Miracle-dz/UniFAR-FTUs huggingface dataset:
Mechanistic insights into central spindle assembly mediated by the centralspindlin complex

Significance Centralspindlin bundles microtubules to assemble the central spindle, being essential for cytokinesis of the cell. It is a heterotetramer formed by ZEN-4 and CYK-4 in a 2:2 manner. We determined the crystal structures of centralspindlin, which revealed the detailed mechanism of complex formation. We found that centralspindlin clustered to undergo liquid–liquid phase separation (LLPS), which depended on the complementary charged residues located at ZEN-4 and CYK-4, respectively, explaining the synergy of the two subunits for the function. The LLPS of centralspindlin is critical for the microtubule bundling activity in vitro and the assembly of the central spindle in vivo. Together, our study provides angstrom-to-micron mechanistic insights into central spindle assembly mediated by the centralspindlin complex. The central spindle spatially and temporally regulates the formation of division plane during cytokinesis in animal cells. The heterotetrameric centralspindlin complex bundles microtubules to assemble the central spindle, the mechanism of which is poorly understood. Here, we determined the crystal structures of the molecular backbone of ZEN-4/CYK-4 centralspindlin from Caenorhabditis elegans, which revealed the detailed mechanism of complex formation. The molecular backbone of centralspindlin has the intrinsic propensity to undergo liquid–liquid phase separation. The condensation of centralspindlin requires two patches of basic residues at ZEN-4 and multiple acidic residues at the intrinsically disordered region of CYK-4, explaining the synergy of the two subunits for the function. These complementary charged residues were critical for the microtubule bundling activity of centralspindlin in vitro and for the assembly of the central spindle in vivo. Together, our findings provide insights into the mechanism of central spindle assembly mediated by centralspindlin through charge-driven macromolecular condensation.
Electrosynthesis of novel polyheterocycles

The electropolymerisation of a wide-range of derivatised (E)-styrylthiophenes, pyrroles and furans has been investigated. Stable coherent films of low conductivity (cr: 1Q-6 S cm-1), which were characterised by a number of electrochemical, spectroscopic and microscopic techniques, were formed. The polymers were redox inactive as shown by cyclic voltammetry. This was possibly due to oxidation of the alkene spacer linkage resulting in formation of a crosslinked polymeric matrix in which the conjugation of the backbone had been disrupted. To protect the double bond from electro-oxidation, without causing a disruption in planarity, an electron withdrawing nitrile group was introduced at the alkene spacer linkage. Electropolymerisation of (Z)-a,B-diarylacrylonitriles containing one heterocyclic species produced thick adherent films, but in the majority of cases, the nitrile substituent was unable to suppress oxidation of the double bond and crosslinked redox inactive films of low conductivity (cr: 10-6 S cm-1) were produced. In contrast, electropolymerisation of (Z)-a,�-diarylacrylonitriles containing two heterocycles produced highly doped redox active polymers of enhanced conductivity ( cr: 104 S cm-1). Dendritic structures, thought to be the result of unidirectional polymer growth via a,a'-linkages, were observed in some cases. Density functional theory (DFT) was used to predict the outcome of electropolymerisation reactions by calculating the n-spin density distribution of monomeric radical cations in order to determine coupling positions in resultant polymers. High positive 1t-spin densities were found at the alkene spacer linkage of (E)-styrylheterocycles, suggesting crosslinking reactions via the double bond during electropolymerisation, in agreement with experimental observations. In contrast, DFT calculations of some (Z)-a,B-2-diarylacrylonitriles containing two heterocycles showed high n-spin density located at the heterocyclic a-positions, a prerequisite for the formation of a,a'-linkages necessary for electroactivity. The electropolymerisation of some sterically hindered five member heterocycles (2,5dimethylthiophene and 1, 1', 1 " , 1 "'-silanetetrayltetrakis-J H-pyrrole) illustrated the importance of a, a-linkages and extended conjugation in polymer conduction. Final studies addressed the use of polymers for enzyme immobilisation. STM investigations of enzymes such as the 51 kD/66 kD heterodimer and 66 kD/66 kD homodimer of the HIV -1 reverse transcriptase and RNNDNA hybrids, which may be used in the immobilisation studies, on an n-MoTe2 substrate were carried out. AFM studies of poly((E)-2-styrylpyrrole), an extremely smooth polymer, revealed a micro­ corrugated topology with features of heights ranging from 2-5 nm and widths of approx. 80 nm.
Influence of the implementation of a multidisciplinary consultation program on adherence to the first ever course of oral antineoplastic treatment in patients with cancer

