An Insertion Within SIRPß1 Shows a Dual Effect Over Alzheimer's Disease Cognitive Decline Altering the Microglial Response.

Background: Microglial dysfunction plays a causative role in Alzheimer's disease (AD) pathogenesis. Here we focus on a germline insertion/deletion variant mapping SIRPß1, a surface receptor that triggers amyloid-ß(Aß) phagocytosis via TYROBP. Objective: To analyze the impact of this copy-number variant in SIRPß1 expression and how it affects AD molecular etiology. Methods: Copy-number variant proxy rs2209313 was evaluated in GERALD and GR@ACE longitudinal series. Hippocampal specimens of genotyped AD patients were also examined. SIRPß1 isoform-specific phagocytosis assays were performed in HEK393T cells. Results: The insertion alters the SIRPß1 protein isoform landscape compromising its ability to bind oligomeric Aß and its affinity for TYROBP. SIRPß1 Dup/Dup patients with mild cognitive impairment show an increased cerebrospinal fluid t-Tau/Aß ratio (p = 0.018) and a higher risk to develop AD (OR = 1.678, p = 0.018). MRIs showed that Dup/Dup patients exhibited a worse initial response to AD. At the moment of diagnosis, all patients showed equivalent Mini-Mental State Examination scores. However, AD patients with the duplication had less hippocampal degeneration (p < 0.001) and fewer white matter hyperintensities. In contrast, longitudinal studies indicate that patients bearing the duplication allele show a slower cognitive decline (p = 0.013). Transcriptional analysis also shows that the SIRPß1 duplication allele correlates with higher TREM2 expression and an increased microglial activation. Conclusions: The SIRPß1 internal duplication has opposite effects over MCI-to-Dementia conversion risk and AD progression, affecting microglial response to Aß. Given the pharmacological approaches focused on the TREM2-TYROBP axis, we believe that SIRPß1 structural variant might be considered as a potential modulator of this causative pathway.

Interspecific variability in plastic ingested by Procellariiformes off the Uruguayan coast.

We assessed the interspecific variability in plastic ingested by albatrosses and petrels using bycaught birds from fisheries of the Southwest Atlantic. From 107 stomachs examined, 4.17 % of the albatrosses and 62.86 % of the petrels contained plastics. Macronectes halli and Ardenna gravis had 100 % of occurrence. They were followed by Procellaria conspicillata (75 %), Procellaria aequinoctialis (47.62 %), T. melanophris (4.35 %) and T. chlororhynchos (0 %). The most common groups of plastics by size, type and color, were mesoplastics (5-20 mm), user plastics and white-clear items, respectively. Larger species tend to ingest larger items with greater surfaces. Together with evidence from other studies, our results indicate that interspecific differences in the occurrence and the dimensions of plastics appear to be associated with digestive tract morphology, foraging techniques, body size, interaction with fishing vessels, and with the availability of plastics at the sea surface.

The Performance Diagnostic Checklist-Human Services (1.1): An initial assessment of validity and reliability.

The Performance Diagnostic Checklist-Human Services (PDC-HS) is an assessment used to identify variables contributing to staff performance concerns in human-service settings. In the current study, we introduce and assess the test validity, interrater reliability, and test-retest reliability of the PDC-HS (1.1), a revised version of the assessment that included revised instructions, questions, and intervention planning references. We measured the psychometric properties of the revised assessment by analyzing answers obtained from watching video vignettes of simulated interviews between consultants and a supervisor. Twenty-one participants watched the vignettes and completed the PDC-HS (1.1) based on the answers provided during the interview. We also included an item analysis to identify questions on which participants made errors and an intervention selection task to assess whether participants selected an appropriate intervention to target the indicated domain. The results support the use of the PDC-HS (1.1) in human services settings.

Pancreatic intraductal papillary mucinous neoplasm evolving into adenocarcinoma. Continual follow-up necessary.

