The mARS complex: a critical mediator of immune regulation and homeostasis.

Over the course of evolution, many proteins have undergone adaptive structural changes to meet the increasing homeostatic regulatory demands of multicellularity. Aminoacyl tRNA synthetases (aaRS), enzymes that catalyze the attachment of each amino acid to its cognate tRNA, are such proteins that have acquired new domains and motifs that enable non-canonical functions. Through these new domains and motifs, aaRS can assemble into large, multi-subunit complexes that enhance the efficiency of many biological functions. Moreover, because the complexity of multi-aminoacyl tRNA synthetase (mARS) complexes increases with the corresponding complexity of higher eukaryotes, a contribution to regulation of homeostatic functions in multicellular organisms is hypothesized. While mARS complexes in lower eukaryotes may enhance efficiency of aminoacylation, little evidence exists to support a similar role in chordates or other higher eukaryotes. Rather, mARS complexes are reported to regulate multiple and variegated cellular processes that include angiogenesis, apoptosis, inflammation, anaphylaxis, and metabolism. Because all such processes are critical components of immune homeostasis, it is important to understand the role of mARS complexes in immune regulation. Here we provide a conceptual analysis of the current understanding of mARS complex dynamics and emerging mARS complex roles in immune regulation, the increased understanding of which should reveal therapeutic targets in immunity and immune-mediated disease.

Rapid profiling of transcription factor-cofactor interaction networks reveals principles of epigenetic regulation.

Transcription factor (TF)-cofactor (COF) interactions define dynamic, cell-specific networks that govern gene expression; however, these networks are understudied due to a lack of methods for high-throughput profiling of DNA-bound TF-COF complexes. Here we describe the Cofactor Recruitment (CoRec) method for rapid profiling of cell-specific TF-COF complexes. We define a lysine acetyltransferase (KAT)-TF network in resting and stimulated T cells. We find promiscuous recruitment of KATs for many TFs and that 35% of KAT-TF interactions are condition specific. KAT-TF interactions identify NF-κB as a primary regulator of acutely induced H3K27ac. Finally, we find that heterotypic clustering of CBP/P300-recruiting TFs is a strong predictor of total promoter H3K27ac. Our data supports clustering of TF sites that broadly recruit KATs as a mechanism for widespread co-occurring histone acetylation marks. CoRec can be readily applied to different cell systems and provides a powerful approach to define TF-COF networks impacting chromatin state and gene regulation.

Adaptive foraging behaviours in the Horn of Africa during Toba supereruption.

Although modern humans left Africa multiple times over 100,000 years ago, those broadly ancestral to non-Africans dispersed less than 100,000 years ago1. Most models hold that these events occurred through green corridors created during humid periods because arid intervals constrained population movements2. Here we report an archaeological site-Shinfa-Metema 1, in the lowlands of northwest Ethiopia, with Youngest Toba Tuff cryptotephra dated to around 74,000 years ago-that provides early and rare evidence of intensive riverine-based foraging aided by the likely adoption of the bow and arrow. The diet included a wide range of terrestrial and aquatic animals. Stable oxygen isotopes from fossil mammal teeth and ostrich eggshell show that the site was occupied during a period of high seasonal aridity. The unusual abundance of fish suggests that capture occurred in the ever smaller and shallower waterholes of a seasonal river during a long dry season, revealing flexible adaptations to challenging climatic conditions during the Middle Stone Age. Adaptive foraging along dry-season waterholes would have transformed seasonal rivers into 'blue highway' corridors, potentially facilitating an out-of-Africa dispersal and suggesting that the event was not restricted to times of humid climates. The behavioural flexibility required to survive seasonally arid conditions in general, and the apparent short-term effects of the Toba supereruption in particular were probably key to the most recent dispersal and subsequent worldwide expansion of modern humans.

Small Warriors of Nature: Novel Red Emissive Chlorophyllin Carbon Dots Harnessing Fenton-Fueled Ferroptosis for In Vitro and In Vivo Cancer Treatment.

