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Objective:Using the African Neuropsychology Battery (ANB), we seek to develop normative data by examining the demographic effects for two learning process scores: initial learning (Trial One) and learning ratio (LR, the percentage of items learned relative of to-be-learned material following Trial 1).Methods:Healthy participants from the Democratic Republic of Congo completed the four memory tests of the ANB: the African Story Memory Test (ASMT), African List Memory Test (ALMT), African Visuospatial Memory Test (AVMT), and African Contextual Visuospatial Memory Test (ACVMT). We developed indices of learning for each subtest, as well as aggregate learning indices for Trial 1 and LR, and composite indices examining verbal, visual, contextual, and noncontextual learning, and grand indices comprising all four subtests.Results:Trial 1 and LR scores each demonstrated acceptable intercorrelations across memory tests. We present normative data for Trial 1 and LR by age and education.Conclusion:These data provide normative standards for evaluating learning in Sub-Saharan Africa.

Purpose This paper aims to provide a comparative analysis of sustainable tourism development across the Anglophone Caribbean region from the post-independence period of 1962 to the 2020s. The perspective explores the implications of insularity, tourism investment and the pace of technology adoption on the potential realisation of the sustainable development goals (SDGs) in the islands of Jamaica, Barbados, Trinidad and Tobago and the Eastern Caribbean States. Design/methodology/approach The viewpoint uses secondary data from grey literature such as government policy documents, academic literature, newspapers and consultancy reports to explore the central themes and provide a conceptual framework for the paper. Findings The findings reveal that Caribbean Small Island Developing States (SIDS) are nearer to the light-green single-sector approach to sustainable tourism development. The overarching findings reveal that the region’s heavy focus on economic priorities results in less attention to competitiveness challenges such as environmental management, social equity and technological innovations. Research limitations/implications The research presents a comprehensive overview of the tourism development trajectory of other tourism-dependent island-states. The research offers lessons and cross-learning opportunities that may be useful to decision-makers within SIDS. The main limitation is that the findings may only be transferable and generalised to the extent that other jurisdictions bear similar macroeconomic governance structures and cultural characteristics to Caribbean SIDS. Practical implications This paper provides a meaningful discussion and contributes to the body of knowledge on the history of Caribbean tourism development, the challenges and future potential of sustainability and lends itself to opportunities for future research in the Caribbean and other SIDS. Social implications The study outlines the social implications for inclusive, responsible and sustainable tourism that can potentially take Caribbean SIDS from slow growth to efficiency in developing the tourism product, including the technological environment. This can reduce inequalities, contribute to socio-economic development and improve the region’s human capital. Originality/value This paper provides a comprehensive comparative analysis of Caribbean tourism development specific to Jamaica, Trinidad and Tobago, Barbados and the Eastern Caribbean States. No previous work has been done to compare tourism development within this grouping. Hence, this paper is essential in informing decision-makers and providing the foundation for continuing research in this area.

We show that infrared telescopes can be constructed at low cost using consumer-grade thermal infrared imagers and commercially available germanium lenses. Using these telescopes in the laboratory, introductory astronomy students can image nearby celestial objects to observe properties that are not seen in the visible region, in particular, variations in temperature across the surface.

The COVID-19 pandemic has led to a boom in the use of V-V ECMO for ARDS secondary to COVID. Comparisons of outcomes of ECMO for COVID to ECMO for influenza have emerged. Very few comparisons of ECMO for COVID to ECMO for ARDS of all etiologies are available.To compare clinically important outcome measures in recipients of ECMO for COVID to those observed in recipients of ECMO for ARDS of other etiologies.V-V ECMO recipients between March 2020 and March 2022 consisted exclusively of COVID patients and formed the COVID ECMO group. All patients who underwent V-V ECMO for ARDS between January 2014 and March 2020 were eligible for analysis as the non-COVID ECMO comparator group. The primary outcome was survival to hospital discharge. Secondary outcomes included ECMO decannulation, ECMO duration30 days, and serious complications.Thirty-six patients comprised the COVID ECMO group and were compared to 18 non-COVID ECMO patients. Survival to hospital discharge was not significantly different between the two groups (33% in COVID vs. 50% in non-COVID; p = 0.255) nor was there a significant difference in the rate of non-palliative ECMO decannulation. The proportion of patients connected to ECMO for30 days was significantly higher in the COVID ECMO group: 69% vs. 17%; p = 0.001. There was no significant difference in serious complications.This study could not identify a statistically significant difference in hospital survival and rate of successful ECMO decannulation between COVID ECMO and non-COVID ECMO patients. Prolonged ECMO may be more common in COVID. Complications were not significantly different.

