Complete Loss Research Articles

Neuroimaging features of WOREE syndrome: a mini-review of the literature.

The WWOX gene encodes a 414-amino-acid protein composed of two N-terminal WW domains and a C-terminal short-chain dehydrogenase/reductase (SDR) domain. WWOX protein is highly conserved among species and mainly expressed in the cerebellum, cerebral cortex, brain stem, thyroid, hypophysis, and reproductive organs. It plays a crucial role in the biology of the central nervous system, and it is involved in neuronal development, migration, and proliferation. Biallelic pathogenic variants in WWOX have been associated with an early infantile epileptic encephalopathy known as WOREE syndrome. Both missense and null variants have been described in affected patients, leading to a reduction in protein function and stability. The most severe WOREE phenotypes have been related to biallelic null/null variants, associated with the complete loss of function of the protein. All affected patients showed brain anomalies on magnetic resonance imaging (MRI), suggesting the pivotal role of WWOX protein in brain homeostasis and developmental processes. We provided a literature review, exploring both the clinical and radiological spectrum related to WWOX pathogenic variants, described to date. We focused on neuroradiological findings to better delineate the WOREE phenotype with diagnostic and prognostic implications.

Complete or partial loss of the Y chromosome in an unselected cohort of 865 non-vasectomized, azoospermic men

BackgroundStructural abnormalities as well as minor variations of the Y chromosome may cause disorders of sex differentiation or, more frequently, azoospermia. This study aimed to determine the prevalence of loss of Y chromosome material within the spectrum ranging from small microdeletions in the azoospermia factor region (AZF) to complete loss of the Y chromosome in azoospermic men.ResultsEleven of 865 azoospermic men (1.3%) collected from 1997 to 2022 were found to have a karyotype including a 45,X cell line. Two had a pure 45,X karyotype and nine had a 45,X/46,XY mosaic karyotype. The AZF region, or part of it, was deleted in eight of the nine men with a structural abnormal Y-chromosome. Seven men had a karyotype with a structural abnormal Y chromosome in a non-mosaic form. In addition, Y chromosome microdeletions were found in 34 men with a structural normal Y chromosome. No congenital malformations were detected by echocardiography and ultrasonography of the kidneys of the 11 men with a 45,X mosaic or non-mosaic cell line.ConclusionsIn men with azoospermia, Y chromosome loss ranging from small microdeletions to complete loss of the Y chromosome was found in 6.1% (53/865). Partial AZFb microdeletions may give a milder testicular phenotype compared to complete AZFb microdeletions.

Beyond boundaries: new perspectives on Italian communist historiography

In 1989, the Italian Communist Party (PCI) was going through a period of transition. The fall of the Berlin Wall posed an enormous challenge to Marxist beliefs and the communist political project. In this situation, party secretary Achille Occhetto and his close collaborators planned to embark on a new social-democratic path, as a significant part of the elderly leaders and rank-and-file members feared the abandonment of communist ideals. ‘We are a different party … and I continue to believe it,’ a Milanese communist militant shouted while Nanni Moretti was shooting La Cosa (1990), a documentary about the last days of the PCI, crystallising the perceived sense of uniqueness and diversity that pervaded Italian communism despite the complete loss of meaning for the communist movement worldwide.

The efficacy of intranasal leptin for opioid-induced respiratory depression depends on sex and obesity state.