The appeal of carbon dots (CDs) has grown recently, due to their established biocompatibility, adjustable photoluminescence properties, and excellent water solubility. For the first time in the literature, copper chlorophyllin-based carbon dots (Chl-D CDs) are successfully synthesized. Chl-D CDs exhibit unique spectroscopic traits and are found to induce a Fenton-like reaction, augmenting photodynamic therapy (PDT) efficacies via ferroptotic and apoptotic pathways. To bolster the therapeutic impact of Chl-D CDs, a widely used cancer drug, temozolomide, is linked to their surface, yielding a synergistic effect with PDT and chemotherapy. Chl-D CDs' biocompatibility in immune cells and in vivo models showed great clinical potential.Proteomic analysis was conducted to understand Chl-D CDs' underlying cancer treatment mechanism. The study underscores the role of reactive oxygen species formation and pointed toward various oxidative stress modulators like aldolase A (ALDOA), aldolase C (ALDOC), aldehyde dehydrogenase 1B1 (ALDH1B1), transaldolase 1 (TALDO1), and transketolase (TKT), offering a deeper understanding of the Chl-D CDs' anticancer activity. Notably, the Chl-D CDs' capacity to trigger a Fenton-like reaction leads to enhanced PDT efficiencies through ferroptotic and apoptotic pathways. Hence, it is firmly believed that the inherent attributes of Chl-CDs can lead to a secure and efficient combined cancer therapy.

Neoadjuvant Chemotherapy is Associated with Increased Risk of Postoperative DVT After Distal Pancreatectomy for Pancreatic Adenocarcinoma: a NSQIP Analysis.

BACKGROUND: Venous thromboembolism (VTE) remains a persistent source of postoperative morbidity despite prevention and mitigation efforts. Cancer, surgery, and chemotherapy are known risk factors for VTE. Existing literature suggests that neoadjuvant therapy (NAT) may contribute to increased VTE risk in the postoperative period, but few authors specifically examine this relationship in distal pancreatic adenocarcinoma (PDAC). In this study, we analyze the association of NAT and postoperative VTE in patients who underwent distal pancreatectomy (DP) for PDAC. PATIENTS AND METHODS: Using the American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) database, we analyzed the Procedure Targeted files for pancreatectomy from 2014 to 2020. Adults with PDAC who underwent DP were grouped by receipt of NAT. The primary outcome was the rate of deep venous thrombosis (DVT) and the secondary outcome was the rate of pulmonary embolism (PE). We performed univariate and multivariate logistic regression analysis to determine risk factors associated with postoperative DVT. RESULTS: There were 4327 patients with PDAC who underwent DP. Of these, 1414 (32.7%) had NAT. Receipt of NAT was significantly associated with postoperative DVT requiring therapy (3.5% vs. 2.3%, p = 0.02), but was not associated with PE (p = 0.42). On MVA, NAT was associated with a 73% greater chance of developing postoperative DVT [odds ratio (OR) 1.73, 95% CI 1.18-2.55]. CONCLUSIONS: Patients who receive NAT prior to DP for PDAC are 73% more likely to develop postoperative DVT compared with upfront resection. As NAT becomes more commonplace, these high-risk patients should be prioritized for guideline-recommended extended duration prophylaxis.

Autologous humanized PDX modeling for immuno-oncology recapitulates features of the human tumor microenvironment.

