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Following the capture of Inka Atawallpa in Cajamarca, Spanish conquistadors took control of several Inka provincial centers that subsequently became the sites of colonial towns. This was the case at Tambo Viejo, the Inka provincial center in the Acarí Valley of the Peruvian south coast. Recent archaeological excavation at that site revealed that the Spanish modified existing buildings and added new constructions to suit their needs. The excavation also uncovered multiple interments that had been closely stacked next to each other and buried with a small wooden cross, the most salient symbol of the Christian faith. The new findings highlight the outcome of the Spanish presence in the former Inka territory which manifested in substantial modification of a provincial Inka center, the likely conversion to Christianity of the local population, and what appears to be the devastation caused by the diseases introduced by the conquistadors.

IMPORTANCE: Extramammary Paget disease (EMPD) is a rare, highly recurrent cutaneous malignant neoplasm of unclear origin. EMPD arises most commonly on the vulvar and penoscrotal skin. It is not presently known how anatomic subtype of EMPD affects disease presentation and management. OBJECTIVE: To compare demographic and tumor characteristics and treatment approaches for different EMPD subtypes. Recommendations for diagnosis and treatment are presented. DATA SOURCES: MEDLINE, Embase, Web of Science Core Collection, and Cochrane Reviews CENTRAL from December 1, 1990, to October 24, 2022. STUDY SELECTION: Articles were excluded if they were not in English, reported fewer than 3 patients, did not specify information by anatomic subtype, or contained no case-level data. Metastatic cases on presentation were also excluded. DATA EXTRACTION AND SYNTHESIS: Abstracts of 1295 eligible articles were independently reviewed by 5 coauthors, and 135 articles retained. Reporting was in accordance with Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines. The analysis was cunducted in August 2019 and updated in November 2022. FINDINGS: Most vulvar EMPD cases were asymptomatic, and diagnosis was relatively delayed (mean, 25.1 months). Although most vulvar EMPD cases were intraepidermal (1247/1773 [70.3%]), radical surgeries were still performed in almost one-third of cases. Despite this aggressive surgical approach, 481 of 1423 (34%) recurred, commonly confined to the skin and mucosa (177/198 [89.4%]). By contrast, 152 of 1101 penoscrotal EMPD cases (14%) recurred, but more than one-third of these recurrences were regional or associated with distant metastases (54 of 152 [35.5%]). Perianal EMPD cases recurred in one-third of cases (74/218 [33.9%]), with one-third of these recurrences being regional or associated with distant metastasis (20 of 74 [27.0%]). Perianal EMPD also had the highest rate of invasive disease (50% of cases). CONCLUSIONS AND RELEVANCE: The diagnosis and treatment of EMPD should differ based on anatomic subtypes. Considerations for updated practice may include less morbid treatments for vulvar EMPD, which is primarily epidermal, and close surveillance for local recurrence in vulvar EMPD and metastatic recurrence in perianal EMPD. Recurrences in penoscrotal subtype were less common, and selective surveillance in this subtype may be considered. Limitations of this study include the lack of replication cohorts and the exclusion of studies that did not stratify outcomes by anatomic subtype.

Programmed death-1 (PD-1) inhibitors are approved for therapy of gynecologic cancers with DNA mismatch repair deficiency (dMMR), although predictors of response remain elusive. We conducted a single-arm phase 2 study of nivolumab in 35 patients with dMMR uterine or ovarian cancers. Co-primary endpoints included objective response rate (ORR) and progression-free survival at 24 weeks (PFS24). Secondary endpoints included overall survival (OS), disease control rate (DCR), duration of response (DOR) and safety. Exploratory endpoints included biomarkers and molecular correlates of response. The ORR was 58.8% (97.5% confidence interval (CI): 40.7–100%), and the PFS24 rate was 64.7% (97.5% one-sided CI: 46.5–100%), meeting the pre-specified endpoints. The DCR was 73.5% (95% CI: 55.6–87.1%). At the median follow-up of 42.1 months (range, 8.9–59.8 months), median OS was not reached. One-year OS rate was 79% (95% CI: 60.9–89.4%). Thirty-two patients (91%) had a treatment-related adverse event (TRAE), including arthralgia (n= 10, 29%), fatigue (n= 10, 29%), pain (n= 10, 29%) and pruritis (n= 10, 29%); most were grade 1 or grade 2. Ten patients (29%) reported a grade 3 or grade 4 TRAE; no grade 5 events occurred. Exploratory analyses show that the presence of dysfunctional (CD8+PD-1+) or terminally dysfunctional (CD8+PD-1+TOX+) T cells and their interaction with programmed death ligand-1 (PD-L1)+cells were independently associated with PFS24. PFS24 was associated with presence of MEGF8or SETD1Bsomatic mutations. This trial met its co-primary endpoints (ORR and PFS24) early, and our findings highlight several genetic and tumor microenvironment parameters associated with response to PD-1 blockade in dMMR cancers, generating rationale for their validation in larger cohorts.