Purpose To evaluate adherence (as measured by the medication possession ratio) to the first ever course of oral antineoplasic treatment in cancer patients before and after the implementation of a multidisciplinary consultation program (involving an oncologist, a pharmacist, and a nurse) and to investigate the program's impact on adverse events and drug-related problems. Patients and Methods In a retrospective single-center study, we compared the medication possession ratio 2 months after treatment initiation in a control group (before multidisciplinary consultation program implementation) versus an interventional group (after multidisciplinary consultation program implementation). Results Two months after oral antineoplasic treatment initiation, the mean ± standard deviation medication possession ratio did not differ significantly when comparing the interventional (multidisciplinary consultation program) group (n = 33; 0.99 ± 0.06) with the control group (n = 64; 0.94 ± 0.16) (p = 0.062). Patients in the multidisciplinary consultation program group had fewer adverse events in general (41, vs 109 in the control group; p = 0.048) and digestive adverse events in particular (6 vs 29, respectively; p = 0.007). A total of 53 and 40 drug-related problems were identified in the control and multidisciplinary consultation program groups, respectively (p = 0.074). Conclusions Implementation of an multidisciplinary consultation program was not associated with a significant difference in drug adherence (as assessed by the medication possession ratio), which was good before and after implementation. The multidisciplinary consultation program was associated with a lower incidence of adverse events.
Conquering the Host: Determinants of Pathogenesis Learned from Murine Gammaherpesvirus 68

Gammaherpesviruses are an important class of oncogenic pathogens that are exquisitely evolved to their respective hosts. As such, the human gammaherpesviruses Epstein-Barr virus (EBV) and Kaposi sarcoma herpesvirus (KSHV) do not naturally infect nonhuman primates or rodents. There is a clear need to fully explore mechanisms of gammaherpesvirus pathogenesis, host control, and immune evasion in the host. A gammaherpesvirus pathogen isolated from murid rodents was first reported in 1980; 40 years later, murine gammaherpesvirus 68 (MHV68, MuHV-4, γHV68) infection of laboratory mice is a well-established pathogenesis system recognized for its utility in applying state-of-the-art approaches to investigate virus-host interactions ranging from the whole host to the individual cell. Here, we highlight recent advancements in our understanding of the processes by which MHV68 colonizes the host and drives disease. Lessons that inform KSHV and EBV pathogenesis and provide future avenues for novel interventions against infection and virus-associated cancers are emphasized.
Nutritional Risk in Early Childhood and School Readiness.

BACKGROUND Nutrition in early childhood is important for healthy growth and development. Achieving school readiness is considered one of the most important developmental milestones for young children. OBJECTIVES The purpose of this study is to determine if nutritional risk in early childhood is associated with school readiness in kindergarten. METHODS A prospective cohort study was conducted through The Applied Research Group for Kids (TARGet Kids! ) primary care research network in Toronto, Canada, 2015-2020. Nutritional risk was measured (18 mo to 5 y) using validated parent-completed questionnaires called Nutrition Screening for Toddlers and Preschoolers (NutriSTEP). High nutritional risk was categorized as scores ≥21. School readiness was measured using the validated teacher-completed Early Developmental Instrument (EDI), which measures 5 developmental domains in kindergarten (2 y of schooling, ages 4-6 y, before they enter grade 1). Vulnerability indicates scores lower than a population-based cutoff at the 10th percentile on at least 1 domain. Multiple logistic and linear regression models were conducted adjusting for relevant confounders. RESULTS The study included 896 children: 53% were male, 9% had high nutritional risk, and 17% were vulnerable on the EDI. A 1-SD increase in NutriSTEP total score was associated with 1.54 times increased odds of being vulnerable on the EDI among children in year 2 of kindergarten (P = 0.001). High nutritional risk cutoff was associated with 4.28 times increased odds of being vulnerable on the EDI among children in year 2 of kindergarten (P < 0.001). NutriSTEP total score and high nutritional risk were associated with lower scores on all 5 EDI domains, with the strongest association observed for the domains of language and cognitive development and communication skills and general knowledge. CONCLUSIONS Higher nutritional risk in early childhood is associated with lower school readiness in year 2 of kindergarten. Nutritional interventions early in life may offer opportunities to enhance school readiness. This trial was registered www.clinicaltrials. gov as NCT01869530.
Telemedicine in paediatric emergency care: A systematic review