Introduction: Opioid-induced respiratory depression (OIRD) is the primary cause of death associated with opioids and individuals with obesity are particularly susceptible due to comorbid obstructive sleep apnea (OSA). Repeated exposure to opioids, as in the case of pain management, results in diminished therapeutic effect and/or the need for higher doses to maintain the same effect. With limited means to address the negative impact of repeated exposure it is critical to develop drugs that prevent deaths induced by opioids without reducing beneficial analgesia. Methods: We hypothesized that OIRD as a result of chronic opioid use can be attenuated by administration of IN leptin while also maintaining analgesia in both lean mice and mice with diet-induced obesity (DIO) of both sexes. To test this hypothesis, an opioid tolerance protocol was developed and a model of OIRD in mice chronically receiving morphine and tolerant to morphine analgesia was established. Subsequently, breathing was recorded by barometric plethysmography in four experimental groups: obese male, obese female, lean male, and lean female following acute administration of IN leptin. Respiratory data were complemented with measures of arterial blood gas. Operant behavioral assays were used to determine the impact of IN leptin on the analgesic efficacy of morphine. Results: Acute administration of IN leptin significantly attenuated OIRD in DIO male mice decreasing the apnea index by 58.9% and apnea time by 60.1%. In lean mice leptin was ineffective. Blood gas measures confirmed the effectiveness of IN leptin for preventing respiratory acidosis in DIO male mice. However, IN leptin was not effective in lean mice of both sexes and appeared to exacerbate acid-base disturbances in DIO female mice. Additionally, morphine caused a complete loss of temperature aversion which was not reduced by intranasal leptin indicating IN leptin does not decrease morphine analgesia. Discussion: IN leptin effectively treated OIRD in morphine-tolerant DIO male mice without impacting analgesia. In contrast, IN leptin had no effect in lean mice of either sex or DIO female mice. The arterial blood gas data were consistent with ventilatory findings showing that IN leptin reversed morphine-induced respiratory acidosis only in DIO male mice but not in other mouse groups. Finally, a hypercapnic sensitivity study revealed that IN leptin rescued minute ventilation under hypercapnic conditions only in DIO male mice, which suggests that differential responses to IN leptin are attributable to different leptin sensitivities depending on sex and the obesity status.

Insight into chloroplast genome structural variation of the Mongolian endemic species Adonis mongolica (Ranunculaceae) in the Adonideae tribe

Adonis mongolica is a threatened species that is endemic to Mongolia. It is a medicinal plant from the Adonis genus and has been used to treat heart diseases. However, the genomics and evolution of this species have not been thoroughly studied. We sequenced the first complete plastome of A. mongolica and compared it with ten Adonideae species to describe the plastome structure and infer phylogenetic relationships. The complete plastome of A. mongolica was 157,521 bp long and had a typical quadripartite structure with numerous divergent regions. The plastomes of Adonideae had relatively constant genome structures and sizes, except for those of Adonis. The plastome structure was consistent across Adonis. We identified a 44.8 kb large-scale inversion within the large single-copy region and rpl32 gene loss in the Adonis plastomes compared to other members of the Adonideae tribe. Additionally, Adonis had a smaller plastome size (156,917–157,603 bp) than the other genera within the tribe (159,666–160,940 bp), which was attributed to deletions of intergenic regions and partial and complete gene losses. These results suggested that an intramolecular mutation occurred in the ancestor of the Adonis genus. Based on the phylogenetic results, Adonis separated earlier than the other genera within the Adonideae tribe. The genome structures and divergences of specific regions in the Adonis genus were unique to the Adonideae tribe. This study provides fundamental knowledge for further genomic research in Mongolia and a better understanding of the evolutionary history of endemic plants.

Synergistic effects of putative Ca2+-binding sites of calmodulin in fungal development, temperature stress and virulence of Aspergillus fumigatus

ABSTRACT In pathogenic fungi, calcium-calmodulin-dependent serine-threonine-specific phosphatase calcineurin is involved in morphogenesis and virulence. Therefore, calcineurin and its tightly related protein complexes are attractive antifungal drug targets. However, there is limited knowledge available on the relationship between in vivo Ca2+-binding sites of calmodulin (CaM) and its functions in regulating stress responses, morphogenesis, and pathogenesis. In the current study, we demonstrated that calmodulin is required for hyphal growth, conidiation, and virulence in the human fungal pathogen, Aspergillus fumigatus. Site-directed mutations of calmodulin revealed that a single Ca2+-binding site mutation had no significant effect on A. fumigatus hyphal development, but multiple Ca2+-binding site mutations exhibited synergistic effects, especially when cultured at 42 °C, indicating that calmodulin function in response to temperature stress depends on its Ca2+-binding sites. Western blotting implied that mutations in Ca2+-binding sites caused highly degraded calmodulin fragments, suggesting that the loss of Ca2+-binding sites results in reduced protein stability. Moreover, normal intracellular calcium homeostasis and the nuclear translocation of the transcriptional factor CrzA are dependent on Ca2+-binding sites of AfCaM, demonstrating that Ca2+-binding sites of calmodulin are required for calcium signalling and its major transcription factor CrzA. Importantly, in situ mutations for four Ca2+-binding sites of calmodulin resulted in an almost complete loss of virulence in the Galleria mellonella wax moth model. This study shed more light on the functional characterization of putative calcium-binding sites of calmodulin in the morphogenesis and virulence of A. fumigatus, which enhances our understanding of calmodulin biological functions in cells of opportunistic fungal pathogens.