We report a 62-year-old female with chronic pancreatitis after three episodes of severe acute pancreatitis. In 2008, an uneven main pancreatic duct (MPD) of 16 mm was found during an abdominal ultrasound. The follow-up was not continued until 2020, when a dilation of 27 mm of the MPD was discovered at magnetic resonance imaging (MRI). In 2022, another radiological test was carried out showing a dilation of the MPD of 40 mm with an intraductal tumoral lesion of 30 mm at the head of the pancreas). An echo-endoscopy was carried out and a pancreatic-duodenal tumour with a mixed pattern was discovered. Atypic cells were observed at the fine needle punction. A total duodenopancreatectomy was successfully carried out. In the anatomopathological macroscopic study a 14 cm-multi-cystic neoformation was seen and a solid tumour was discovered at the head of the pancreas that infiltrated the wall of the duodenum. In the longitudinal cross-section of the pancreatic body the MPD was seen to be severely dilated. A focal adenocarcinoma in a intraductal papillary mucinous neoplasm (IPMN) was finally diagnosed. Pancreatic lesions are usually asymptomatic and are detected by chance during other imaging tests. The IPMN rates of malignancy have been reported of between 19 to 30%. The management of pancreatic cystic lesions still represents a clinical challenge. As always, the multi-disciplinary management is mandatory in this type of tumour.

Extended Sentinel Monitoring of Helicoverpa zea Resistance to Cry and Vip3Aa Toxins in Bt Sweet Corn: Assessing Changes in Phenotypic and Allele Frequencies of Resistance.

Transgenic corn and cotton that produce Cry and Vip3Aa toxins derived from Bacillus thuringiensis (Bt) are widely planted in the United States to control lepidopteran pests. The sustainability of these Bt crops is threatened because the corn earworm/bollworm, Helicoverpa zea (Boddie), is evolving a resistance to these toxins. Using Bt sweet corn as a sentinel plant to monitor the evolution of resistance, collaborators established 146 trials in twenty-five states and five Canadian provinces during 2020-2022. The study evaluated overall changes in the phenotypic frequency of resistance (the ratio of larval densities in Bt ears relative to densities in non-Bt ears) in H. zea populations and the range of resistance allele frequencies for Cry1Ab and Vip3Aa. The results revealed a widespread resistance to Cry1Ab, Cry2Ab2, and Cry1A.105 Cry toxins, with higher numbers of larvae surviving in Bt ears than in non-Bt ears at many trial locations. Depending on assumptions about the inheritance of resistance, allele frequencies for Cry1Ab ranged from 0.465 (dominant resistance) to 0.995 (recessive resistance). Although Vip3Aa provided high control efficacy against H. zea, the results show a notable increase in ear damage and a number of surviving older larvae, particularly at southern locations. Assuming recessive resistance, the estimated resistance allele frequencies for Vip3Aa ranged from 0.115 in the Gulf states to 0.032 at more northern locations. These findings indicate that better resistance management practices are urgently needed to sustain efficacy the of corn and cotton that produce Vip3Aa.

Generation of Periventricular Reactive Astrocytes Overexpressing Aquaporin 4 Is Stimulated by Mesenchymal Stem Cell Therapy.

Aquaporin-4 (AQP4) plays a crucial role in brain water circulation and is considered a therapeutic target in hydrocephalus. Congenital hydrocephalus is associated with a reaction of astrocytes in the periventricular white matter both in experimental models and human cases. A previous report showed that bone marrow-derived mesenchymal stem cells (BM-MSCs) transplanted into the lateral ventricles of hyh mice exhibiting severe congenital hydrocephalus are attracted by the periventricular astrocyte reaction, and the cerebral tissue displays recovery. The present investigation aimed to test the effect of BM-MSC treatment on astrocyte reaction formation. BM-MSCs were injected into the lateral ventricles of four-day-old hyh mice, and the periventricular reaction was detected two weeks later. A protein expression analysis of the cerebral tissue differentiated the BM-MSC-treated mice from the controls and revealed effects on neural development. In in vivo and in vitro experiments, BM-MSCs stimulated the generation of periventricular reactive astrocytes overexpressing AQP4 and its regulatory protein kinase D-interacting substrate of 220 kDa (Kidins220). In the cerebral tissue, mRNA overexpression of nerve growth factor (NGF), vascular endothelial growth factor (VEGF), hypoxia-inducible factor-1 (HIF1α), and transforming growth factor beta 1 (TGFß1) could be related to the regulation of the astrocyte reaction and AQP4 expression. In conclusion, BM-MSC treatment in hydrocephalus can stimulate a key developmental process such as the periventricular astrocyte reaction, where AQP4 overexpression could be implicated in tissue recovery.

Monocyte-derived cells invade brain parenchyma and amyloid plaques in human Alzheimer's disease hippocampus.

