Anti-Ro52 positivity is associated with progressive interstitial lung disease in systemic sclerosis-an exploratory study.
Interstitial lung disease (ILD) is the most common cause of death in patients with systemic sclerosis (SSc). Prognostic biomarkers are needed to identify SSc-ILD patients at risk for progressive pulmonary fibrosis. This study investigates autoantibodies measured in bronchoalveolar lavage (BAL) fluid and in serum in reference to the clinical disease course of SSc-ILD. Fifteen patients with new onset SSc-ILD underwent bronchoscopy. Autoantibody levels were analyzed using addressable laser bead immunoassay from BAL fluid and the serum. In a separate longitudinal cohort of 43 patients with early SSc-ILD, autoantibodies in serum were measured at baseline and pulmonary function tests were performed at least 2 times over the course of at least 2 or more years. Linear mixed effect models were created to investigate the relationship between specific autoantibodies and progression of SSc-ILD. Finally, lung tissue from healthy controls and from subjects with SSc was analyzed for the presence of the Ro52 antigen using immunohistochemistry. Among SSc-ILD patients who were positive for anti-Ro52 (N = 5), 3 (60%) had enrichment of anti-Ro52 in BAL fluid at a ratio exceeding 50x. In the longitudinal cohort, 10/43 patients (23%) were anti-Ro52 positive and 16/43 (37%) were anti-scl-70 positive. Presence of anti-Scl-70 was associated with a lower vital capacity (VC) at baseline (-12.6% predicted VC [%pVC]; 95%CI: -25.0, -0.29; p = 0.045), but was not significantly associated with loss of lung function over time (-1.07%pVC/year; 95%CI: -2.86, 0.71; p = 0.230). The presence of anti-Ro52 was significantly associated with the loss of lung function over time (-2.41%pVC/year; 95% CI: -4.28, -0.54; p = 0.013). Rate of loss of lung function increased linearly with increasing anti-Ro52 antibody levels (-0.03%pVC per arbitrary units/mL and year; 95%CI: -0.05, -0.02; p < 0.001). Immunohistochemical staining localized the Ro52 antigen to alveolar M2 macrophages in peripheral lung tissue both in subjects with and without SSc. This study suggests that antibodies targeting Ro52 are enriched in the lungs of patients with new-onset SSc-ILD, linking Ro52 autoimmunity to the pulmonary pathology of SSc. Clinical and immunohistochemical data corroborates these findings and suggest that anti-Ro52 may serve as a potential biomarker of progressive SSc-ILD.


Development of a histologically validated segmentation protocol for the hippocampal body.
Recent findings have demonstrated that hippocampal subfields can be selectively affected in different disease states, which has led to efforts to segment the human hippocampus with in vivo magnetic resonance imaging (MRI). However, no studies have examined the histological accuracy of subfield segmentation protocols. The presence of MRI-visible anatomical landmarks with known correspondence to histology represents a fundamental prerequisite for in vivo hippocampal subfield segmentation. In the present study, we aimed to: 1) develop a novel method for hippocampal body segmentation, based on two MRI-visible anatomical landmarks (stratum lacunosum moleculare [SLM] & dentate gyrus [DG]), and assess its accuracy in comparison to the gold standard direct histological measurements; 2) quantify the accuracy of two published segmentation strategies in comparison to the histological gold standard; and 3) apply the novel method to ex vivo MRI and correlate the results with histology. Ultra-high resolution ex vivo MRI was performed on six whole cadaveric hippocampal specimens, which were then divided into 22 blocks and histologically processed. The hippocampal bodies were segmented into subfields based on histological criteria and subfield boundaries and areas were directly measured. A novel method was developed using mean percentage of the total SLM distance to define subfield boundaries. Boundary distances and subfield areas on histology were then determined using the novel method and compared to the gold standard histological measurements. The novel method was then used to determine ex vivo MRI measures of subfield boundaries and areas, which were compared to histological measurements. For direct histological measurements, the mean percentages of total SLM distance were: Subiculum/CA1 = 9.7%, CA1/CA2 = 78.4%, CA2/CA3 = 97.5%. When applied to histology, the novel method provided accurate measures for CA1/CA2 (ICC = 0.93) and CA2/CA3 (ICC = 0.97) boundaries, but not for the Subiculum/CA1 (ICC = -0.04) boundary. Accuracy was poorer using previous techniques for CA1/CA2 (maximum ICC = 0.85) and CA2/CA3 (maximum ICC = 0.88), with the previously reported techniques also performing poorly in defining the Subiculum/CA1 boundary (maximum ICC = 0.00). Ex vivo MRI measurements using the novel method were linearly related to direct measurements of SLM length (r2 = 0.58), CA1/CA2 boundary (r2 = 0.39) and CA2/CA3 boundary (r2 = 0.47), but not for Subiculum/CA1 boundary (r2 = 0.01). Subfield areas measured with the novel method on histology and ex vivo MRI were linearly related to gold standard histological measures for CA1, CA2, and CA3/CA4/DG. In this initial proof of concept study, we used ex vivo MRI and histology of cadaveric hippocampi to develop a novel segmentation protocol for the hippocampal body. The novel method utilized two anatomical landmarks, SLM & DG, and provided accurate measurements of CA1, CA2, and CA3/CA4/DG subfields in comparison to the gold standard histological measurements. The relationships demonstrated between histology and ex vivo MRI supports the potential feasibility of applying this method to in vivo MRI studies.


