Climate change and health in the Sahel: a systematic review.

The Sahel region is projected to be highly impacted by the more frequent hazards associated with climate change, including increased temperature, drought and flooding. This systematic review examined the evidence for climate change-related health consequences in the Sahel. The databases used were Medline (PubMed), Embase (Ovid), Web of Science (Clarivate) and CABI Global Health. Hand searches were also conducted, which included directly engaging Sahelian researchers and hand-searching in the African Journals Online database. Of the 4153 studies found, 893 were identified as duplicates and the remaining 3260 studies were screened (title and abstract only) and then assessed for eligibility. A total of 81 studies were included in the systematic review. Most studies focused on vector-borne diseases, food security, nutrition and heat-related stress. Findings suggest that mosquito distribution will shift under different climate scenarios, but this relationship will not be linear with temperature, as there are other variables to consider. Food insecurity, stunting (chronic malnutrition) and heat-related mortality are likely to increase if no action is taken owing to the projected impact of climate change on environmental factors and agriculture. Seventy-one per cent of manuscripts (n = 58) had first authors from institutions in North America or Europe, of which 39.7% (n = 23) included co-authors from African institutions.

A microfluidic co-culture model for investigating colonocytes-microbiota interactions in colorectal cancer.

Changes in the abundance of certain bacterial species within the colorectal microbiota correlate with colorectal cancer (CRC) development. While carcinogenic mechanisms of single pathogenic bacteria have been characterized in vitro, limited tools are available to investigate interactions between pathogenic bacteria and both commensal microbiota and colonocytes in a physiologically relevant tumor microenvironment. To address this, we developed a microfluidic device that can be used to co-culture colonocyte spheroids and colorectal microbiota. The device was used to explore the effect of Fusobacterium nucleatum, an opportunistic pathogen associated with colorectal cancer development in humans, on colonocyte gene expression and microbiota composition. F. nucleatum altered the transcription of genes involved in cytokine production, epithelial-to-mesenchymal transition, and proliferation in colonocytes in a contact-independent manner; however, most of these effects were significantly diminished by the presence of commensal microbiota. Interestingly, F. nucleatum significantly altered the abundance of multiple bacterial clades associated with mucosal immune responses and cancer development in the colon. Our results highlight the importance of evaluating the potential carcinogenic activity of pathogens in the context of a commensal microbiota, and the potential to discover novel inter-species microbial interactions in the CRC microenvironment.

The importance of incorporating systems thinking and One Health in global health classrooms: findings from a One Health simulation activity.

There are several challenges and opportunities in health education in global health. Given the field's rapid expansion, demand for including systems thinking and One Health (a unifying approach that considers human, animal, and environmental health) in global health courses has recently increased. Simulation activities provide an avenue to attain and assess learning objectives that foster critical and systems thinking. This study carried out a One Health simulation activity in an undergraduate global health course, conducted a focus group discussion, and obtained responses from written questionnaires from students who participated in the activity. Data were analyzed using thematic analysis. Results show that the One Health simulation was instrumental for students to understand the complex interactions between different actors and stakeholders in global health systems. The One Health simulation also improved class dynamics, peer-to-peer interactions, and collaborations in the remaining part of the course. The activity helped assess two of the critical thinking learning objectives of the course, and there was some evidence that student agency and confidence may have been improved. Evidence shows that the activity helped students understand the principles of systems thinking and apply them in complex scenarios. Findings support including interactive simulation activities in global health courses to include elements of system science and One Health into classroom activities innovatively and engagingly.

Biosensor and machine learning-aided engineering of an amaryllidaceae enzyme.