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We present a simple and cost-effective strategy for developing gelatin methacryloyl (GelMA) hydrogels supplemented with minimally processed tissue (MPT) to fabricate densely packed skeletal-muscle-like tissues. MPT powder was prepared from skeletal muscle by freeze-drying, grinding, and sieving. Cell-culture experiments showed that the incorporation of 0.5–2.0% (w/v) MPT into GelMA hydrogels enhances the proliferation of murine myoblasts (C2C12 cells) compared to proliferation in pristine GelMA hydrogels and GelMA supplemented with decellularized skeletal-muscle tissues (DCTs). MPT-supplemented constructs also preserved their three-dimensional (3D) integrity for 28 days. By contrast, analogous pristine GelMA constructs only maintained their structure for 14 days or less. C2C12 cells embedded in MPT-supplemented constructs exhibited a higher degree of cell alignment and reached a significantly higher density than cells loaded in pristine GelMA constructs. Our results suggest that the addition of MPT incorporates a rich source of biochemical and topological cues, such as growth factors, glycosaminoglycans (GAGs), and structurally preserved proteins (e.g., collagen). In addition, GelMA supplemented with MPT showed suitable rheological properties for use as bioinks for extrusion bioprinting. We envision that this simple and cost-effective strategy of hydrogel supplementation will evolve into an exciting spectrum of applications for tissue engineers, primarily in the biofabrication of relevant microtissues for in vitromodels and cultured meat and ultimately for the biofabrication of transplant materials using autologous MPT.

Background: Esophageal cancer and gastric cancer are two important causes of upper GI malignancies. Literature has shown that minimally invasive esophagectomies (MIE) and gastrectomies (MIG), have shorter length of stay and fewer complications. However, limited literature exists about the association between race and access to MIE and MIG. This study aims to identify the racial disparities in the different approaches to esophagectomy and gastrectomy. We further evaluate the relationship between the race and postoperative complications. Methods: This IRB-approved retrospective study utilized data from the American College of Surgeons National Quality Improvement Program. All recorded cases of MIE, MIG, open gastrectomy, and esophagectomy between 2012 and 2019 were isolated. Propensity score matching and univariate analysis was performed to assess the independent effect of black self-identified race on access and outcomes. p< 0.05 was required to achieve statistical significance. Results: 7891 cases of esophagectomy and 5,132 cases of gastrectomy cases were identified. Using Propensity and logistic regression, we identified that black self-reported race is an independent predictor of open approach to gastrectomy (OR 1.6871943, 95% CI 1.431464–1.989829, p< 0.001). Black self-reported race was not predictive of operative approach among esophagectomy patients (OR 0.7942576, 95% CI 0.5698645–1.124228, p= 0.183). In contrast, black self-reported is an independent predictor of postoperative complications among esophagectomy patients only. Esophagectomy patients of black self-reported race were more likely to experience any complication (OR 1.4373437, 95% CI 1.1129239–1.8557096, p= 0.00537), severe complications (OR 1.3818966, 95% CI 1.0653087–1.7888454, p= 0.0144), and death (OR 2.00779762, 95% CI 1.08034921–3.56117535, p= 0.0211) within 30 days of their surgeries. Conclusion: Our analysis revealed a significant racial disparity in access to MIG and a higher incidence of post-operative complications amongst esophagectomy patients. Minimally invasive techniques are underutilized in racial minorities. The findings herein warrant further investigation to eliminate barriers and disparities. Graphical abstract:

Soil-transmitted helminths cause widespread disease, infecting ~1.5 billion people living within poverty-stricken regions of tropical and subtropical countries. As adult worms inhabit the intestine alongside bacterial communities, we determined whether the bacterial microbiota impacted on host resistance against intestinal helminth infection. We infected germ-free, antibiotic-treated and specific pathogen-free mice, with the intestinal helminth Heligmosomoides polygyrus bakeri. Mice harboured increased parasite numbers in the absence of a bacterial microbiota, despite mounting a robust helminth-induced type 2 immune response. Alterations to parasite behaviour could already be observed at early time points following infection, including more proximal distribution of infective larvae along the intestinal tract and increased migration in a Baermann assay. Mice lacking a complex bacterial microbiota exhibited reduced levels of intestinal acetylcholine, a major excitatory intestinal neurotransmitter that promotes intestinal transit by activating muscarinic receptors. Both intestinal motility and host resistance against larval infection were restored by treatment with the muscarinic agonist bethanechol. These data provide evidence that a complex bacterial microbiota provides the host with resistance against intestinal helminths via its ability to regulate intestinal motility.