Microglia have long been thought to be responsible for the initiation of the central nervous system (CNS) immune response to pathogen exposure. However, we recently reported that depleting CNS microglia and circulating monocytes does not abrogate the sickness response in male rats or mice to bacterial endotoxin, lipopolysaccharide (LPS). How the central immune response to an endotoxin challenge is initiated and resolved in the absence of microglia and monocytes remains unclear. Here we investigated the role of microglia and monocytes in driving the behavioral, febrile and neuroimmune response to LPS using the Cx3cr1-Dtr rat model of conditional microglia/monocyte depletion, assessed if this role is similar in females and males, and examined how the response to an immune challenge might be initiated in the absence of these cells. We show that depletion of microglia and monocytes exacerbates the response to LPS at each phase of the immune cascade. Our data indicate that the changes in the central response to immune challenge may be an indirect effect of excess neutrophil expansion into the bloodstream and infiltration into peripheral organs stimulating a rapid and exacerbated cytokine and prostaglandin response to the LPS that is not curtailed by the usual negative feedback mechanisms. Thus, we show that a demonstrable immune response can be generated (and resolved) in the near complete absence of microglia and monocytes and that these cells play a regulatory role in the initiation and resolution of the response to an immune challenge, rather than being critical for it to occur.

A self-tuning proportional-integral control law prescribingmotor torques was tested in experiment on a threedegree-of-freedom wave energy converter. The control objectivewas to maximize electrical power. The control law relied uponan identified model of device intrinsic impedance to generate afrequency-domain estimate of the wave-induced excitation forceand measurements of device velocities. The control law was testedin irregular sea-states that evolved over hours (a rapid, butrealistic time-scale) and that changed instantly (an unrealisticscenario to evaluate controller response). For both cases, thecontroller converges to gains that closely approximate the postcalculatedoptimal gains for all degrees of freedom in a sufficientlyshort-time for realistic sea states. In addition, electricalpower was found to be relatively insensitive to gain tuning overa broad range of gains, implying that an imperfectly tunedcontroller does not result in a large penalty to electrical powercapture. Because the controller relies on an identified model ofdevice intrinsic impedance, the sensitivity of power capture wasevaluated with respect to uncertainty in the constituent termsof intrinsic impedance. Power capture is found to be relativelyinsensitive to uncertainty of 20% in constituent terms of theidentified intrinsic impedance model. An extension of this controllaw that allows for adaptation to a changing device impedancemodel over time is proposed for long-term deployments, aswell as an approach to explicitly handle constraints within thisarchitecture.

Although continuous-flow left ventricular assist devices (CF-LVADs) provide an augmentation in systemic perfusion, there is a scarcity of in vivo data regarding systemic pulsatility on support. Patients supported on CF-LVAD therapy (n = 71) who underwent combined left/right catheterization ramp study were included. Aortic pulsatility was defined by the pulsatile power index (PPI), which was also calculated in a cohort of high-output heart failure (HOHF, n = 66) and standard HF cohort (n = 44). PPI was drastically lower in CF-LVAD-supported patients with median PPI of 0.006 (interquartile range [IQR], 0.002-0.012) compared with PPI in the HF population at 0.09 (IQR, 0.06-0.17) or HOHF population at 0.25 (IQR, 0.13-0.37; p0.0001 among groups). With speed augmentation during ramp, PPI values fell quickly in patients with higher PPI at baseline. PPI correlated poorly with left ventricular ejection fraction (LVEF) in all groups. In CF-LVAD patients, there was a stronger correlation with LV dP/dt (r = 0.41; p = 0.001) than LVEF (r = 0.21; p = 0.08; pint0.001). CF-LVAD support is associated with a dramatic reduction in arterial pulsatility as measured by PPI relative to HOHF and HF cohorts and decreases with speed. Further work is needed to determine the applicability to the next generation of device therapy.

The Response Bias Scale (RBS) is a measure of protocol validity that is composed of items from the Minnesota Multiphasic Personality Inventory - 2. The RBS has been successfully cross-validated as a whole, but the composition of the scale has not been reexamined until recently when three types of items were identified. In this study we sought to examine the reliability of the scale as a whole, as well as the items that are (a) empirically supported and conceptually similar (ES/CS), (b) empirically supported but not conceptually similar (ES/NS), and (c) not empirically supported (NES). Participants included 56 veterans undergoing neuropsychological evaluation for suspected traumatic brain injury. Results generally replicated Ratcliffe et al. finding that removing key NES items improved the internal consistency of the RBS from 0.706 to 0.747. Examined separately, ES/CS and ES/NS had internal consistencies of 0.629 and 0.605, respectively. One of the nine NES items had strong internal consistency, but none of the remaining eight had corrected item-total correlations above 0.194. NES items had an internal consistency of 0.177. Although the RBS is well-validated in detecting non-credible cognitive presentations, it may prove even more valuable after further item refinement whereby items detracting from its reliability and validity are excised.