Patterns of surgical complications after delayed fixation of peripartum pubic symphysis rupture: a report of 5 cases

BackgroundThe disruption of the pubic symphysis during the peripartum period is a rare injury to the pelvic ring. In most cases, conservative treatment is successful. Nonetheless, there are cases where surgical intervention is necessary. We analyzed five surgical cases treated in our department and performed a literature review.Case presentationsFive women, ranging in age from 25 to 38, who experienced peripartum symphysis rupture were primarily treated with a conservative approach. Patients who did not show improvement and met certain criteria, such as experiencing pain starting from childbirth, having a separation in the pubic bone of more than 10 mm, and/or having a vertical instability greater than 5 mm, were recommended to undergo surgery. The average length of time between childbirth and surgery was 5.6 months, ranging from 1 to 14 months. One patient was treated with an external fixator, another patient received a combination of an external fixator and an anterior plate, and three patients were treated with anterior plates. In four cases, we observed a failure in fixation and a partial or complete loss of reduction. The plate and screws were removed in one case, and in three cases, revision surgery was performed. One case involved using a larger plate, while the other used 90-90 plating, known as “box plate fixation.” The mean follow-up was 7.4 years. Two cases had good results, and two had excellent results on the Lindahl scale.ConclusionFor patients with peripartum pubic symphyseal dislocation, our case series and literature review demonstrated that early reduction and fixation correlate with improved clinical outcomes and lower implant failure. For patients with subacute/chronic injuries, there was a higher incidence of implant failure. Orthogonal plate fixation and/or pubic symphysiodesis was associated with improved clinical outcomes.

Genomics of Preaxostyla Flagellates Illuminates the Path Towards the Loss of Mitochondria.

The notion that mitochondria cannot be lost was shattered with the report of an oxymonad Monocercomonoides exilis, the first eukaryote arguably without any mitochondrion. Yet, questions remain about whether this extends beyond the single species and how this transition took place. The Oxymonadida is a group of gut endobionts taxonomically housed in the Preaxostyla which also contains free-living flagellates of the genera Trimastix and Paratrimastix. The latter two taxa harbour conspicuous mitochondrion-related organelles (MROs). Here we report high-quality genome and transcriptome assemblies of two Preaxostyla representatives, the free-living Paratrimastix pyriformis and the oxymonad Blattamonas nauphoetae. We performed thorough comparisons among all available genomic and transcriptomic data of Preaxostyla to further decipher the evolutionary changes towards amitochondriality, endobiosis, and unstacked Golgi. Our results provide insights into the metabolic and endomembrane evolution, but most strikingly the data confirm the complete loss of mitochondria for all three oxymonad species investigated (M. exilis, B. nauphoetae, and Streblomastix strix), suggesting the amitochondriate status is common to a large part if not the whole group of Oxymonadida. This observation moves this unique loss to 100 MYA when oxymonad lineage diversified.

Evolution of runoff components and groundwater discharge under rapid climate warming: Lhasa river basin, Tibetan Plateau

The Tibetan Plateau (TP) is known as the world's third pole and an Asian water tower. Accelerated climate warming on the TP results in glacier retreat and runoff variations. Previous studies on the cryosphere of the TP mainly focused on the impact of climate warming on surface water, and studies on groundwater changes in response to climate warming are limited. In this study, we combine climate change, glacier, snow, surface water, and groundwater into a fully integrated surface–subsurface model based on HydroGeoSphere (HGS) for the Lhasa River basin (LRB), a catchment on the TP undergoing rapid glacier retreat. The model is used to predict river discharge and groundwater evolutions in the LRB from 2021 to 2100. Glacier melt runoff will reach its peak water by the 2060 s under the SSP2-4.5 scenario. Under the SSP5-8.5 scenario, temperature is predicted to rise sharply, leading to almost complete loss of the glaciers by 2100. The annual total runoff will increase consistently as rainfall runoff and groundwater discharge increase from 2020 to 2100 under the SSP2-4.5 and SSP5-8.5 scenarios. Consistent groundwater discharge can compensate the loss of glacier melt and snowmelt runoff to some extent. Groundwater discharge of the LRB will change substantially in response to climate warming in the future, especially in the Yangbajing sub-basin. Average hydraulic heads will increase by 0.130 m and 0.129 m per decade under the SSP2-4.5 and SSP5-8.5 scenarios, respectively. The results of this study will improve our understanding of the important role of groundwater in hydrological processes of alpine watersheds in response to climate change.