BACKGROUND: Interactions between immune and tumor cells are critical to determining cancer progression and response. In addition, preclinical prediction of immune-related drug efficacy is limited by interspecies differences between human and mouse, as well as inter-person germline and somatic variation. To address these gaps, we developed an autologous system that models the tumor microenvironment (TME) from individual patients with solid tumors. METHOD: With patient-derived bone marrow hematopoietic stem and progenitor cells (HSPCs), we engrafted a patient's hematopoietic system in MISTRG6 mice, followed by transfer of patient-derived xenograft (PDX) tissue, providing a fully genetically matched model to recapitulate the individual's TME. We used this system to prospectively study tumor-immune interactions in patients with solid tumor. RESULTS: Autologous PDX mice generated innate and adaptive immune populations; these cells populated the TME; and tumors from autologously engrafted mice grew larger than tumors from non-engrafted littermate controls. Single-cell transcriptomics revealed a prominent vascular endothelial growth factor A (VEGFA) signature in TME myeloid cells, and inhibition of human VEGF-A abrogated enhanced growth. CONCLUSIONS: Humanization of the interleukin 6 locus in MISTRG6 mice enhances HSPC engraftment, making it feasible to model tumor-immune interactions in an autologous manner from a bedside bone marrow aspirate. The TME from these autologous tumors display hallmarks of the human TME including innate and adaptive immune activation and provide a platform for preclinical drug testing.

Courage, camaraderie and compassion: a qualitative exploration into UK military veterans' experiences of self-compassion within the context of alcohol use disorders and recovery.

INTRODUCTION: UK veterans are at increased risk of mental health and alcohol use disorders (AUDs), experiencing specific challenges such as combat exposure and re-integration which may contribute to treatment barriers. Experiences of shame and AUDs, which may precede or become exacerbated during military service, may be mitigated by self-compassion (SC). This study sought to understand how UK veterans make sense of their SC experiences within the context of their relationships with alcohol and recovery. METHODS: Interpretative phenomenological analysis was used to interpret the SC experiences of five ex-military veterans (one female). Semistructured face-to-face interviews were audio-recorded and transcribed verbatim, with a double hermeneutic approach used to interpret meaningful issues which influenced participants' self-perceptions in relation to their alcohol use and wider social world. RESULTS: Two key themes were identified. 'Searching for Safety', which illustrated veterans' SC sense-making within the context of their evolving lifeworld and alcohol use, and 'Healing with Honour' which reflected the significance of purpose and identity within experiences of recovery and SC. Findings were interpreted through the lens of the six bipolar elements of SC, which identified SC as salient within veterans' experiences of AUD and recovery. Although experiences of SC were sometimes perceived as challenging or incongruent to military identity, this was influenced by positive reframing and meaning-making, supported by compassionate narratives and informed trusted relationships. CONCLUSIONS: Veterans' AUD recovery and support-seeking may be impacted by the experience of SC and enhanced by the early implementation of acceptable and feasible interventions which draw on veterans' unique military identities and experience. This may include compassion-focussed interventions which reframe SC as fierce SC, peer support models and educational strategies which support healthcare professionals to understand and identify veterans' military experiences.

Thickness-Dependent Cross-Plane Thermal Conductivity Measurements of Exfoliated Hexagonal Boron Nitride.

Submicrometer-thick layers of hexagonal boron nitride (hBN) exhibit high in-plane thermal conductivity and useful optical properties, and serve as dielectric encapsulation layers with low electrostatic inhomogeneity for graphene devices. Despite the promising applications of hBN as a heat spreader, the thickness dependence of its cross-plane thermal conductivity is not known, and the cross-plane phonon mean free paths (MFPs) have not been measured. We measure the cross-plane thermal conductivity of hBN flakes exfoliated from bulk crystals. We find that submicrometer thick flakes exhibit thermal conductivities up to 8.1 ± 0.5 W m-1 K-1 at 295 K, which exceeds previously reported bulk values by more than 60%. Surprisingly, the average phonon mean free path is found to be several hundred nanometers at room temperature, a factor of 5 larger than previous predictions. When planar twist interfaces are introduced into the crystal by mechanically stacking multiple thin flakes, the cross-plane thermal conductivity of the stack is found to be a factor of 7 below that of individual flakes with similar total thickness, thus providing strong evidence that phonon scattering at twist boundaries limits the maximum phonon MFPs. These results have important implications for hBN integration in nanoelectronics and improve our understanding of thermal transport in two-dimensional materials.

