therapeutic drug for diabetes.

Background and Purpose: Colorectal cancer (CRC) is one of the cancers with the highest incidence in which APC gene mutations occurs in almost 80% of patients. This mutation leads to β-catenin aberrant accumulation and an uncontrolled proliferation. Apoptosis evasion, changes in the immune response and microbiota composition are also events that arise in CRC. Tetracyclines are drugs with proven antibiotic and immunomodulatory properties that have shown cytotoxic activity against different tumor cell lines. Experimental Approach: The effect of tigecycline was evaluated in vitro in HCT116 cells and in vivo in a colitis-associated colorectal cancer (CAC) murine model. 5-fluorouracil was assayed as positive control in both studies. Key Results: Tigecycline showed an antiproliferative activity targeting the Wnt/β-catenin pathway and downregulating STAT3. Moreover, tigecycline induced apoptosis through extrinsic, intrinsic and endoplasmic reticulum pathways converging on an increase of CASP7 levels. Furthermore, tigecycline modulated the immune response in CAC, reducing the cancer-associated inflammation through a downregulation of cytokines expression. Additionally, tigecycline favored the cytotoxic activity of CD8+ T lymphocytes, one of the main immune defenses against tumor cells. Lastly, the antibiotic reestablished the gut dysbiosis in CAC mice increasing the abundance of bacterial genera and species, such as Akkermansia and Parabacteroides distasonis, that act as protectors against tumor development. These findings resulted in a reduction of the numbers of tumors and an amelioration of the tumorigenesis process in CAC. Conclusion and Implications: tigecycline exerts a beneficial effect against CRC supporting the use of this antibiotic for the treatment of this disease.

At the end of 2019 a new coronavirus surfaced in China, SARS-CoV-2, responsible for the ongoing pandemic. There is a need for novel and stable therapies to help patients of COVID-19. Drug repositioning is a strategy to quickly find medicines already used to treatment to another pathology. In this work, we used the PLpro as molecular target for it being responsible for cleaving other viral proteins and interfering with the immune system. In the Brazilian Pharmacopeia is described many different Active Pharmaceutical Ingredients (API) used in Brazil and the world. Using the in silico techniques of virtual screening, the top 44 API pass through Toxicity prediction, where 36 API prove to not be mutagenic. Using molecular weight, distance to the protein, and literature information 19 API go through prediction of chemical interactions, we determine the top 6 APIs with the best chance of interacting with the PLpro. With this result, we determine new possible API that will be tested in vitro to determine its ability to inhibit SARS-CoV-2’s PLpro, and could be readily made available to the infected populous.

The use of adeno-associated viruses (AAV) as vectors for gene and cell therapy has risen considerably in recent years. Consequently, the amount of AAV vectors required during the validation and clinical trials has also increased. AAV serotype 6 (AAV6) is well-documented for its efficiency in transducing different cell types and has been successfully used in gene and cell therapy protocols. However, the number of vectors required to effectively deliver the transgene to one single cell has been estimated at 106 viral genomes (VG). Overall, this means that large-scale production of AAV6 is needed. Suspension cell-based platforms are currently limited to low-cell-density productions, hindering the potential of this production process to increase yields. Here, we investigate the improvement of the production of AAV6 at higher cell densities. The production was performed by transient transfection of HEK293SF cells. When the plasmid DNA is provided on a cell basis, the production can be carried out at medium cell density without effects on cell-specific titer or particle functionality, resulting in titers above 1010 VG/mL. Medium supplementation alleviated the cell density effect, in terms of VG/cell, at high-cell-density productions. On the other hand, the cell-specific functional titer was not maintained, and further studies are necessary to understand the observed limitations. The medium-cell-density production method reported here lays the foundation for large-scale process operations, potentially solving the current vector shortage in AAV manufacturing.

Abstract is not required if manuscript is submitted as Clinical Experience.

