How action structures time: About the perceived temporal order of action and predicted outcomes

Few ideas are as inexorable as the arrow of causation: causes must precede their effects. Explicit or implicit knowledge about this causal order permits humans and other animals to predict and control events in order to produce desired outcomes. The sense of agency is deeply linked with representation of causation, since it involves the experience of a self-capable of acting on the world. Since causes must precede effects, the perceived temporal order of our actions and subsequent events should be relevant to the sense of agency. The present study investigated whether the ability to predict the outcome of an action would impose the classical cause-precedes-outcome pattern on temporal order judgements. Participants indicated whether a visual stimulus (dots moving upward or downward) was presented either before or after voluntary actions of the left or right hand. Crucially, the dot motion could be either congruent or incongruent with an operant association between hand and motion direction learned in a previous learning phase. When the visual outcome of voluntary action was congruent with previous learning, the motion onset was more often perceived as occurring after the action, compared to when the outcome was incongruent. This suggests that the prediction of specific sensory outcomes restructures our perception of timing of action and sensory events, inducing the experience that congruent effects occur after participants' actions. Interestingly, this bias to perceive events according to the temporal order of cause and outcome disappeared when participants knew that motion directions were automatically generated by the computer. This suggests that the reorganisation of time perception imposed by associative learning depends on participants' causal beliefs

PyNAST: a flexible tool for aligning sequences to a template alignment

Motivation: The Nearest Alignment Space Termination (NAST) tool is commonly used in sequence-based microbial ecology community analysis, but due to the limited portability of the original implementation, it has not been as widely adopted as possible. Python Nearest Alignment Space Termination (PyNAST) is a complete reimplementation of NAST, which includes three convenient interfaces: a Mac OS X GUI, a command-line interface and a simple application programming interface (API)

Clinical Epidemiology of Carbapenem-Resistant Enterobacterales in the Greater Houston Region of Texas: a 6-Year Trend and Surveillance analysis

OBJECTIVES: Carbapenem-resistant Enterobacterales (CRE) remain an urgent public health priority in the United States. CRE poses a major threat to patients in healthcare and a potential risk to the community. This study examined the epidemiological trends, clinical, and microbiological data of CRE in the Greater Houston region of Texas. METHODS: A multi-institutional retrospective observational study was conducted using surveillance data collected from 2015 to 2020. Predictors of incidence rates of CRE were determined by a negative binomial regression fit using a generalized estimation equation. RESULTS: Over a 6-year period, 4236 CRE cases were reported, of which Klebsiella pneumoniae accounted for 84.8%. The results show a steady increase in CRE cases, with a sharp rise since 2018. The majority of carbapenemase-producing Enterobacterales were Klebsiella pneumoniae carbapenemase (KPC)-producing (77.2%), followed by other rare carbapenemases, which includes OXA-48, NDM, IMP, VIM, coproduction of KPC with OXA-48, KPC with NDM, and NDM with OXA-48. Acute care hospitals (ACH) accounted for 68.5% of the source of CRE cases. The incidence rate of CRE cases reported from ACH and long-term acute care (LTAC) facilities was 1.16 times that of long-term care facilities (adjusted rate ratio [ARR] = 1.16, 95% confidence interval [CI]:1.04-1.30). The incidence rate of CRE among patients with indwelling devices was 15% (ARR = 0.85, 95% CI: 0.79-0.92) lower than that of patients without indwelling devices. CONCLUSION: The rise in the rate of CRE cases despite aggressive infection prevention and control strategies in the region is alarming. Evaluating and improving the current infection control strategies may be warranted

Clinical Outcomes associated With Co-infection of Carbapenem-Resistant Enterobacterales and Other Multidrug-Resistant organisms

BACKGROUND: Infections with carbapenem-resistant Enterobacterales (CRE) are associated with increased risk of death. Polymicrobial infections with antimicrobial-resistance may add to the burden of clinical care and patients\u27 clinical prognosis. AIM: to examine the impact of CRE co-infection with other multi-drug resistant organisms (MDRO) on patient clinical outcomes. STUDY DESIGN: A retrospective observational study was conducted to compare the clinical outcomes of CRE patients who were co-infected with carbapenem-resistant RESULTS: A total of 224 CRPA and 209 MDRA co-infections with CRE were identified from 4,236 cases from 2015-2020. The overall 90-day all-cause mortality was 21.6% but increased to 35.0% and 33.5% among patients who were co-infected with CRPA and MDRA, respectively. The odds of all-cause mortality among CRE patients who were co-infected with CRPA was twice that of patients identified with CRE alone [adjusted odds ratio (AOR) = 2.02, 95% confidence interval (CI): 1.18-3.46]. Further, the odds of all-cause mortality among CRE patients who were concomitantly identified with MRSA was more than twice that of patients who were not identified with MRSA [AOR = 2.16, 95%CI:1.31-3.56]. The clinical outcome of patients with CRE did not differ significantly depending on the presence of carbapenemase genes. CONCLUSION: The results show that CRPA and CRE co-infections have synergistic effects on clinical outcomes. Further investigation is necessary to understand the mechanism. Screening high risk patients for concomitant antimicrobial-resistant infections may have a significant clinical impact, including effective therapies, antibiotic stewardship, and infection control policies

Use of differential scanning fluorimetry as a high-throughput assay to identify nuclear receptor ligands