Imaging the breaking of electrostatic dams in graphene for ballistic and viscous fluids.

The charge carriers in a material can, under special circumstances, behave as a viscous fluid. In this work, we investigated such behavior by using scanning tunneling potentiometry to probe the nanometer-scale flow of electron fluids in graphene as they pass through channels defined by smooth and tunable in-plane p-n junction barriers. We observed that as the sample temperature and channel widths are increased, the electron fluid flow undergoes a Knudsen-to-Gurzhi transition from the ballistic to the viscous regime characterized by a channel conductance that exceeds the ballistic limit, as well as suppressed charge accumulation against the barriers. Our results are well modeled by finite element simulations of two-dimensional viscous current flow, and they illustrate how Fermi liquid flow evolves with carrier density, channel width, and temperature.

Inhibition of Eicosanoid Degradation Mitigates Fibrosis of the Heart.

BACKGROUND: Organ fibrosis due to excessive production of extracellular matrix by resident fibroblasts is estimated to contribute to >45% of deaths in the Western world, including those due to cardiovascular diseases such as heart failure. Here, we screened for small molecule inhibitors with a common ability to suppress activation of fibroblasts across organ systems. METHODS: High-content imaging of cultured cardiac, pulmonary, and renal fibroblasts was used to identify nontoxic compounds that blocked induction of markers of activation in response to the profibrotic stimulus, transforming growth factor-ß1. SW033291, which inhibits the eicosanoid-degrading enzyme, 15-hydroxyprostaglandin dehydrogenase, was chosen for follow-up studies with cultured adult rat ventricular fibroblasts and human cardiac fibroblasts (CF), and for evaluation in mouse models of cardiac fibrosis and diastolic dysfunction. Additional mechanistic studies were performed with CFs treated with exogenous eicosanoids. RESULTS: Nine compounds, including SW033291, shared a common ability to suppress transforming growth factor-ß1-mediated activation of cardiac, pulmonary, and renal fibroblasts. SW033291 dose-dependently inhibited transforming growth factor-ß1-induced expression of activation markers (eg, α-smooth muscle actin and periostin) in adult rat ventricular fibroblasts and normal human CFs, and reduced contractile capacity of the cells. Remarkably, the 15-hydroxyprostaglandin dehydrogenase inhibitor also reversed constitutive activation of fibroblasts obtained from explanted hearts from patients with heart failure. SW033291 blocked cardiac fibrosis induced by angiotensin II infusion and ameliorated diastolic dysfunction in an alternative model of systemic hypertension driven by combined uninephrectomy and deoxycorticosterone acetate administration. Mechanistically, SW033291-mediated stimulation of extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase signaling was required for the compound to block CF activation. Of the 12 exogenous eicosanoids that were tested, only 12(S)-hydroxyeicosatetraenoic acid, which signals through the G protein-coupled receptor, GPR31, recapitulated the suppressive effects of SW033291 on CF activation. CONCLUSIONS: Inhibition of degradation of eicosanoids, arachidonic acid-derived fatty acids that signal through G protein-coupled receptors, is a potential therapeutic strategy for suppression of pathological organ fibrosis. In the heart, we propose that 15-hydroxyprostaglandin dehydrogenase inhibition triggers CF-derived autocrine/paracrine signaling by eicosanoids, including 12(S)-hydroxyeicosatetraenoic acid, to stimulate extracellular signal-regulated kinase 1/2 and block conversion of fibroblasts into activated cells that secrete excessive amounts of extracellular matrix and contribute to heart failure pathogenesis.

Sequential histologic evolution of gallbladder inflammation in acute cholecystitis over the first 10 days after onset of symptoms.