The Law of the Minimum states that species’ abundance at a location is limited by one single factor. If true, abundance-environment plots should take polygonal shapes constrained by an upper boundary representing the maximum abundance that the species can reach across the environmental gradient. Here, we examine the generality of polygonal plots in the literature and in observational data, and assess how often they are analyzed under the theory of ecological limitation. We also present a proof-of-concept of a method to identify polygon-shaped plots. We found polygonal plots in 76% of reviewed studies and in 73% of the 300 analyzed tree and bird species. We demonstrate that polygonal shapes with upper boundaries are prevalent in abundance-environment plots; yet they are rarely interpreted considering the Law of the Minimum. A wider acknowledgement of limiting relationships would improve our ecological understanding and estimation with further benefits to theoretical and applied ecology.

The number of measles cases reported worldwide has increased in recent years, and in 2015, there was a measles outbreak in Xi’an, China. However, the epidemiology of measles and the seroepidemiology of healthy people after 2015 have not been fully understood. We collected fingertip blood samples from healthy people around each suspected measles case in Xi’an in 2016-2018 and tested IgG using ELISA. Eighty measles cases were reported in Xi’an in 2016–2018, with an average annual incidence of 0.29 per 100,000 persons. Children aged ≤ 5 years and adults aged 25-29 accounted for a large proportion of measles cases. More than half of the cases in the 0-year group were under 8 months. A total of 5476 blood samples from healthy people were collected. Apart from 1-4 years and over 40, other age groups’ seroprevalence was 93%. Our findings suggest that the first vaccine shot should be administered at 6 months or earlier, the second at 12 months, and the third at 10 years, and couples prepared for [pregnancy](javascript:showjdsw(’showlj_1’,’lj_1’)) should be vaccinated with another dose. The findings may provide novel insights into measles elimination.

Background: November 2022, a large number of Omicron infections suddenly appeared in Beijing, but the epidemiological and clinical characteristics of the epidemic cases are unknown. Methods: We collected the data of COVID-19 cases in Fangcang hospital in Beijing from November 20, 2022 to December 8, 2022, and analyzed the epidemiological and clinical characteristics. We used descriptive statistical methods to explore the basic characteristics, used parametric distribution to calculate the time to events, and used ArcGIS to explore the distribution patterns of COVID-19 cases in different areas. Results: There were 1,307 COVID-19 cases in the Fangcang shelter hospital enrolled the study, among which 85.9% were asymptomatic and 14.1% were mild. Epidemiological data showed that the transmission speed Omicron variant is fast and the transmission range is wide, large-scale infections have occurred in both rural and urban areas, and all age groups are susceptible to Omicron variant. In addition, antipyretics and cough drugs were the two most commonly used drugs, because 51.3% and 22.7% patients had fever and cough, respectively, and 10.3% patients took hypnotics. Furthermore, the proportion of patients with chronic diseases was low (13.9%), while the vaccination rate (71.2%) was relatively high. Conclusion: Based on the results of Fangcang shelter hospitals, we found that most mild and asymptomatic cases did not need treatment, which indicates that home isolation is correct and feasible. However, the transmission speed Omicron variant is fast and the transmission range is wide, and all age groups are susceptible to Omicron variant; therefore, the awareness of prevention and control should not be relaxed.

Objective: To determine levels of moral distress in a pediatric unit caring for patients with tracheostomy/ventilator dependence. Hypothesis: Moral distress will be significant in a dedicated pediatric trach/vent unit. Methods: The Moral Distress Survey-Revised (MDS-R) is a 21-question survey measuring moral distress in pediatrics. The MDS-R was anonymously distributed to MD/DOs, advanced practice practitioners (APPs), RNs and RTs in a unit caring for tracheostomy/ventilator dependent patients. Descriptive statistics, bivariate and multivariate analysis were performed. Results: Response rate was 48% (61/127). Mean MDS-R score was 83 (range 43-119), which is comparable to reported levels in the pediatric intensive care unit. APPs had the highest median rate of moral distress (112, IQR 72-138), while MD/DOs had the lowest median score (49, IQR 43-77). RNs and RTs had MDS-R scores between these two groups (Medians of 91 and 84 respectively). Conclusions: Moral distress levels in a unit caring for long term tracheostomy and ventilator dependent patients are high, comparable to levels in pediatric ICUs. APPs had higher levels of distress compared to other groups. This may be attributable to the constant stressors of being the primary provider for complex patients, especially in a high-volume inpatient setting.

