Identification and nucleotide sequences of mxaA, mxaC, mxaK, mxaL, and mxaD genes from Methylobacterium extorquens AM1

The DNA sequence for a 4.4-kb HindIII-XhoI Methylobacterium extorquens AM1 DNA fragment that is known to contain three genes (mxaAKL) involved in incorporation of calcium into methanol dehydrogenase (I. W. Richardson and C. Anthony, Biochem. J. 287:709-7115, 1992) was determined. Five complete open reading frames and two partial open reading frames were found, suggesting that this region contains previously unidentified genes. A combination of sequence analysis, mutant complementation data, and gene expression studies showed that these genes correspond to mxaSACKLDorf1. Of the three previously unidentified genes (mxaC, mxaD, and orf1), mutant complementation studies showed that mxaC is required for methanol oxidation, while the function of the other two genes is still unknown

Gender Equality, Drinking Cultures and Second-Hand Harms from Alcohol in the 50 US States.

BackgroundGender inequality and cultures of binge drinking may increase the risk of second-hand harms from alcohol.MethodsUsing the 2014-2015 National Alcohol Survey and 2015 National Alcohol's Harm to Others Survey (N = 7792), we examine associations of state-level gender equality measures (contraceptive access, abortion rights, women's economic equality) and binge drinking cultures (rates of men's and women's binge drinking) with individual-level indicators of second-hand harms by drinking strangers and partners/spouses.ResultsIn main effects models, only male binge drinking was associated with greater odds of harms from drinking strangers. There were significant interactions of gender equality with male binge drinking: High male binge drinking rates were more strongly associated with stranger-perpetrated harms in states low on contraceptive access or abortion rights compared to states high on these measures. Conversely, male binge drinking was more strongly associated with spouse/partner-perpetrated second-hand harms in states with more economic equality, compared to states lower on this measure.ConclusionsDetrimental effects of high male binge drinking rates may be modified by gender equality. Targeted interventions may reduce alcohol-related harms experienced by women in states with high rates of male binge drinking. Restrictions in access to contraception and abortion may exacerbate harms due to men's drinking

Effects of Spinal Fusion for Idiopathic Scoliosis on Lower Body Kinematics During Gait

Objectives The purpose of this study was to compare gait among patients with scoliosis undergoing posterior spinal fusion and instrumentation (PSFI) to typically developing subjects and determine if the location of the lowest instrumented vertebra impacted results. Summary of Background Data PSFI is the standard of care for correcting spine deformities, allowing the preservation of body equilibrium while maintaining as many mobile spinal segments as possible. The effect of surgery on joint motion distal to the spine must also be considered. Very few studies have addressed the effect of PSFI on activities such as walking and even fewer address how surgical choice of the lowest instrumented vertebra (LIV) influences possible motion reduction. Methods Individuals with scoliosis undergoing PSFI (n = 38) completed gait analysis preoperatively and at postoperative years 1 and 2 along with a control group (n = 24). Comparisons were made with the control group at each time point and between patients fused at L2 and above (L2+) versus L3 and below (L3–). Results The kinematic results of the AIS group showed some differences when compared to the Control Group, most notably decreased range of motion (ROM) in pelvic tilt and trunk lateral bending. When comparing the LIV groups, only minor differences were observed, and the results showed decreased coronal trunk and pelvis ROM at the one-year visit and decreased hip rotation ROM at the two-year visit in the L3– group. Conclusions Patients with AIS showed decreased ROM preoperatively with further decreases postoperatively. These changes remained relatively consistent following the two-year visit, indicating that most kinematic changes occurred in the first year following surgery. Limited functional differences between the two LIV groups may be due to the lack of full ROM used during normal gait, and future work could address tasks that use greater ROM

Elevated glutamatergic compounds in pregenual anterior cingulate in pediatric autism spectrum disorder demonstrated by 1H MRS and 1H MRSI.