BACKGROUND: The timing of cholecystectomy during acute cholecystitis (AC) is controversial, especially whether it is advisable to perform in patients with duration of symptoms between 3 and 10 days. The purpose of this study is to define clearly the sequential evolution of histological changes following symptoms onset to guide recommendations regarding timing of cholecystectomy. METHODS: We identified patients with AC (2005-2018) who had cholecystectomy within 10 days of symptom onset of a first attack of AC. Histologic features of gallbladder injury including cellular and exudative inflammatory response to injury were determined on blinded pathologic slides. RESULTS: One hundred and forty-nine patients were divided into three groups; early-who underwent cholecystectomy 1-3 days after symptom-onset, intermediate-4-6 days, and late-7-10 days. Key features of injury were necrosis and hemorrhage. A subgroup of patients in the early phase developed severe necrosis and hemorrhage of an extent associated with difficult cholecystectomy. Large spikes in extent of necrosis and hemorrhage occurred at 7-10 days. Major inflammatory responses to injury were eosinophilic and lymphocytic infiltration and early fibrosis. CONCLUSIONS: Severe necrosis may develop rapidly and be present in the early period after symptom onset of AC. Cholecystectomy may be reasonable in some patients but by day 7-10, severe necrosis and hemorrhage may be expected to be present in most patients.

An analysis of specific batting demands in the women's The Hundred competition.

Background: No research has investigated the shortest format of the game of cricket, The Hundred competition. Furthermore, women's cricket research is particularly limited, with most focusing on injuries and little literature investigating specific batting demands. These demands are important if training programmes are to mimic the game's movement patterns. Objectives: The purpose of this study was to analyse specific batting demands and variables associated with the women's The Hundred competition. Methods: Thirty-one matches from the Women's 2021 The Hundred competition were analysed using Hudl Sportscode Elite. Variables analysed included: bowler type (seam or spin), free hits, no ball runs, reason for no ball (height/wide/front foot), run scored (0, 1, 2, 3, 4, 6), type of key event (fall of wicket, bowling referral, batting referral, umpire referral, bowling time out, rain delay, or injury) as well as time between deliveries and sets, overall and between the power play and non-power play. A total of 6073 deliveries were analysed. Results: A significant difference (p<0.05) was observed for time between deliveries for spin bowlers (26.90±22.16 s) compared to seam bowlers(31.70±20.37 s) as well as time between sets for the power play (58.00±13.28 s) and non-power play phases (63.70±42.00 s). Additionally, in the power play, most runs were made up of "1's" and "4's". In the non-power play phase, "1's" made up the biggest contribution of runs (as a percentage). Conclusion: The fact that singles make up a significant portion of a typical match means that strength and conditioning coaches should incorporate high-intensity sprint-type training into training programmes to mimic these demands.

Immunomodulatory proteins from hookworms reduce cardiac inflammation and modulate regulatory responses in a mouse model of chronic Trypanosoma cruzi infection.