Microglia are brain-resident myeloid cells and play a major role in the innate immune responses of the CNS and the pathogenesis of Alzheimer's disease (AD). However, the contribution of nonparenchymal or brain-infiltrated myeloid cells to disease progression remains to be demonstrated. Here, we show that monocyte-derived cells (MDC) invade brain parenchyma in advanced stages of AD continuum using transcriptional analysis and immunohistochemical characterization in post-mortem human hippocampus. Our findings demonstrated that a high proportion (60%) of demented Braak V-VI individuals was associated with up-regulation of genes rarely expressed by microglial cells and abundant in monocytes, among which stands the membrane-bound scavenger receptor for haptoglobin/hemoglobin complexes or Cd163. These Cd163-positive MDC invaded the hippocampal parenchyma, acquired a microglial-like morphology, and were located in close proximity to blood vessels. Moreover, and most interesting, these invading monocytes infiltrated the nearby amyloid plaques contributing to plaque-associated myeloid cell heterogeneity. However, in aged-matched control individuals with hippocampal amyloid pathology, no signs of MDC brain infiltration or plaque invasion were found. The previously reported microglial degeneration/dysfunction in AD hippocampus could be a key pathological factor inducing MDC recruitment. Our data suggest a clear association between MDC infiltration and endothelial activation which in turn may contribute to damage of the blood brain barrier integrity. The recruitment of monocytes could be a consequence rather than the cause of the severity of the disease. Whether monocyte infiltration is beneficial or detrimental to AD pathology remains to be fully elucidated. These findings open the opportunity to design targeted therapies, not only for microglia but also for the peripheral immune cell population to modulate amyloid pathology and provide a better understanding of the immunological mechanisms underlying the progression of AD.

The Influence of Therapeutic Exercise on Survival and the Quality of Life in Survivorship of Women with Ovarian Cancer.

BACKGROUND: Ovarian cancer is the most difficult of all gynaecological cancers to treat, mainly due to its late diagnosis. Although exercise interventions have been reported to be safe and beneficial for ovarian cancer, treatment does not include it and is usually a combination of chemotherapy and surgery. It is increasingly common to include exercise as a tool to increase survival in the cancer population. The aim of this study was to determine the influence of therapeutic exercise on survival and the quality of life in survivorship in women with ovarian cancer. METHODS: Literature review of clinical trials, reviews and pilot studies compiled in three databases collected in PubMed, PEDro and Scopus. RESULTS: Of the 44 articles found, 10 were selected. Improvements in survival, quality of life and comorbidities associated with ovarian cancer were found with exercise interventions as a treatment tool. CONCLUSIONS: Through the application of therapeutic exercise, improvements in survival and quality of life were observed, as well as in the general symptomatology of ovarian cancer. No adverse effects have been found with its use, but future studies with larger sample sizes with more detailed and individualised interventions combined with conventional treatment are needed.

Aß oligomers trigger necroptosis-mediated neurodegeneration via microglia activation in Alzheimer's disease.

Alzheimer's disease (AD) is a major adult-onset neurodegenerative condition with no available treatment. Compelling reports point amyloid-ß (Aß) as the main etiologic agent that triggers AD. Although there is extensive evidence of detrimental crosstalk between Aß and microglia that contributes to neuroinflammation in AD, the exact mechanism leading to neuron death remains unknown. Using postmortem human AD brain tissue, we show that Aß pathology is associated with the necroptosis effector pMLKL. Moreover, we found that the burden of Aß oligomers (Aßo) correlates with the expression of key markers of necroptosis activation. Additionally, inhibition of necroptosis by pharmacological or genetic means, reduce neurodegeneration and memory impairment triggered by Aßo in mice. Since microglial activation is emerging as a central driver for AD pathogenesis, we then tested the contribution of microglia to the mechanism of Aßo-mediated necroptosis activation in neurons. Using an in vitro model, we show that conditioned medium from Aßo-stimulated microglia elicited necroptosis in neurons through activation of TNF-α signaling, triggering extensive neurodegeneration. Notably, necroptosis inhibition provided significant neuronal protection. Together, these findings suggest that Aßo-mediated microglia stimulation in AD contributes to necroptosis activation in neurons and neurodegeneration. As necroptosis is a druggable degenerative mechanism, our findings might have important therapeutic implications to prevent the progression of AD.

Trade-offs between bycatch and target catches in static versus dynamic fishery closures.