A major challenge to achieving industry-scale biomanufacturing of therapeutic alkaloids is the slow process of biocatalyst engineering. Amaryllidaceae alkaloids, such as the Alzheimer's medication galantamine, are complex plant secondary metabolites with recognized therapeutic value. Due to their difficult synthesis they are regularly sourced by extraction and purification from the low-yielding daffodil Narcissus pseudonarcissus. Here, we propose an efficient biosensor-machine learning technology stack for biocatalyst development, which we apply to engineer an Amaryllidaceae enzyme in Escherichia coli. Directed evolution is used to develop a highly sensitive (EC50 = 20 µM) and specific biosensor for the key Amaryllidaceae alkaloid branchpoint 4'-O-methylnorbelladine. A structure-based residual neural network (MutComputeX) is subsequently developed and used to generate activity-enriched variants of a plant methyltransferase, which are rapidly screened with the biosensor. Functional enzyme variants are identified that yield a 60% improvement in product titer, 2-fold higher catalytic activity, and 3-fold lower off-product regioisomer formation. A solved crystal structure elucidates the mechanism behind key beneficial mutations.

RAD51 restricts DNA over-replication from re-activated origins.

Eukaryotic cells rely on several mechanisms to ensure that the genome is duplicated precisely once in each cell division cycle, preventing DNA over-replication and genomic instability. Most of these mechanisms limit the activity of origin licensing proteins to prevent the reactivation of origins that have already been used. Here, we have investigated whether additional controls restrict the extension of re-replicated DNA in the event of origin re-activation. In a genetic screening in cells forced to re-activate origins, we found that re-replication is limited by RAD51 and enhanced by FBH1, a RAD51 antagonist. In the presence of chromatin-bound RAD51, forks stemming from re-fired origins are slowed down, leading to frequent events of fork reversal. Eventual re-initiation of DNA synthesis mediated by PRIMPOL creates ssDNA gaps that facilitate the partial elimination of re-duplicated DNA by MRE11 exonuclease. In the absence of RAD51, these controls are abrogated and re-replication forks progress much longer than in normal conditions. Our study uncovers a safeguard mechanism to protect genome stability in the event of origin reactivation.

DNA replication and replication stress response in the context of nuclear architecture.

The DNA replication process needs to be coordinated with other DNA metabolism transactions and must eventually extend to the full genome, regardless of chromatin status, gene expression, secondary structures and DNA lesions. Completeness and accuracy of DNA replication are crucial to maintain genome integrity, limiting transformation in normal cells and offering targeting opportunities for proliferating cancer cells. DNA replication is thus tightly coordinated with chromatin dynamics and 3D genome architecture, and we are only beginning to understand the underlying molecular mechanisms. While much has recently been discovered on how DNA replication initiation is organised and modulated in different genomic regions and nuclear territories-the so-called "DNA replication program"-we know much less on how the elongation of ongoing replication forks and particularly the response to replication obstacles is affected by the local nuclear organisation. Also, it is still elusive how specific components of nuclear architecture participate in the replication stress response. Here, we review known mechanisms and factors orchestrating replication initiation, and replication fork progression upon stress, focusing on recent evidence linking genome organisation and nuclear architecture with the cellular responses to replication interference, and highlighting open questions and future challenges to explore this exciting new avenue of research.

Advances in enzymatic and organismal technologies for the recycling and upcycling of petroleum-derived plastic waste.

Biological catalysts are emerging with the capability to depolymerize a wide variety of plastics. Improving and discovering these catalysts has leveraged a range of tools, including microbial ecology studies, high-throughput selections, and computationally guided mutational studies. In this review, we discuss the prospects for biological solutions to plastic recycling and upcycling with a focus on major advances in polyethylene terephthalate depolymerization, expanding the range of polymers with known biological catalysts, and the utilization of derived products. We highlight several recent improvements in enzymes and reaction properties, the discovery of a wide variety of novel plastic-depolymerizing biocatalysts, and how depolymerization products can be utilized in recycling and upcycling.

Nuclear actin polymerization rapidly mediates replication fork remodeling upon stress by limiting PrimPol activity.

Cells rapidly respond to replication stress actively slowing fork progression and inducing fork reversal. How replication fork plasticity is achieved in the context of nuclear organization is currently unknown. Using nuclear actin probes in living and fixed cells, we visualized nuclear actin filaments in unperturbed S phase and observed their rapid extension in number and length upon genotoxic treatments, frequently taking contact with replication factories. Chemically or genetically impairing nuclear actin polymerization shortly before these treatments prevents active fork slowing and abolishes fork reversal. Defective fork remodeling is linked to deregulated chromatin loading of PrimPol, which promotes unrestrained and discontinuous DNA synthesis and limits the recruitment of RAD51 and SMARCAL1 to nascent DNA. Moreover, defective nuclear actin polymerization upon mild replication interference induces chromosomal instability in a PRIMPOL-dependent manner. Hence, by limiting PrimPol activity, nuclear F-actin orchestrates replication fork plasticity and is a key molecular determinant in the rapid cellular response to genotoxic treatments.

