Miracle-dz/UniFAR-FTUs huggingface dataset:
Can ‘life writing’ be therapeutic in response to trauma? An exploratory research project in Medical Humanities in South Africa

The therapeutic benefit of expressive writing has been well researched in the Global North but there is no literature from the Global South. Potentially healing interventions need to be investigated in different contexts, particularly where there is a need to build social cohesion. South Africa has a violent past and is a highly stressed society. An exploration of self-reports by a diverse group of South Africans on the effects of life writing on their health and well-being was conducted using qualitative methods. Twenty members of a writing collective, the Life Righting Collective (LRC: www.liferighting.co.za), were purposively sampled and interviewed by medical students as part of a Medical Humanities special study module. Five major interconnected themes emerged. The LRC as a specific intervention was central to the benefits described. The findings of this study indicated that life writing is a useful non-medical, cost-efficient method to improve resilience to trauma, as well as improving the psychological well-being of the participants. In addition, participants reported positive experiences regarding personal development, overall wellness and mental health, and that life writing can engender a sense of community. Resource-constrained countries in the Global South, like South Africa, where there have been historical and ongoing multiple traumas, need interventions for healing and wellness that are low cost and can be replicated.
Encouraging self-blinding in hiring

One strategy for minimizing bias in hiring is blinding—purposefully limiting the information used when screening applicants to that which is directly relevant to the job and does not elicit bias based on race, gender, age, or other irrelevant characteristics. Blinding policies remain rare, however. An alternative to blinding policies is self-blinding, in which people performing hiring-related evaluations blind themselves to biasing information about applicants. Using a mock-hiring task, we tested ways to encourage self-blinding that take into consideration three variables likely to affect whether people self-blind: default effects on choices, people’s inability to assess their susceptibility to bias, and people’s tendency not to recognize the full range of information that can elicit that bias. Participants with hiring experience chose to receive or be blind to various pieces of information about applicants, some of which were potentially biasing. They selected potentially biasing information less often when asked to specify the applicant information they wanted to receive than when asked to specify the information they did not want to receive, when prescribing selections for other people than when making the selections for themselves, and when the information was obviously biasing than when it was less obviously so. On the basis of these findings, we propose a multipronged strategy that human resources leaders could use to enable and encourage hiring managers to self-blind when screening job applicants.
New Pleistocene avian ichnosites on South Africa’s Cape south coast

Twelve new avian ichnosites have been identified on South Africa’s Cape south coast, adding to the 29 sites previously identified. More than half of these 41 avian ichnosites are found along a 9-km stretch of coastline east of Still Bay. The new sites provide the first southern African trace fossil records of the dove, stork and heron families, as well as a possible ostrich trackway and evidence of probable ostrich eggshell fragments. They buttress the previous inference of large avian chronospecies during the Pleistocene. The preponderance of large- and mediumsized tracks can be attributed to a bias whereby fossil tracks of larger, heavier birds are easier to recognise and interpret. Four of the longest fossil avian trackways ever to be identified occur within a 350-m stretch of coastline in the Driefontein area, east of Still Bay. The new findings provide an enhanced picture of the Pleistocene avifauna of the region. Many of the new sites are fragile and have limited prospects to endure, emphasising the need to document them through photogrammetry, and to regularly explore the coastline in high-yield areas in search of further sites.
T and Z, Partial Seed Coat Patterning Genes in Common Bean, Provide Insight into the Structure and Protein Interactions of a Plant MBW Complex