Cancer in patients with obesity has become increasingly common throughout much of the world. Based on our experiences in a specialized cancer center, we have developed a set of standards and expectations that should streamline the surgical journey for this patient population. These recommendations should inform the perioperative management of oncology patients with obesity and help raise awareness of this critical and under-discussed topic.

Mucosal melanoma involving the urethra is a rare disease with distinct clinical and molecular characteristics and poor outcomes. Our current knowledge is limited by the small number of reports regarding this disease. To describe the clinical, pathological, and molecular characteristics of urethral melanoma. We summarized the clinicopathologic data for 31 patients treated for urethral melanoma from 1986–2017 at our institution. Genomic data from our institutional sequencing platform MSK-IMPACT (n = 5) and gene-specific PCR data on BRAF, KIT, and/or NRAS(n = 8) were compared to genomic data of cutaneous melanomas (n = 143), vulvar/vaginal melanomas (n = 24), and primary non-melanoma urethral tumors (n = 5) from our institutional database. Twenty-three patients were diagnosed with localized disease, 7 had regional/nodal involvement and one had metastases. Initial treatment included surgery in 25 patients; seven had multimodal treatment. Median follow-up was 46 months (IQR 33–123). Estimated 5-year cancer-specific survival was 45%. No significant change in survival was observed based on a year of treatment. Primary urethral melanomas showed a higher frequency of TP53mutations compared to cutaneous (80.0% vs. 18.2%, p = 0.006) and vulvar/vaginal melanomas (80.0 vs. 25.0%, p = 0.04). BRAFmutations were absent in urethral primaries (0% vs. 46% in cutaneous melanoma, p = 0.02). Tumor mutation burden was higher in cutaneous than urethral melanomas (p = 0.04). Urethral melanomas had a higher number of somatic alterations compared to non-melanoma urethral tumors (median 11 vs. 5, p = 0.03). Our findings support a unique mutational landscape of urethral melanoma compared to cutaneous melanoma. Survival remains poor and is unchanged over the time studied.

The purpose of an industrial plant is to get a product, anything from electricity to minerals or shoes, to customers on time and on budget. Sometimes the concentration on output [...]

Efficient cellular fusion of mononuclear precursors is the prerequisite for the generation of fully functional multinucleated bone-resorbing osteoclasts. However, the exact molecular factors and mechanisms controlling osteoclast fusion remain incompletely understood. Here we identify RANKL-mediated activation of caspase-8 as early key event during osteoclast fusion. Single cell RNA sequencing-based analyses suggested that activation of parts of the apoptotic machinery accompanied the differentiation of osteoclast precursors into mature multinucleated osteoclasts. A subsequent characterization of osteoclast precursors confirmed that RANKL-mediated activation of caspase-8 promoted the non-apoptotic cleavage and activation of downstream effector caspases that translocated to the plasma membrane where they triggered activation of the phospholipid scramblase Xkr8. Xkr8-mediated exposure of phosphatidylserine, in turn, aided cellular fusion of osteoclast precursors and thereby allowed generation of functional multinucleated osteoclast syncytia and initiation of bone resorption. Pharmacological blockage or genetic deletion of caspase-8 accordingly interfered with fusion of osteoclasts and bone resorption resulting in increased bone mass in mice carrying a conditional deletion of caspase-8 in mononuclear osteoclast precursors. These data identify a novel pathway controlling osteoclast biology and bone turnover with the potential to serve as target for therapeutic intervention during diseases characterized by pathologic osteoclast-mediated bone loss.

Enhanced osteoclastogenesis and osteoclast activity contribute to the development of osteoporosis, which is characterized by increased bone resorption and inadequate bone formation. As novel antiosteoporotic therapeutics are needed, understanding the genetic regulation of human osteoclastogenesis could help identify potential treatment targets. This study aimed to provide an overview of transcriptional reprogramming during human osteoclast differentiation. Osteoclasts were differentiated from CD14+monocytes from eight female donors. RNA sequencing during differentiation revealed 8 980 differentially expressed genes grouped into eight temporal patterns conserved across donors. These patterns revealed distinct molecular functions associated with postmenopausal osteoporosis susceptibility genes based on RNA from iliac crest biopsies and bone mineral density SNPs. Network analyses revealed mutual dependencies between temporal expression patterns and provided insight into subtype-specific transcriptional networks. The donor-specific expression patterns revealed genes at the monocyte stage, such as filamin B (FLNB) and oxidized low-density lipoprotein receptor 1 (OLR1, encoding LOX-1), that are predictive of the resorptive activity of mature osteoclasts. The expression of differentially expressed G-protein coupled receptors was strong during osteoclast differentiation, and these receptors are associated with bone mineral density SNPs, suggesting that they play a pivotal role in osteoclast differentiation and activity. The regulatory effects of three differentially expressed G-protein coupled receptors were exemplified by in vitro pharmacological modulation of complement 5 A receptor 1 (C5AR1), somatostatin receptor 2 (SSTR2), and free fatty acid receptor 4 (FFAR4/GPR120). Activating C5AR1 enhanced osteoclast formation, while activating SSTR2 decreased the resorptive activity of mature osteoclasts, and activating FFAR4 decreased both the number and resorptive activity of mature osteoclasts. In conclusion, we report the occurrence of transcriptional reprogramming during human osteoclast differentiation and identified SSTR2 and FFAR4 as antiresorptive G-protein coupled receptors and FLNB and LOX-1 as potential molecular markers of osteoclast activity. These data can help future investigations identify molecular regulators of osteoclast differentiation and activity and provide the basis for novel antiosteoporotic targets.

