Miracle-dz/UniFAR-FTUs huggingface dataset:
Accelerated reproduction is not an adaptive response to early-life adversity in wild baboons

Significance If an individual can anticipate an early death, should they also “live fast”? Fast reproduction is often proposed to be an adaptive response to harsh conditions in early life because early adversity predicts shorter lifespans. Individuals who speed up reproduction after experiencing early adversity might therefore have higher fitness than those who do not. Here, we use extensive data on wild female baboons to test if fast reproduction offers fitness advantages to females who experience nutritional and psychosocial sources of early adversity. Contrary to several influential hypotheses, females who experienced early adversity did not improve their fitness if they sped up reproduction. Our results raise doubts that accelerated reproduction is an adaptive response to early adversity in long-lived, slow-reproducing species. In humans and other long-lived species, harsh conditions in early life often lead to profound differences in adult life expectancy. In response, natural selection is expected to accelerate the timing and pace of reproduction in individuals who experience some forms of early-life adversity. However, the adaptive benefits of reproductive acceleration following early adversity remain untested. Here, we test a recent version of this theory, the internal predictive adaptive response (iPAR) model, by assessing whether accelerating reproduction following early-life adversity leads to higher lifetime reproductive success. We do so by leveraging 48 y of continuous, individual-based data from wild female baboons in the Amboseli ecosystem in Kenya, including prospective, longitudinal data on multiple sources of nutritional and psychosocial adversity in early life; reproductive pace; and lifetime reproductive success. We find that while early-life adversity led to dramatically shorter lifespans, individuals who experienced early adversity did not accelerate their reproduction compared with those who did not experience early adversity. Further, while accelerated reproduction predicted increased lifetime reproductive success overall, these benefits were not specific to females who experienced early-life adversity. Instead, females only benefited from reproductive acceleration if they also led long lives. Our results call into question the theory that accelerated reproduction is an adaptive response to both nutritional and psychosocial sources of early-life adversity in baboons and other long-lived species.
Bipedal hopping as a new measure to detect subtle sensorimotor impairment in people with multiple sclerosis

Abstract Background Bipedal hopping has the potential to detect subtle multiple sclerosis (MS)-related impairments, especially among patients who “pass” typical movement tests. In this narrative review, we outline the biomechanics of bipedal hopping and propose its usefulness as a novel outcome measure for people with MS having mild disability. Methods We summarize articles that (1) examined the biomechanics of jumping or hopping and (2) tested the validity and/or reliability of hopping tests. We consolidated consistencies and gaps in research and opportunities for future development of the bipedal hop test. Results Bipedal hopping requires immense power, coordination, balance, and ability to reduce co-contraction; movement components typically affected by MS. These impairments can be measured and differentiated by examining specific variables, such as hop length (power), symmetry (coordination), center of pressure (balance), and coefficient of variability (co-contraction/spasticity). Bipedal hopping challenges these aspects of movement and exposes sensorimotor impairments that may not have been apparent during walking. Conclusions Testing of bipedal hopping on an instrumented walkway may detect and monitor sensorimotor control in people with MS who do not currently present with clinical deficits. Early measurement is imperative for precise rehabilitation prescription to slow disability progression prior to onset of measurable gait impairment. Implications for rehabilitation Jumping and hopping tests detect lower limb and balance impairments in children, athletes, and older adults. Bipedal hop test measures multiple domains: power, coordination, balance, and muscle timing. Bipedal hop test may expose subtle sensorimotor impairments in people with multiple sclerosis. Multiple variables measured can discern type of sensorimotor impairment to direct personalized rehabilitation programs.
The Integrated UPR and ERAD in Oligodendrocytes Maintain Myelin Thickness in Adults by Regulating Myelin Protein Translation