Flavonoids are secondary metabolites associated with seed and flower color. A ternary MBW protein complex consisting of interfacing MYB, beta-helix-loop-helix (bHLH), and WD40 repeat (WDR) proteins controls the expression of late biosynthetic genes in the flavonoid pathway. P, the master regulator gene of flavonoid expression in common bean (Phaseolus vulgaris L.) was recently determined to encode a bHLH protein. Two other genes, T and Z, are also historically considered regulators since they determine the distribution of color in seeds and flowers. These two genes were cloned using reverse genetics based on genetic mapping, candidate gene selection, phylogenetic analysis, and mutant analysis. Domain and AlphaFold2 structure analyses determined T encoded a seven-bladed β-propeller WDR protein, while Z encoded a R2R3 MYB protein. Modeling of the Z MYB/P bHLH/T WDR MBW complex identified interfacing sequence domains and motif in all three genes that are conserved in dicots. One Z MYB motif is a possible β-MoRF that only appears in a structured state when Z MYB is modeled in a MBW complex. Complexes containing mutant T and Z proteins changed the interaction of members of the complex in ways that would alter their role in regulating expression of genes in the flavonoid pathway. Highlight The MBW complex of bean comprised of the classic Z, P, and T genes associated with seed coat patterning defines critical proteins interactions for flavonoid gene expression.
Shared mechanisms drive ocular following and motion perception

How features of complex visual patterns combine to drive perception and eye movements is not well understood. We simultaneously assessed human observers’ perceptual direction estimates and ocular following responses (OFR) evoked by moving plaids made from two summed gratings with varying contrast ratios. When the gratings were of equal contrast, observers’ eye movements and perceptual reports followed the motion of the plaid pattern. However, when the contrasts were unequal, eye movements and reports during early phases of the OFR were biased toward the direction of the high-contrast grating component; during later phases, both responses more closely followed the plaid pattern direction. The shift from component- to pattern-driven behavior resembles the shift in tuning seen under similar conditions in neuronal responses recorded from monkey MT. Moreover, for some conditions, pattern tracking and perceptual reports were correlated on a trial-by-trial basis. The OFR may therefore provide a precise behavioural read-out of the dynamics of neural motion integration for complex visual patterns.
BBQ methods: Streamlined workflows for Bacterial Burden Quantification in infected cells by confocal microscopy

Accurate quantification of bacterial burden within macrophages, termed Bacterial Burden Quantification (BBQ), is crucial for understanding host-pathogen interactions. Various methods have been employed, each with strengths and weaknesses. This article addresses limitations in existing techniques and introduces two novel automated methods for BBQ within macrophages based on confocal microscopy data analysis. The first method refines total fluorescence quantification by incorporating filtering steps to exclude uninfected cells, while the second method calculates total bacterial volume per cell to mitigate potential biases in fluorescence-based readouts. These workflows utilize PyImageJ and Cellpose software, providing reliable, unbiased, and rapid quantification of bacterial load. The proposed workflows were validated using Salmonella enterica serovar Typhimurium and Mycobacterium tuberculosis models, demonstrating their effectiveness in accurately assessing bacterial burden. These automated workflows offer valuable tools for studying bacterial interactions within host cells and provide insights for various research applications.
Old foe, new host: epidemiology, genetic diversity and pathogenic characterization of maize streak virus in rice fields from Burkina Faso

Rice is of critical significance regarding food security worldwide including in Africa. Only two viruses impacting rice production in Africa have been deeply investigated for decades: the rice yellow mottle virus (Solemoviridae) and the rice stripe necrosis virus (Benyviridae). Using viral metagenomics, we aimed at exploring the diversity of viruses circulating in Burkina Faso rice fields. We performed an epidemiological survey in this country between 2016 and 2019 involving 57 small farmer’s rice fields under two production systems (rainfed lowlands and irrigated areas). More than 2700 rice samples were collected without a priori (not based on symptom observation) following a regular scheme. In addition, wild and cultivated (maize and sugarcane) Poaceae growing nearby rice fields were also collected. Unexpectedly, metagenomics detected maize streak virus (MSV, Geminiviridae) in analyzed rice samples. Further molecular analyses using RCA-PCR showed that MSV is widely distributed and highly prevalent in both rainfed lowlands and irrigated rice areas. MSV-A and MSV-G strains were identified. MSV-G, exclusively identified so far in wild grasses, was the most prevalent strain while MSV-A, known to cause severe symptoms in maize, was sporadically identified. No genetic differentiation was detected between MSV isolates either infecting wild or cultivated plant species. Using infectious clones in experimental conditions, we confirmed the pathogenicity of both MSV strains on rice. Thus, in addition to contribute to the epidemiological surveillance of rice production in Africa, our results illuminate new epidemiological and pathogenic aspects of one of the most studied plant viruses with significant economic consequences in Africa. Funding French National Research Agency «Investissements d’avenir» program (ANR-10-LABX-001-01), Agropolis Fondation (ANR-16-IDEX-006), French National Research Agency “young researchers” program (ANR-20-CE35-0008-01), CGIAR Research Program on Rice Agri-food Systems (RICE), Cooperation and cultural action department of the French Embassy (SCAC) in Burkina Faso.
A novel iPSC model reveals selective vulnerability of neurons in Multiple Sulfatase Deficiency