Gastrointestinal motility is crucial to gut health and has been associated with different disorders such as inflammatory bowel diseases and postoperative ileus. Despite rat and mouse being the two animal models most widely used in gastrointestinal research, minimal studies in rats have investigated gastrointestinal motility. Therefore, our study provides a comparison of colonic motility in the mouse and rat to clarify species differences and assess the relative effectiveness of each animal model for colonic motility research. We describe the protocol modifications and optimization undertaken to enable video imaging of colonic motility in the rat. Apart from the broad difference in terms of gastrointestinal diameter and length, we identified differences in the fundamental histology of the proximal colon such that the rat had larger villus height-to-width and villus height-to-crypt depth ratios compared with mouse. Since gut motility is tightly regulated by the enteric nervous system (ENS), we investigated how colonic contractile activity within each rodent species responds to modulation of the ENS inhibitory neuronal network. Here we used

Free testosterone (FT) determination may be helpful in evaluating men suspected of testosterone deficiency especially in conditions with altered binding-protein concentrations. However, methods for measuring FT by equilibrium dialysis and reference intervals vary among laboratories.To determine reference intervals for FT in healthy, nonobese men by age groups as well as in healthy young men, 19-39 years, using a standardized equilibrium dialysis procedure METHODS: We measured FT in 145 healthy, nonobese men, 19 years or older, using a standardized equilibrium dialysis method performed for 16-h at 37°C using undiluted serum and dialysis buffer that mimicked the ionic composition of human plasma. FT in dialysate was measured using a CDC-certified liquid chromatography tandem mass spectrometry assay.In healthy nonobese men, the 2.5th, 10th, 50th, 90th, and 97.5th percentile values for FT were 66, 91, 141, 240, and 309 pg/ml, respectively; corresponding values for men, 19-39 years, were 120, 128, 190, 274, and 368 pg/ml, respectively. FT levels by age groups exhibit the expected age-related decline. FT levels were negatively associated with body mass index, age, and sex hormone-binding globulin (SHBG) levels. Percent FT was lower in middle-aged and older men than young men adjusting for SHBG level.Further studies are needed to determine how these reference intervals apply to the diagnosis of androgen deficiency in clinical populations and in men of different races and ethnicities in different geographic regions.Reference intervals for free FT levels (normative range 66-309 pg/ml [229-1072 pmol/L] in all men and 120-368 pg/ml [415-1274 pmol/L] in men, 19-39 years), measured using a standardized equilibrium dialysis method in healthy nonobese men, provide a rational basis for categorizing FT levels. These intervals require further validation in other populations, in relation to outcomes, and in randomized trials.

Recurrent cervical cancer has a grim prognosis with 5-year survival

Pharmacologic inhibition of LSD1 induces molecular and morphologic differentiation of blast cells in acute myeloid leukemia (AML) patients harboring MLL gene translocations. In addition to its demethylase activity, LSD1 has a critical scaffolding function at genomic sites occupied by the SNAG domain transcription repressor GFI1. Importantly, inhibitors block both enzymatic and scaffolding activities, in the latter case by disrupting the protein:protein interaction of GFI1 with LSD1. To explore the wider consequences of LSD1 inhibition on the LSD1 protein complex we applied mass spectrometry technologies. We discovered that the interaction of the HMG-box protein HMG20B with LSD1 was also disrupted by LSD1 inhibition. Downstream investigations revealed that HMG20B is co-located on chromatin with GFI1 and LSD1 genome-wide; the strongest HMG20B binding co-locates with the strongest GFI1 and LSD1 binding. Functional assays demonstrated that HMG20B depletion induces leukemia cell differentiation and further revealed that HMG20B is required for the transcription repressor activity of GFI1 through stabilizing LSD1 on chromatin at GFI1 binding sites. Interaction of HMG20B with LSD1 is through its coiled-coil domain. Thus, HMG20B is a critical component of the GFI1:LSD1 transcription repressor complex which contributes to leukemia cell differentiation block.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned coprimary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. The purpose of this update was to determine differences in patient-reported chronic toxicity and disease outcomes with intensity-modulated radiation therapy (IMRT) compared with conventional pelvic radiation. Patients with cervical and endometrial cancers who received postoperative pelvic radiation were randomly assigned to conventional radiation therapy (CRT) or IMRT. Toxicity and quality of life were assessed using Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events, Expanded Prostate Cancer Index Composite (EPIC) bowel and urinary domains, and Functional Assessment of Cancer Therapy–General. Between 2012 and 2015, 279 eligible patients were enrolled to the study with a median follow-up of 37.8 months. There were no differences in overall survival ( P = .53), disease-free survival ( P = .21), or locoregional failure ( P = .81). One year after RT, patients in the CRT arm experienced more high-level diarrhea frequency (5.8% IMRT v 15.1% CRT, P = .042) and a greater number had to take antidiarrheal medication two or more times a day (1.2% IMRT v 8.6% CRT, P = .036). At 3 years, women in the CRT arm reported a decline in urinary function, whereas the IMRT arm continued to improve (mean change in EPIC urinary score = 0.5, standard deviation = 13.0, IMRT v –6.0, standard deviation = 14.3, CRT, P = .005). In conclusion, IMRT reduces patient-reported chronic GI and urinary toxicity with no difference in treatment efficacy at 3 years.