Myelin proteins, which are produced in the endoplasmic reticulum (ER), are essential and necessary for maintaining myelin structure. The integrated unfold protein response (UPR) and ER-associated degradation (ERAD) are the primary ER quality control mechanism. The adaptor protein Sel1L (Suppressor/Enhancer of Lin-12-like) controls the stability of the E3 ubiquitin ligase Hrd1 (hydroxymethylglutaryl reductase degradation protein 1), and is necessary for the ERAD activity of the Sel1L-Hrd1 complex. Myelin proteins, which are produced in the endoplasmic reticulum (ER), are essential and necessary for maintaining myelin structure. The integrated unfold protein response (UPR) and ER-associated degradation (ERAD) are the primary ER quality control mechanism. The adaptor protein Sel1L (Suppressor/Enhancer of Lin-12-like) controls the stability of the E3 ubiquitin ligase Hrd1 (hydroxymethylglutaryl reductase degradation protein 1), and is necessary for the ERAD activity of the Sel1L-Hrd1 complex. Herein, we showed that Sel1L deficiency specifically in oligodendrocytes caused ERAD impairment, the UPR activation, and attenuation of myelin protein biosynthesis; and resulted in late-onset, progressive myelin thinning in the CNS of adult mice (both male and female). The pancreatic ER kinase (PERK) branch of the UPR functions as the master regulator of protein translation in ER-stressed cells. Importantly, PERK inactivation reversed attenuation of myelin protein biosynthesis in oligodendrocytes and restored myelin thickness in the CNS of oligodendrocyte-specific Sel1L-deficient mice (both male and female). Conversely, blockage of proteolipid protein production exacerbated myelin thinning in the CNS of oligodendrocyte-specific Sel1L-deficient mice (both male and female). These findings suggest that impaired ERAD in oligodendrocytes reduces myelin thickness in the adult CNS through suppression of myelin protein translation by activating PERK. SIGNIFICANCE STATEMENT Myelin is an enormous extended plasma membrane of oligodendrocytes that wraps and insulates axons. Myelin structure, including thickness, was thought to be extraordinarily stable in adults. Myelin proteins, which are produced in the endoplasmic reticulum (ER), are essential and necessary for maintaining myelin structure. The integrated unfolded protein response (UPR) and ER-associated degradation (ERAD) are the primary mechanism that maintains ER protein homeostasis. Herein, we explored the role of the integrated UPR and ERAD in oligodendrocytes in regulating myelin protein production and maintaining myelin structure using mouse models. The results presented in this study imply that the integrated UPR and ERAD in oligodendrocytes maintain myelin thickness in adults by regulating myelin protein production.
Influence of Bile Composition on Membrane Incorporation of Transient Permeability Enhancers

Transient permeability enhancers (PEs), such as caprylate, caprate, and salcaprozate sodium (SNAC), improve the bioavailability of poorly permeable macromolecular drugs. However, the effects are variable across individuals and classes of macromolecular drugs and biologics. Here, we examined the influence of bile compositions on the ability of membrane incorporation of three transient PEs—caprylate, caprate, and SNAC—using coarse-grained molecular dynamics (CG-MD). The availability of free PE monomers, which are important near the absorption site, to become incorporated into the membrane was higher in fasted-state fluids than that in fed-state fluids. The simulations also showed that transmembrane perturbation, i.e., insertion of PEs into the membrane, is a key mechanism by which caprylate and caprate increase permeability. In contrast, SNAC was mainly adsorbed onto the membrane surface, indicating a different mode of action. Membrane incorporation of caprylate and caprate was also influenced by bile composition, with more incorporation into fasted- than fed-state fluids. The simulations of transient PE interaction with membranes were further evaluated using two experimental techniques: the quartz crystal microbalance with dissipation technique and total internal reflection fluorescence microscopy. The experimental results were in good agreement with the computational simulations. Finally, the kinetics of membrane insertion was studied with CG-MD. Variation in micelle composition affected the insertion rates of caprate monomer insertion and expulsion from the micelle surface. In conclusion, this study suggests that the bile composition and the luminal composition of the intestinal fluid are important factors contributing to the interindividual variability in the absorption of macromolecular drugs administered with transient PEs.
On the determination of local species richness and abundance