Clinical and genomic characterisation of early-onset pancreatic cancer.

BACKGROUND: The incidence of early-onset pancreatic cancer (EOPC) has risen dramatically in recent years. We aimed to characterise the clinical and genomic features of EOPC and evaluate their therapeutic implications. METHODS: We performed a comparative, single-centre, retrospective analysis of clinical, germline, and genomic features in EOPC (≤50 years) patients and compared them with a control group of average-onset pancreatic cancer patients (AOPC, ≥70 years). Key molecular findings were compared with an external, publicly available cohort. RESULTS: We reviewed 336 patients who met all inclusion criteria (EOPC N = 139, AOPC N = 197). EOPC was associated with smoking status, lower prevalence of diabetes, better performance status, higher CA19.9 levels, and higher albumin levels at diagnosis. After adjustment for baseline covariates, we observed no differences in overall survival (OS). Age was associated with an increase in the incidence of KRASMUT both in our cohort and the validation cohort. EOPC were enriched in potentially actionable alterations according to ESCAT tiers I-IIIA when compared with AOPC in discovery and validation cohorts (19% versus 14% and 14% versus 8%, respectively). In the first-line metastatic setting, EOPC had a longer progression-free survival (hazard ratio [HR] 0.61, 95% confidence interval (CI) 0.43-0.87) and OS (HR 0.65, 95% CI 0.45-0.95), although there were no differences in response rate. After adjusting for the number of treatment lines, EOPC patients who did receive targeted therapies exhibited longer OS compared with EOPC who did not (HR 0.34, 95% CI 0.12-0.93). CONCLUSIONS: EOPC patients have improved outcomes in the metastatic setting when compared to AOPC and are enriched for targetable alterations that open opportunities for precision oncology-based approaches.

Replication fork plasticity upon replication stress requires rapid nuclear actin polymerization.

Cells rapidly respond to replication stress actively slowing fork progression and inducing fork reversal. How replication fork plasticity is achieved in the context of nuclear organization is currently unknown. Using nuclear actin probes in living and fixed cells, we visualized nuclear actin filaments in unperturbed S phase, rapidly extending in number and thickness upon genotoxic treatments, and taking frequent contact with replication factories. Chemically or genetically impairing nuclear actin polymerization shortly before these treatments prevents active fork slowing and abolishes fork reversal. Defective fork plasticity is linked to reduced recruitment of RAD51 and SMARCAL1 to nascent DNA. Conversely, PRIMPOL gains access to replicating chromatin, promoting unrestrained and discontinuous DNA synthesis, which is associated with increased chromosomal instability and decreased cellular resistance to replication stress. Hence, nuclear F-actin orchestrates replication fork plasticity and is a key molecular determinant in the rapid cellular response to genotoxic treatments.

The infected and the affected: A longitudinal study of the impact of the COVID-19 pandemic on schoolchildren in Florida.

Objectives: To identify risk factors associated with symptoms of anxiety, depression, and obsessive-compulsive disorder (OCD) among children during the 1st year of the COVID-19 pandemic. Methods: A longitudinal study with three cross-sectional timepoints [April 2020 (n = 273), October 2020 (n = 180), and April 2021 (n = 116)] was conducted at a K-12 public school in Florida. Infection and sero-positivity for SARS-CoV-2 was determined by molecular and serologic approaches. Adjusted odds ratios using mixed effect logistic regression models for symptom-derived indicators of anxiety, depression, and OCD in children in April 2021 are presented; past infection and seropositivity were included in the models. Results: The prevalence of anxiety, depression, or OCD moved from 47.1, to 57.2, to 42.2% across the three timepoints during the study. By endline of the study, in April 2021, non-white children were at higher risk for depression and OCD. Risk for anxiety, depression, and OCD was associated with students who lost a family member due to COVID-19 and who were identified as at-risk in previous timepoints. Rates of SARS-CoV-2 infection and seropositivity were low and not statistically associated with assessed outcomes. Conclusions: In situations like the COVID-19 pandemic, targeted mental health interventions and screenings are needed in children and adolescents, especially among minority children.