Multiple sulfatase deficiency (MSD) is an ultra-rare, inherited lysosomal storage disease caused by mutations in the gene sulfatase modifying factor 1 (SUMF1). MSD is characterized by the functional deficiency of all sulfatase enzymes, leading to the storage of sulfated substrates including glycosaminoglycans (GAGs), sulfolipids, and steroid sulfates. Patients with MSD experience severe neurological impairment, hearing loss, organomegaly, corneal clouding, cardiac valve disease, dysostosis multiplex, contractures, and ichthyosis. Here, we generated a novel human model of MSD by reprogramming patient peripheral blood mononuclear cells to establish an MSD iPSC line (SUMF1 p.A279V). We also generated an isogenic control iPSC line by correcting the pathogenic variant with CRISPR/Cas9 gene editing. We successfully differentiated these iPSC lines into neural progenitor cells (NPCs) and NGN2-induced neurons (NGN2-iN) to model the neuropathology of MSD. Mature neuronal cells exhibited decreased SUMF1 gene expression, increased lysosomal stress, impaired neurite outgrowth and maturation, reduced sulfatase activities, and GAG accumulation. Interestingly, MSD iPSCs and NPCs did not exhibit as severe of phenotypes, suggesting that as neurons differentiate and mature, they become more vulnerable to loss of SUMF1. In summary, we demonstrate that this human iPSC-derived neuronal model recapitulates the cellular and biochemical features of MSD. These cell models can be used as tools to further elucidate the mechanisms of MSD pathology and for the development of therapeutics.
Allosteric activation of VCP, a AAA unfoldase, by small molecule mimicry

The loss of function of AAA (ATPases associated with diverse cellular activities) mechanoenzymes has been linked to diseases, and small molecules that activate these proteins can be powerful tools to probe mechanisms and test therapeutic hypotheses. Unlike chemical inhibitors that can bind a single conformational state to block enzyme activity, activator binding must be permissive to different conformational states needed for enzyme function. However, we do not know how AAA proteins can be activated by small molecules. Here, we focus on valosin-containing protein (VCP)/p97, a AAA unfoldase whose loss of function has been linked to protein aggregation-based disorders, to identify druggable sites for chemical activators. We identified VCP Activator 1 (VA1), a compound that dose-dependently stimulates VCP ATPase activity up to ∼3-fold. Our cryo-EM studies resulted in structures (∼2.9-3.5 Å-resolution) of VCP in apo and ADP-bound states, and revealed VA1 binding an allosteric pocket near the C-terminus in both states. Engineered mutations in the VA1 binding site confer resistance to VA1, and furthermore, modulate VCP activity to a similar level as VA1-mediated activation. The VA1 binding site can alternatively be occupied by a phenylalanine residue in the VCP C-terminal tail, a motif that is post-translationally modified and interacts with cofactors. Together, our findings uncover a druggable allosteric site and a mechanism of enzyme regulation that can be tuned through small molecule mimicry. Significance The loss of function of valosin-containing protein (VCP/p97), a mechanoenzyme from the AAA superfamily that hydrolyzes ATP and uses the released energy to extract or unfold substrate proteins, is linked to protein aggregation-based disorders. However, druggable allosteric sites to activate VCP, or any AAA mechanoenzyme, have not been identified. Here, we report cryo-EM structures of VCP in two states in complex with VA1, a compound we identified that dose-dependently stimulates VCP’s ATP hydrolysis activity. The VA1 binding site can also be occupied by a phenylalanine residue in the VCP C-terminal tail, suggesting that VA1 acts through mimicry of this interaction. Our study reveals a druggable allosteric site and a mechanism of enzyme regulation.
The Mid-Atlantic Regional Assessment: motivation and approach