The diagnostic utility of methylthioadenosine phosphorylase immunohistochemistry for pancreatic ductal adenocarcinoma in FNA and small biopsy specimens.

Accurate diagnosis of pancreatic lesions by endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) or fine-needle biopsy can be challenging. Although surrogate immunohistochemical markers for genetic alterations associated with pancreatic ductal adenocarcinoma (PDAC) have been identified, they have modest sensitivity. Biallelic loss of CDKN2A occurs in up to 46% of PDACs, and methylthioadenosine phosphorylase (MTAP) immunohistochemistry (IHC) has been identified as a reliable surrogate marker for this alteration. The current study evaluates the utility of MTAP IHC for the diagnosis of PDAC. In total, 136 cases of EUS-FNA cell block or core biopsy targeting solid pancreatic masses were identified. MTAP IHC was performed and evaluated for complete loss of expression in neoplastic cells. These results were correlated with available clinical next-generation sequencing that was performed on a subset of cases. Complete loss of MTAP expression was identified in 23 of 80 (29%) PDACs. A subset of cases classified as suspicious (4 of 21) and atypical (4 of 22) showed MTAP loss. All morphologically indeterminate cases with MTAP loss were confirmed as PDAC on resection/additional sampling. No benign samples (n=13) showed loss of MTAP. In samples that had available clinical next-generation sequencing data (n=13), copy number loss of CDKN2A was detected in all cases that had loss of MTAP expression (n=4). Loss of MTAP was identified in approximately 30% of PDAC small biopsy specimens. As loss of MTAP expression is not expected in nonneoplastic cells, and these findings suggest that MTAP IHC can support a diagnosis of PDAC in small biopsy samples.

Climate Change Habitat Model Forecasts for Eight Owl Species in the Southwestern US.

The high-resolution forecasting of vegetation type shifts may prove essential in anticipating and mitigating the impacts of future climate change on bird populations. Here, we used the US Forest Service Ecological Response Unit (ERU) classification to develop and assess vegetation-based breeding habitat profiles for eight owl species occurring in the foothills and mountains of the Southwestern US. Shifts in mapped habitat were forecast using an ecosystem vulnerability model based on the pre-1990 climate envelopes of ERUs and the Intergovernmental Panel on Climate Change's (IPCC) A1B moderate-emission scenario for the future climate. For five of the eight owl species, the regional breeding habitat extent was projected to decline by at least 60% by 2090. Three species, the boreal owl (Aegolius funereus; at the trailing edge of its distribution), flammulated owl (Psiloscops flammeolus), and northern pygmy-owl (Glaucidium gnoma), were projected to experience the steepest habitat loss rates of 85%, 85%, and 76%, respectively. Projected vegetation shifts overlaid with well-documented flammulated owl breeding populations showed the complete or near complete loss of habitat by 2090 in areas of montane forest currently supporting dense aggregations of owl territories. Generalist or lower-elevation owl species were predicted to be less impacted, while, for the whiskered screech-owl (Megascops trichopsis), the contraction of the current habitat was nearly offset by a projected northward expansion. In general, the results of this study suggest high exposure to climate change impacts for the upper-elevation forest owls of semi-arid Southwestern North America. Long-distance migration and low natal philopatry may prove important to some montane owl populations in adapting to the regional loss of habitat.

Signal regulatory protein beta 2 is a novel positive regulator of innate anticancer immunity.

