bluuebunny/crossref_metadata_2025 huggingface dataset:
Etiology, Risk Factors, and Outcomes of Bacteremia in Patients With Hematologic Malignancies and Febrile Neutropenia in Uganda
Authors: Lubwama Margaret , Holte Sarah E , Zhang Yuzheng , Mubiru Kelvin R , Katende George , Orem Jackson , Kateete David P , Bwanga Freddie , Phipps Warren
Published: November 2024

Background

We determined the etiology, risk factors, and outcomes associated with bacteremia in patients with hematologic malignancies and febrile neutropenia (FN) at the Uganda Cancer Institute (UCI).

Methods

UCI adult and pediatric inpatients with hematologic malignancies and FN were prospectively enrolled and followed up to determine 30-day mortality. Blood drawn from participants with FN was cultured in the BACTEC 9120 blood culture system. Antimicrobial susceptibility testing was performed with the disk diffusion method on identified bacteria. Logistic regression and Cox proportional hazards regression were applied to estimate associations between participant characteristics and FN, bacteremia, and mortality.

Results

Of 495 participants, the majority (n = 306 [62%]) were male. Median age was 23 years (interquartile range, 11–42 years). Of the 132 participants who experienced FN, 43 (33%) had bacteremia. Participants with younger age (odds ratio [OR], 0.98; P = .05), severe neutropenia (OR, 2.9; P = .01), hypotension (OR, 2.46; P = .04), mucositis (OR, 2.77; P = .01), and receipt of chemotherapy (OR, 2.25; P = .03) were more likely to have bacteremia. Fifty (78%) bacteria isolated were gram negative. Escherichia coli (n = 25 [50%]) was predominant. Thirty-seven of 43 (86%) episodes were caused by multidrug-resistant (MDR) bacteria. Thirty-day overall survival for participants with bacteremia was significantly lower than that for participants with no bacteremia (P = .05). MDR bacteremia (hazard ratio, 1.84; P = .05) was associated with increased risk of death.

Conclusions

Bacteremia was frequent in patients with hematologic cancer and FN and was associated with poor survival. MDR bacteria were the main cause of bacteremia and mortality. There is a need for robust infection control and antimicrobial stewardship programs in cancer centers in sub-Saharan Africa.
Prosper’s Law: putting the lex back into orandi and credendi
Authors: Wright O T I
Published: November 2024

This article demonstrates the centrality of ‘law’ to the famous dictum of Prosper of Aquitaine, lex orandi lex credendi. In its various appearances since the fifth century AD, the relationship in Prosper’s dictum between worship and belief has been, at best, assumed. I propose that the nature of that relationship is actually explicit in the dictum itself. That is, Prosper’s invocation of law—‘lex’. In particular, I demonstrate the importance of that term from a modern and an ancient perspective: the modern notion of speech-act theory; and the historical context of the Codex Theodosius, newly promulgated at the time of Prosper’s writing. From those perspectives, Prosper’s dictum is newly perceived as words which do things. It is both an example of heresiology and also seeks to establish the law. On the one hand, there appears to be a normativity newly prescribed for doctrine (credendi) following the lead of worship (orandi). On the other hand, I argue that Prosper’s prescription is for something more lively than ‘mere’ ritual normativity, namely established custom. This, as I will show, emerges from the contribution of the familiar Roman pair ius and lex.
Global Comparative Law?
Authors: Pirie Fernanda
Published: November 2024

The Cambridge Handbook of Comparative Law, edited by Matthias Siems and Po Jen Yap, continues recent calls to expand the field of comparative law. By including authors drawn from all parts of the world, it presents ‘new perspectives’ on the field. This wide geographic remit proves successful as a way of moving beyond traditional ‘families’ and doctrinal topics. The contributors raise new themes for comparison, many related to public law and processes of change. But this, in turn, raises questions about the purposes of expanding the field. The volume largely concerns the laws and legal issues of modern states, and the authors do not venture far into history. Nor do they consider the alternatives offered by religious and traditional legal systems or forms of non-state ordering. I suggest that these subjects could productively expand the field even further, raising more theoretical questions about what law is and does.
Maternally expressed FERTILIZATION-INDEPENDENT ENDOSPERM1 regulates seed dormancy and aleurone development in rice
Authors: Cheng Xiaojun , Zhang Su , E Zhiguo , Yang Zongju , Cao Sijia , Zhang Rui , Niu Baixiao , Li Qian-Feng , Zhou Yong , Huang Xin-Yuan , Liu Qiao-Quan , Chen Chen
Published: November 2024

Seed dormancy, an essential trait for plant adaptation, is determined by the embryo itself and the surrounding tissues. Here, we found that rice (Oryza sativa) FERTILIZATION-INDEPENDENT ENDOSPERM1 (OsFIE1) regulates endosperm-imposed dormancy and the dorsal aleurone thickness in a manner dependent on the parent of origin. Maternally expressed OsFIE1 suppresses gibberellin (GA) biosynthesis in the endosperm by depositing trimethylation of lysine 27 on histone H3 (H3K27me3) marks on GA biosynthesis-related genes, thus inhibiting germination and aleurone differentiation. Knockout of rice GA 20-oxidase1 (OsGA20ox1) alleviated the phenotypic defects in osfie1. The aleurone-positive determinant Crinkly 4 (OsCR4) is another target of the OsFIE1-containing Polycomb repressive complex 2 (PRC2). We found that OsFIE1 plays an important role in genomic imprinting in the endosperm of germinating seeds, particularly for paternally expressed genes associated with H3K27me3. The increased aleurone thickness of osfie1 substantially improved grain nutritional quality, indicating that the osfie1 gene may be utilized for breeding nutrient-enriched rice. The findings provide insights into the essential roles of PRC2-mediated H3K27me3 methylation in the acquisition of seed dormancy and endosperm cell differentiation in rice.
How far have we advanced in simulation-based training for policing and law enforcement? A literature review 2014–24
Authors: See Pei Jun , Davies Amanda
Published: November 2024