The IRS and "your health care".
At most times, the IRS is one of America's least loved institutions, but this past month has been a particularly bad period for the agency.


Classroom Teachers' Perceived Barriers to Implementing Comprehensive School Physical Activity Programs (TPB- CSPAP): Instrument Development.
Although physical education teachers generally act as the physical activity champion and promote adherence to whole-school physical activity programs, classroom teachers manage the majority of students' access to movement throughout the school day. Purpose: To support the adoption of a whole-school physical activity program, this study developed an instrument that identifies barriers perceived by classroom teachers related to adopting this type of program in their school. Method: A four-step process provided the conceptual framework for this instrument development (literature review, expert review, quantitative evaluation, and validation). The final validation phase (N = 520 teachers) included two individual analyses to separately evaluate respondents from elementary (K-5) and secondary levels (6-12). Each group was randomly split to run exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) of the models. Results: CFA results support models with adequate fit to the data for barriers for elementary, e.g., (SRMR = 0.0726; Bentler CFI = 0.92.79) and secondary (SRMR = 0.0813; Bentler CFI = 0.9374) teachers for whole-school programming. Conclusion: This instrument can be used by school personnel and researchers to understand perceived barriers for classroom teachers to implement a whole-school physical activity program in their context and then follow up to remove or reduce the barriers.


Enhanced spinal neuronal responses as a mechanism for increased number and size of active acupoints in visceral hyperalgesia.
Acupuncture has been used to treat a variety of illness and involves the insertion and manipulation of needles into specific points on the body (termed "acupoints"). It has been suggested that acupoints are not merely discrete, static points, but can be dynamically changed according to the pathological state of internal organs. We investigated in a rat model of mustard oil (MO)-induced visceral hyperalgesia whether the number and size of acupoints were modified according to the severity of the colonic pain, and whether the changes were associated with enhanced activity of the spinal dorsal horn. In MO-treated rats, acupoints showing neurogenic inflammation (termed "neurogenic spots" or Neuro-Sps) were found both bilaterally and unilaterally on the leg. The number and size of these acupoints increased along with increasing doses of MO. Electroacupuncture of the acupoints generated analgesic effects on MO-induced visceral hypersensitivity. The MO-treated rats showed an increase in c-Fos expression in spinal dorsal horn neurons and displayed increased evoked activity and a prolonged after-discharge in spinal wide dynamic response (WDR) neurons in response to colorectal distension. Increased number and size of neurogenic inflammatory acupoints following MO treatment were reduced by inhibiting AMPA and NMDA receptors in the spinal cord. Our findings suggest that acupoints demonstrate increased number and size along with severity of visceral pain, which may be associated with enhanced neuronal responses in spinal dorsal horn neurons.