Quantitative data of biological systems provide valuable baseline information for understanding pathology, experimental perturbations, and computational modeling. In mouse colon, calcitonin gene-related peptide (CGRP) is expressed by myenteric neurons with multiaxonal (Dogiel type II) morphology, characteristic of intrinsic primary afferent neurons (IPANs). Analogous neurons in other species and gut regions represent 5-35% of myenteric neurons. We aimed to quantify proportions of CGRP-immunopositive (CGRP+) myenteric neurons. Colchicine-treated wholemount preparations of proximal, mid, and distal colon were labeled for HuC/D, CGRP, nitric oxide synthase (NOS), and peripherin (Per). The pan-neuronal markers (Hu+/Per+) co-labeled 94% of neurons. Hu+/Per- neurons comprised ∼6%, but Hu-/Per+ cells were rare. Thus, quantification was based on Hu+ myenteric neurons (8576 total; 1225 ± 239 per animal, n = 7). CGRP+ cell bodies were significantly larger than the average of all Hu+ neurons (329 ± 13 vs. 261 ± 12 μm

Early life microglia are essential for brain development, and developmental disruption in microglial activity may have long-term implications for the neuroendocrine control of reproduction. We and others have previously shown that early life immune activation compromises the long-term potential for reproductive function in females. However, the supportive role of microglia in female reproductive development is still unknown. Here, we examined the long-term programming effects of transient neonatal microglial and monocyte ablation on hypothalamic–pituitary–gonadal (HPG) axis function in female rats. We employed a Cx3cr1-Dtr transgenic Wistar rat model to acutely ablate microglia and monocytes, commencing on either postnatal day (P) 7 or 14, since the development of the HPG axis in female rodents primarily occurs during the first two to three postnatal weeks. After an acutely diminished expression of microglia and monocyte genes in the brain and ovaries, respectively, microglia had repopulated the brain by P21, albeit that cellular complexity was still reduced in both groups at this time. Removal of microglia and monocytes on P7, but not P14 reduced circulating luteinising hormone levels in adulthood and ovarian gonadotropin receptors mRNA. These changes were notably associated with fewer primary and antral follicles in these rats. These data suggest that transient ablation of microglia and monocytes at the start of the second but not the third postnatal week has long-term effects on ovarian health. The findings highlight the important developmental role of a healthy immune system for female potential reproductive capacity and the importance of critical developmental periods to adult ovarian health.

U–Pb geochronology, Hf isotopes and trace-element chemistry of zircon grains from migmatite of the upper Sutlej valley (Leo Pargil), Northwest Himalaya, reveal a protracted geological evolution and constrain anatexis and tectonothermal processes in response to Himalayan orogenesis. U–Pb geochronology and ϵHf record separate clusters of ages on the concordia plots in the migmatite (1050–950 Ma, 850–790 Ma and 650–500 Ma). The 1050–950 Ma zircon population supports a provenance from magmatic units related to the assembly of Rodinia. A minor amount of Palaeoproterozoic grains were likely derived from the Indian craton. The potential source rock of the 930–800 Ma detrital zircons may be granitoid present in Greater Himalayan rocks themselves and the Aravalli Range, which has 870–800 Ma granitic rocks. The arc-type basement within the Himalayan–Tibet orogen recorded (900–600 Ma) igneous activity, which may depict a northeasterly extension of juvenile terranes in the Arabian–Nubian Shield. The granitoid of 800 Ma may be a potential source for 790 Ma detrital zircons owing to scatter in 206/238 dates. The 650–500 Ma zircon population suggests their derivation from the East African Orogen and Ross–Delamerian Orogen of Gondwana. The Cambrian–Ordovician magmatism during the Bhimphedian Orogeny and observed late Neoproterozoic to Ordovician detrital zircons have been derived to some extent from Greater Himalayan magmatic sources. We found no detrital zircon grains that cannot be explained as coming from local sources. One sample yielded a discordia lower intercept age of 15.6 ± 2.2 Ma, the age of melt crystallization.