The twenty-first century demands on police and law enforcement similarly demand effective, efficient and relevant officer training endeavours. Guided by the PRISMA literature review model this study identified and analysed a total of 35 peer-reviewed studies (2014–24) centred on simulation scenario-based training offering insight into (1) what are the different types and platforms used in scenario-based simulation training and (2) what skills are being trained in simulation-based exercises. The findings revealed a preference for high-fidelity technological tools for short training scenarios centred on tactical and procedural knowledge. Conversely, incidents that require conversations and negotiations remain restricted to platforms with limited technological integration or live role-players. The review identified (1) skills for daily operations, decision making, de-escalation training, major incident management were those most commonly attributed to simulation-based training and (2) the extent to which virtual environments can replicate major incidents that are sufficiently immersive for training continues to be a work in progress.
Reconceptualizing Administrative Burden Around Onerous Experiences
Authors: Daigneault Pierre-Marc
Published: November 2024

Despite ongoing discussions on the need to improve the conceptualization and measurement of administrative burden, several conceptual problems remain. This study offers the first systematic analysis and evaluation of this increasingly central public management concept. Using an ontological-semantic approach, I show that the current conceptualization fails to fully and directly account for individuals’ onerous experiences. I address five interrelated issues, including the overlap of cost categories and the conflation of state actions with onerous experiences. While psychological costs should be retained, I argue for abandoning the other cost categories. Building on previous reconceptualization efforts, I propose a new framework focused on time, money, effort, and psychological costs. Additionally, I explore the structure of the concept and propose specific indicators for each dimension. I then discuss the independence of these dimensions, their capacity to reflect the distributive nature of burdens, and avenues for empirical validation.
Long-term effects of the Targeting the Ultra Poor program—A reproducibility and replicability assessment of Banerjee et al. (2021)
Authors: Rose Julian , Neubauer Florian , Ankel-Peters Jörg
Published: November 2024

Banerjee, Duflo, and Sharma (BDS, 2021, American Economic Review: Insights, 3, 471–86) conduct a 10-year follow-up of a randomized transfer program in West Bengal. BDS find large effects on consumption, food security, income, and health. We conduct a replicability assessment. First, we successfully reproduce the results, thanks to a perfectly documented reproduction package. Results are robust across alternative specifications. We furthermore assess the paper's pre-specification diligence and the reporting in terms of external and construct validity. While the paper refers to a pre-registration, it lacks a pre-analysis plan. Assessing the validity of findings for other contexts is difficult absent necessary details about the exact treatment delivery.
Anti- Inflammatory Activities Of The Methanol Leaf Extract And Fractions Of Elaesis Guineensis In In-Vivo Animals
Authors: Uwamusi Marvellous
Published: November 2024

Objective

Objective of this paper is to investigate the preliminary anti-inflammatory property of the leaves and its fractions of Elaesis guineensis using egg induced albumin and formaldehyde induced arthritis models in rats.

Method

Egg albumin induced inflammation was induced by sub-plantar injection of 0.1 ml of fresh undiluted egg albumin. The volume of distilled water displaced by the treated paw was measured at 0.5,1, 2, 3, 4, 5, and 6 hours after induction of inflammation. Formaldehyde-induced arthritis was induced after 30 min by sub-plantar injection of 0.1 ml of 2.5% formaldehyde solution and was repeated on day 3. Arthritis was assessed by measuring the volume of distilled water displaced by the paw before induction of arthritis and once every day for ten days, starting from day one, after induction of arthritis.

Results

The acute toxicity test revealed that the plant extract was safe even at 5000 mg/kg dose level. The methanol extract (ME) showed a dose-dependent inhibition of egg albumin-induced acute inflammation that peaked at the dose of 200 mg/kg, while the fractions of the extract showed that the hexane and ethyl acetate fractions had the highest activity during the experiment. Similarly, the crude extract of the formaldehyde induced arthritis showed a dose-dependent inhibition making the 200 mg/kg the most active dose level. Additionally, it was observed that among the fractions of the extract the hexane fraction (HF) showed the most significant inhibitory activity when compared to other fractions

Conclusion

this study establishes that the methanol leaf extract and fractions ofElaesis guineensis possess significant anti-inflammatory activity
Defenders of the status quo: energy protests and policy (in)action in Sweden
Authors: Uba Katrin , Engeman Cassandra
Published: November 2024