In recent years, the therapeutic (re)activation of innate anticancer immunity has gained prominence, with therapeutic blocking of the interaction of Signal Regulatory Protein (SIRP)-α with its ligand CD47 yielding complete responses in refractory and relapsed B cell lymphoma patients. SIRP-α has as crucial inhibitory role on phagocytes, with e.g., its aberrant activation enabling the escape of cancer cells from immune surveillance. SIRP-α belongs to a family of paired receptors comprised of not only immune-inhibitory, but also putative immune-stimulatory receptors. Here, we report that an as yet uninvestigated SIRP family member, SIRP-beta 2 (SIRP-ß2), is strongly expressed under normal physiological conditions in macrophages and granulocytes at protein level. Endogenous expression of SIRP-ß2 on granulocytes correlated with trogocytosis of cancer cells. Further, ectopic expression of SIRP-ß2 stimulated macrophage adhesion, differentiation and cancer cell phagocytosis as well as potentiated macrophage-mediated activation of T cell Receptor-specific T cell activation. SIRP-ß2 recruited the immune activating adaptor protein DAP12 to positively regulate innate immunity, with the charged lysine 202 of SIRP-ß2 being responsible for interaction with DAP12. Mutation of lysine 202 to leucine lead to a complete loss of the increased adhesion and phagocytosis. In conclusion, SIRP-ß2 is a novel positive regulator of innate anticancer immunity and a potential costimulatory target for innate immunotherapy.

The Gβ-like protein Bcgbl1 regulates development and pathogenicity of the gray mold Botrytis cinerea via modulating two MAP kinase signaling pathways.

The fungal Gβ-like protein has been reported to be involved in a variety of biological processes, such as mycelial growth, differentiation, conidiation, stress responses and infection. However, molecular mechanisms of the Gβ-like protein in regulating fungal development and pathogenicity are largely unknown. Here, we show that the Gβ-like protein gene Bcgbl1 in the gray mold fungus Botrytis cinerea plays a pivotal role in development and pathogenicity by regulating the mitogen-activated protein (MAP) kinases signaling pathways. The Bcgbl1 deletion mutants were defective in mycelial growth, sclerotial formation, conidiation, macroconidial morphogenesis, plant adhesion, and formation of infection cushions and appressorium-like structures, resulting in a complete loss of pathogenicity. Bcgbl1 interacted with BcSte50, the adapter protein of the cascade of MAP kinase (MAPK). Bcgbl1 mutants had reduced phosphorylation levels of two MAPKs, namely Bmp1 and Bmp3, thereby reducing infection. However, deletion of Bcgbl1 did not affect the intracellular cAMP level, and exogenous cAMP could not restore the defects. Moreover, Bcgbl1 mutants exhibited defects in cell wall integrity and oxidative stress tolerance. Transcriptional profiling revealed that Bcgbl1 plays a global role in regulation of gene expression upon hydrophobic surface induction. We further uncovered that three target genes encoding the hydrophobic surface binding proteins (HsbAs) contributed to the adhesion and virulence of B. cinerea. Overall, these findings suggest that Bcgbl1 had multiple functions and provided new insights for deciphering the Bcgbl1-mediated network for regulating development and pathogenicity of B. cinerea.

Enhanced bioremediation of pesticides contaminated soil using organic (compost) and inorganic (NPK) fertilizers

This research examined the bioremediation of pesticides (Carbofuran and Paraquat) contaminated farmyard soil using compost and Nitrogen, Phosphorus, and Potassium (NPK) fertilizer. Microcosms representing each treatment were set-up in triplicates. Biostimulation was done using two concentrations (0.5 % and 1.0 % w/w) of NPK fertilizer and compost, following pesticides application at recommended rates [Carbofuran (1 g/kg) and Paraquat (5 ml/kg)] and four times the recommended rates. Two control soils were set-up; Abiotic control (sterile farmyard soil + pesticide) and Control (farmyard soil without treatment). Monitoring of the dynamics in microbial community abundance, and pesticide residues during the biostimulation period was done weekly for 28 days, using standard enumeration method, and High Performance Liquid Chromatography (HPLC), respectively. At the end of the monitoring period, considerable reduction in pesticide residues across the treatment set-ups was recorded. In Carbofuran-treated soils, there were no complete, but considerable losses in residual pesticide, however, in most of the Paraquat-treated soils, there were complete losses within 21 days. Lower pesticide residues were recorded in set-ups amended with compost than NPK, across both Carbofuran and Paraquat-treated soils. After pesticides application, decreases in microbial counts were recorded at Day 7 across all the treatments, followed by increases from Day 14–21, then decreases at Day 28. Microbial counts were lower in Carbofuran than in Paraquat-treated soils irrespective of nutrient (compost and NPK) amendments. Bacterial and fungal counts were in the magnitude of 106 and 105 CFU/g soil, respectively. Also, increased counts were recorded for Actinomycetes, Nitrifiers, Phosphate solubilizers across all treatments, and were in magnitude of 103–104 CFU/g soil. Soil microorganisms could breakdown and eliminate large concentrations of Carbofuran and Paraquat in compost-amended soils than in NPK-amended soils. This study suggests that bioremediation of pesticides contaminated soils can be achieved and enhanced by stimulating the indigenous microbial community with requisite nutrients (compost).