While there have been recent improvements in reducing bycatch in many fisheries, bycatch remains a threat for numerous species around the globe. Static spatial and temporal closures are used in many places as a tool to reduce bycatch. However, their effectiveness in achieving this goal is uncertain, particularly for highly mobile species. We evaluated evidence for the effects of temporal, static, and dynamic area closures on the bycatch and target catch of 15 fisheries around the world. Assuming perfect knowledge of where the catch and bycatch occurs and a closure of 30% of the fishing area, we found that dynamic area closures could reduce bycatch by an average of 57% without sacrificing catch of target species, compared to 16% reductions in bycatch achievable by static closures. The degree of bycatch reduction achievable for a certain quantity of target catch was related to the correlation in space and time between target and bycatch species. If the correlation was high, it was harder to find an area to reduce bycatch without sacrificing catch of target species. If the goal of spatial closures is to reduce bycatch, our results suggest that dynamic management provides substantially better outcomes than classic static marine area closures. The use of dynamic ocean management might be difficult to implement and enforce in many regions. Nevertheless, dynamic approaches will be increasingly valuable as climate change drives species and fisheries into new habitats or extended ranges, altering species-fishery interactions and underscoring the need for more responsive and flexible regulatory mechanisms.

An Unusual Case of Desmoplastic Melanoma With Monster Cells Imitating an Atypical Fibroxanthoma.

Numerous cells with very large and irregular nuclei ("monster" cells) have not hitherto been reported in desmoplastic melanoma (DM). Their prognostic significance in melanomas is a matter of debate, although some authors have associated them with more aggressive tumor behavior. We report a mixed DM on the scalp of an 88-year-old woman imitating an atypical fibroxanthoma. Tumor cells stained positive for SOX10, S100, and cyclin D1; BRAF mutation status was negative, and fluorescence in situ hybridization analysis showed copy number gains in 11q13 (cyclin D1) and 6p25 (RREB1), and loss in 6q23 (MYB). Cyclin D1 amplification is associated with poor prognosis in melanoma.

Plaque-Associated Oligomeric Amyloid-Beta Drives Early Synaptotoxicity in APP/PS1 Mice Hippocampus: Ultrastructural Pathology Analysis.

Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by initial memory impairments that progress to dementia. In this sense, synaptic dysfunction and loss have been established as the pathological features that best correlate with the typical early cognitive decline in this disease. At the histopathological level, post mortem AD brains typically exhibit intraneuronal neurofibrillary tangles (NFTs) along with the accumulation of amyloid-beta (Abeta) peptides in the form of extracellular deposits. Specifically, the oligomeric soluble forms of Abeta are considered the most synaptotoxic species. In addition, neuritic plaques are Abeta deposits surrounded by activated microglia and astroglia cells together with abnormal swellings of neuronal processes named dystrophic neurites. These periplaque aberrant neurites are mostly presynaptic elements and represent the first pathological indicator of synaptic dysfunction. In terms of losing synaptic proteins, the hippocampus is one of the brain regions most affected in AD patients. In this work, we report an early decline in spatial memory, along with hippocampal synaptic changes, in an amyloidogenic APP/PS1 transgenic model. Quantitative electron microscopy revealed a spatial synaptotoxic pattern around neuritic plaques with significant loss of periplaque synaptic terminals, showing rising synapse loss close to the border, especially in larger plaques. Moreover, dystrophic presynapses were filled with autophagic vesicles in detriment of the presynaptic vesicular density, probably interfering with synaptic function at very early synaptopathological disease stages. Electron immunogold labeling showed that the periphery of amyloid plaques, and the associated dystrophic neurites, was enriched in Abeta oligomers supporting an extracellular location of the synaptotoxins. Finally, the incubation of primary neurons with soluble fractions derived from 6-month-old APP/PS1 hippocampus induced significant loss of synaptic proteins, but not neuronal death. Indeed, this preclinical transgenic model could serve to investigate therapies targeted at initial stages of synaptic dysfunction relevant to the prodromal and early AD.

Should We Open Fire on Microglia? Depletion Models as Tools to Elucidate Microglial Role in Health and Alzheimer's Disease.

Microglia play a critical role in both homeostasis and disease, displaying a wide variety in terms of density, functional markers and transcriptomic profiles along the different brain regions as well as under injury or pathological conditions, such as Alzheimer's disease (AD). The generation of reliable models to study into a dysfunctional microglia context could provide new knowledge towards the contribution of these cells in AD. In this work, we included an overview of different microglial depletion approaches. We also reported unpublished data from our genetic microglial depletion model, Cx3cr1CreER/Csf1rflx/flx, in which we temporally controlled microglia depletion by either intraperitoneal (acute model) or oral (chronic model) tamoxifen administration. Our results reported a clear microglial repopulation, then pointing out that our model would mimic a context of microglial replacement instead of microglial dysfunction. Next, we evaluated the origin and pattern of microglial repopulation. Additionally, we also reviewed previous works assessing the effects of microglial depletion in the progression of Aß and Tau pathologies, where controversial data are found, probably due to the heterogeneous and time-varying microglial phenotypes observed in AD. Despite that, microglial depletion represents a promising tool to assess microglial role in AD and design therapeutic strategies.