Are the positions that protesters take—in favor or against change—consequential for their ability to affect policy? While previous research suggests that protests can inform legislative priorities and facilitate policy introduction, this paper emphasizes policy inaction and stasis as goals of some protest actions. Analysis uses novel and detailed data on energy-related protest and policy actions in Sweden covering a forty-year period and considers protest frequency and size in relation to proposal introduction. The research design uniquely distinguishes between protests in favor or against a specific energy source and proposal activity in line with those demands and also controls for public opinion on each energy source. Findings suggest that pro-renewable energy protests do not yield pro-renewable policies but prevent undesired policies that support non-renewable energy sources. In contrast to pro-renewable protests, protests against renewable energy sources are somewhat more influential. They likewise prevent the introduction of their undesired proposals and also influence the introduction of proposals supporting non-renewable energy sources. Overall, the paper examines policy inaction as a desired protest outcome and argues protest—as a tactic—may be more effective when pushing against rather than for policy change.
Development of slow oscillation–spindle coupling from infancy to toddlerhood
Authors: Kurz Eva-Maria , Bastian Lisa , Mölle Matthias , Born Jan , Friedrich Manuela
Published: November 2024

Sleep has been demonstrated to support memory formation from early life on. The precise temporal coupling of slow oscillations (SOs) with spindles has been suggested as a mechanism facilitating this consolidation process in thalamocortical networks. Here, we investigated the development of sleep spindles and SOs and their coordinate interplay by comparing frontal, central, and parietal electroencephalogram recordings during a nap between infants aged 2–3 months (n = 31) and toddlers aged 14–17 months (n = 49). Spindles and SOs showed quite different maturational patterns between age groups, as to topography, amplitude, and density. Notably, spindle–SO co-occurrence in the infants did not exceed chance levels and was increased to significant levels only in the toddlers. In the infants, the slow SO upstate over frontocortical regions was even associated with a significant decrease in spindles, contrasting with the adult-like increase in spindles seen in toddlers. These results point to an immature processing in thalamocortical networks during sleep in early infancy, possibly diminishing the efficacy of sleep-dependent memory formation at this age.
Microglia in the spinal cord stem cell niche regulate neural precursor cell proliferation via soluble CD40 in response to myelin basic protein
Authors: Lakshman Nishanth , Stojic Filip , Morshead Cindi M
Published: November 2024

Neural stem cells (NSCs) are found along the neuraxis of the developing and mature central nervous system. They are found in defined niches that have been shown to regulate NSC behavior in a regionally distinct manner. Specifically, previous research has shown that myelin basic protein (MBP), when presented in the spinal cord niche, inhibits NSC proliferation and oligodendrogenesis. Herein, we investigate the cell-based mechanism(s) underlying this spinal-cord niche-derived MBP-mediated inhibition. We used reporter mice to sort for subpopulations of cells and found that spinal cord niche-derived microglia release a soluble factor in response to MBP that is responsible for NSC inhibition. Microglia, but not other niche cells, release soluble CD40/TNFRSF5 (sCD40) in the presence of MBP which may indirectly reduce activation of transmembrane CD40/TNFRSF5 receptor on both spinal cord and brain NSCs. This is consistent with sCD40 binding to CD40 ligand (CD40L) thereby preventing CD40 receptor binding on NSCs and inhibiting NSC proliferation. The identification of the cell-based mechanism that regulates NSC behavior in response to MBP, which is dysregulated in injury/disease, provides insight into a potential target for strategies to enhance neural repair through endogenous stem cell activation.
The effect of processing or concentration of dried distillers grain with solubles on the growth of finishing lambs
Authors: Thompson Brayden , Relling Alejandro E , Ferreira Evandro M , Campbell Braden J
Published: November 2024

Dried distiller grains with solubles (DDGS) are a popular byproduct used in the livestock feed industry as it is a cost-effective feedstuff that is rich in crude protein and minerals. However, a common concern related to the use of DDGS in livestock diets is the negative impact that affects animal dry matter intake (DMI) and growth. To further investigate this challenge, the experiments aimed to evaluate the effect of feeding 1) two different diets, control versus heat processed DDGS or 2) increasing the concentration of DDGS and its effect on body weight (BW), average daily gain (ADG), DMI, and gain to feed ratio (G:F) in finishing lambs. In experiment 1, both diets were the same except for the heat processing of DDGS; the control diet used a commercial DDGS source directly from the supplier and the processed diet contained the same commercial DDGS source that differed through additional heat processing. For DDGS heat processing, 40% moisture was added to the DDGS and heated at 150 °C for 70 min. After the heating process, the DDGS was placed in a second oven at 56 °C for 2 d to allow for humidity evaporation. Lambs (n = 34), blocked by sex and BW, were housed in pens (2 to 3 lambs/pen, 6 pens/treatment) and were fed for 42 d. Lamb DMI was measured daily, and BW was measured every 14 d. In experiment 2, lambs (n = 75) were blocked by BW (5 lambs/ pen, 5 pens/treatment) and fed diets differing in inclusion rates of DDGS (10%, 20%, and 30%). The feeding period lasted for 56 d, and lamb DMI and BW were measured daily or every 28 d, respectively. In both experiments, diets were isonitrogenous, and the feeding procedure utilized slick bunk management. Data were analyzed in SAS using a mixed model considering the treatments as fixed effects and pen and block as random effects. In experiment 1, there were no treatment differences (P ≥ 0.13) in ADG, DMI, and G:F in finishing lambs. In experiment 2, a linear and quadratic contrast were used to separate the mean and demonstrated that increasing the concentration of DDGS decreased lamb DMI (linear P < 0.01; quadratic P = 0.05), but did not affect lamb BW, ADG, or G:F (P ≥ 0.26). Despite that previous research shows differences in animal growth because of an increase in DDGS concentration, our experiments illustrated that heat processing or increased concentrations of DDGS up to 30% in finishing lamb diets are not responsible for a decrease in lamb performance.
Empowering older workers through self-regulation: how job crafting and leisure crafting enhance mindfulness and well-being at work
Authors: Xin Xun , Gao Lili , He Yuting
Published: November 2024