Recent research in autism spectrum disorder (ASD) has aroused interest in anterior cingulate cortex and in the neurometabolite glutamate. We report two studies of pregenual anterior cingulate cortex (pACC) in pediatric ASD. First, we acquired in vivo single-voxel proton magnetic resonance spectroscopy ((1)H MRS) in 8 children with ASD and 10 typically developing controls who were well matched for age, but with fewer males and higher IQ. In the ASD group in midline pACC, we found mean 17.7% elevation of glutamate + glutamine (Glx) (p<0.05) and 21.2% (p<0.001) decrement in creatine + phosphocreatine (Cr). We then performed a larger (26 subjects with ASD, 16 controls) follow-up study in samples now matched for age, gender, and IQ using proton magnetic resonance spectroscopic imaging ((1)H MRSI). Higher spatial resolution enabled bilateral pACC acquisition. Significant effects were restricted to right pACC where Glx (9.5%, p<0.05), Cr (6.7%, p<0.05), and N-acetyl-aspartate + N-acetyl-aspartyl-glutamate (10.2%, p<0.01) in the ASD sample were elevated above control. These two independent studies suggest hyperglutamatergia and other neurometabolic abnormalities in pACC in ASD, with possible right-lateralization. The hyperglutamatergic state may reflect an imbalance of excitation over inhibition in the brain as proposed in recent neurodevelopmental models of ASD

Sigma1 Targeting to Suppress Aberrant Androgen Receptor Signaling in Prostate Cancer.

Suppression of androgen receptor (AR) activity in prostate cancer by androgen depletion or direct AR antagonist treatment, although initially effective, leads to incurable castration-resistant prostate cancer (CRPC) via compensatory mechanisms including resurgence of AR and AR splice variant (ARV) signaling. Emerging evidence suggests that Sigma1 (also known as sigma-1 receptor) is a unique chaperone or scaffolding protein that contributes to cellular protein homeostasis. We reported previously that some Sigma1-selective small molecules can be used to pharmacologically modulate protein homeostasis pathways. We hypothesized that these Sigma1-mediated responses could be exploited to suppress AR protein levels and activity. Here we demonstrate that treatment with a small-molecule Sigma1 inhibitor prevented 5α- dihydrotestosterone-mediated nuclear translocation of AR and induced proteasomal degradation of AR and ARV, suppressing the transcriptional activity and protein levels of both full-length and splice-variant AR. Consistent with these data, RNAi knockdown of Sigma1 resulted in decreased AR levels and transcriptional activity. Furthermore, Sigma1 physically associated with ARV7 and A

RRx-001 in Refractory Small-Cell Lung Carcinoma: A Case Report of a Partial Response after a Third Reintroduction of Platinum Doublets.

RRx-001 is a pan-active, systemically nontoxic epigenetic inhibitor under investigation in advanced non-small cell lung cancer, small-cell lung cancer and high-grade neuroendocrine tumors in a Phase II clinical trial entitled TRIPLE THREAT (NCT02489903), which reexposes patients to previously effective but refractory platinum doublets after treatment with RRx-001. The purpose of this case study is first to report a partial response to carboplatin and etoposide in a patient with small-cell lung cancer pretreated with RRx-001, indicating episensitization or resensitization by epigenetic mechanisms, and second to discuss the literature related to small-cell lung cancer and episensitization

Novel components of the Toxoplasma inner membrane complex revealed by BioID.