Improving Mobile Robot Maneuver Performance Using Fractional-Order Controller.

In this paper, the low-level velocity controller of an autonomous vehicle is studied. The performance of the traditional controller used in this kind of system, a PID, is analyzed. This kind of controller cannot follow ramp references without error, so when the reference implies a change in the speed, the vehicle cannot follow the proposed reference, and there is a significant difference between the actual and desired vehicle behaviors. A fractional controller is proposed which changes the ordinary dynamics allowing faster responses for small times, at the cost of slower responses for large times. The idea is to take advantage of this fact to follow fast setpoint changes with a smaller error than that obtained with a classic non-fractional PI controller. Using this controller, the vehicle can follow variable speed references with zero stationary error, significantly reducing the difference between reference and actual vehicle behavior. The paper presents the fractional controller, studies its stability in function of the fractional parameters, designs the controller, and tests its stability. The designed controller is tested on a real prototype, and its behavior is compared to a standard PID controller. The designed fractional PID controller overcomes the results of the standard PID controller.

Improving Odometric Model Performance Based on LSTM Networks.

This paper presents a localization system for an autonomous wheelchair that includes several sensors, such as odometers, LIDARs, and an IMU. It focuses on improving the odometric localization accuracy using an LSTM neural network. Improved odometry will improve the result of the localization algorithm, obtaining a more accurate pose. The localization system is composed by a neural network designed to estimate the current pose using the odometric encoder information as input. The training is carried out by analyzing multiple random paths and defining the velodyne sensor data as training ground truth. During wheelchair navigation, the localization system retrains the network in real time to adjust any change or systematic error that occurs with respect to the initial conditions. Furthermore, another network manages to avoid certain random errors by using the relationship between the power consumed by the motors and the actual wheel speeds. The experimental results show several examples that demonstrate the ability to self-correct against variations over time, and to detect non-systematic errors in different situations using this relation. The final robot localization is improved with the designed odometric model compared to the classic robot localization based on sensor fusion using a static covariance.

Low Cost Magnetic Field Control for Disabled People.

Our research presents a cost-effective navigation system for electric wheelchairs that utilizes the tongue as a human-machine interface (HMI) for disabled individuals. The user controls the movement of the wheelchair by wearing a small neodymium magnet on their tongue, which is held in place by a suction pad. The system uses low-cost electronics and sensors, including two electronic compasses, to detect the position of the magnet in the mouth. One compass estimates the magnet's position while the other is used as a reference to compensate for static magnetic fields. A microcontroller processes the data using a computational algorithm that takes the mathematical formulations of the magnetic fields as input in real time. The system has been tested using real data to control an electric wheelchair, and it has been shown that a trained user can effectively use tongue movements as an interface for the wheelchair or a computer.

On-Body Piezoelectric Energy Harvesters through Innovative Designs and Conformable Structures.

Recent advancements in wearable technology have improved lifestyle and medical practices, enabling personalized care ranging from fitness tracking, to real-time health monitoring, to predictive sensing. Wearable devices serve as an interface between humans and technology; however, this integration is far from seamless. These devices face various limitations such as size, biocompatibility, and battery constraints wherein batteries are bulky, are expensive, and require regular replacement. On-body energy harvesting presents a promising alternative to battery power by utilizing the human body's continuous generation of energy. This review paper begins with an investigation of contemporary energy harvesting methods, with a deep focus on piezoelectricity. We then highlight the materials, configurations, and structures of such methods for self-powered devices. Here, we propose a novel combination of thin-film composites, kirigami patterns, and auxetic structures to lay the groundwork for an integrated piezoelectric system to monitor and sense. This approach has the potential to maximize energy output by amplifying the piezoelectric effect and manipulating the strain distribution. As a departure from bulky, rigid device design, we explore compositions and microfabrication processes for conformable energy harvesters. We conclude by discussing the limitations of these harvesters and future directions that expand upon current applications for wearable technology. Further exploration of materials, configurations, and structures introduce interdisciplinary applications for such integrated systems. Considering these factors can revolutionize the production and consumption of energy as wearable technology becomes increasingly prevalent in everyday life.