Introduction The impact of telemedicine on the access and quality of paediatric emergency care remains largely unexplored because most studies to date are focused on adult emergency care. We performed a systematic review of the literature to determine if telemedicine is effective in improving quality of paediatric emergency care with regards to access, process measures of care, appropriate disposition, patient-centred outcomes and cost-related outcomes. Methods We developed a systematic review protocol in accordance with PRISMA (Preferred Reporting Items for Systematic Review) guidelines. We included studies that evaluated the impact of synchronous and asynchronous forms of telemedicine on patient outcomes and process measures in the paediatric emergency care setting. Inclusion criteria were study setting, study design, intervention type, age, outcome measures, publication year and language. Results Overall, 1.9% (28/1434) studies met study inclusion and exclusion criteria. These studies revealed that telemedicine increased accuracy of patient assessment in the pre-clinical setting, improved time-to disposition, guided referring emergency department (ED) physicians in performing appropriate life-saving procedures and led to cost savings when compared to regular care. Studies focused on telepsychiatry demonstrated decreased length of stay (LOS), transfer rates and improved patient satisfaction scores. Discussion Our comprehensive review revealed that telemedicine enhances paediatric emergency care, enhances therapeutic decision-making and improves diagnostic accuracy, and reduces costs. Specifically, telemedicine has its most significant impact on LOS, access to specialized care, cost savings and patient satisfaction. However, there was a relative lack of randomized control trials, and more studies are needed to substantiate its impact on morbidity and mortality.
Identity and Liberalism in Public Health: A Response to the Open Peer Commentaries

I would like to thank all who have taken the time to read and comment on my target article in which I compare state neutrality and perfectionism as approaches to justify public health policy and argue that perfectionism is the most promising approach (Ismaili M’hamdi 2021). The article has yielded seven commentaries. It is impossible for me to do justice to the commentators within the limits of this response. Given that criterion (d) of the liberal proviso, the role of identity and my description of state neutrality and liberalism elicited the most attention and critique I will focus on these topics.
Intake of Calcium, Magnesium, and Phosphorus and Risk of Pancreatic Cancer in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial.

ObjectiveFew epidemiological studies have investigated the associations between calcium, magnesium, and phosphorus intake and pancreatic cancer. We examined these associations in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial.MethodsDiet was assessed using the Dietary Questionnaire (DQX) at baseline in the intervention arm and the Dietary History Questionnaire (DHQ) in 1999 or around the third anniversary of randomization in both the intervention and control arms. During a median follow-up of 12.2 years, 279 cases of pancreatic cancer occurred from 58,477 participants who completed DQX; 380 cases arose from 101,622 participants who responded to DHQ over a median follow-up of 8.9 years. Cox proportional hazards regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI). ResultsTotal calcium intake was inversely associated with pancreatic cancer [HR (95% CI) for the fourth vs. the first quartiles in the DHQ cohort: 0.67 (0.47, 0.96); p-trend: 0.035]. An inverse association was also observed for total magnesium intake [HR (95% CI) for the fourth vs. the first quartiles in the DQX cohort: 0.61 (0.37, 1.00); p-trend: 0.023]. Reduced risk associated with total calcium intake was confined to subjects with a high fat intake (>73 g/day) in the DHQ cohort (p-interaction: 0.16). ConclusionsThere was not a significant association between dietary phosphorus intake and pancreatic cancer risk in both cohorts. Total intake of calcium and magnesium are associated with a lower pancreatic cancer risk. The effect of total calcium intake was modified by fat intake.
Association between systemic sclerosis and peripheral arterial disease: a nationwide observation retrospective claim records cohort study in Taiwan