Model organisms such as the Gram-positive bacterium Bacillus subtilis have been studied intensively for decades. However, even for such model organisms no function has been identified for about one fourth of all proteins. It has recently been realized that such understudied proteins as well as poorly studied functions set a limitation to our understanding of the requirements for cellular life, and the Understudied Proteins Initiative has been launched. Obviously, poorly studied proteins that are strongly expressed, are likely to be most important to the cell and should therefore have priority in further studies. Since the functional analysis of unknown proteins can be extremely laborious, a minimal knowledge is required prior to targeted functional studies. In this review, we discuss strategies to obtain such a minimal annotation, e.g. from global interaction, expression or localization studies. We present a set of 41 highly expressed and poorly studied proteins of B. subtilis. Several of these proteins are thought or known to bind RNA and/or the ribosome, some may may control the metabolism of B. subtilis, and another subset of particularly small proteins may act as regulatory elements to control the expression of downstream genes. Moreover, we discuss the challenges of poorly studied functions with a focus on RNA-binding proteins, amino acid transport and the control of metabolic homeostasis. The identification of the functions of the selected proteins will strongly advance our knowledge on B. subtilis, but also on other organisms since many of the proteins are conserved in many groups of bacteria.

Biological invasions have caused the loss of freshwater biodiversity worldwide. The interplay between adaptive responses and demographic characteristics is expected to be important for the resilience of populations to biological invasions, but the interaction between these factors is poorly understood. The native freshwater gastropod Amnicola limosa is distributed along spatial variation in impact from an invasive molluscivorous fish (Neogobius melanostomus), as well as calcium concentrations, limiting the distribution of this invader (refuges). We investigated the potential for genetic adaptation of A. limosa to the invasive predator and the low calcium habitats. We conducted pooled whole-genome sequencing of twelve gastropod populations from the Upper St. Lawrence River, complemented with a laboratory reciprocal transplant of wild F0 A. limosa to measure survival and fecundity in treatments of water calcium concentration (low/high) and round goby cue (present/absent). We quantified gene flow between the habitat types to test how population structure might interact with adaptation. We found that low calcium, uninvaded habitats could act as refugia for the gastropods from the invasive fish and provide migrants to declining invaded gastropod populations through strong gene flow (i.e., demographic rescue), which also maintained genetic diversity (i.e., genetic rescue). However, we also detected signatures of divergent selection between habitat types and evidence of low fitness of individuals from refuge populations in both habitat types. This suggests that migrants from refuges could introduce maladapted alleles to recipient populations in high calcium, invaded habitats, thereby reducing fitness via outbreeding depression and producing conflict between demographic, genetic, and evolutionary rescue.

Title: Developing and testing complex behaviour change interventions to support proactive deprescribingRunning title: Behaviour change and deprescribing

Deprescribing search filters aiming at maximizing sensitivity for MEDLINE and for Embase were recently developed. Simultaneously, The US Deprescribing Network (USden) developed a deprescribing search strategy that included a deprescribing search filter for MEDLINE. The aim of this case study was to implement these deprescribing search filters in original search strategies from deprescribing related systematic reviews (SRs) and to calculate their performances. Two deprescribing SRs were included. Authors were asked to repeat the selection process described in SRs original methods. Performances of search strategies implemented with deprescribing search filters (ISS) were calculated and compared to original search strategies (OSS). In MEDLINE, sensitivity for SR 1 was 50% for OSS (Precision: 2.8%), 58% for ISS with maximised sensitivity filter (Precision: 1.7%) and 42% for ISS with USden filter (Precision: 5.1%). Sensitivity for SR 2 was 25% for all search strategies (Precision: 0.1%, 0.2% and 1,2% respectively). In Embase, sensitivity for SR 1 was 33% (Precision: 4,1%) for OSS and 58% for ISS (Precision 2.1%). No articles were included through Embase search strategies for SR 2. Using maximized sensitivity deprescribing filters may increase the exhaustivity of deprescribing SRs. Precision offered by the USDeN deprescribing filter is a convenient alternative for non-systematic reviews.