Recurrent gene fusions have been observed in epithelioid and myxoid variants of uterine leiomyosarcoma. PGR::NR4A3fusions were recently described in a subset of epithelioid leiomyosarcomas exhibiting rhabdoid morphology. In this study, we sought to expand the clinical, morphologic, immunohistochemical, and genetic features of gynecologic leiomyosarcomas harboring NR4A3rearrangements with PGRand novel fusion partners. We identified 9 gynecologic leiomyosarcomas harboring PGR::NR4A3, CARMN::NR4A3, ACTB::NR4A3, and possible SLCO5A1::NR4A3fusions by targeted RNA sequencing. Tumors frequently affected premenopausal women, involving the uterine corpus, uterine cervix, or pelvis. All were similarly characterized by lobules of monomorphic epithelioid and/or spindled cells arranged in sheets, cords, trabeculae, and micro- and macrocysts associated with abundant myxoid matrix and hemorrhage, creating labyrinth-like or pulmonary edema–like architecture. Myogenic differentiation with frequent estrogen receptor and progesterone receptor staining and no CD10 expression characterized all tumors. All cases showed high NR4A3RNA expression levels and NOR1 (NR4A3) nuclear staining similar to salivary gland acinic cell carcinomas and a subset of extraskeletal myxoid chondrosarcomas harboring NR4A3rearrangements. NOR1 (NR4A3) immunohistochemistry may serve as a useful diagnostic marker of NR4A3fusion–positive gynecologic leiomyosarcomas.

This study is the first in an auditing context to examine auditor susceptibility to memory conjunction errors, a type of systematic memory error that is related to the memory reconstruction process. Conjunction errors occur when memory traces associated with one event are incorrectly attributed to another event during memory reconstruction. Auditors may be particularly susceptible to memory conjunction errors due to their simultaneous exposure to multiple audit clients and their use of standardized audit forms and checklists to capture information. Unrecognized, such errors could adversely affect the efficiency and/or effectiveness of the financial statement audit process. We conducted an experiment that employed practicing audit professionals addressing multiple audit clients. Consistent with our hypotheses, the results indicate that memory conjunction errors in an audit environment are a complex function of (1) the consistency between the audit evidence recalled from an unrelated audit and the characteristics of the client that is the target of the memory reconstruction, (2) the consistency between this recalled audit evidence and the characteristics of the client to which the evidence is actually associated, and (3) the level of risk present in the audit environment that is the target of the memory reconstruction. While research has shown that audit risk factors can generally serve to decrease some types of auditors' memory recognition errors in single client situations (e.g., Sprinkle and Tubbs 1998), our results show that increases in audit risk can actually exacerbate memory errors involving multiple audit clients and memory conjunction errors. Finally, the findings of the study suggest that auditors are not only susceptible to memory conjunction errors, but also that such errors may play a significant role in elements of the audit-planning process related to auditors' likelihood of material error assessments. Keywords: memory conjunction errors; reconstruction of memory; audit risk; schemata. Data Availability: Contact the authors., INTRODUCTION This research focuses on auditor susceptibility to memory errors that are related to the memory reconstruction process. Due to the sheer volume of evidence typically documented in an audit [...]