Introduction: Hookworms are parasitic helminths that secrete a variety of proteins that induce anti-inflammatory immune responses, stimulating increased CD4 + Foxp3+ regulatory T cells and IL-10 production. Hookworm-derived recombinant proteins AIP-1 and AIP-2 have been shown to reduce inflammation in mouse models of inflammatory bowel disease and inflammatory airway disease by inducing CD4+Foxp3+ cells and IL-10 production. In contrast, chronic infection with the protozoal parasite Trypanosoma cruzi, the causative agent of Chagas disease, leads to chronic inflammation in tissues. Persistence of the parasites in tissues drives chronic low-grade inflammation, with increased infiltration of inflammatory cells into the heart, accompanied by increased production of inflammatory cytokines. There are no current antiparasitic drugs that effectively reduce or prevent chronic myocarditis caused by the onset of Chagas disease, thus new therapies are urgently needed. Therefore, the impact of AIP-1 and AIP-2 on myocarditis was investigated in a mouse model of chronic T. cruzi infection. Methods: Female BALB/c mice infected with bioluminescent T. cruzi H1 strain trypomastigotes for 70 days were treated once daily for 7 days with 1mg/kg AIP-1 or AIP-2 protein by intraperitoneal injection. Control mice were left untreated or treated once daily for 14 days with 25mg/kg aspirin in drinking water. At 84 days of infection, splenocytes, cardiac tissue and serum were collected for evaluation. Results: Treatment with both AIP-1 and AIP-2 proteins significantly reduced cardiac cellular infiltration, and reduced cardiac levels of IFNγ, IL-6 and IL-2. AIP-2 treatment reduced cardiac expression of COX-2. Further, while incubation with AIP-1 and AIP-2 proteins did not induce a significant upregulation of an immunoregulatory phenotype in dendritic cells (DC), there was a modest upregulation of CD11c +CD11b+MHCII+SIRPα+ expression, suggesting a regulatory phenotype. Ex-vivo stimulation of splenocytes from the treatment groups with AIP-1 loaded DC induced reduced levels of cytotoxic and pro-inflammatory T cells, stimulation with AIP-2 loaded DC specifically induced enhanced levels of CD4+CD25+Foxp3+ regulatory T cells among treatment groups. Discussion: All in vivo and in vitro results demonstrate that hookworm-derived AIP-1 and AIP-2 proteins reduce T. cruzi induced cardiac inflammation, possibly through multiple anti-inflammatory mechanisms.

Spatially restricted drivers and transitional cell populations cooperate with the microenvironment in untreated and chemo-resistant pancreatic cancer.

Pancreatic ductal adenocarcinoma is a lethal disease with limited treatment options and poor survival. We studied 83 spatial samples from 31 patients (11 treatment-naïve and 20 treated) using single-cell/nucleus RNA sequencing, bulk-proteogenomics, spatial transcriptomics and cellular imaging. Subpopulations of tumor cells exhibited signatures of proliferation, KRAS signaling, cell stress and epithelial-to-mesenchymal transition. Mapping mutations and copy number events distinguished tumor populations from normal and transitional cells, including acinar-to-ductal metaplasia and pancreatic intraepithelial neoplasia. Pathology-assisted deconvolution of spatial transcriptomic data identified tumor and transitional subpopulations with distinct histological features. We showed coordinated expression of TIGIT in exhausted and regulatory T cells and Nectin in tumor cells. Chemo-resistant samples contain a threefold enrichment of inflammatory cancer-associated fibroblasts that upregulate metallothioneins. Our study reveals a deeper understanding of the intricate substructure of pancreatic ductal adenocarcinoma tumors that could help improve therapy for patients with this disease.

DFMO Carbon Dots for Treatment of Neuroblastoma and Bioimaging.

Neuroblastoma (NB) is a pediatric malignancy affecting the peripheral nervous system. Despite recent advancements in treatment, many children affected with NB continue to submit to this illness, and new therapeutic strategies are desperately needed. In recent years, studies of carbon dots (CDs) as nanocarriers have mostly focused on the delivery of anticancer agents because of their biocompatibility, good aqueous dissolution, and photostability. Their fluorescence properties, surface functionalities, and surface charges differ on the basis of the type of precursors used and the synthetic approach implemented. At present, most CDs are used as nanocarriers by directly linking them either covalently or electrostatically to drug molecules. Though most modern CDs are synthesized from large carbon macromolecules and conjugated to anticancerous drugs, constructing CDs from the anticancerous drugs and precursors themselves to increase antitumoral activity requires further investigation. Herein, CDs were synthesized using difluoromethylornithine (DFMO), an irreversible ornithine decarboxylase inhibitor commonly used in high-risk neuroblastoma treatment regiments. In this study, NB cell lines, SMS-KCNR and SK-N-AS, were treated with DFMO, the newly synthesized DFMO CDs, and conventional DFMO conjugated to black carbon dots. Bioimaging was done to determine the cellular localization of a fluorescent drug over time. The mobility of DNA mixed with DFMO CDs was evaluated by gel electrophoresis. DFMO CDs were effectively synthesized from DFMO precursor and characterized using spectroscopic methods. The DFMO CDs effectively reduced cell viability with increasing dose. The effects were dramatic in the N-MYC-amplified line SMS-KCNR at 500 µM, which is comparable to high doses of conventional DFMO at a 60-fold lower concentration. In vitro bioimaging as well as DNA electrophoresis showed that synthesized DFMO CDs were able to enter the nucleus of neuroblastoma cells and neuronal cells and interact with DNA. Our new DFMO CDs exhibit a robust advantage over conventional DFMO because they induce comparable reductions in viability at a dramatically lower concentration.