Severe autoimmune lymphoproliferative syndrome phenotype in a pediatric patient with a germline FAS gene variant Authors: Alexandra Dreyzin MD MS1; Jinjun Cheng MD PhD2, David Leitenberg MD PhD3, and Yaser Diab MBBS1Center for Cancer and Blood Disorders, Children’s National Hospital, Washington, DCDivision of Pathology and Laboratory Medicine, Children’s National Hospital, Washington, DCDepartment of Microbiology, Immunology and Tropical Medicine, The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia, USA.

WHEN BONE PAIN AND BLEEDING MEAN MORE THAN LEUKEMIA:

Cancer cell plasticity is the ability of tumor cells to switch phenotypes and is one of the predominant requisites of cancer cells capable of undergoing metastasis. Cancer cell plasticity is also recognised as one of the major contributors to intra-tumoral heterogeneity, a critical factor underlying the progression of malignant tumors which is known to modify tumor response and induce resistance against various modes of therapy thus posing a barrier to efficient cancer management. Cancer cell plasticity is acquired by the subversion of cell signaling pathways like MAPK, PI3K, STAT3, Wnt, Hedgehog and Notch as well as cellular programs such as epithelial to mesenchymal transition (EMT) and phenotypic plasticity. This complex phenomenon has been studied in many cancer types like pancreatic cancer, colon cancer and breast cancer. Some cancers like breast cancer are known to exhibit a hierarchical organization with cancer stem cells (CSCs) at the pinnacle of the pyramid due to their ability to promote tumorigenesis, metastasis and therapy resistance. CSCs which can undergo phenotypic changes resulting in heterogenous cell populations with differing potential to develop programs necessary for the metastatic process lies at the core of the cancer cell plasticity hypothesis. Our expanding knowledge of this field can lead to the development of more therapeutic strategies that can be used in cancer and other solid tumors that exhibit similar mechanisms of plasticity. This review will explore the current understanding we have of breast cancer on the intrinsic molecular mechanisms of cancer cell plasticity and the resistance to various types of cancer therapy that arise as a result of plasticity. We conclude by exploring the potential novel therapies that specifically target the pathways leading to plasticity and can be leveraged to treat patients living with the disease. Keywords: Cancer cell plasticity, Epithelial to Mesenchymal Transition (EMT), therapy resistance, targeted therapy.

Single-nucleotide polymorphism (SNP) analyses are a powerful tool for population genetics, pedigree reconstruction and phenotypic trait mapping. SNPs could also be useful for sexing individuals in species with reduced sexual dimorphism, yet this possibility remains poorly explored. Here, we develop a novel protocol for molecular sexing of birds based on the detection of unique Z- and W-linked SNP markers. Our method is based on the identification of two unique loci, one in each sexual chromosome. Individuals are considered males when they are heterozygotic for the Z-linked SNP and females when they are homozygote for the Z-linked SNP and have the W-linked SNP. We validated the method in the Jackdaw (Corvus monedula), a species whose reduced sexual dimorphism makes it difficult to sex individuals in the wild. We assessed the reliability of the method with 36 individuals of known sex, and found that their sex was correctly assigned in 100% of cases. The sex-linked markers also proved to be widely applicable to discriminate males and females from a sample of 927 genotyped individuals of different maturity stages with an accuracy of 99.5%. Given that SNP markers are increasingly used in quantitative genetic analyses of wild populations, the approach we propose has a great potential to be integrated into broader genetic research programmes without the need of additional sexing techniques.