Targeting the tumor microenvironment as a potential therapeutic approach in colorectal cancer: Rational and progress.
Colorectal cancer (CC) is often diagnosed at a late stage when tumor metastasis may have already occurred. Current treatments are often ineffective in metastatic disease, and consequently late diagnosis is often associated with poor outcomes in CC. Alternative strategies are therefore urgently required. An interaction between epithelial cancer cells and their tissue microenvironment is a contributor to metastasis, and therefore recent studies are beginning to focus on the properties of the tumor microenvironment and the mechanism by which the metastatic cells exploit the tumor microenvironment for survival, immune evasion, and growth. We have reviewed the development of the combined therapeutic approaches that have focused on targeting the microenvironment of CC.


Metronomic treatment in immunocompetent preclinical GL261 glioblastoma: effects of cyclophosphamide and temozolomide.
Glioblastoma (GBM) causes poor survival in patients even when applying aggressive treatment. Temozolomide (TMZ) is the standard chemotherapeutic choice for GBM treatment, but resistance always ensues. In previous years, efforts have focused on new therapeutic regimens with conventional drugs to activate immune responses that may enhance tumor regression and prevent regrowth, for example the "metronomic" approaches. In metronomic scheduling studies, cyclophosphamide (CPA) in GL261 GBM growing subcutaneously in C57BL/6 mice was shown not only to activate antitumor CD8+ T-cell response, but also to induce long-term specific T-cell tumor memory. Accordingly, we have evaluated whether metronomic CPA or TMZ administration could increase survival in orthotopic GL261 in C57BL/6 mice, an immunocompetent model. Longitudinal in vivo studies with CPA (140 mg/kg) or TMZ (range 140-240 mg/kg) metronomic administration (every 6 days) were performed in tumor-bearing mice. Tumor evolution was monitored at 7 T with MRI (T2 -weighted, diffusion-weighted imaging) and MRSI-based nosological images of response to therapy. Obtained results demonstrated that both treatments resulted in increased survival (38.6 ± 21.0 days, n = 30) compared with control (19.4 ± 2.4 days, n = 18). Best results were obtained with 140 mg/kg TMZ (treated, 44.9 ± 29.0 days, n = 12, versus control, 19.3 ± 2.3 days, n = 12), achieving a longer survival rate than previous group work using three cycles of TMZ therapy at 60 mg/kg (33.9 ± 11.7 days, n = 38). Additional interesting findings were, first, clear edema appearance during chemotherapeutic treatment, second, the ability to apply the semi-supervised source analysis previously developed in our group for non-invasive TMZ therapy response monitoring to detect CPA-induced response, and third, the necropsy findings in mice cured from GBM after high TMZ cumulative dosage (980-1400 mg/kg), which demonstrated lymphoma incidence. In summary, every 6 day administration schedule of TMZ or CPA improves survival in orthotopic GL261 GBM with respect to controls or non-metronomic therapy, in partial agreement with previous work on subcutaneous GL261.


Transesophageal endoscopic ultrasound with bronchoscope-guided fine-needle aspiration for diagnostic and staging purposes: a narrative review.
Transesophageal endoscopic ultrasound with bronchoscope-guided fine-needle aspiration (EUS-B-FNA) is a feasible and well-tolerated modality that is increasingly used to diagnose intrathoracic lesions. This narrative review summarizes the current application of EUS-B-FNA for diagnosing lung cancer, thoracic sarcoidosis, and metastases from extrathoracic malignancies. A comprehensive and systematic online literature search via Medline/PubMed for the period January 2005 to December 2022 was conducted for articles published using the keywords "EUS-B-FNA", "endobronchial ultrasound transbronchial needle aspiration (EBUS-TBNA)", "endoscopic ultrasound fine-needle aspiration (EUS-FNA)", "lung cancer", "staging", and "sarcoidosis". Recent data prove the efficacy and safety of EUS-B-FNA for providing complete lung cancer staging, when combined with EBUS-TBNA, and in the evaluation of para-esophageal lesions. EUS-B-FNA allows access to inferior mediastinal lymph nodes and para-esophageal masses that are not accessible by EBUS-TBNA. Additional advantages of using EUS-B-FNA include significantly lower doses of anesthetics and sedatives, a shorter procedural time, fewer incidents of oxygen desaturation due to a poor respiratory reserve, significantly less cough, and higher operator satisfaction. Moreover, this procedure can be performed sequentially in the same setting with EBUS-TBNA by one operator. Other benefits include a lower cost, a single setting, and scope use. As EUS-B-FNA and EBUS-TBNA have complementary access to the mediastinum, the diagnostic yield of EUS-B-FNA combined with EBUS-TBNA is higher than that of endosonographic techniques alone in the diagnostic workup of intrathoracic lesions.