IMPORTANCE: Extramammary Paget disease (EMPD) is a frequently recurring malignant neoplasm with metastatic potential that presents in older adults on the genital, perianal, and axillary skin. Extramammary Paget disease can precede or occur along with internal malignant neoplasms. OBJECTIVE: To develop recommendations for the care of adults with EMPD. EVIDENCE REVIEW: A systematic review of the literature on EMPD from January 1990 to September 18, 2019, was conducted using MEDLINE, Embase, Web of Science Core Collection, and Cochrane Libraries. Analysis included 483 studies. A multidisciplinary expert panel evaluation of the findings led to the development of clinical care recommendations for EMPD. FINDINGS: The key findings were as follows: (1) Multiple skin biopsies, including those of any nodular areas, are critical for diagnosis. (2) Malignant neoplasm screening appropriate for age and anatomical site should be performed at baseline to distinguish between primary and secondary EMPD. (3) Routine use of sentinel lymph node biopsy or lymph node dissection is not recommended. (4) For intraepidermal EMPD, surgical and nonsurgical treatments may be used depending on patient and tumor characteristics, although cure rates may be superior with surgical approaches. For invasive EMPD, surgical resection with curative intent is preferred. (5) Patients with unresectable intraepidermal EMPD or patients who are medically unable to undergo surgery may receive nonsurgical treatments, including radiotherapy, imiquimod, photodynamic therapy, carbon dioxide laser therapy, or other modalities. (6) Distant metastatic disease may be treated with chemotherapy or individualized targeted approaches. (7) Close follow-up to monitor for recurrence is recommended for at least the first 5 years. CONCLUSIONS AND RELEVANCE: Clinical practice guidelines for EMPD provide guidance regarding recommended diagnostic approaches, differentiation between invasive and noninvasive disease, and use of surgical vs nonsurgical treatments. Prospective registries may further improve our understanding of the natural history of the disease in primary vs secondary EMPD, clarify features of high-risk tumors, and identify superior management approaches.

Benzodiazepines are widely administered drugs to treat anxiety and insomnia. In addition to tolerance development and abuse liability, their chronic use may cause cognitive impairment and increase the risk for dementia. However, the mechanism by which benzodiazepines might contribute to persistent cognitive decline remains unknown. Here we report that diazepam, a widely prescribed benzodiazepine, impairs the structural plasticity of dendritic spines, causing cognitive impairment in mice. Diazepam induces these deficits via the mitochondrial 18 kDa translocator protein (TSPO), rather than classical γ-aminobutyric acid type A receptors, which alters microglial morphology, and phagocytosis of synaptic material. Collectively, our findings demonstrate a mechanism by which TSPO ligands alter synaptic plasticity and, as a consequence, cause cognitive impairment.

A range of safe and effective vaccines against SARS CoV 2 are needed to address the COVID 19 pandemic. We aimed to assess the safety and efficacy of the COVID-19 vaccine SCB-2019.

Cancer chemotherapy has undergone a vast and interesting evolution since its origins. Mustard gas-based agents were first used in the early 20th century, and they resulted in dramatic responses in [...]

Narrow-gap semiconductors are sought-after materials due to their potential for long-wavelength detectors, thermoelectrics, and more recently nontrivial topology. Here, we report the synthesis and characterization of a new family of narrow-gap semiconductors, R3Cd2As6(R= La and Ce). Single-crystal X-ray diffraction at room temperature reveals that the As square nets distort and Cd vacancies order in a monoclinic superstructure. A putative charge-density ordered state sets in at 279 K in La3Cd2As6and at 136 K in Ce3Cd2As6and is accompanied by a substantial increase in the electrical resistivity in both compounds. The resistivity of the La member increases by 13 orders of magnitude on cooling, which points to a remarkably clean semiconducting ground state. Our results suggest that light square-net materials within an I4/mmmparent structure are promising clean narrow-gap semiconductors.

High-grade endometrial stromal sarcoma (HGESS) may harbor YWHAE-NUTM2A/Bfusion, ZC3H7B-BCORfusion, and BCORinternal tandem duplication (ITD). NTRK3upregulation and pan-Trk expression were reported in soft tissue lesions that share similar morphology and genetic abnormalities. To confirm these findings in HGESS, differential expression analysis was performed at gene level comparing 11 HGESS with 48 other uterine sarcomas, including 9 low-grade endometrial stromal sarcomas, 23 undifferentiated uterine sarcomas, and 16 leiomyosarcomas, using targeted RNA sequencing data. Pan-Trk immunohistochemistry was performed on 35 HGESS, including 10 tumors with RNA expression data, with genotypes previously confirmed by targeted RNA sequencing, fluorescence in situ hybridization, and/or genomic PCR. Unsupervised hierarchical clustering of the top 25% of differentially expressed probes identified three molecular groups: (1) high NTRK3, FGFR3, RET, BCOR, GLI1, and PTCH1and low ESR1expression; (2) low NTRK3, FGFR3, RET, BCOR, GLI1, and PTCH1and high ESR1expression; and (3) low NTRK3, FGFR3, RET, BCOR, GLI1, PTCH1, and ESR1expression. Among HGESS, 64% of tumors clustered in group 1, while 27% clustered in group 2. Cytoplasmic and/or nuclear pan-Trk staining of variable extent and intensity was seen in 91% of HGESS regardless of cyclin D1 and/or BCOR positivity. ER and PR expression was seen in 44% of HGESS despite ESR1downregulation. Two patients with ER and PR positive but ESR1downregulated stage I HGESS were treated with endocrine therapy, and both recurred at 12 and 36 months after primary resection. By RNA expression, HGESS appear homogenous and distinct from other uterine sarcomas by activation of kinases, including NTRK3, and sonic hedgehog pathway genes along with downregulation of ESR1. Most HGESS demonstrate pan-Trk staining which may serve as a diagnostic biomarker. ESR1downregulation is seen in some HGESS that express ER and PR which raises implications in the utility of endocrine therapy in these patients.