Clinical classification of symptomatic heterotopic pancreas of the stomach and duodenum: A case series and systematic literature review.

BACKGROUND: Heterotopic pancreas (HP) is an aberrant anatomic malformation that occurs most commonly in the upper gastrointestinal tract. While the majority of heterotopic pancreatic lesions are asymptomatic, many manifest severe clinical symptoms which require surgical or endoscopic intervention. Understanding of the clinical manifestations and symptoms of HP is limited due to the lack of large volume studies in the literature. The purpose of this study is to review symptomatic cases at a single center and compare these to a systematic review of the literature in order to characterize common clinical manifestations and treatment of this disease. AIM: To classify the common clinical manifestations of heterotopic pancreas. METHODS: A retrospective review was conducted of pathologic samples containing heterotopic pancreas from 2000-2018. Review was limited to HP of the upper gastrointestinal tract due to the frequency of presentation in this location. Symptomatic patients were identified from review of the medical records and clinical symptoms were tabulated. These were compared to a systematic review of the literature utilizing PubMed and Embase searches for papers pertaining to heterotopic pancreas. Publications describing symptomatic presentation of HP were selected for review. Information including demographics, symptoms, presentation and treatment were compiled and analyzed. RESULTS: Twenty-nine patient were identified with HP at a single center, with six of these identified has having clinical symptoms. Clinical manifestations included, gastrointestinal bleeding, gastric ulceration with/without perforation, pancreatitis, and gastric outlet obstruction. Systemic review of the literature yielded 232 publications detailing symptomatic cases with only 20 studies describing ten or more patients. Single and multi-patient studies were combined to form a cohort of 934 symptomatic patients. The majority of patients presented with abdominal pain (67%) combined with one of the following clinical categories: (1) Dyspepsia, (n = 445, 48%); (2) Pancreatitis (n = 260, 28%); (3) Gastrointestinal bleeding (n = 80, 9%); and (4) Gastric outlet obstruction (n = 80, 9%). The majority of cases (n = 832, 90%) underwent surgical or endoscopic resection with 85% reporting resolution or improvement in their symptoms. CONCLUSION: Heterotopic pancreas can cause significant clinical symptoms in the upper gastrointestinal tract. Better understanding and classification of this disease may result in more accurate identification and treatment of this malformation.

Structure-Activity Relationship of Carbon Nitride Dots in Inhibiting Tau Aggregation.

Due to the numerous failed clinical trials of anti-amyloid drugs, microtubule associated protein tau (MAPT) now stands out as one of the most promising targets for AD therapy. In this study, we report for the first time the structure-dependent MAPT aggregation inhibition of carbon nitride dots (CNDs). CNDs have exhibited great promise as a potential treatment of Alzheimer's disease (AD) by inhibiting the aggregation of MAPT. In order to elucidate its structure-activity relationship, CNDs were separated via column chromatography and five fractions with different structures were obtained that were characterized by multiple spectroscopy methods. The increase of surface hydrophilic functional groups is consistent with the increase of polarity from fraction 1 to 5. Particle sizes (1-2 nm) and zeta potentials (~-20 mV) are similar among five fractions. With the increase of polarity from fraction 1 to 5, their MAPT aggregation inhibition capacity was weakened. This suggests hydrophobic interactions between CNDs and MAPT, validated via molecular dynamics simulations. With a zebrafish blood-brain barrier (BBB) model, CNDs were observed to cross the BBB through passive diffusion. CNDs were also found to inhibit the generation of multiple reactive oxygen species, which is an important contributor to AD pathogenesis.