Mitotic count: A need for standardization.

PURPOSE: The mitotic count (MC), number of mitosis per unit area, is a very important parameter frequently used for classification and grading of some tumors. Traditionally, the MC has been expressed in terms of number of mitoses per high power field. The size of the field of view can vary greatly among different microscopes. In order to avoid under or overestimation of mitotic count, a conversion needs to be made. METHODS: A simple formula based on a simple rule of three has been devised to standardize the mitotic count to the reference area by multiplying the number of mitotic figures by a correction factor which has been calculated for the most frequently used microscopes and various common tumors. RESULTS AND CONCLUSIONS: We propose this simple method, which involves only a single multiplication, to standardize the mitotic count to the reference area.

Influence of Biometric and Seasonal Parameters on the Metal Content of Scomber colias in Northwestern African Waters.

Studies of the content of heavy metals and trace elements in fish and other marine organisms are of great importance to know the state of the marine ecosystem. This study has been carried out in northwestern African waters, Scomber colias being the target species, sampling a total of 345 specimens over 2 years. For the determination of metals and trace elements (Al, B, Cd, Cr, Cu, Fe, Li, Ni, Pb, V, and Zn) in the muscle, the ICP-OES (inductively coupled plasma optical emission spectrometry) was used. In the statistical study, the factors (oceanographic and maturity in the seasons, size of the specimens) were used. The samples sampled in the cold season that had high concentrations of metals may be due to the influence that African upwelling has on the Canary Islands. The metallic contents of our samples are lower than those found in the studies in Mauritania and Morocco due to the greater influence that upwelling has in these areas.

Amyloid-ß impairs the phagocytosis of dystrophic synapses by astrocytes in Alzheimer's disease.

Reactive astrocytes and dystrophic neurites, most aberrant presynaptic elements, are found surrounding amyloid-ß plaques in Alzheimer's disease (AD). We have previously shown that reactive astrocytes enwrap, phagocytose, and degrade dystrophic synapses in the hippocampus of APP mice and AD patients, but affecting less than 7% of dystrophic neurites, suggesting reduced phagocytic capacity of astrocytes in AD. Here, we aimed to gain insight into the underlying mechanisms by analyzing the capacity of primary astrocyte cultures to phagocytose and degrade isolated synapses (synaptoneurosomes, SNs) from APP (containing dystrophic synapses and amyloid-ß peptides), Tau (containing AT8- and AT100-positive phosphorylated Tau) and WT (controls) mice. We found highly reduced phagocytic and degradative capacity of SNs-APP, but not AT8/AT100-positive SNs-Tau, as compared with SNs-WT. The reduced astrocyte phagocytic capacity was verified in hippocampus from 12-month-old APP mice, since only 1.60 ± 3.81% of peri-plaque astrocytes presented phagocytic structures. This low phagocytic capacity did not depend on microglia-mediated astrocyte reactivity, because removal of microglia from the primary astrocyte cultures abrogated the expression of microglia-dependent genes in astrocytes, but did not affect the phagocytic impairment induced by oligomeric amyloid-ß alone. Taken together, our data suggest that amyloid-ß, but not hyperphosphorylated Tau, directly impairs the capacity of astrocytes to clear the pathological accumulation of oligomeric amyloid-ß, as well as of peri-plaque dystrophic synapses containing amyloid-ß, perhaps by reducing the expression of phagocytosis receptors such as Mertk and Megf10, thus increasing neuronal damage in AD. Therefore, the potentiation or recovery of astrocytic phagocytosis may be a novel therapeutic avenue in AD.

A remarkable Newportia from the Colombian Andes, with the proposition of a new subgenus (Scolopendromorpha, Scolopocryptopidae, Newportiinae).

A new monotypic subgenus Newportia (Andeocryptops) subgen. n is described based on 18 specimens of N. (A.) shelleyi sp. n. This form is endemic to the Colombian Andes showing the following unique combination of morphological features: very short and thin, a cylindrical and not segmented ultimate tarsus 2, a "spinning-spur" (see below) on the ultimate tarsus 1, short paramedian sutures close to the anterior and posterior margins of cephalic plate, a tibial lateral spur and a glandular pore fields in the ultimate femur. An identification key to the Newportia subgenera, as well as a key to the Ectonocryptops, Ectonocryptoides and Andeocryptops species are included.