The gluten-free bread (GFB) market is steadily growing. Nonetheless, GFB-making still remains more of an art than a science. Although there are studies showing the effect of certain starchy materials on the final GFB quality, mechanistic understanding on the fundamental principles governing the mesoscale structural changes and interactions of starchy tissues during the different stages of processing is limited. This work highlights the importance of understanding GFB as a multistage, thermodynamically unstable system and the enormous potential of starchy ingredients to stabilize it (from batter to retail-packed long-self life GFB). This review will also expand on the structuring potential of starchy flour particles, starch granules and dispersed starch molecules to improve GFB quality in terms of loaf specific volume and crumb hardness, cohesiveness, elasticity and staling.

Starch plays a major structural role in many foods and it is responsible for a large portion of daily dietary caloric intake. However, the stress on the body caused by the high demand for insulin after high-glycemic starch-rich meals is a major contributor in the development of type-2 diabetes. Recently, positive benefits from the consumption of indigestible starch and a slow glucose release from starchy foods have emerged. However, further harmonized metrics considering foods as complex matrices of nutrients, ingredients, and processing characteristics are still needed for the complete depiction of starch nutritional quality and its effect on human health. This review expands on potential metrics for starch nutritional quality and the importance of harmonized and simple in vitrostarch digestion models, and highlights opportunities for minimally processed foods, breeding and gene editing, and food by-products based on consumer’s expectations for climate friendly ingredients and individual variation in metabolic responses.

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disorder that primarily affects the joints. One hypothesis for the pathogenesis of RA is that disease begins at mucosal sites as a consequence of interactions between the mucosal immune system and an aberrant local microbiota, and then transitions to involve the synovial joints. Alterations in the composition of the microbial flora in the lungs, mouth and gut in individuals with preclinical and established RA suggest a role for mucosal dysbiosis in the development and perpetuation of RA, although establishing whether these alterations are the specific consequence of intestinal involvement in the setting of a systemic inflammatory process, or whether they represent a specific localization of disease, is an ongoing challenge. Data from mouse models of RA and investigations into the preclinical stages of disease also support the hypothesis that these alterations to the microbiota predate the onset of disease. In addition, several therapeutic options widely used for the treatment of RA are associated with alterations in intestinal microbiota, suggesting that modulation of intestinal microbiota and/or intestinal barrier function might be useful in preventing or treating RA.

Introduction The aim of this study in patients with acute posterior ischaemic stroke (PS) and atrial fibrillation (AF) was to evaluate (1) the risks of recurrent ischaemic event and severe bleeding and (2) these risks in relation with oral anticoagulant therapy (OAT) and its timing.Materials and Methods Patients with PS were prospectively included; the outcome events of these patients were compared with those of patients with anterior stroke (AS) which were taken from previous registries. The primary outcome was the composite of stroke recurrence, transient ischaemic attack, symptomatic systemic embolism, symptomatic cerebral bleeding and major extracranial bleeding occurring within 90 days from acute stroke.Results A total of 2470 patients were available for the analysis: 473 (19.1%) with PS and 1997 (80.9%) with AS. Over 90 days, 213 (8.6%) primary outcome events were recorded: 175 (8.7%) in patients with AS and 38 (8.0%) in those with PS. In patients who initiated OAT within 2 days, the primary outcome occurred in 5 out of 95 patients (5.3%) with PS compared to 21 out of 373 patients (4.3%) with AS (OR 1.07; 95% CI 0.39–2.94). In patients who initiated OAT between days 3 and 7, the primary outcome occurred in 3 out of 103 patients (2.9%) with PS compared to 26 out of 490 patients (5.3%) with AS (OR 0.54; 95% CI 0.16–1.80).Discussion our findings suggest that, when deciding the time to initiate oral anticoagulation, the location of stroke, either anterior or posterior, does not predict the risk of outcome events.Conclusions Patients with PS or AS and AF appear to have similar risks of ischaemic or haemorrhagic events at 90 days with no difference concerning the timing of initiation of OAT.