The capacity for self-regulation is crucial for older workers to maintain adaptability and well-being under aging-related challenges. Building on recent research suggesting that practices of self-regulation can enhance self-regulatory capacity, our study employs self-regulation theory to investigate how two distinct self-regulatory practices—job crafting (JC) and leisure crafting (LC)—support older workers in enhancing their work well-being through the lens of self-regulatory capacity, specifically mindfulness. Within this theoretical framework, we further explore the combined effects of JC and LC on adaptation to the aging process. A three-wave time-lagged survey was conducted among 227 older Chinese workers from science and technology enterprises. The results from latent structural equation modeling indicate that mindfulness at work mediates the relationship between crafting practices (both JC and LC) and work well-being. Moreover, JC and LC exhibit a compensatory relationship in facilitating mindfulness at work, which in turn promotes the work well-being of older workers. These findings offer a novel perspective grounded in self-regulation theory, highlighting how JC and LC contribute to successful aging by strengthening mindfulness capacity.
Oxidative stress drives endometrial fibrosis via TGF‐β1/MAPK signaling pathway in breast cancer
Authors: Chen Hui , Wang Minghua , Zhang Zhejun , Lin Fangfang , Guo Bihui , Lu Qinsheng , Lash Gendie E. , Li Ping
Published: November 2024

Breast cancer patients have high serum reactive oxygen species (ROS) levels, which exert toxicity on the ovary. However, it is still unclear whether tumor‐derived ROS play a role in endometrial development and function in breast cancer. Breast cancer patients and healthy controls were recruited and endometrial thickness was measured by transvaginal ultrasound (TVUS). Xenograft tumors of the breast cancer cell line MDA–MB–231 in a female BALB/c nude mice model were established, and the therapeutic mechanism of vitamin C (VC) was investigated on uterine pathology in vivo and the contribution of co‐culture of breast cancer cell and endometrial epithelial cell on this process was examined in vitro. Median thickness in endometria was lower in breast cancer patients and tumor‐bearing mice compared to controls. A gene signature of uteri in tumor‐bearing mice demonstrated differential expression of genes (DEGs) regulating extracellular matrix (ECM) and epithelial–mesenchymal transition (EMT), and activation of TGF‐β and MAPK signaling pathways. In addition, ROS, EMT‐ and ECM‐related protein levels were enhanced in uteri in tumor‐bearing mice, as well as in Ishikawa cells which were co‐cultured with MDA‐MB‐231 cells compared to controls. Supplementation with VC reduced endometrial damage, inhibited the EMT process and collagen deposition, and maintained better histologic architecture of uteri in tumor‐bearing mice via inactivation of the TGF‐β1/p38MAPK pathway. In women with breast cancer oxidative stress in the endometrium results in a fibrotic response as a consequence of EMT. VC could alleviate endometrial fibrosis via TGF‐β1/p38MAPK pathway and provide new predictive and therapeutic targets for fertility preservation in younger breast cancer patients.
Mutations in Mig6 reduce inhibition of the epidermal growth factor receptor
Authors: Hayashi Samantha Y. , Pak Steven , Torlentino Antonio , Rizzo Robert C. , Miller W. Todd
Published: November 2024

Mitogen‐inducible gene 6 (Mig6) is a cellular inhibitor of epidermal growth factor receptor (EGFR) that binds directly to the EGFR kinase domain and interferes with signaling. Reduced Mig6 expression is correlated with increased EGFR activity in multiple cancer models. Here, we investigated whether disease‐associated point mutations could reduce the inhibitory potency of Mig6. We show that several cancer‐associated mutations, and a mutation derived from Alzheimer's Disease patients, diminish the ability of Mig6 to bind and inhibit EGFR in vitro. In mammalian cells, the mutations decreased the Mig6‐induced suppression of basal and EGF‐stimulated autophosphorylation, MAP kinase phosphorylation, and cell migration. To probe the mechanisms by which the mutations could lead to reduced Mig6 inhibition, we constructed atomic‐level computational models of Mig6 complexed with the EGFR catalytic domain, and performed molecular dynamics simulations for wild‐type and mutant complexes.
Reassessing Asymmetry Reduction in Psychosis: Cingulate Folding and Gyrification Covariance in Patients with Auditory Hallucinations
Authors: Wu Shun-Chin Jim , de Vareilles Héloïse , Mitchell Samantha C. , Al-Manea Atheer , Garrison Jane , Mamalakis Michail , Simons Jon S. , Cachia Arnaud , Mangin Jean-François , Nerland Stener , Mørch-Johnsen Lynn , Agartz Ingrid , Suckling John , Murray Graham K.
Published: November 2024

Background and Hypothesis

Prior research links a shorter paracingulate sulcus (PCS) to hallucinations in schizophrenia, but its symmetry hemispheric specificity and relevance to bipolar disorders remain unclear. We hypothesized that reduced PCS asymmetry and interhemispheric gyrification covariance in salience and auditory networks are associated with lifetime auditory hallucinations (AH) in psychotic spectrum disorders.

Study Design

We compared patients with and without AH, and healthy controls, focusing on PCS asymmetry in five ordinal classes, sulcal length and depth, and interhemispheric gyrification covariance.