UNLABELLED:The inner membrane complex (IMC) of Toxoplasma gondii is a peripheral membrane system that is composed of flattened alveolar sacs that underlie the plasma membrane, coupled to a supporting cytoskeletal network. The IMC plays important roles in parasite replication, motility, and host cell invasion. Despite these central roles in the biology of the parasite, the proteins that constitute the IMC are largely unknown. In this study, we have adapted a technique named proximity-dependent biotin identification (BioID) for use in T. gondii to identify novel components of the IMC. Using IMC proteins in both the alveoli and the cytoskeletal network as bait, we have uncovered a total of 19 new IMC proteins in both of these suborganellar compartments, two of which we functionally evaluate by gene knockout. Importantly, labeling of IMC proteins using this approach has revealed a group of proteins that localize to the sutures of the alveolar sacs that have been seen in their entirety in Toxoplasma species only by freeze fracture electron microscopy. Collectively, our study greatly expands the repertoire of known proteins in the IMC and experimentally validates BioID as a strategy for discovering novel constituents of specific cellular compartments of T. gondii. IMPORTANCE:The identification of binding partners is critical for determining protein function within cellular compartments. However, discovery of protein-protein interactions within membrane or cytoskeletal compartments is challenging, particularly for transient or unstable interactions that are often disrupted by experimental manipulation of these compartments. To circumvent these problems, we adapted an in vivo biotinylation technique called BioID for Toxoplasma species to identify binding partners and proximal proteins within native cellular environments. We used BioID to identify 19 novel proteins in the parasite IMC, an organelle consisting of fused membrane sacs and an underlying cytoskeleton, whose protein composition is largely unknown. We also demonstrate the power of BioID for targeted discovery of proteins within specific compartments, such as the IMC cytoskeleton. In addition, we uncovered a new group of proteins localizing to the alveolar sutures of the IMC. BioID promises to reveal new insights on protein constituents and interactions within cellular compartments of Toxoplasma

Digital-analog hybrid matrix multiplication processor for optical neural networks

The computational demands of modern AI have spurred interest in optical neural networks (ONNs) which offer the potential benefits of increased speed and lower power consumption. However, current ONNs face various challenges,most significantly a limited calculation precision (typically around 4 bits) and the requirement for high-resolution signal format converters (digital-to-analogue conversions (DACs) and analogue-to-digital conversions (ADCs)). These challenges are inherent to their analog computing nature and pose significant obstacles in practical implementation. Here, we propose a digital-analog hybrid optical computing architecture for ONNs, which utilizes digital optical inputs in the form of binary words. By introducing the logic levels and decisions based on thresholding, the calculation precision can be significantly enhanced. The DACs for input data can be removed and the resolution of the ADCs can be greatly reduced. This can increase the operating speed at a high calculation precision and facilitate the compatibility with microelectronics. To validate our approach, we have fabricated a proof-of-concept photonic chip and built up a hybrid optical processor (HOP) system for neural network applications. We have demonstrated an unprecedented 16-bit calculation precision for high-definition image processing, with a pixel error rate (PER) as low as $1.8\times10^{-3}$ at an signal-to-noise ratio (SNR) of 18.2 dB. We have also implemented a convolutional neural network for handwritten digit recognition that shows the same accuracy as the one achieved by a desktop computer. The concept of the digital-analog hybrid optical computing architecture offers a methodology that could potentially be applied to various ONN implementations and may intrigue new research into efficient and accurate domain-specific optical computing architectures for neural networks

Retinoic Acid Can Enhance Conversion of Naive into Regulatory T Cells Independently of Secreted Cytokines

It has been reported that retinoic acid (RA) enhances regulatory T (T reg) cell conversion by inhibiting the secretion of cytokines that interfere with conversion. This report shows that these conclusions provide a partial explanation at best. First, RA not only interfered with cytokine secretion but also with the ability of these cytokines to inhibit T reg cell conversion of naive T cells. Furthermore, RA enhanced conversion even in the absence of inhibitory cytokines. The latter effect depended on the RA receptor α (RARα) but did not require Smad3, despite the fact that RA enhanced Smad3 expression. The RARα1 isoform was not essential for RA-dependent enhancement of transforming growth factor β–driven conversion, suggesting that conversion can also be mediated by RARα2. Interleukin (IL)-6 strongly reduced RARα expression levels such that a deficiency of the predominant RARα1 isoform leaves too little RARα2 for RA to inhibit the generation of Th17 cells in the presence of IL-6