No-till has many environmental advantages, but concerns are growing about vehicle-induced topsoil compaction limiting crop growth. We performed a wheeling experiment in a long-term no-till field on an Oxisol with sandy loam texture. The objectives were to measure changes in soil bulk density and corresponding impacts on the least limiting water range (LLWR) due to passage of a maize harvester, and to compare bulk density and LLWR measurements with values simulated using the SoilFlex-LLWR soil compaction model. Soil cores were sampled before and after wheeling, for bulk density measurements and to determine LLWR. Simulated increase in bulk density due to vehicle wheeling agreed well with measurements. However, simulated LLWR and its decrease with compaction were inaccurate. This was ascribed to the pedo-transfer function used in SoilFlex-LLWR to estimate LLWR parameters, which was developed based on data from conventionally tilled sugarcane fields, whereas our site was a long-term no-till soil under a wheat/soybean–maize/black oats rotation. Our measurements showed that LLWR was strongly restricted by soil penetration resistance, which was not captured by the pedo-transfer function incorporated in SoilFlex-LLWR. For better prediction of LLWR, we recommend development of specific pedo-transfer functions or of mechanistic models that can be incorporated in SoilFlex-LLWR.

ABSTRACTInvasive pulmonary aspergillosis (IPA) is a severe infection that is difficult to diagnose due to the ubiquitous presence of fungal spores, the underlying diseases of risk patients, and limitations of currently available markers. In this study, we performed a comprehensive liquid chromatography tandem mass spectrometry (LC-MS/MS)-based identification of host and fungal proteins expressed during IPA in mice and humans. The proteomic analysis of bronchoalveolar lavage samples of individual IPA and control cases allowed the description of common host factors that had significantly increased abundance in both infected animals and IPA patients compared to their controls. Although increased levels of these individual host proteins might not be sufficient to distinguish bacterial from fungal infection, a combination of these markers might be beneficial to improve diagnosis. We also identified 16 fungal proteins that were specifically detected during infection and may be valuable candidates for biomarker evaluation.

Afamin is an 87 kDa glycoprotein with five predicted N-glycosylation sites. Afamin’s glycan abundance contributes to conformational and chemical inhomogeneity presenting great challenges for molecular structure determination. For the purpose of studying the structure of afamin, various forms of recombinantly expressed human afamin (rhAFM) with different glycosylation patterns were thus created. Wild-type rhAFM and various hypoglycosylated forms were expressed in CHO, CHO-Lec1, and HEK293T cells. Fully nonglycosylated rhAFM was obtained by transfection of point-mutated cDNA to delete all N-glycosylation sites of afamin. Wild-type and hypo/nonglycosylated rhAFM were purified from cell culture supernatants by immobilized metal ion affinity and size exclusion chromatography. Glycan analysis of purified proteins demonstrated differences in micro- and macro-heterogeneity of glycosylation enabling the comparison between hypoglycosylated, wild-type rhAFM, and native plasma afamin. Because antibody fragments can work as artificial chaperones by stabilizing the structure of proteins and consequently enhance the chance for successful crystallization, we incubated a Fab fragment of the monoclonal anti-afamin antibody N14 with human afamin and obtained a stoichiometric complex. Subsequent results showed sufficient expression of various partially or nonglycosylated forms of rhAFM in HEK293T and CHO cells and revealed that glycosylation is not necessary for expression and secretion.

Background: Glucose transport across the intestinal brush border membrane plays a key role in metabolic regulation. Depending on the luminal glucose concentration, glucose is mainly transported by the sodium- dependent glucose transporter (SGLT1) and the facilitated-transporter glucose transporter (GLUT2). SGLT1 is apical membrane-constitutive and it is active at a low luminal glucose concentration, while at concentrations higher than 50 mM, glucose is mainly transported by GLUT2 (recruited from the basolateral membrane). Dietary phenolic compounds can modulate glucose homeostasis by decreasing the postprandial glucose response through the inhibition of SGLT1 and GLUT2. Methods: Phenolic inhibition of intestinal glucose transport has been examined using brush border membrane vesicles from rats, pigs or rabbits, Xenopus oocytes and more recently Caco-2 cells, which are the most promising for harmonizing in vitro experiments. Results: Phenolic concentrations above 100 μM has been proved to successfully inhibit the glucose transport. Generally, the aglycones quercetin, myricetin, fisetin or apigenin have been reported to strongly inhibit GLUT2, while quercetin-3-O-glycoside has been demonstrated to be more effective in SGLT1. Additionally, epigallocatechin as well as epicatechin and epigallocatechin gallates were observed to be inhibited on both SGLT1 and GLUT2. Conclusion: Although, valuable information regarding the phenolic glucose transport inhibition is known, however, there are some disagreements about which flavonoid glycosides and aglycones exert significant inhibition, and also the inhibition of phenolic acids remains unclear. This review aims to collect, compare and discuss the available information and controversies about the phenolic inhibition of glucose transporters. A detailed discussion on the physicochemical mechanisms involved in phenolics-glucose transporters interactions is also included.