A new therapeutic approach to Tauopathies: targeting presynaptic tau with antisense oligonucleotides to Synaptogyrin‐3

AbstractBackgroundThe protein Tau is central to several neurodegenerative disorders (“tauopathies”). “Tau‐tangles” (aggregations of the Tau protein) are a key hallmark of Alzheimer’s and many other diseases and Tau‐protein is mutated in several forms of dementia. In all these conditions, Tau causes complex, multifactorial defects in neurons that lead to cognitive decline. Under normal conditions, Tau is attached to axonal microtubules, but under pathogenic conditions it detaches and spreads throughout the neuron, including synapses. Work from my lab indicated that when Tau is present at pre‐synaptic terminals it binds to and clusters synaptic vesicles and identified Synaptogyrin‐3 as a physical interactor of Tau. My lab demonstrated that the partial loss of Synaptogyrin‐3 (Syngr3) restores working memory and rescues synaptic degeneration in mice that express pathogenic P301S Tau (“PS19”), a well‐accepted model for tauopathy that recapitulates features seen in patients, including synaptic loss, neuroinflammation and cognitive decline. Partial (and complete) loss of Syngr3 is benign in mice and fruit flies. Based on this, we pursued a radical alternative and innovative approach, supported by strong pre‐clinical data, to tackle Tau‐induced cognitive decline.MethodWe designed and synthetized oligonucleotides covering the whole Syngr3 transcript, and tested their activity in Neuro2A cells and primary cortical murine neurons in transfection and unassisted uptake conditions.ResultThrough this screen we found several active molecules, that were able to significantly downregulate Syngr3 transcript and protein levels. To find the best candidates, we performed dose‐response curves and time course evaluations in primary murine neurons, and we found several molecules that targeted different regions of the Syngr3 transcript with good activity, potency, and no evident toxic effects.ConclusionWe found several molecules that induce an effective and sustained reduction of Syngr3 expression. As part of the pre‐clinical evaluation, these molecules will be tested in vivo in PK/PD and acute toxicity studies in WT mice, to determine the best administration dosage and therapeutic window. Finally, we will evaluate the effect of our best candidates in a therapeutic setting, treating PS19 tau mice to assess if the acute removal of the protein can alleviate presynaptic tau toxicity and revert tau induced synaptic and cognitive defects.

Abstract C074: VPS34 inhibition delays activation-induced STING degradation to prolong STING signaling and improve anti-tumor efficacy in preclinical models