The Araçuaí-West Congo Orogen is the result of convergence between the São Francisco and Congo cratons during the assembly of West Gondwana. Within this orogen, the Araçuaí Belt in SE Brazil reflects the western external domain. The Araçuaí Belt is characterized by major east-dipping structures and high- to medium pressure metamorphic rocks developed during crustal thickening at ca. 585–560 Ma and are juxtaposed along crustal-scale structures to the crystalline core of the orogen. The Guanhães Block in the southern Araçuaí Belt is characterized by higher metamorphic grade and dominantly shallowly west-dipping structures compared to the neighboring tectonic domains. While several studies have focused on the evolution of the axial crystalline core of the Araçuaí orogen and on the early collisional stages in the Araçuaí Belt, little attention has been given to the structural and metamorphic history of the poorly studied Guanhães Block. The supracrustal rocks in the central Guanhães Block record two tectono-metamorphic stages: D2/M2 and D3 /M3, with potential D1/M1 relicts rarely preserved within D2/M2 low-strain domains. The D2/M2 overprinting stage is associated with the development of a dominant, shallow axial planar foliation (S2) of isoclinal F2 folds under low-pressure and high-temperature (LP–HT) conditions (ca. 6 kbar and 750 °C). During this D2/M2 stage continuous segregation of syn-kinematic partial melting and generation of granitoid rocks occurred. The 530 Ma, syn- D2/M2 granitoid has negative εHf(i) at ca. −32 which indicates the source of magma from melting of older, isotopically evolved, Archaean or Paleoproterozoic crust. U–Pb geochronology on monazite, titanite and hydrothermal zircon constrain the retrograde D3/M3 event at ca. 510 Ma. The Guanhães Block uniquely records dominant deformation under LP–HT metamorphic conditions during the late-orogenic stages and its evolution could have important tectonic implications for the concurrent models suggested for the late Neoproterozoic Araçuaí-West Congo Orogen.

PURPOSE. Genomic screening for Lynch syndrome (LS) could prevent colorectal cancer (CRC) by identifying high-risk patients and instituting intensive CRC screening. We estimated the cost-effectiveness of population-wide LS genomic screening versus family history-based screening alone in an unselected U.S. population. METHODS. We developed a decision-analytic Markov model including health states for pre-cancer, stage-specific CRC, and death, and assumed an inexpensive test cost of $200. We conducted sensitivity and threshold analyses to evaluate model uncertainty. RESULTS. Screening unselected 30-year-olds for LS variants resulted in 48 (95% credible range [CR]: 35 to 63) fewer overall CRC cases per 100,000 screened individuals, leading to 187 quality-adjusted life-years (QALYs; 95% CR: 123 to 260) gained at an incremental cost of $24.6 million (95% CR: $20.3 million to $29.1 million). The incremental cost-effectiveness ratio was $132,200, with an 8% and 71% probability of being cost-effective at $100,000 and $150,000 per QALY willingness-to-pay thresholds, respectively. CONCLUSIONS. Population LS screening may be cost-effective in younger patient populations under a $150,000 willingness-to-pay per QALY threshold and with a relatively inexpensive test cost. Further reductions in testing costs and/or the inclusion of LS testing within a broader multiplex screening panel are needed for screening to be highly cost-effective.

Interpretation of Earth's oldest preserved crustal archive, the Jack Hills zircon of Western Australia, has been controversial in terms of the onset of plate tectonics. We conduct time-series analysis on hafnium isotopes of the Jack Hills zircon and reveal an array of statistically significant cycles that are reminiscent of plate-tectonic subduction. At face value, such cycles may suggest early Earth conditions similar to those of today—the uniformitarian hypothesis that plate tectonics was essentially operational since “day one”. On the other hand, in the context of expected secular changes due to planetary evolution and geological observations, the cycles could instead imply that modern plate-tectonic subduction inherited mantle convective harmonics already facilitated by an early phase of stagnant-lid delamination—the “lid-to-plates” hypothesis. Either way, any model for the nature of plate tectonics must incorporate conditions operating during Hadean time, either by initiation of plate tectonics then or by later inheritance of preexisting cycles of mantle convection.