Study Results

Among 351 patients with schizophrenia or bipolar spectrum disorders (SSD/BSD), 194 (55.3%) had AH, compared to 157 without and 278 healthy controls. We found no significant PCS class asymmetry between hemispheres (V = 6648.5,P= .097) and decreased leftward asymmetry in PCS length (F(2,626) = 3.19,P= .013) in patients with AH, compared with those without and healthy controls. Compared to patients without AH, those with AH showed increased gyrification covariance in the auditory network (F(2,625) = 42.5,P< .001). In the salience network, patients with SSD and AH had increased covariance (F(2,625) = 299,P< .001), while patients with BSD and AH displayed decreased covariance (F(2,625) = 102,P< .001).

Conclusions

This study, featuring the largest cohort to date, links the AH trait to replicable reduced leftward PCS asymmetry and altered interhemispheric covariance in psychotic spectrum disorders, supporting theories of reduced asymmetry and altered brain network coordination as part of the mechanistic pathway to psychosis.
The Impact of Spinal Manipulation on Lumbar Proprioception and its Link to Pain Relief: A Randomized Controlled Trial
Authors: Luana Nyirö , Monika Dörig , Magdalena Suter , Lukas Connolly , Noemi Vogel , Stadler Carla , John-Cecere Giovanna , Petra Schweinhardt , Lukas Meier Michael
Published: November 2024

Manual therapy, such as spinal manipulation (SM), is commonly used to treat non-specific chronic low back pain (CLBP), although its mechanisms remain poorly understood. It has been hypothesized that the mechanical forces applied during spinal manipulation (SM) influence proprioceptive function, which is often impaired in patients with CLBP. This study aimed to investigate the effect of a single SM intervention on lumbar proprioceptive function and its potential relationship with analgesic effects in patients with CLBP. In a single-blind randomized controlled trial, data from 142 adults with or without CLBP were analyzed after random assignment to receive lumbar spinal manipulation (LMANIP), lumbar mobilization (LMOB), or no intervention (NI). The primary outcome was the proprioceptive weighting (PW) ratio, which reflects the central nervous system’s preferred source of proprioceptive input for balance control, specifically from the lumbar and ankle muscles. PW ratios were assessed immediately before and after intervention by analyzing postural sway changes during vibrotactile stimulation (60 Hz). PW changed in both healthy participants and patients after the intervention, with a significantly stronger lumbar-steered PW following LMANIP compared to NI (β = -0.047, t(422) = -2.71, p = 0.007) and LMOB (β = -0.039, t(422) = - 2.17, p = 0.030). Moreover, LMANIP was particularly effective in reducing pain in patients with stronger lumbar-steered PW before intervention (p < 0.017). These findings suggest that a single SM session enhances proprioceptive input from the lumbar muscles and that the strength of the analgesic effect is associated with the baseline PW status.
Primary Central Nervous System Lymphoma Tumor Biopsies Show Heterogeneity in Gene Expression Profiles, Genetic Subtypes, and in vitro Drug Sensitivity to Kinase Inhibitors
Authors: Zhu Yuan Xiao , Wong Jasper CH , Hilal Talal , Maguire Alanna , Ocal Jon , Zellner Katie , Chen Xianfeng , Link Brian K , Habermann Thomas M , Maurer Matthew J , Cerhan James R , Johnston Patrick B , Feldman Andrew L , Scott David W. , Rosenthal Allison , Rimsza Lisa
Published: November 2024

Primary central nervous system lymphoma (PCNSL) is clinically challenging due to its location and small biopsy size, leading to a lack of comprehensive molecular and biologic description. We previously demonstrated that 91% of PCNSL belong to the activated B-cell-like (ABC) molecular subtype of diffuse large B-cell lymphoma (DLBCL). Here we investigated the expression of 739 cancer related genes in HIV (-) patients using NanoString digital gene expression profiling in 25 ABC-PCNSL and 43 ABC-systemic DLBCL, all tumors were EBV (-). We found that two-thirds of ABC-PCNSL samples had a transcriptional landscape distinct from ABC-systemic DLBCL samples. Of the 739 genes measured, 135 were identified as differentially expressed between these ABC-PCNSL and ABC-systemic DLBCL (p<0.05). Compared with ABC-systemic DLBCL, ABC-PCNSL showed higher gene expression in several cancer related gene sets including genes related to Hedgehog, DNA damage repair, Wnt and MAPK signaling. Hierarchical clustering 28 PCNSL samples (25 ABC and 3 GCB subtypes) identified two transcriptional subgroups, P1 (n=9) and P2 (n=19). P2 showed higher activities across most of the cancer related pathways and had a significantly shorter patient survival time (p<0.01). Whole exome sequencing showed that some distinct genetic features of PCNSL compared to DLBCL. The genetic subtypes (“LymphGen”) of PCNSL consisted mainly of “MCD” and “Other” subtypes, which did not correlate with clinical survival. These data provide more information about unique characters of PCNSL, which may help to identify novel drug targets for developing therapeutic strategies.
Open-source 3D Printable Forearm Crutch
Authors: Mottaghi Maryam , Woods Morgan , Danier Laura , So Anita , Reeves Jacob M. , Pearce Joshua M.
Published: November 2024