Stress-triggered hematopoietic stem cell proliferation relies on PrimPol-mediated repriming.

Stem cell division is linked to tumorigenesis by yet-elusive mechanisms. The hematopoietic system reacts to stress by triggering hematopoietic stem and progenitor cell (HSPC) proliferation, which can be accompanied by chromosomal breakage in activated hematopoietic stem cells (HSCs). However, whether these lesions persist in their downstream progeny and induce a canonical DNA damage response (DDR) remains unclear. Inducing HSPC proliferation by simulated viral infection, we report that the associated DNA damage is restricted to HSCs and that proliferating HSCs rewire their DDR upon endogenous and clastogen-induced damage. Combining transcriptomics, single-cell and single-molecule assays on murine bone marrow cells, we found accelerated fork progression in stimulated HSPCs, reflecting engagement of PrimPol-dependent repriming, at the expense of replication fork reversal. Ultimately, competitive bone marrow transplantation revealed the requirement of PrimPol for efficient HSC amplification and bone marrow reconstitution. Hence, fine-tuning replication fork plasticity is essential to support stem cell functionality upon proliferation stimuli.

Machine learning-aided engineering of hydrolases for PET depolymerization.

Plastic waste poses an ecological challenge1-3 and enzymatic degradation offers one, potentially green and scalable, route for polyesters waste recycling4. Poly(ethylene terephthalate) (PET) accounts for 12% of global solid waste5, and a circular carbon economy for PET is theoretically attainable through rapid enzymatic depolymerization followed by repolymerization or conversion/valorization into other products6-10. Application of PET hydrolases, however, has been hampered by their lack of robustness to pH and temperature ranges, slow reaction rates and inability to directly use untreated postconsumer plastics11. Here, we use a structure-based, machine learning algorithm to engineer a robust and active PET hydrolase. Our mutant and scaffold combination (FAST-PETase: functional, active, stable and tolerant PETase) contains five mutations compared to wild-type PETase (N233K/R224Q/S121E from prediction and D186H/R280A from scaffold) and shows superior PET-hydrolytic activity relative to both wild-type and engineered alternatives12 between 30 and 50 °C and a range of pH levels. We demonstrate that untreated, postconsumer-PET from 51 different thermoformed products can all be almost completely degraded by FAST-PETase in 1 week. FAST-PETase can also depolymerize untreated, amorphous portions of a commercial water bottle and an entire thermally pretreated water bottle at 50 ºC. Finally, we demonstrate a closed-loop PET recycling process by using FAST-PETase and resynthesizing PET from the recovered monomers. Collectively, our results demonstrate a viable route for enzymatic plastic recycling at the industrial scale.

Who Has Access to Livestock Vaccines? Using the Social-Ecological Model and Intersectionality Frameworks to Identify the Social Barriers to Peste des Petits Ruminants Vaccines in Karamoja, Uganda.

Access to veterinary services is important in Karamoja, northeastern part of Uganda, as livestock is a primary source of livelihood. Gender is often overlooked in animal health programs, let alone intersectionality. However, given the socio-cultural intricacies of Karamoja, ignoring these factors may hinder animal vaccination practices, limiting the success of programs designed to control and prevent animal diseases, such as peste des petits ruminants (PPR). The study used qualitative research methods, including focus group discussions, individual interviews, and key informant interviews in a participatory research approach to investigate the constraints faced by livestock keepers when accessing vaccines. The study was carried out in Abim, Amudat, Kotido, and Moroto, four districts in the Karamoja Subregion of Uganda. A modified version of the socio-ecological model (SEM) blended with an intersectional approach were used as frameworks to analyze underlying individual, social and structural determinants of vaccine access with intersecting factors of social inequalities. The results show there are seven intersecting factors that influence access to vaccination the most. These are: gender, ethnicity, geographic location, age, physical ability, marital status, and access to education. The impact of these intersections across the different levels of the SEM highlight that there are vast inequalities within the current system. Access to vaccines and information about animal health was most limited among women, widows, the elderly, the disabled, geographically isolated, and those with unfavorable knowledge, attitudes, and practices about vaccination. Cultural norms of communities were also important factors determining access to PPR vaccines. Norms that burden women with household chores and beliefs that women cannot manage livestock, combined with gender-based violence, leaves them unable to participate in and benefit from the livestock vaccine value chain. Trainings and sensitization on gendered intersectional approaches for those involved in the distribution and delivery of vaccines are necessary to avoid exacerbating existing inequalities in Karamoja.