Abstract Background: The STING/interferon (IFN) response pathway has been a target of cancer immunotherapy for many years, as a method for reactivating the anti-tumor immune response. Stimulation of the STING pathway leads to activation and infiltration of immune cells into the tumor, and cancer cell death. However, multiple STING agonists have failed in the clinic due to poor efficacy or toxicity1. STING activation leads to its degradation within a few hours through trafficking to the lysosome, as a mechanism to control immune cell hyperactivation2. Although this safety mechanism is important for preventing autoimmunity and chronic inflammation, it diminishes the continuous activation of immune-mediated cancer cell killing, especially in an immunosuppressive tumor microenvironment. VPS34 is a lipid kinase which plays an integral role in endosomal trafficking and autophagy3. Previous publications have demonstrated a role for VPS34 inhibition in increased effector immune cell infiltration, which synergizes with anti-PD1 therapy, demonstrating a link to immune activation4. Herein, we demonstrate that the in vivo combination efficacy with a VPS34 inhibitor and a STING agonist is due to reduced degradation of activated STING, through the inhibition of VPS34-mediated endosomal trafficking. Materials and Methods: Cancer cell lines were cultured using recommended medium. STING activity was measured by Western blot and via a CisBio pTBK1 kit. ADU-S100/MSA-2 were sourced from MedChemExpress. CCL5, CXCL10 and IFNb ELISA’s were purchased from R&D systems. Primers used to measure mRNA expression were obtained from IDT. Results: DP-9244 is a potent and selective VPS34 inhibitor. The combination of DP-9244 with the STING agonist, ADU-S100, enhances IFN-mediated gene expression and cytokine secretion in the murine melanoma cell line, B16F10, and in the human and murine myeloid cell lines THP-1 and DC2.4, demonstrating combination activity in both cancer and immune cells. This combination activity is STING-dependent as demonstrated by the complete loss of IRF and NFκB activity in the THP-1 STING-/- cell line when treated with ADU-S100, DP-9244 or the combination. Mechanistically, VPS34 inhibition delays degradation of activated STING and prolongs downstream signaling of pTBK1 in multiple human and murine cancer cell lines. Importantly, the in vitro effects extend to in vivo efficacy in the B16F10 model, in which the combination of DP-9244 and ADU-S100 results in increased tumor growth control and number of mice responding to treatment. Conclusions: These data provide a strong preclinical rationale to combine a VPS34 inhibitor with a STING agonist as a method of improving STING pathway mediated anti-tumor efficacy.

Molluscan Genomes Reveal Extensive Differences in Photopigment Evolution Across the Phylum.

In animals, opsins and cryptochromes are major protein families that transduce light signals when bound to light-absorbing chromophores. Opsins are involved in various light-dependent processes, like vision, and have been co-opted for light-independent sensory modalities. Cryptochromes are important photoreceptors in animals, generally regulating circadian rhythm, they belong to a larger protein family with photolyases, which repair UV-induced DNA damage. Mollusks are great animals to explore questions about light sensing as eyes have evolved multiple times across, and within, taxonomic classes. We used molluscan genome assemblies from 80 species to predict protein sequences and examine gene family evolution using phylogenetic approaches. We found extensive opsin family expansion and contraction, particularly in bivalve xenopsins and gastropod Go-opsins, while other opsins, like retinochrome, rarely duplicate. Bivalve and gastropod lineages exhibit fluctuations in opsin repertoire, with cephalopods having the fewest number of opsins and loss of at least 2 major opsin types. Interestingly, opsin expansions are not limited to eyed species, and the highest opsin content was seen in eyeless bivalves. The dynamic nature of opsin evolution is quite contrary to the general lack of diversification in mollusk cryptochromes, though some taxa, including cephalopods and terrestrial gastropods, have reduced repertoires of both protein families. We also found complete loss of opsins and cryptochromes in multiple, but not all, deep-sea species. These results help set the stage for connecting genomic changes, including opsin family expansion and contraction, with differences in environmental, and biological features across Mollusca.

Association of Gut Microbiome with Diabetes Mellitus and Alzheimer’s Disease in a Puerto Rican Adult Population: A Preliminary Report