This research paper reports a unique autonomous robot design with reduced blind spot areas. The new robot is not only cost-effective but also has improved sensing and accuracy capabilities. The design and fabrication of the new autonomous robot involved the use of the following hardware components: servo motors, infrared or ultrasonic sensors, and a microcontroller. The developmental work involved the design of the line follower and obstacle avoidance robot system using two pairs of line follower circuits and five (5) ultrasonic sensors circuits, including some supporting circuits. The better solution for the line follower and obstacle avoidance functions are provided by using four (4) pairs of LEDs for the receiver, line dependent resistor (LDR) for the line tracking sensor, and five (5) ultrasonic sensors to detect the obstacles. A mechanical structure and motor placement for the electronic device has been fabricated that can perform functions of sensing the obstacle and avoiding it. An 8051 microcontroller has been programmed to control the robot’s movement and to respond accurately to the sensor.

Carnivores are threatened across Sub-Saharan Africa mostly due to retaliatory killing by people, the loss of prey species and their habitats. Due to their food and space requirements, they regularly come into conflict with humans. In many regions, information about carnivore occurrence and human-carnivore conflict remains poorly known particularly in parts of West-and Central Africa. Here, we assessed the local ecological knowledge on carnivores and associated conflicts in the forest-savannah transition zone in Cameroon. We conducted a semi-structured questionnaire survey with 649 local inhabitants from 23 villages around the Tchabal Mbabo Mountain Range, Yoko Council Forest and Mpem et Djim National Park. The majority of local people could easily identify the lions (73.8%, n=479) and correctly named (90.2%, n=432), whereas other species (e.g. leopards, cheetahs, hyenas, African wild dogs, as well as the medium-sized carnivores) were identified with more difficulty. Most respondents (71.3%, n=463) reported depredation of their livestock, mostly by lions, spotted hyenas, civets and foxes and half of respondents (50.2%, n=326) reported retaliation against predators as the main action resorted to protect their livestock. The use of poisons against wild predators was advocated by some respondents, an additional threat to wild carnivores. Local people suggested construction of enclosures (46.4%, n=301) as the most important mitigation measures. Our study provides baseline information on carnivore occurrence in Cameroon’s transitional forest savannah environments and threats to these animals from local people.

Simultaneous implant placement with sinus floor augmentations is possible when appropriate primary stability could be achieved. In current study, a novel technique is described to perform a single stage implant placement with bicortical stability in severe atrophic maxilla that can shorten the treatment time of an edentulous patient.

Aims: Mirvetuximab soravtansine is the first-in-class antibody-drug conjugate approved in November 2022 for the treatment of folate receptor-α positive ovarian cancer. The aim of this study was to develop a population pharmacokinetic (PK) model to describe the concentration-time profiles of mirvetuximab soravtansine, the payload (DM4) and a metabolite (S-methyl-DM4). Methods: Mirvetuximab soravtansine was administered intravenously from 0.15 to 7 mg/kg to 543 patients with predominantly platinum-resistant ovarian cancer in three clinical studies, and the plasma drug concentrations were analyzed using a nonlinear mixed-effects modelling approach to estimate the PK parameters, inter-individual variabilities, and residual errors. Stepwise covariate modelling was performed to identify covariates. Results: We developed a semi-mechanistic population PK model that included linear and nonlinear routes for the elimination of mirvetuximab soravtansine and a target compartment for the formation and disposition of the payload and metabolite in tumor cells. The model adequately described the concentration-time profiles for the three analytes. Patient body weight, serum albumin, and age were identified as the major covariates. Exposures in patients with renal or hepatic impairment were estimated. The effect of inhibition of cytochrome P450 (CYP) 3A4 on drug exposures was also evaluated. Conclusions: There is no need for dose adjustment due to covariate effects for mirvetuximab soravtansine administered at the recommended dose of 6 mg/kg based on adjusted ideal body weight. The model also showed that dose adjustment is not required for patients with mild or moderate renal impairment, mild hepatic impairment, or when concomitant weak and moderate CYP3A4 inhibitors are used.