Geological observations and numerical models imply that Archean continents were mostly submarine. In contrast, approximately one third of modern earth's surface area consists of subaerial continental crust. To temporally constrain changes in the subaerial exposure of continents, we evaluate the eruptive environment (submarine vs subaerial) of 3.4–2.0 Ga continental large igneous provinces (LIPs). Our results indicate that up until 2.4 Ga LIPs predominantly erupted onto submerged continents. This period of low freeboard was punctuated by local subaerial eruptions at 2.8–2.7 Ga and 2.5 Ga. From 2.4 Ga–2.2 Ga, extensive subaerial continental volcanism is recorded in six different cratons, supporting widespread subaerial continents at this time. An increase in exposed continental crust significantly impacts atmospheric and oceanic geochemical cycles and the supply of nutrients for marine bioproductivity. Thus, the 2.4–2.2 Ga high-freeboard conditions may have triggered the earliest global glaciation event and the first significant rise of atmospheric oxygen.

Geochemical similarities between the continental crust and arc magmas have led to the inference that subduction zones may be the primary sites of crustal growth. Thus, it is necessary to unravel the petrogenetic mechanism(s) of granitoid generation in subduction-related settings to understand crustal growth through magmatic differentiation processes. In this study, we focused on granitoid generation in oceanic-continental subduction zones. We analyzed the whole-rock geochemistry and Sr-Nd isotopes, together with zircon U-Pb-Hf-O isotopes, of the newly identified Middle Triassic granitoids in the Ailaoshan high-grade metamorphic complex (Yunnan, SW China). All the studied granite samples were characterized by large ion lithophile element (e.g., Rb, Sr, and Ba) enrichments and high field strength element (e.g., Nb, Ta, and Ti) depletions, similar to arc-type rocks. They also showed a range of whole-rock Sr-Nd, (87Sr/86Sr)i = 0.7020–0.7048, εNd(t) = +0.6 to +4.2, and zircon Hf-O, εHf(t) = +10.3 to +18.1, δ18Ozircon = 5.09‰–6.65‰, isotope compositions, which overlap with those of previously reported coeval (ca. 237–235 Ma) hornblende diorite and granodiorite, the formation of which was interpreted to have originated from a mantle wedge metasomatized by a sediment-derived melt. Furthermore, the fractionation trends of some of the granitic samples and diorite-granodiorite suite overlap. They can be divided into two geochemical groups: Group 1 has intermediate to high SiO2 (66.9–73.8 wt%) and K2O (3.40–5.42 wt%) and low MgO (0.19–1.09 wt%) contents and shows depletion in heavy rare earth elements (HREEs; e.g., Yb and Y), resulting in adakite-like high Sr/Y (61–183) and La/Yb (47–90) ratios. Group 1 shows positive SiO2 versus Sr/Y and La/Yb correlations and negative SiO2 versus HREE and Y correlations, implying fractionation of a garnet-bearing assemblage. The negative correlations between SiO2 and εNd(t) and Nb/La reveal a crustal assimilation trend. Group 2 has relatively high SiO2 (72.6–76.5 wt%) and low K2O (1.93–3.82 wt%) and MgO (0.05–0.83 wt%) contents and shows depletion in middle REEs (MREEs; e.g., Gd and Dy) with low Sr/Y (1–10) and La/Yb (4–11) ratios. Group 2 granites show negative Gd/Yb versus SiO2 correlation, which indicates significant fractionation of an amphibole-bearing assemblage. Our results suggest that both group 1 and 2 granites were formed in a subduction setting from a common mantle-derived parental dioritic magma, but they experienced two distinct fractionation processes. While group 1 granites were likely formed by crustal assimilation and high-pressure (lower-crustal) garnet-dominated fractionation, group 2 granites were generated through low-pressure (middle-/upper-crustal) amphibole-/plagioclase-dominated fractionation. We suggest that these two fractionation trends are critical to crustal growth and the development of a more fractionated (felsic) upper crust.

The release of extracellular vesicles is observed across numerous cell types and serves a range of biological functions including intercellular communication and waste disposal. One cell type which stands out for its robust capacity to release extracellular vesicles is the vertebrate photoreceptor cell. For decades, the release of extracellular vesicles by photoreceptors has been documented in many different animal models of photoreceptor degeneration and, more recently, in wild type photoreceptors. Here, I review all studies describing extracellular vesicle release by photoreceptors and discuss the most unifying theme among them–a photoreceptor cell fully, or partially, diverts its light sensitive membrane material to extracellular vesicles when it has defects in the delivery or morphing of this material into the photoreceptor’s highly organized light sensing organelle. Because photoreceptors generate an enormous amount of light sensitive membrane every day, the diversion of this material to extracellular vesicles can cause a massive accumulation of these membranes within the retina. Little is known about the uptake of photoreceptor derived extracellular vesicles, although in some cases the retinal pigment epithelial cells, microglia, Müller glia, and/or photoreceptor cells themselves have been shown to phagocytize them.