Drug delivery of memantine with carbon dots for Alzheimer's disease: blood-brain barrier penetration and inhibition of tau aggregation.

Neurofibrillary tangle, composed of aggregated tau protein, is a pathological hallmark of Alzheimer's disease (AD). The inhibition of tau aggregation is therefore an important direction for AD drug discovery. In this work, we explored the efficacy of two types of carbon dots in targeting tau aggregation, as versatile nano-carriers for the development of carbon dots (CDs)-based AD therapy. We carried out synthesis, biophysical and biochemical characterizations of two types of CDs, namely, carbon nitride dots (CNDs) and black carbon dots (B-CDs). CDs, which are biocompatible and non-toxic, were successfully conjugated with memantine hydrochloride (MH) through EDC/NHS mediated amidation reactions followed by systematic characterizations using various biophysical techniques including UV-vis spectroscopy (UV-vis), photoluminescence (PL), Fourier-transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), mass spectrometry (MS), Transmission electron microscopy (TEM) and atomic force microscopy (AFM). The surface diversity along with small particle sizes of CDs allowed facile delivery of MH across the blood-brain barrier (BBB), as demonstrated using a zebrafish in vivo model. The tau aggregation inhibition experiments were conducted using the thioflavin-T (ThT) assay to identify the most effective inhibitor. The kinetics and magnitude of tau aggregation were measured in the presence of CDs, which demonstrates that both B-CDs-MH and B-CDs alone are the most effective inhibitors of tau aggregation with IC50 values of 1.5 ± 0.3 and 1.6 ± 1.5 µg/mL, respectively. Taken together, our findings hold therapeutic significance to enhance the efficient delivery of MH to target AD pathology in the brain for improved efficacy.

Rose Bengal and Riboflavin Mediated Photodynamic Antimicrobial Therapy Against Selected South Florida Nocardia Keratitis Isolates.

Purpose: To examine and compare the efficacy of in vitro growth inhibition using rose bengal and riboflavin photodynamic antimicrobial therapy (PDAT) for Nocardia keratitis isolates. Methods: Nocardia asteroides complex, Nocardia amikacinitolerans, and Nocardia farcinica species were isolated from patients with confirmed Nocardia keratitis. Isolates were tested against three experimental groups: (1) no photosensitizer/no irradiation, (2) photosensitizer/no irradiation, and (3) photosensitizer/irradiation. Each isolate was prepared in suspension to a concentration of 1.5 × 108 CFU/mL. Bacterial suspensions were mixed with water or prepared 0.1% photosensitizer solution for a final bacterial concentration of 1.5 × 107 CFU/mL. Aliquots of 1 mL were plated on 5% sheep blood agar. Rose bengal and riboflavin PDAT plates were irradiated for 15 minutes with a 525- or 375-nm custom 6-mW/cm2 powered light source for a total fluence of 5.4 J/cm2. All experimental groups were repeated in triplicate. Plates were incubated in a 35°C non-CO2 incubator for 96 hours and photographed. Percent inhibition was evaluated using LabVIEW-based software. Results: All strains of Nocardia tested with 0.1% rose bengal and irradiated for 15 minutes demonstrated statistically significant inhibition of growth (P < 0.05). No other experimental groups displayed any bacterial inhibition. Conclusions: Rose bengal is superior to riboflavin PDAT against selected Nocardia isolates. In vivo testing is warranted to investigate the utility of rose bengal PDAT for severe Nocardia keratitis. Translational Relevance: In vitro results for three clinical strains of Nocardia support the possible use of rose bengal PDAT as a complementary treatment of Nocardia keratitis.