Objectives Recent studies have proposed associations between systemic sclerosis (SSc) and atherosclerosis and between SSc and cardiovascular disease. However, in Asia, no large-scale studies have focused on the association between peripheral arterial disease (PAD) and SSc. Setting A nationwide observation retrospective cohort study. Participants The National Health Insurance Research Database was used for selecting patients diagnosed with SSc from 2000 to 2011. Patients diagnosed with PAD before the index date were excluded. Primary and secondary outcome measures The SSc cohort comprised 1106 patients with SSc, and the non-SSc cohort comprised 4424 matched controls. The Cox proportional hazards regression model was used for analysing the adjusted risk of PAD between the case and control patients. Results The SSc cohort exhibited a significantly higher risk (HR=2.15, 95% CI=1.47 to 3.14) of PAD than did the non-SSc cohort. Patients with heart failure exhibited the highest risk of PAD (adjusted HR=2.10, 95% CI=1.20 to 3.70). Moreover, even without any comorbidities, the SSc cohort exhibited a significantly higher risk (adjusted HR=4.17 fold, 95% CI=1.98 to 8.77) of PAD than did the non-SSc cohort. Conclusion SSc is associated with a significantly high risk of PAD. Further studies are required to reduce the PAD risk among patients with SSc.
No evidence for modulation of facial mimicry by attachment tendencies in adulthood: an EMG investigation

ABSTRACT Mimicking another individual functions as a social glue: it smoothens the interaction and fosters affiliation. Here, we investigated whether the intrinsic motivation to affiliate with others, stemming from attachment relationships, modulates individuals’ engagement in facial mimicry (FM). Participants (N = 100; MAge = 24.54 years, SDAge = 3.90 years) observed faces with happy, sad, and neutral expressions, while their facial muscle activity was recorded with electromyography. Attachment was measured with the Attachment Styles Questionnaire, which provides a multidimensional profile for preoccupied and dismissing styles. It was proposed that the preoccupied and dismissing styles are characterized by high and low intrinsic affiliation motivation, respectively, and these were hypothesized to manifest in enhanced and diminished FM. Participants showed happy and sad FM, yet attachment styles did not significantly predict FM. Bayes Factor analyses lend evidence favoring the null hypothesis, suggesting that adult attachment do not contribute to FM.
Dynamic sumoylation of promoter-bound general transcription factors facilitates transcription by RNA polymerase II

Transcription-related proteins are frequently identified as targets of sumoylation, including multiple subunits of the RNA polymerase II (RNAPII) general transcription factors (GTFs). However, it is not known how sumoylation affects GTFs or whether they are sumoylated when they assemble at promoters to facilitate RNAPII recruitment and transcription initiation. To explore how sumoylation can regulate transcription genome-wide, we performed SUMO ChIP-seq in yeast and found, in agreement with others, that most chromatin-associated sumoylated proteins are detected at genes encoding tRNAs and ribosomal proteins (RPGs). However, we also detected 147 robust SUMO peaks at promoters of non-ribosomal protein-coding genes (non-RPGs), indicating that sumoylation also regulates this gene class. Importantly, SUMO peaks at non-RPGs align specifically with binding sites of GTFs, but not other promoter-associated proteins, indicating that it is GTFs specifically that are sumoylated there. Predominantly, non-RPGs with SUMO peaks are among the most highly transcribed, have high levels of TFIIF, and show reduced RNAPII levels when cellular sumoylation is impaired, linking sumoylation with elevated transcription. However, detection of promoter-associated SUMO by ChIP might be limited to sites with high levels of substrate GTFs, and promoter-associated sumoylation at non-RPGs may actually be far more widespread than we detected. Among GTFs, we found that TFIIF is a major target of sumoylation, specifically at lysines 60/61 of its Tfg1 subunit, and elevating Tfg1 sumoylation resulted in decreased interaction of TFIIF with RNAPII. Interestingly, both reducing promoter-associated sumoylation, in a sumoylation-deficient Tfg1-K60/61R mutant strain, and elevating promoter-associated SUMO levels, by constitutively tethering SUMO to Tfg1, resulted in reduced RNAPII occupancy at non-RPGs. This implies that dynamic GTF sumoylation at non-RPG promoters, not simply the presence or absence of SUMO, is important for maintaining elevated transcription. Together, our findings reveal a novel mechanism of regulating the basal transcription machinery through sumoylation of promoter-bound GTFs.
Single-cell analysis of prostaglandin E2-induced human decidual cell in vitro differentiation: a minimal ancestral deciduogenic signal