The US Global Change Research Program has initiated a National Assessment of poten- tial impacts from climate change. This paper summarizes the National Assessment process, and the Mid-Atlantic Regional Assessment (MARA) as an example of how the process is being implemented. At the national level, 5 sectoral working groups are assessing impacts on agriculture, forests, freshwater resources, coastal zones and human health. Because different areas of the country will experience impacts to differing degrees, regional assessments simultaneously are examining sectoral impacts identified as likely to be most important within each of 18 US regions. An independent panel of experts, the National Assessment Synthesis Team, is synthesizing the sectoral and regional findings for a national report that provides regional texture. The approach adopted for the MARA is described in the context of the National Assessment process. Such a complex undertaking relies on multiple extensive data sets. The MARA approach to managing the diverse data sets is outlined as a potential guide for similar efforts.
Nicotinic Acetylcholine Receptors on Osteocytes Impact Bone Mechanoadaptation in a Sexually Dimorphic Manner

Bone’s ability to adapt to mechanical loads is attributed the osteocyte. Osteocytes reside embedded in calcified bone matrix, where they function as the resident tissue mechanosensor. Ca2+ signaling is a key second messenger in mechanotransduction in osteocytes. It is used to encode mechanical load magnitude and has been linked to downstream signaling pathways which regulate bone resorbing and bone formation cell activity, however the details regarding Ca2+ signaling regulation in osteocytes in vivo are not well stratified. Osteocytes express components for nicotinic acetylcholine receptors (nAChRs) are known for calcium signaling at the neuromuscular junction. Indeed, cholinergic signaling is known to impact bone mass and fracture risk from studies in both humans and rodents. Despite this convincing evidence of the role of ACh, the details regarding cholinergic signaling in bone mechanotransduction remain largely unexplored. Here, we determine osteocytes as a functional target of cholinergic signaling for bone mechanoadaptation. We generated osteocyte-targeted conditional knockout mice for Chrna1 or Rapsn using the 10kb DMP1 promotor to delete the cholinergic receptor subunit α1 and the channel grouping protein raspyn, respectively. We then performed longitudinal studies to assess skeletal morphology, tissue material make-up, and dynamic responses to anabolic challenge. Our results show sexually dimorphic differences in bone formation rates and bone structure between Cre-negative controls and conditional knockout mice. In females, the reductions to bone geometry were rescued with anabolic loading, but not in males. Our results confirm osteocytes as direct cholinergic targets with an impact on bone mechanoadaptation and suggest a direct link between bone mechanobiology and the central nervous system.
Growth Dynamics of Ductal Carcinoma in Situ Recapitulate Normal Breast Development

Ductal carcinoma in situ (DCIS) and invasive breast cancer share many morphologic, proteomic, and genomic alterations. Yet in contrast to invasive cancer, many DCIS tumors do not progress and may remain indolent over decades. To better understand the heterogenous nature of this disease, we reconstructed the growth dynamics of 18 DCIS tumors based on the geo-spatial distribution of their somatic mutations. The somatic mutation topographies revealed that DCIS is multiclonal and consists of spatially discontinuous subclonal lesions. Here we show that this pattern of spread is consistent with a new ‘Comet’ model of DCIS tumorigenesis, whereby multiple subclones arise early and nucleate the buds of the growing tumor. The discontinuous, multiclonal growth of the Comet model is analogous to the branching morphogenesis of normal breast development that governs the rapid expansion of the mammary epithelium during puberty. The branching morphogenesis-like dynamics of the proposed Comet model diverges from the canonical model of clonal evolution, and better explains observed genomic spatial data. Importantly, the Comet model allows for the clinically relevant scenario of extensive DCIS spread, without being subjected to the selective pressures of subclone competition that promote the emergence of increasingly invasive phenotypes. As such, the normal cell movement inferred during DCIS growth provides a new explanation for the limited risk of progression in DCIS and adds biologic rationale for ongoing clinical efforts to reduce DCIS overtreatment.
Targeting Acute Myeloid Leukemia Stem Cells Through Perturbation of Mitochondrial Calcium