A goal of commun i t y eco logy is to unders tand the p rocesses control l ing local spec ies r ichness and abundance . I used two exper imenta l sys tems to examine this: a moss-mic roar th ropod sys tem and the larval insect c o m m u n i t y of a water-f i l led bromel iad tank. In chapter 2, I test the ef fects of local d is turbance f requency and undis turbed habitat loss on local spec ies r ichness of m o s s microar thropods. Diversi ty dec l ined l inearly with d is turbance rate, and the decl ine d e p e n d e d on the sur round ing reg ion: it w a s st rongest in local patches d isconnected f rom the reg ion. Fragmenta t ion resul ted in loss of sys tem resi l ience, wi th a threshold effect in the local patches of the smal lest , unconnec ted region s ize. All t reatments had similar g a m m a diversity: reduced a lpha diversi ty w a s of fset by increased beta diversity. Dispersal f rom undis turbed habitat mainta ins local r ichness and a b u n d a n c e , though this can be overr idden by decreased region s ize be low a threshold level, as wel l as f ragmenta t ion , and edge ef fects. In Chapter 3, I examined the impact of the number of spec ies present in regions o n the commun i t y in local pa tches . Over 16 months , local r ichness was independent of regional r ichness. T h e number of local spec ies var ied wi th t ime, due to compet i t ion and dispersal f rom the reg ion, but mos t st rongly because of seasonal i ty . Even w h e n local r ichness did not change , c o m m u n i t y compos i t ion d id. Thus , regional compos i t ion w a s more important than regional spec ies r ichness, and the imprint of b iogeography (the compos i t ion of regional species pools) , is only seasonal ly ev ident . Chapter 4 examined posit ive and negat ive interact ions in determin ing species ' abundances in bromel iad phy to te lmata . T h e top predator reduces the a b u n d a n c e of detr i t ivorous insect larvae, but an in termediate predator has little effect. Wi thout the top predator, a process ing chain takes place be tween severa l detr i t ivore spec ies, a n d these posit ive interact ions increase the emergence rate of ch i ronomids at the end of the cha in . T h e mechan ism of faci l i tat ion is l ikely the process ing , by t ipul ids and scir t ids, of detr i tus into smal l part ic les wh ich the detr i t ivore ch i ronomids can feed on . This a lso increases the sur face :vo lume ratio of detr i tus, and m a y indirect ly benef i t ch i ronomids by increasing their food, bacter ia, a lgae, and fung i . 'The aim of science is not to open the door to infinite wisdom, but to set a limit to infinite error. '
Quantitative proteomics reveals a broad‐spectrum antiviral property of ivermectin, benefiting for COVID‐19 treatment

Viruses such as human cytomegalovirus (HCMV), human papillomavirus (HPV), Epstein–Barr virus (EBV), human immunodeficiency virus (HIV), and coronavirus (severe acute respiratory syndrome coronavirus 2 [SARS‐CoV‐2]) represent a great burden to human health worldwide. FDA‐approved anti‐parasite drug ivermectin is also an antibacterial, antiviral, and anticancer agent, which offers more potentiality to improve global public health, and it can effectively inhibit the replication of SARS‐CoV‐2 in vitro. This study sought to identify ivermectin‐related virus infection pathway alterations in human ovarian cancer cells. Stable isotope labeling by amino acids in cell culture (SILAC) quantitative proteomics was used to analyze human ovarian cancer cells TOV‐21G treated with and without ivermectin (20 μmol/L) for 24 h, which identified 4447 ivermectin‐related proteins in ovarian cancer cells. Pathway network analysis revealed four statistically significant antiviral pathways, including HCMV, HPV, EBV, and HIV1 infection pathways. Interestingly, compared with the reported 284 SARS‐CoV‐2/COVID‐19‐related genes from GencLip3, we identified 52 SARS‐CoV‐2/COVID‐19‐related protein alterations when treated with and without ivermectin. Protein–protein network (PPI) was constructed based on the interactions between 284 SARS‐CoV‐2/COVID‐19‐related genes and between 52 SARS‐CoV‐2/COVID‐19‐related proteins regulated by ivermectin. Molecular complex detection analysis of PPI network identified three hub modules, including cytokines and growth factor family, MAP kinase and G‐protein family, and HLA class proteins. Gene Ontology analysis revealed 10 statistically significant cellular components, 13 molecular functions, and 11 biological processes. These findings demonstrate the broad‐spectrum antiviral property of ivermectin benefiting for COVID‐19 treatment in the context of predictive, preventive, and personalized medicine in virus‐related diseases.
Stroke in the adult Qatari population (Q-stroke) a hospital-based retrospective cohort study