Abstract The decidua is a hallmark of reproduction in many placental mammals. Differentiation of decidual stromal cells is known to be induced by progesterone and the cyclic AMP/protein kinase A (cAMP/PKA) pathway. Several candidates have been identified as the physiological stimulus for adenylyl cyclase activation, but their relative importance remains unclear. To bypass this uncertainty, the standard approach for in vitro experiments uses membrane-permeable cAMP and progestin. We phylogenetically infer that prostaglandin E2 (PGE2) likely was the signal that ancestrally induced decidualization in conjunction with progesterone. This suggests that PGE2 and progestin should be able to activate the core gene regulatory network of decidual cells. To test this prediction, we performed a genome-wide study of gene expression in human endometrial fibroblasts decidualized with PGE2 and progestin. Comparison to a cAMP-based protocol revealed shared activation of core decidual genes and decreased induction of senescence-associated genes. Single-cell transcriptomics of PGE2-mediated decidualization revealed a distinct, early-activated state transitioning to a differentiated decidual state. PGE2-mediated decidualization was found to depend upon progestin-dependent induction of PGE2 receptor 2 (PTGER2) which in turn leads to PKA activation upon PGE2 stimulation. Progesterone-dependent induction of PTGER2 is absent in opossum, an outgroup taxon of placental mammals which is incapable of decidualization. Together, these findings suggest that the origin of decidualization involved the evolution of progesterone-dependent activation of the PGE2/PTGER2/PKA axis, facilitating entry into a PKA-dominant rather than AKT-dominant cellular state. We propose the use of PGE2 for in vitro decidualization as an alternative to 8-Br-cAMP. Summary sentence In vitro decidualization of human endometrial stromal fibroblasts with PGE2 and progestin induces a different but genuine decidual cell state through PTGER2-dependent PKA activation when compared to the conventional cyclic AMP/MPA protocol. Graphical Abstract
Who has a beef with reducing red and processed meat consumption? A media framing analysis

Abstract Objective: Diets high in red and processed meat (RPM) contribute substantially to environmental degradation, greenhouse gas emissions and the global burden of chronic disease. High-profile reports have called for significant global RPM reduction, especially in high-income settings. Despite this, policy attention and political priority for the issue are low. Design: The study used a theoretically guided framing analysis to identify frames used by various interest groups in relation to reducing RPM in online news media articles published in the months around the release of four high-profile reports by authoritative organisations that included a focus on the impacts of high RPM production and/or consumption. Setting: Four major RPM producing and consuming countries – USA, United Kingdom, Australia and New Zealand. Participants: None. Results: Hundred and fifty news media articles were included. Articles reported the views of academics, policymakers, industry representatives and the article authors themselves. RPM reduction was remarkably polarising. Industry frequently framed RPM reduction as part of a ‘Vegan Agenda’ or as advocated by an elite minority. Reducing RPM was also depicted as an infringement on personal choice and traditional values. Many interest groups attempted to discredit the reports by citing a lack of consensus on the evidence, or that only certain forms of farming and processing were harmful. Academics and nutrition experts were more likely to be cited in articles that were aligned with the findings of the reports. Conclusions: The polarisation of RPM reduction has led to a binary conflict between pro- and anti-meat reduction actors. This division may diminish the extent to which political leaders will prioritise this in policy agendas. Using nuanced and context-dependent messaging could ensure the narratives around meat are less conflicting and more effective in addressing health and environmental harms associated with RPM.