Background The relationship between different patterns of atrial fibrillation and early recurrence after an acute ischaemic stroke is unclear.Purpose In a prospective cohort study, we evaluated the rates of early ischaemic recurrence after an acute ischaemic stroke in patients with paroxysmal atrial fibrillation or sustained atrial fibrillation which included persistent and permanent atrial fibrillation.Methods In patients with acute ischaemic stroke, atrial fibrillation was categorised as paroxysmal atrial fibrillation or sustained atrial fibrillation. Ischaemic recurrences were the composite of ischaemic stroke, transient ischaemic attack and symptomatic systemic embolism occurring within 90 days from acute index stroke.Results A total of 2150 patients (1155 females, 53.7%) were enrolled: 930 (43.3%) had paroxysmal atrial fibrillation and 1220 (56.7%) sustained atrial fibrillation. During the 90-day follow-up, 111 ischaemic recurrences were observed in 107 patients: 31 in patients with paroxysmal atrial fibrillation (3.3%) and 76 with sustained atrial fibrillation (6.2%) (hazard ratio (HR) 1.86 (95% CI 1.24–2.81)). Patients with sustained atrial fibrillation were on average older, more likely to have diabetes mellitus, hypertension, history of stroke/ transient ischaemic attack, congestive heart failure, atrial enlargement, high baseline NIHSS-score and implanted pacemaker. After adjustment by Cox proportional hazard model, sustained atrial fibrillation was not associated with early ischaemic recurrences (adjusted HR 1.23 (95% CI 0.74–2.04)).Conclusions After acute ischaemic stroke, patients with sustained atrial fibrillation had a higher rate of early ischaemic recurrence than patients with paroxysmal atrial fibrillation. After adjustment for relevant risk factors, sustained atrial fibrillation was not associated with a significantly higher risk of recurrence, thus suggesting that the risk profile associated with atrial fibrillation, rather than its pattern, is determinant for recurrence.

Pregnancy can be a dangerous trigger for patients with paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), or hemolysis, elevated liver enzymes and low platelet (HELLP) syndrome. Due to the possibility of several serious complications, pregnancy is somewhat discouraged in the presence of the above diseases. Eculizumab is a humanized antibody that may dramatically change the clinical course of PNH, aHUS and HELLP syndrome. However, data on the safety of eculizumab in pregnancy are scarce. In this narrative overview, we summarize current evidence on the use of eculizumab during pregnancy in women with PNH, aHUS and HELLP syndrome. Eculizumab is not present in breast milk, and the levels observed in umbilical cord blood samples are not sufficient to affect the concentrations of complement in newborns. Therefore, eculizumab may be regarded as safe in pregnancy. Nonetheless, given that data on eculizumab in pregnancy are limited, it is not possible to completely exclude risks for both mother and fetus in treating PNH, aHUS and HELLP syndrome.

Presents a speech by New York Governor Mario M. Cuomo, delivered to the New York Press Club in New York City on November 25, 1986. Relation between the shift in Supreme Court Law and the right to a free press; Significance of the criticism of the press; Discussion on the interpretation of the constitutional right of free press.

Presents a speech by Mario M. Cuomo, Governor of New York, delivered at Harvard Class Day in Cambridge, Massachusetts, June 5, 1985. Reason some people despise Harvard; Significance of Harvard to students; Ways the U.S. people helped people with the leadership of Harvard graduates named Franklin Roosevelt and John Kennedy.

Consider a multipriority batch computer system which users from several different classes may join, with toll, service, and waiting charges. Such a system is formulated here as a semi- Markov decision process, In which the aim of arriving users Is to minimize their expected loss. The optimal joining policy of arriving users who may join the system at some of its queues is a control limit policy, with a single control number for any possible queue and the user's class; a newly arriving user will join a queue that is not filled up to the control number corresponding to this queue and the user's class. In this paper control numbers, as well as lower and upper bounds for the control numbers and the capacities of the system's queues, are derived. [ABSTRACT FROM AUTHOR]

Maxio Cuomo, former governor of New York The beginning of the Bush administration is going to be critical, Bush assumes the presidency uniquely burdened--not just burdened, but uniquely burdened--by no [...]

MARIO M. ALBERTO [+] ABSTRACT Ten Mozambican hardwood species were tested for their compatibility with two classes of Portland cement. Instantaneous heat flux of cement hydration was measured by isothermal [...]

Diabetes affects your risk of stroke. Here's what you can do to decrease it. Stroke is the third leading cause of death in the United States today, claiming 160,000 lives [...]

Conservative; liberal challenge advisers to take stock of the state of the nation In a breakfast speech on the second day of IMPACT 1999, conservative columnist George Will told investment [...]