Background Studies assessing the burden of stroke in Qataris are limited. We aim to study stroke in the Qatari population. Methods A retrospective review was undertaken of all Qatari adults presenting with stroke to Hamad Medical Corporation over a 5-year period. Descriptive statistics were used to summarize demographic and all other clinical characteristics of the patients. The primary outcome was the incidence of stroke in the Qatari patients. Comparison was made between the sexes. Results 862 patients were included, with 58.9% being male. The average incidence of stroke over the 5-year period was 92.04 per 100,000 adult Qatari population. The mean age of the cohort was 64.3±14.4 years, (range 19–105 years). The mean age of first ever cerebrovascular event was 63.2±14.5 years. The diagnosis was ischemic stroke in (73.7%), transient ischemic attack in (13.8%), intracerebral hemorrhage (ICH) in (11.6%), subarachnoid hemorrhage in (0.7%) and (0.2%) cerebral venous sinus thrombosis. Small vessel disease was the most common cause of ischemic stroke accounting for (46.5%), followed by large artery atherosclerosis (24.5%). Hypertension (82.7%) and diabetes (71.6%) were particularly prevalent in this cohort. Females were older (65.8±14.1 vs 63.4±14.5 years), had more hypertension and diabetes and more disability or death at 90 days (p<0.05) compared to Qatari males. Conclusion Stroke occurs at a significantly lower age in Qataris compared to the western population. This study has uncovered sex differences that need to be studied further.
Impact of Loading Dose of Caspofungin in Pharmacokinetic-Pharmacodynamic Target Attainment for Severe Candidiasis Infections in Patients in Intensive Care Units: the CASPOLOAD Study

This study evaluated the impact of a high loading dose of caspofungin (CAS) on the pharmacokinetics of CAS and the pharmacokinetic-pharmacodynamic (PK-PD) target attainment in patients in intensive care units (ICU). ICU patients requiring CAS treatment were prospectively included to receive a 140-mg loading dose of CAS. Plasma CAS concentrations (0, 2, 3, 5, 7, and 24 h postinfusion) were determined to develop a two-compartmental population PK model. A Monte Carlo simulation was performed and the probabilities of target attainment (PTAs) were computed using previously published MICs. ABSTRACT This study evaluated the impact of a high loading dose of caspofungin (CAS) on the pharmacokinetics of CAS and the pharmacokinetic-pharmacodynamic (PK-PD) target attainment in patients in intensive care units (ICU). ICU patients requiring CAS treatment were prospectively included to receive a 140-mg loading dose of CAS. Plasma CAS concentrations (0, 2, 3, 5, 7, and 24 h postinfusion) were determined to develop a two-compartmental population PK model. A Monte Carlo simulation was performed and the probabilities of target attainment (PTAs) were computed using previously published MICs. PK-PD targets were ratios of area under the concentration-time curve from 0 to 24 h (AUC0–24h) divided by the MIC (AUC0–24h/MIC) of 250, 450, and 865 and maximal concentration (Cmax) divided by the MIC (Cmax/MIC) of 5, 10, 15, and 20. Among 13 included patients, CAS clearance was 0.98 ± 0.13 liters/h and distribution volumes were V1 = 9.0 ± 1.2 liters and V2 = 11.9 ± 2.9 liters. Observed and simulated CAS AUC0–24h were 79.1 (IQR 55.2; 108.4) and 81.3 (IQR 63.8; 102.3) mg · h/liter during the first 24 h of therapy, which is comparable to values usually observed in ICU patients at day 3 or later. PTAs were >90% for MICs of 0.19 and 0.5 mg/liter, considering AUC/MIC = 250 and Cmax/MIC = 10 as PK-PD targets, respectively. Thus, a high loading dose of CAS (140 mg) increased CAS exposure in the first 24 h of therapy, allowing early achievement of PK-PD targets for most Candida strains. Such a strategy seems to improve treatment efficacy, though further studies are needed to assess the impact on clinical outcomes. (This study has been registered at ClinicalTrials.gov under identifier NCT02413892.)
Integrated meta-analysis, network pharmacology, and molecular docking to investigate the efficacy and potential pharmacological mechanism of Kai-Xin-San on Alzheimer's disease