AbstractBackgroundAlzheimer’s disease (AD) is the most common cause of dementia, consisting in a highly debilitating disorder, progressing from slight memory impairments to a complete loss of mental function, resulting in significant disability and death. In Puerto Rico, AD is the fourth leading cause of death. Caribbean Hispanics, including Puerto Ricans living on the island have shown a more severe AD symptomatology and disease mortality than any other ethnic group. This disparity may be due to health, diet, lifestyle, socioeconomic risk factors and more prevalent chronic health conditions such as diabetes in Hispanic people. Diabetes Mellitus is nowadays considered a risk factor for AD. Evidence suggests that the gut microbiome plays a role in the pathophysiology of AD through neuroinflammation and amyloid deposition leading to cognitive impairment. Main objective: Study the microbiome composition and diversity of Puerto Ricans with AD compared to cognitive‐intact controls in association with Diabetes Mellitus.MethodFifty‐three participants (n = 53), 28 with AD and 25 controls were evaluated clinically and cognitively with the Montreal Cognitive Assessment (MoCA) to associate the gut microbiome with cognitive impairment. Stool was collected for genomic DNA extractions and microbiome characterization. NextGen Illumina MiSeq was used to sequence 16S rRNA genes (V4 region) and analyzed with standard pipelines.ResultNo statistically significant differences in bacterial diversity and richness between AD vs. controls. We found slight differences in composition, including an abundance of Euryachaeota in AD, while controls had higher levels of Bacteroidetes. Compared to cognitively intact, a decrease in gut microbiome diversity was seen among participants with cognitive decline (p = 0.02). Roseburia (butyrate producing bacteria) seems to decrease with cognitive impairment severity. Diabetics have significantly reduced Anaerostipes and Ruminococcus also butyrate producing bacteria. AD participants with/without Diabetes have predominance of Euryarchaeota. Controls with Diabetes have more Proteobacteria and Bacteroidetes compared to cognitively impaired.ConclusionBoth Diabetes and neurocognitive decline appear to reduce butyrate‐producing bacterias, which may be related to a decrease in the homeostasis of the gut‐brain axis and lead to microbiome dysbiosis in the setting of disease. A better understanding of the gut microbiome will be an invaluable approach for development of modulation‐based therapeutic interventions.

Multi-decadal degradation and fragmentation of palsas and peat plateaus in coastal Labrador, northeastern Canada

Peatland permafrost landforms, such as palsas and peat plateaus, often represent the most southern lowland permafrost occurrences in the Northern Hemisphere. While peatland permafrost is often found in continental conditions, over a thousand permafrost peatlands were recently identified along the previously understudied coastline of the Labrador Sea in northeastern Canada. The vulnerability of these landscapes to thaw is unknown but is expected to have hydrological and ecological impacts on important caribou habitat, the abundance of culturally relevant berries, and permafrost carbon storage. Using a combination of aerial photography (from 1948, 1985, 1992, 1994, and 2021) and high-resolution satellite imagery (from 2017, 2020, and 2021), we assess multi-decadal areal changes to peatland permafrost landforms at seven peatlands along the Labrador Sea coastline spanning from Red Bay (51.7° N) to north of Hopedale (55.7° N). Analyses reveal declines in permafrost extent of 33%–93% at individual sites, occurring at mean rates of 0.8%–1.5%/a. Permafrost loss was found to occur most rapidly at mixed palsa and peat plateau sites (mean rate of 1.4%/a), followed by palsa sites (mean rate of 1.2%/a) and peat plateau sites (mean rate of 0.9%/a). Patterns of permafrost loss also differed between landform types, with more complete loss of individual landforms at palsa sites and more lateral and internal loss of existing landforms at peat plateau and mixed sites. This widespread degradation of peatland permafrost over the past 28–73 years is attributed to regional warming and peatland greening. Understanding recent change to permafrost peatlands in coastal Labrador is an important step towards predicting future habitat change in northeastern Canada and will inform regional land management in areas dominated by these culturally important landforms.

Multisensory gaze stabilization in response to subchronic alteration of vestibular type I hair cells

The functional complementarity of the vestibulo-ocular reflex (VOR) and optokinetic reflex (OKR) allows for optimal combined gaze stabilization responses (CGR) in light. While sensory substitution has been reported following complete vestibular loss, the capacity of the central vestibular system to compensate for partial peripheral vestibular loss remains to be determined. Here, we first demonstrate the efficacy of a 6-week subchronic ototoxic protocol in inducing transient and partial vestibular loss which equally affects the canal- and otolith-dependent VORs. Immunostaining of hair cells in the vestibular sensory epithelia revealed that organ-specific alteration of type I, but not type II, hair cells correlates with functional impairments. The decrease in VOR performance is paralleled with an increase in the gain of the OKR occurring in a specific range of frequencies where VOR normally dominates gaze stabilization, compatible with a sensory substitution process. Comparison of unimodal OKR or VOR versus bimodal CGR revealed that visuo-vestibular interactions remain reduced despite a significant recovery in the VOR. Modeling and sweep-based analysis revealed that the differential capacity to optimally combine OKR and VOR correlates with the reproducibility of the VOR responses. Overall, these results shed light on the multisensory reweighting occurring in pathologies with fluctuating peripheral vestibular malfunction.