The monocytic/macrophage system is essential for skeletal muscle homeostasis, but its dysregulation contributes to the pathogenesis of muscle degenerative disorders. Despite our increasing knowledge of the role of macrophages in degenerative disease, it still remains unclear how macrophages contribute to muscle fibrosis. Here, we used single-cell transcriptomics to determine the molecular attributes of dystrophic and healthy muscle macrophages. We identified six novel clusters. Unexpectedly, none corresponded to traditional definitions of M1 or M2 macrophage activation. Rather, the predominant macrophage signature in dystrophic muscle was characterized by high expression of fibrotic factors, galectin-3 and spp1. Spatial transcriptomics and computational inferences of intercellular communication indicated that spp1 regulates stromal progenitor and macrophage interactions during muscular dystrophy. Galectin-3+macrophages were chronically activated in dystrophic muscle and adoptive transfer assays showed that the galectin-3+phenotype was the dominant molecular program induced within the dystrophic milieu. Histological examination of human muscle biopsies revealed that galectin-3+macrophages were also elevated in multiple myopathies. These studies advance our understanding of macrophages in muscular dystrophy by defining the transcriptional programs induced in muscle macrophages, and reveal spp1 as a major regulator of macrophage and stromal progenitor interactions.

The activation of P2X7 is a well-known stimulus for the NLRP3-caspase 1 inflammasome and subsequent rapid IL-1β secretion from monocytes and macrophages. Here we show that positive allosteric modulators of P2X7, ginsenosides, can enhance the release of three important cytokines, IL-1β, IL-6 and TNF-α from LPS-primed rodent macrophages using the J774 mouse macrophage cell line and primary rat peritoneal macrophages. We compared the immediate P2X7 responses in un-primed and LPS-primed macrophages and found no difference in calcium response amplitude or kinetics. These results suggest that under inflammatory conditions positive allosteric modulators are capable of increasing cytokine secretion at lower concentrations of ATP, thus boosting the initial pro-inflammatory signal. This may be important in the control of intracellular infections.

Granitoids with evolved chemical signatures, intruding both oceanic crustal rocks and mantle peridotite, are well known in the Samail supra-subduction ophiolite of Oman and United Arab Emirates. The former are metaluminous tonalites and trondhjemites have positive εNd, relatively low δ18O values, resemble ridge ‘tholeiitic’ granitoids with MORB-like affinity, and formed by fractionation of basalt/gabbro or anatexis of oceanic crust. In contrast, the mantle-hosted granitoids are peraluminous, with negative εNd and high δ18O values. They can be modeled as having formed by mixing between partial melts of metabasalt and metasedimentary rocks with minimal mantle contribution. The mantle-hosted granitoids resemble typical peraluminous S-type granitoids (e.g. Himalaya, Variscan, Lachlan) but are compositionally distinct in having notably scattered data values of K2O, Na2O, CaO, Rb/Sr, relatively higher silica and, lower (Al2O3 + FeO + MgO + TiO2 wt%) and Th/Yb as compared to typical S-types. The mantle-hosted granitoids mainly originate from the subducted slab, and mostly intruded mantle peridotite in the lithospheric mantle, with no apparent association with the overriding oceanic plate and little interaction (e.g. assimilation) with the mantle. While the specific controls on geochemical variations remain speculative, results from this study show that the Samail mantle-hosted S-type granitoids are compositionally distinct from classic S-type granitoids formed in orogenic belts. While global S-type granitoids may be mineralogically similar, the Samail mantle-hosted granitoids preserve different geochemical signatures, reflecting their formation in distinct tectonic setting, including the mantle.

Funder: NIHR Cambridge Biomedical Research Centre, Funder: Schmidt Futures, Funder: Alan Turing Institute, Funder: MQ: Transforming Mental Health; Grant(s): MQF17_24, Funder: King's Health Partners, BACKGROUND AND HYPOTHESIS: Mapping a patient's speech as a network has proved to be a useful way of understanding formal thought disorder in psychosis. However, to date, graph theory tools have not explicitly modelled the semantic content of speech, which is altered in psychosis. STUDY DESIGN: We developed an algorithm, "netts," to map the semantic content of speech as a network, then applied netts to construct semantic speech networks for a general population sample (N = 436), and a clinical sample comprising patients with first episode psychosis (FEP), people at clinical high risk of psychosis (CHR-P), and healthy controls (total N = 53). STUDY RESULTS: Semantic speech networks from the general population were more connected than size-matched randomized networks, with fewer and larger connected components, reflecting the nonrandom nature of speech. Networks from FEP patients were smaller than from healthy participants, for a picture description task but not a story recall task. For the former task, FEP networks were also more fragmented than those from controls; showing more connected components, which tended to include fewer nodes on average. CHR-P networks showed fragmentation values in-between FEP patients and controls. A clustering analysis suggested that semantic speech networks captured novel signals not already described by existing NLP measures. Network features were also related to negative symptom scores and scores on the Thought and Language Index, although these relationships did not survive correcting for multiple comparisons. CONCLUSIONS: Overall, these data suggest that semantic networks can enable deeper phenotyping of formal thought disorder in psychosis. Whilst here we focus on network fragmentation, the semantic speech networks created by Netts also contain other, rich information which could be extracted to shed further light on formal thought disorder. We are releasing Netts as an open Python package alongside this manuscript.