Abstract Context Kai-Xin-San (KXS) has been used to treat Alzheimer’s disease (AD) for thousands of years. However, no quantitative data regarding AD treatment using KXS are available. Moreover, its active compounds and mechanism of action for the treatment of AD remain largely unclear. Objectives To evaluate the efficacy and the potential pharmacological mechanisms of KXS in AD treatment. Materials and methods A systematic collection of KXS experiments was conducted from PubMed, Web of Science, Embase, CNKI, VIP, and Wanfang Data up to February, 2020. Review Manager 5 software was used for meta-analysis. In network pharmacology, components of KXS were screened, AD-related genes were then identified and the ‘component-target-pathway’ network constructed. Molecular docking was finally employed for in silico simulation matching between representative KXS compounds and their target genes. Results Meta-analysis revealed that KXS improves the cognitive benefits in AD models by reducing the time of escape latency (SMD = −16.84) as well as increasing the number of cross-platform (SMD = 2.56) and proportion of time in the target quadrant (SMD = 7.52). Network pharmacology identified 25 KXS active compounds and 44 genes targets. DRD2, MAOA, ACHE, ADRA2A and CHRM2 were core target proteins. Besides, 22 potential pathways of KXS were identified, like cholinergic synapses, the cGMP/PKG pathway and calcium signalling. Molecular docking showed that stigmasterol, aposcopolamine and inermin can closely bind three targets (ACHE, ADRA2A and CHRM2). Discussion and conclusion These findings suggest that KXS exerts effect on AD through multi-target, multi-component and multi-pathway mechanism. Future studies may explore the active components of KXS.
Changes over time in pulmonary inflammatory response in rat lungs after intratracheal instillation of nickel oxide nanoparticles

Nickel oxide nanoparticles (NiONPs) are representative metal oxide NPs and are categorized as an insoluble nickel compound. Our previous studies suggested that NiONPs have more pulmonary toxicity than micron‐sized NiO because they may dissolve slowly and produce many more Ni ions. We confirmed the hypothesis that the slow dissolution of NiONPs induces a change in inflammatory response over time.
Predicting non-small-volume central lymph node metastases (>5 or ≥2 mm) preoperatively in cN0 papillary thyroid microcarcinoma without extrathyroidal extension

Abstract The ability to identify patients with aggressive papillary thyroid microcarcinoma (PTMC) from the low-risk patients is critical to planning proper management of PTMC. Lymph node metastases showed association with recurrence and low survival rate, especially in patients with >5 or ≥2 mm metastatic lymph nodes. Therefore, this study aimed to investigate the preoperatively predictive factors of non-small-volume (metastatic lymph nodes >5 or ≥2 mm in size) central lymph node metastases (NSVCLNM) in PTMC patients. A total of 420 patients with clinically node-negative (cN0) PTMC without extrathyroidal extension underwent thyroidectomy plus central neck dissection (CND) between January 2013 and December 2015, were retrospectively analyzed. Of the 420 patients, 33 (7.9%) had NSVCLNM. The 5-year recurrence-free survival was significantly less in cN0 PTMC patients with NSVCLNM, when compared with patients without NSVCLNM (80.8% vs 100%, P < .001). Multivariate logistic regression revealed age ≤36 years (P < .001), male sex (P = .002), ultrasonic tumor sizes of >0.65 cm (P < .001), and ultrasonic multifocality (P = .039) were independent predictive factors of NSVCLNM. A prediction equation (Y = 1.714 × age + 1.361 × sex + 1.639 × tumor size + 0.842 × multifocality −5.196) was developed, with a sensitivity (69.7%) and a specificity (84.0%), respectively, at an optimal cutoff point of −2.418. In conclusion, if the predictive value was >−2.418 according to the equation, immediate surgery including CND rather than active surveillance might be considered for cN0 PTMC patients.