ESMO Scale for Clinical Actionability of Molecular Targets Driving Targeted Treatment in Patients with Cholangiocarcinoma.

PURPOSE: Treatment options for advanced cholangiocarcinoma are limited and prognosis is poor. Cholangiocarcinomas are highly heterogeneous at the molecular level, with divergent patterns between intrahepatic and extrahepatic forms, intrahepatic being particularly rich in actionable alterations. We compared survival in patients with advanced cholangiocarcinoma harboring alterations matched to targeted drugs, with patients harboring nonactionable alterations. EXPERIMENTAL DESIGN: Patients with cholangiocarcinoma treated between 2011 and 2020 at one institution, with available molecular analyses, were retrospectively reviewed. Genomic alteration actionability was classified according to the ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT) and correlated with efficacy endpoints. RESULTS: Of 327 patients included, 78.9% had intrahepatic cholangiocarcinoma, 97.9% had received chemotherapy for metastatic disease. Actionable molecular alterations per ESCAT were identified in 184 patients (56.3%), including IDH1 mutations and FGFR2 fusions (23.1% and 8.0% of patients with intrahepatic cholangiocarcinoma, respectively). Median overall survival in 50 patients with ESCAT I-IV alterations who received matched therapy (48 with intrahepatic cholangiocarcinoma) was 22.6 months [95% confidence interval (CI), 20.1-32.8], compared with 14.3 months (95% CI 11.9-18.1) in 130 patients without actionable ESCAT alterations (HR, 0.58; 95% CI, 0.40-0.85; P = 0.005). Among patients receiving matched targeted therapy, median progression-free survival was longer for patients with alterations classified as ESCAT I-II compared with ESCAT III-IV (5.0 vs. 1.9 months; HR, 0.36; 95% CI, 0.15-0.87; P = 0.02). CONCLUSIONS: ESCAT represents a tool to guide clinicians in fine-tuning use of molecular profiling data to choose matched targeted therapies. Our data demonstrate that targeted treatment administered per alteration actionability according to ESCAT is associated with improved survival in cholangiocarcinoma, particularly in ESCAT I-II intrahepatic cholangiocarcinoma.

Psychosocial Health of K-12 Students Engaged in Emergency Remote Education and In-Person Schooling: A Cross-Sectional Study.

As online classes became the norm in many countries as a response to the COVID-19 pandemic, the concern for child and adolescent mental health became an issue of concern. This study evaluates the differences in the psychosocial status of school children based on engagement in in-person or Emergency Remote Education (ERE) and assessed the prevalence and predictors of symptom-derived risk levels for anxiety, depression, and obsessive-compulsive disorders (OCD). Cross-sectional data were collected from students at a Florida K-12 school and their household members through an online survey conducted in October 2020 (n = 145). No significant difference was found between ERE and in-person learning for risk of anxiety, depression, or OCD. Prevalence of students presenting as at risk for anxiety, depression, and OCD was 42.1%, 44.8%, and 41.4%. Several student factors (e.g., child sex, school level) and parental factors (e.g., parental COVID-19 attitudes) were associated with students presenting as at risk for anxiety, depression, or OCD; child's participation in sports was protective against all three outcomes. Participation in sports was found to be protective against risk of anxiety (aOR = 0.36, CI = 0.14-0.93), depression (aOR = 0.38, CI = 0.15-0.93), and OCD (aOR = 0.31, CI = 0.11-0.85).