Introduction Penile amputation causes severe physical and psychosocial distress. Microsurgical implementation in penile replantation is presumed to be superior to surgical repair. This assumption has been difficult to verify. Objectives The purpose of this study was threefold: (1) to produce an updated review of penile replantation, substantiated by the largest sample size to date; (2) to appraise the comparative value of the novel PENIS Score and propose the PACKAGE Checklist, a guide for standardization of future case reports and reviews; and (3) to improve confusing terminology and recommend the standardization of vocabulary. Methods A literature review assessed 432 full-text case reports in 20 languages and identified 123 microsurgical and 40 surgical cases of penile replantation. The novel PENIS Score stratified penile amputations based on 5 criteria: position along the shaft, extension through the penis, neurovascular repair, ischemia time and type, and severed edge condition and contamination. For the outcome measurements, a Kendall tau coefficient evaluated the association between each PENIS criterion for short-term postoperative complications and 3 outcome measures: erection, urination, and sensation. Results Less than half of surgical reports on penile replantation are sufficiently detailed to complete all PENIS Score criteria. The viability of microsurgical and surgical replantation was equivalent at 92% and 94%, respectively. A statistically significant correlation was found between microsurgical repair and the return of sensation but not with nerve repair. Return of sensation with nerve repair was 51%, and microsurgical replantation without nerve repair was 42%; both were significantly higher than the 14% for surgical replantation. Preservation of a skin bridge was associated with a 40% reduction in severe postoperative complications. Conclusion Microsurgical replantation is superior in return of sensation, with or without nerve repair. Implementing the PACKAGE Checklist and PENIS Score will help inform case reports and reviews.

The photoreceptor outer segment is a modified cilium filled with hundreds of flattened “disc” membranes responsible for efficient light capture. To maintain photoreceptor health and functionality, outer segments are continuously renewed through the addition of new discs at their base. This process is driven by branched actin polymerization nucleated by the Arp2/3 complex. To induce actin polymerization, Arp2/3 requires a nucleation promoting factor. Here, we show that the nucleation promoting factor driving disc morphogenesis is the pentameric WAVE complex and identify all protein subunits of this complex. We further demonstrate that the knockout of one of them, WASF3, abolishes actin polymerization at the site of disc morphogenesis leading to formation of disorganized membrane lamellae emanating from the photoreceptor cilium instead of an outer segment. These data establish that, despite the intrinsic ability of photoreceptor ciliary membranes to form lamellar structures, WAVE-dependent actin polymerization is essential for organizing these membranes into a proper outer segment.

Gastrointestinal (GI) motility is largely dependent upon activity within the enteric nervous system (ENS) and is an important part of the digestive process. Dysfunction of the ENS can impair GI motility as is seen in the case of constipation where gut transit time is prolonged. Animal models mimicking symptoms of constipation have been developed by way of pharmacological manipulations. Studies have reported an association between altered GI motility and gut microbial population. Little is known about the changes in gut microbiota profile resulting specifically from pharmacologically induced slowed GI motility in rats. Moreover, the relationship between gut microbiota and altered intestinal motility is based on studies using faecal samples, which are easier to obtain but do not accurately reflect the intestinal microbiome. The aim of this study was to examine how delayed GI transit due to opioid receptor agonism in the ENS modifies caecal microbiota composition. Differences in caecal microbial composition of loperamide-treated or control male Sprague Dawley rats were determined by 16S rRNA gene amplicon sequencing. The results revealed that significant differences were observed at both genus and family level between treatment groups. Bacteroides were relatively abundant in the loperamide-induced slowed GI transit group, compared to controls. Richness and diversity of the bacterial communities was significantly lower in the loperamide-treated group compared to the control group. Understanding the link between specific microbial species and varying transit times is crucial to design interventions targeting the microbiome and to treat intestinal motility disorders.