Although there has been considerable progress in distributed manufacturing of open-source designs for mobility aids, there is a notable lack of affordable, open-source crutches. Crutches are a vital tool for many individuals with mobility impairments, yet the high costs limit accessibility. Even more, they are in short supply in regions undergoing conflict. The goal of this study is to address this need by leveraging the principles of free and open-source hardware and the capabilities of digital distributed manufacturing to create a low-cost, functional crutch that can be easily produced and customized locally using inexpensive desktop 3D printers. All the design files are open-source, and the design process incorporated load-bearing tests using a hydraulic actuator under static loading conditions to meet the ISO 11334-1:2007 standard for walking aids. The open-source forearm crutch developed in this study not only surpasses the requirements of the ISO method for load capacity (1,516.3 ± 169.9 N, which is 51.6% percent above needs), weighs a fraction of comparable commercial systems (0.612 kg or 27%% of proprietary devices), and is customizable, but also offers a highly cost-effective solution; costing CAD $36 in material, which is less than all equivalent crutches on the open market. If recycled plastic is used, the material cost of the crutch could be further reduced to under CAD $13, making it much more accessible.
Unveiling novel conserved HIV-1 open reading frames encoding T cell antigens using ribosome profiling
Authors: Bertrand Lisa , Nelde Annika , Ramirez Bertha Cecilia , Hatin Isabelle , Arbes Hugo , François Pauline , Demais Stephane , Labaronne Emmanuel , Decimo Didier , Guiguettaz Laura , Grégoire Sylvie , Bet Anne , Beauclair Guillaume , Gross Antoine , Ziegler Maja C. , Pereira Mathias , Jeger-Madiot Raphaël , Verdier Yann , Vinh Joelle , Cardinaud Sylvain , Graff-Dubois Stéphanie , Esclatine Audrey , Gouttefangeas Cécile , Altfeld Marcus , Hocqueloux Laurent , Samri Assia , Autran Brigitte , Lambotte Olivier , Rammensee Hans-Georg , Ricci Emiliano P. , Walz Juliane , Namy Olivier , Moris Arnaud
Published: November 2024

The development of ribosomal profiling (Riboseq) revealed the immense coding capacity of human and viral genomes. Here, we used Riboseq to delineate the first translatome of HIV-1 in infected CD4+T cells. In addition to canonical viral protein coding sequences (CDSs), we identify 98 alternative open reading frames (ARFs), corresponding to small Open Reading Frames (sORFs) that are distributed across the HIV genome including the UTR regions. Using a database of HIV genomes, we observed that most ARF amino-acid sequences are likely conserved among clade B and C of HIV-1, with 8 ARF-encoded amino-acid sequences being more conserved than the overlapping CDSs. Using T cell-based assays and mass spectrometry-based immunopeptidomics, we demonstrate that ARFs encode viral polypeptides. In the blood of HIV-infected individuals, ARF-derived peptides elicit potent poly-functional T cell responses mediated by both CD4+and CD8+T cells. Our discovery expands the list of conserved viral polypeptides that are targets for vaccination strategies and might reveal the existence of viral microproteins or pseudogenes.
Covalent adducts formed by the androgen receptor transactivation domain and small molecule drugs remain disordered
Authors: Zhu Jiaqi , Robustelli Paul J.
Published: November 2024

Intrinsically disordered proteins are implicated in many human diseases. Small molecules that target the disordered androgen receptor transactivation domain have entered human trials for the treatment of castration-resistant prostate cancer. These molecules have been shown to react with cysteine residues of the androgen receptor transactivation domain and form covalent adducts under physiological conditions. It is currently unclear how covalent attachment of these molecules alters the conformational ensemble of the androgen receptor. Here, we utilize all-atom molecular dynamics computer simulations to simulate covalent adducts of the small molecule ligands EPI-002 and EPI-7170 bound to the disordered androgen receptor transactivation domain. Our simulations reveal that the conformational ensembles of androgen receptor transactivation domain covalent adducts are heterogeneous and disordered. We find that covalent attachment of EPI-002 and EPI-7170 increases the population of collapsed helical transactivation domain conformations relative to the populations observed in non-covalent binding simulations and we identify networks of protein-ligand interactions that stabilize collapsed conformations in covalent adduct ensembles. We compare the populations of protein-ligand interactions observed in covalent adduct ensembles to those observed in non-covalent ligand-bound ensembles and find substantial differences. Our results provide atomically detailed descriptions of covalent adducts formed by small molecules and an intrinsically disordered protein and suggest strategies for developing more potent covalent inhibitors of intrinsically disordered proteins.
Butyrophilin 2A2 promotes T cell immunoregulation by enhancing CD45 phosphatase activity within the immune synapse
Authors: Ali Shafat , Berg Anders H. , Yamashita Michifumi , Covarrubias Ambart E. , Zhang Ruan , Dupont Vincent , Shin Bong-Ha , Yang Shen , Murali Ramachandran , Katiki Madhusudhanarao , Pisarska Margareta D. , Thadhani Ravi , Heeger Peter S. , Jordan Stanley C. , Karumanchi S. Ananth
Published: November 2024