Synthesis and Reactivity of Fluoroalkyl Copper Complexes by the Oxycupration of Tetrafluoroethylene.
The copper(I)-mediated generation of -OCF2 CF2 - moieties by the oxycupration of tetrafluoroethylene (TFE) using either copper aryloxides or alkoxides is disclosed. The key intermediates, 2-aryloxy-1,1,2,2-tetrafluoroethyl and 2-alkoxy-1,1,2,2-tetrafluoroethyl copper complexes, were obtained from the reaction of the corresponding aryloxy and alkoxy copper complexes with TFE, and their structures in solution and in the solid state were unambiguously determined by multinuclear NMR spectroscopy and X-ray diffraction analysis. These copper complexes subsequently reacted with aryl iodides (ArI) to afford ROCF2 CF2 Ar (R=aryl or alkyl) in high yields.


Emergence of Nanoplatelet Light-Emitting Diodes.
Since 2014, nanoplatelet light-emitting diodes (NPL-LEDs) have been emerged as a new kind of LEDs. At first, NPL-LEDs are mainly realized by CdSe based NPLs. Since 2016, hybrid organic-inorganic perovskite NPLs are found to be effective to develop NPL-LEDs. In 2017, all-inorganic perovskite NPLs are also demonstrated for NPL-LEDs. Therefore, the development of NPL-LEDs is flourishing. In this review, the fundamental concepts of NPL-LEDs are first introduced, then the main approaches to realize NPL-LEDs are summarized and the recent progress of representative NPL-LEDs is highlighted, finally the challenges and opportunities for NPL-LEDs are presented.


Cor triatriatum sinister in a 43-year-old man with syncope.
Cor triatriatum sinister, a congenital cardiac anomaly involving a fibromuscular membrane that partitions the left atrium into 2 chambers, has been reported in only 0.1% to 0.4% of patients with congenital heart disease. The posterosuperior chamber receives blood from the pulmonary veins, and the anteroinferior chamber contains the left atrial appendage and mitral valve orifice. Most patients are diagnosed with the condition in infancy or childhood; adult cases are rare. We describe a case of cor triatriatum sinister in a 43-year-old man whose only presenting symptom was recurrent syncope. He underwent corrective resection of the membrane and was asymptomatic thereafter. In addition to discussing the patient's case, we review the relevant medical literature.


Tetrandrine triggers an alternative autophagy in DU145 cells.
Tetrandrine (Tet), a potent lysosomal inhibitor, blocks autophagic flux and induces cancer cell death. Previously, the present authors identified the prostate cancer cell line DU145 to exhibit high sensitivity towards Tet in 11 cancer cell lines. In the present study, autophagy in Tet-treated DU145 cells was investigated. Similar to other cell lines, such as PC-3 and 786-O cells, Tet neutralized the acidity of lysosome and blocked autophagy in DU145 cells. However, Tet failed to induce microtubule-associated protein 1 light chain 3 (LC3) conversion in DU145 cells. By contrast, it was observed by transmission electron microscopy that Tet induced an accumulation of autophagosomes in the cytoplasm. These contrasting results indicated that Tet triggered an LC3-independent autophagy in DU145 cells. Alkalizing lysosome with chloroquine enhanced Tet-induced cell death. The results of the present study indicated that detection of autophagy in tumor cells may assist in selecting lysosome inhibitors for chemotherapy treatment in prostate cancer.