Identification of ligands that interact with nuclear receptors is both a major biological problem and an important initial step in drug discovery. Several in vitro and in vivo techniques are commonly used to screen ligand candidates against nuclear receptors; however, none of the current assays allow screening without modification of either the protein and/or the ligand in a high-throughput fashion. Differential scanning fluorimetry (DSF) allows unmodified potential ligands to be screened as 10µL reactions in 96-well format against partially purified protein, revealing specific interactors. As a proof of principle, we used a commercially-available nuclear receptor ligand candidate chemical library to identify interactors of the human estrogen receptor α ligand binding domain (ERα LBD). Compounds that interact specifically with ERα LBD stabilize the protein and result in an elevation of the thermal denaturation point, as monitored by the environmentally-sensitive dye SYPRO orange. We successfully identified all three compounds in the library that have previously been identified to interact with ERα, with no false positive results

NAST: a multiple sequence alignment server for comparative analysis of 16S rRNA genes

Microbiologists conducting surveys of bacterial and archaeal diversity often require comparative alignments of thousands of 16S rRNA genes collected from a sample. The computational resources and bioinformatics expertise required to construct such an alignment has inhibited high-throughput analysis. It was hypothesized that an online tool could be developed to efficiently align thousands of 16S rRNA genes via the NAST (Nearest Alignment Space Termination) algorithm for creating multiple sequence alignments (MSA). The tool was implemented with a web-interface at . Each user-submitted sequence is compared with Greengenes' ‘Core Set’, comprising ∼10 000 aligned non-chimeric sequences representative of the currently recognized diversity among bacteria and archaea. User sequences are oriented and paired with their closest match in the Core Set to serve as a template for inserting gap characters. Non-16S data (sequence from vector or surrounding genomic regions) are conveniently removed in the returned alignment. From the resulting MSA, distance matrices can be calculated for diversity estimates and organisms can be classified by taxonomy. The ability to align and categorize large sequence sets using a simple interface has enabled researchers with various experience levels to obtain bacterial and archaeal community profiles

Three-Dimensional Reconstructions of Tadpole Chondrocrania from Historical Sections

Reconstructing three dimensional structures (3DR) from histological sections has always been difficult but is becoming more accessible with the assistance of digital imaging. We sought to assemble a low cost system using readily available hardware and software to generate 3DR for a study of tadpole chondrocrania. We found that a combination of RGB can1era, stereomicro­scope, and Apple Macintosh PowerPC computers running NIH Image, Object Image, Rotater, and SURFdriver software provided acceptable reconstruc­tions. These are limited in quality primarily by the distortions arising from histological protocols rather than hardware or software

Foregut microbiome in development of esophageal adenocarcinoma

Esophageal adenocarcinoma (EA), the type of cancer linked to heartburn due to gastroesophageal reflux diseases (GERD), has increased six fold in the past 30 years. This cannot currently be explained by the usual environmental or by host genetic factors. EA is the end result of a sequence of GERD-related diseases, preceded by reflux esophagitis (RE) and Barrett’s esophagus (BE). Preliminary studies by Pei and colleagues at NYU on elderly male veterans identified two types of microbiotas in the esophagus. Patients who carry the type II microbiota are >15 fold likely to have esophagitis and BE than those harboring the type I microbiota. In a small scale study, we also found that 3 of 3 cases of EA harbored the type II biota. The findings have opened a new approach to understanding the recent surge in the incidence of EA. 

Our long-term goal is to identify the cause of GERD sequence. The hypothesis to be tested is that changes in the foregut microbiome are associated with EA and its precursors, RE and BE in GERD sequence. We will conduct a case control study to demonstrate the microbiome disease association in every stage of GERD sequence, as well as analyze the trend in changes in the microbiome along disease progression toward EA, by two specific aims. Aim 1 is to conduct a comprehensive population survey of the foregut microbiome and demonstrate its association with GERD sequence. Furthermore, spatial relationship between the esophageal microbiota and upstream (mouth) and downstream (stomach) foregut microbiotas as well as temporal stability of the microbiome-disease association will also be examined. Aim 2 is to define the distal esophageal metagenome and demonstrate its association with GERD sequence. Detailed analyses will include pathway-disease and gene-disease associations. Archaea, fungi and viruses, if identified, also will be correlated with the diseases. A significant association between the foregut microbiome and GERD sequence, if demonstrated, will be the first step for eventually testing whether an abnormal microbiome is required for the development of the sequence of phenotypic changes toward EA. If EA and its precursors represent a microecological disease, treating the cause of GERD might become possible, for example, by normalizing the microbiota through use of antibiotics, probiotics, or prebiotics. Causative therapy of GERD could prevent its progression and reverse the current trend of increasing incidence of EA

Targeting angiogenesis in multiple myeloma by the VEGF and HGF blocking DARPin® protein MP0250: a preclinical study

The investigational drug MP0250 is a multi-specific DARPin® molecule that simultaneously binds and neutralizes VEGF and HGF with high specificity and affinity. Here we studied the antiangiogenic effects of the MP0250 in multiple myeloma (MM). In endothelial cells (EC) isolated from bone marrow (BM) of MM patients (MMEC) MP0250 reduces VEGFR2 and cMet phosphorylation and affects their downstream signaling cascades. MP0250 influences the secretory profile of MMEC and inhibits their in vitro angiogenic activities (spontaneous and chemotactic migration, adhesion, spreading and capillarogenesis). Compared to anti-VEGF or anti-HGF neutralizing mAbs, MP0250 strongly reduces capillary network formation and vessel-sprouting in a Matrigel angiogenesis assay. MP0250 potentiates the effect of bortezomib in the same in vitro setting. It significantly reduces the number of newly formed vessels in the choriollantoic membrane assay (CAM) and the Matrigel plug assay. In the syngeneic 5T33MM tumor model, MP0250 decreases the microvessel density (MVD) and the combination MP0250/bortezomib lowers the percentage of idiotype positive cells and the serum levels of M-protein. Overall results define MP0250 as a strong antiangiogenic agent with potential as a novel combination drug for treatment of MM patients