B7 costimulatory family member Butyrophilin 2A2(BTN2A2) is predominantly expressed by antigen presenting cells and regulates T cell immunity, but molecular mechanisms are unclear. Using immunoblots analyzing TCR-initiated signaling intermediaries, co-immunoprecipitation studies, confocal microscopy, structural modeling-guided mutational analyses, and microscale thermophoresis, we demonstrate that BTN2A2 directly interacts with CD45RO, resulting in CD45 retention within the immune synapse during TCR activation. Recombinant BTN2A2 increased murine CD4+Foxp3+ regulatory T cells (Treg) and reduced T helper 17 (Th17) cells in vitro through mechanisms dependent on CD45 phosphatase activity. BTN2A2 treatment reduced clinical expression of two murine autoimmune disease models and increased Treg/Th17 ratios. Analyses of BTN2A2-deficient animals showed exacerbated disease associated with reduced Treg/Th17 ratios. Addition of BTN2A2 to human mixed lymphocyte responses similarly enhanced human Treg and suppressed Th17 cells and was CD45 phosphatase dependent. Together, our studies identify BTN2A2 as a physiological CD45RO ligand that enhances CD45 phosphatase activity in murine and human T cells, providing mechanisms for BTN2A2-mediated amelioration of autoimmunity.

Butyrophilin 2A2 ameliorates autoimmunity by binding to CD45RO on activated T cell surfaces leading to dampened TCR signaling which in turn leads to expansion of T regulatory cells and reduction of Th17 differentiation.
Antiviral defense in agedCaenorhabditis elegansdeclines due to loss of DRH-1/RIG-I deSUMOylation via ULP-4/SENP7
Authors: Zhang Yun , Samuelson Andrew V.
Published: November 2024

Innate host defense mechanisms require posttranslational modifications (PTM) to protect against viral infection. Age-associated immunosenescence results in increased pathogenesis and mortality in the elderly, but the contribution of altered PTM regulation to immunosenescence is unknown. SUMOylation is a rapid and reversible post-translational modification that has been implicated in age-associated disease and plays conflicting roles in viral replication and antiviral defenses in mammals. We have discovered inCaenorhabditis elegansthat induction of antiviral defense is regulated through SUMOylation of DRH-1, the ortholog of the DEAD/H-box helicase and cytosolic pattern recognition receptor RIG-I, and that this regulation breaks down during aging. We find the SUMO isopeptidase ULP-4 is essential for deSUMOylation of DRH-1 and activation of the intracellular pathogen response (IPR) after exposure to Orsay virus (OV), a natural entericC. eleganspathogen. ULP-4 promotes stabilization of DRH-1, which translocates to the mitochondria to activate the IPR in young animals exposed to virus. Loss of eitherdrh-1orulp-4compromises antiviral defense resulting in a failure to clear the virus and signs of intestinal pathogenesis. During aging, expression ofulp-4decreases, which results in increased proteosomal degradation of DRH-1 and loss of the IPR. Mutating the DRH-1 SUMOylated lysines resulted in the constitutive activation of the IPR in young animals and partially rescued the age-associated lost inducibility of the IPR. Our work establishes that aging results in dysregulated SUMOylation and loss of DRH-1, which compromises antiviral defense and creates a physiological shift to favor chronic pathological infection in older animals.
INCIDENCE AND FACTORS ASSOCIATED WITH LATE SPUTUM CULTURE CONVERSION AMONG MULTI- DRUG-RESISTANT TUBERCULOSIS PATIENTS ON TREATMENT IN NATIONAL REFERAL HOSPITAL UGANDA
Authors: Adolphus Cherop , Lydia Nakiyingi , Kalyango Joan , Katamba Achiles , Mupere Ezekiel , Emmanuel Ssendikwanawa , Bayowa Joan Rokani , Norman Cwinyaai , Ssemasaazi Amutuhaire Judith , Tom Okello , Lynn Bagoloire Kolosi , Kinya Asilaza Vincent , William Worodria
Published: November 2024

Background

Tuberculosis (TB) remains one of the most common causes of death from an infectious disease. Late sputum culture conversion among Multi-Drug-Resistant Tuberculosis (MDR-TB) patients poses a risk for poor treatment outcomes. The study aimed to determine the incidence and factors associated with late sputum culture conversion among MDR-TB patients on treatment at the tuberculosis (TB) unit of Mulago National Referral Hospital.

Methods

A retrospective cohort study of 255 MDR-TB patient records between January 1st2012 to December 31st2018 were reviewed. Consecutive sampling was employed. Demographic characteristics, clinical factors and social factors were studied. STATA version 15 was used for analysis. Incidence was calculated as the ratio of MDR -TB patients with late sputum culture conversion result to the total number of participants studied. Factors associated were evaluated using generalized linear model (GLM) with Poisson family and log link using robust standard errors to adjust for over inflated variances.

Results

The incidence of late sputum culture conversion was 32% (95% CI 26.3-37.8). increasing age in years (incidence rate ratio IRR 1.004, 95%CI 1.000 1.008, P value 0.044), increasing weight (IRR 0.995, 95% CI 0.991-0.999, P value 0.020) and 9-12 months multi drug tuberculosis MDR-TB regimen (IRR 0.893, 95% CI 0.805-0.989, P value 0.030) were factors associated with late sputum culture conversion.