We previously reported that acute myeloid leukemia stem cells (LSCs) are uniquely reliant on oxidative phosphorylation (OXPHOS) for survival. Moreover, maintenance of OXPHOS is dependent on BCL2, creating a therapeutic opportunity to target LSCs using the BCL2 inhibitor drug venetoclax. While venetoclax-based regimens have indeed shown promising clinical activity, the emergence of drug resistance is prevalent. Thus, in the present study, we investigated how mitochondrial properties may influence mechanisms that dictate venetoclax responsiveness. Our data show that utilization of mitochondrial calcium is fundamentally different between drug responsive and non-responsive LSCs. By comparison, venetoclax-resistant LSCs demonstrate a more active metabolic (i.e., OXPHOS) status with relatively high steady-state levels of calcium. Consequently, we tested genetic and pharmacological approaches to target the mitochondrial calcium uniporter, MCU. We demonstrate that inhibition of calcium uptake sharply reduces OXPHOS and leads to eradication of venetoclax-resistant LSCs. These findings demonstrate a central role for calcium signaling in the biology of LSCs and provide a therapeutic avenue for clinical management of venetoclax resistance. Significance We identify increased utilization of mitochondrial calcium as distinct metabolic requirement of venetoclax-resistant LSCs and demonstrate the potential of targeting mitochondrial calcium uptake as a therapeutic strategy.
Intrigue: Personalized recommendation of tourist attractions for desktop and hand held devices

This paper presents INTRIGUE, a prototype tourist-information server that presents information about the area around Turin City, Italy, on desktop and hand held devices.This system recommends sightseeing destinations and itineraries by taking into account the preferences of heterogeneous tourist groups (such as families with children or the elderly) and explains the recommendations by addressing the group members' requirements. Moreover, the system provides an interactive agenda for scheduling the tour. The services offered by INTRIGUE rely on user modeling and adaptive hypermedia techniques; furthermore, XML-based technologies support the generation of the user interface and its adaptation to Web browsers and WAP minibrowsers.
Large Covariance Matrix Estimation with Oracle Statistical Rate

The ℓ1 penalized covariance estimator has been widely used for estimating large sparse covariance matrices. It was recognized that ℓ1 penalty introduces a non-negligible estimation bias, while a proper utilization of non-convex penalty may lead to an estimator with a refined statistical rate of convergence. In this paper, to eliminate the estimation bias we propose to estimate large sparse covariance matrices using the non-convex penalty. It is a challenging task to analyze the theoretical properties of the resulting covariance estimator because popular iterative algorithms for convex optimization no longer have global convergence guarantees for non-convex optimization. To tackle this issue, an efficient algorithm based on the majorization-minimization (MM) is developed by solving a sequence of convex relaxation subproblems. We prove that the proposed estimator computed exactly by the MM-based algorithm achieves the oracle statistical rate under weak assumptions. Our theoretical findings are corroborated through extensive numerical experiments.
Radiative forcing due to changes in tropospheric ozone in the period 1980 to 1996

Radiative forcing calculations of changes in tropospheric ozone in the period 1980 to 1996 are performed. The tropospheric ozone changes used in this study are from a chemistry transport model [Karlsdottir et al., this issue]. For the radiative transfer calculations, schemes for thermal infrared radiation and shortwave radiation are used. Effects of reduced stratospheric ozone and emissions of tropospheric ozone precursors on the changes in tropospheric ozone are taken into account. Large positive radiative forcing is estimated over Southeast Asia, due to emissions of ozone precursors. Effects of decreased stratospheric ozone have reduced the radiative forcing due to change in tropospheric ozone from 1980 to 1996, particularly at high latitudes where the radiative forcing is negative.