Conclusions

The incidence of late sputum culture conversion among MDR-TB patients on treatment was high (32%), occurring in about three out of every ten patients. Increasing weight, increasing age and 9-12 months MDR-TB drug regimen were significantly associated. Isolation of patients for a minimum of two months to minimize community transmission, starting eligible patients on the 9-12months MDR-TB regimen and categorization of patients into high-risk groups (elderly and underweight) with special targeted packages.
Rare predicted loss-of-function and damaging missense variants inCFHR5associate with protection from age-related macular degeneration
Authors: Holleman Aaron M. , Deaton Aimee M. , Hoffing Rachel A. , Krohn Lynne , LoGerfo Philip , Nioi Paul , Plekan Mollie E. , Akle Serrano Sebastian , Ticau Simina , Walshe Tony E. , Borodovsky Anna , Ward Lucas D.
Published: November 2024

Age-related macular degeneration (AMD) is a leading cause of blindness among older adults worldwide, but treatment options are limited. Prior genetics studies have implicated theCFHlocus, which containsCFHand the fiveCFHR1-5genes, in AMD. While theCFHgene has been robustly linked with AMD risk, the potential additional role of the fiveCFHRgenes remains unclear, with strong linkage disequilibrium across the locus hindering the identification of individual gene contributions. Investigation of rare coding variants can help to identify causal genes in such regions. We used whole exome sequencing data from 406,952 UK Biobank participants to examine AMD associations with genes at theCFHlocus. For each gene, we used burden testing to examine the association of rare (MAF<1%) predicted loss-of-function (pLOF) and predicted-damaging missense variants with AMD. When adjusting forCFH-region variants previously established to independently associate with AMD, we find thatCFHR5rare variant burden significantly associates with decreased risk of AMD (OR=0.75, p=7×10−4), and that this association is primarily driven by pLOF variants. Furthermore, the association ofCFHR5rare variants with AMD protection is estimated as stronger for individuals carrying theCFHY402H variant, which increases AMD risk (interaction p=0.04). We also identify increased thinning of the outer segment of the photoreceptor layer of the retina to be a strong predictor of AMD and find thatCFHR5rare variant burden significantly associates with increased thickness of this retinal layer (+0.34 SD, p=4×10−4). These findings suggestCFHR5inhibition as a potential therapeutic approach for AMD.
Challenges Hindering the Translation of Plant Anticonvulsants from Bench to Bedside: A Scoping Review
Authors: Opoku Joana , Amoateng Patrick , Kukuia Kennedy Kwami Edem , Ankamah Samuel , Oppong Bekoe Emelia , Adjei Samuel , Osei-Safo Dorcas , Kombian Samuel Binamin
Published: November 2024

Aim

To identify the challenges that hinder the successful translation of anticonvulsants from plant origins, from preclinical research to clinical application.

Design

This review was conducted using the Joanna Briggs Institute (JBI) guidance for a scoping review.

Data Sources

The following bibliographic databases were searched between November 11th and 20th, 2023: PubMed, Scopus, Google Scholar and ClinicalTrials.gov. The search in Google Scholar was done via a third-party application called Harzing’s Publish or Perish, where the search results limit was set at 1000 relevant articles. After full-text review, the reference lists of the included articles were examined to identify additional sources.

Review Methods

The Population, Intervention, Comparison, Outcome, Time, Setting (PICOTS) framework was employed in developing the eligibility criteria. The articles were uploaded to Rayyan.ai for title and abstract screening, as well as full-text article review. Data was extracted and synthesised from included studies using a table.

Results

Thirty-seven articles met the eligibility criteria. From these articles, six distinct categories of challenges were identified: (1) methodologic issues; (2) insufficient evidence to support the use of herbal drugs in clinical settings; (3) financial disincentives; (4) challenges in obtaining natural products or its active principles; (5) poor pharmacokinetics; clinical trials and regulatory challenges.

Conclusion

Understanding and effectively addressing these challenges will ensure that more plant-based anticonvulsants are successfully translated into clinical practice, thereby enhancing the treatment of epilepsy. This review also made recommendations to tackle some of these challenges that plant anticonvulsants face in the drug development process.
Minus the Error: EstimatingdN/dSand Testing for Natural Selection in the Presence of Residual Alignment Errors
Authors: Selberg Avery G , Chikina Maria , Sackton Tim , Muse Spencer V , Lucaci Alexander G , Weaver Steven , Nekrutenko Anton , Clark Nathan , Pond Sergei L Kosakovsky
Published: November 2024

Errors in multiple sequence alignments (MSAs) are known to bias many comparative evolutionary methods. In the context of natural selection analyses, specifically codon evolutionary models, excessive rates of false positives result. A characteristic signature of error-driven findings is unrealistically high estimates of dN/dS (e.g., >100), affecting only a small fraction (e.g., ∼0.1%) of the alignment. Despite the widespread use of codon models to assess alignment quality, their potential for error correction remains unexplored. We present BUSTED-E: a novel method designed to detect positive selection while concurrently identifying alignment errors. This method is a straightforward adaptation of the BUSTED flexible branch-site random effects model used to fit distributions of dN/dS, with an important modification: it integrates an “error-sink” component representing an abiological evolutionary regime (dN/dS > 100), and provides the option for masking errors in the MSA for downstream analyses. Statistical performance of BUSTED-E on data simulated without errors shows that there is a small loss of power, which can be mitigated by model averaged inference. Using four published empirical datasets, we show BUSTED-E reduces unrealistic rates of positive selection detection, often by an order of magnitude, and improves biological interpretability of results. BUSTED-E also detects errors that are largely distinct from other popular alignment cleaning tools (HMMCleaner and BMGE). Overall, BUSTED-E is a robust and scalable solution for improving the accuracy of evolutionary analyses in the presence of residual alignment errors, contributing to a more nuanced understanding of natural selection and adaptive evolution.