Differential regulation by Ca(2+) of calmodulin- and PKC-dependent contractile pathways in cat lower oesophageal sphincter.
1. In the present investigation we examined the regulation of calmodulin (CaM)- and protein kinase C (PKC)-dependent pathways by cytosolic Ca(2+) in the contraction of cat lower oesophageal sphincter (LES). 2. Force developed in response to increasing doses of acetylcholine (ACh) was directly related to the increase of the [Ca(2+)](i) measured by fura-2. Thapsigargin, which depletes Ca(2+) stores, reduced the contraction and the [Ca(2+)](i). In addition, contraction in response to maximal ACh was reduced by the CaM inhibitor CGS9343B but not by the PKC inhibitor chelerythrine. The contraction in response to submaximal ACh was reduced by chelerythrine but not by CGS9343B. 3. In permeabilized cells, the contraction in response to low Ca(2+) (0.54 microm) was also reduced by CGS9343B. 4. The response to high Ca(2+) (1.0 microm) was reduced by CGS9343B. ACh also inhibited PKC activation induced by diacylglycerol, which activation is inhibited by the N-myristoylated peptide inhibitor derived from pseudosubstrate sequences of PKCalphabetagamma (myr-PKC-alphabetagamma), but not of myr-PKC-alpha. 5. These data are consistent with the view that activated CaM-dependent pathways inhibit PKC-dependent pathways, this switch mechanism might be regulated by Ca(2+) in the LES.


The impact of respite use on nursing home placement.
The results of experimental studies of the effects of respite care have been difficult to interpret because researchers have lacked experimental control over who actually received the treatment. Data from one such study are reanalyzed, focusing on the linear relationship between amount of respite use and probability of nursing home placement at the end of the treatment period. The results indicate a significant negative relationship between amount of respite use and nursing home placement.


Structural and functional understanding of disease-associated mutations in V-ATPase subunit a1 and other isoforms.
The vacuolar-type ATPase (V-ATPase) is a multisubunit protein composed of the cytosolic adenosine triphosphate (ATP) hydrolysis catalyzing V1 complex, and the integral membrane complex, Vo, responsible for proton translocation. The largest subunit of the Vo complex, subunit a, enables proton translocation upon ATP hydrolysis, mediated by the cytosolic V1 complex. Four known subunit a isoforms (a1-a4) are expressed in different cellular locations. Subunit a1 (also known as Voa1), the neural isoform, is strongly expressed in neurons and is encoded by the ATP6V0A1 gene. Global knockout of this gene in mice causes embryonic lethality, whereas pyramidal neuron-specific knockout resulted in neuronal cell death with impaired spatial and learning memory. Recently reported, de novo and biallelic mutations of the human ATP6V0A1 impair autophagic and lysosomal activities, contributing to neuronal cell death in developmental and epileptic encephalopathies (DEE) and early onset progressive myoclonus epilepsy (PME). The de novo heterozygous R740Q mutation is the most recurrent variant reported in cases of DEE. Homology studies suggest R740 deprotonates protons from specific glutamic acid residues in subunit c, highlighting its importance to the overall V-ATPase function. In this paper, we discuss the structure and mechanism of the V-ATPase, emphasizing how mutations in subunit a1 can lead to lysosomal and autophagic dysfunction in neurodevelopmental disorders, and how mutations to the non-neural isoforms, a2-a4, can also lead to various genetic diseases. Given the growing discovery of disease-causing variants of V-ATPase subunit a and its function as a pump-based regulator of intracellular organelle pH, this multiprotein complex warrants further investigation.


Reversible assembly and disassembly of micelles by a polymer that switches between hydrophilic and hydrophobic wettings.
Supramolecular complexes involving nanoscopic amphiphilic assemblies (AAs) and polyelectrolytes have been used to prepare a variety of materials, wherein the dynamic AAs retain the structural features, but the polyelectrolytes undergo conformational changes. Here we show that a charge bearing rigid conjugated polymer can alter the structural features and disassemble AAs. We also demonstrate reversible assembly and disassembly of AAs by controlling the number of charges on the rigid polymer. During the disassembly, the guest molecules sequestered in the AAs are released. The rate of release has been modulated by changing the morphology of the charge bearing polymer. Concomitant to the AAs disassembly, the polymer surface becomes hydrophobic due to the binding of the amphiphiles on the charges of the polymer backbone. By controlling the charges on the polymer, the surface wettability was varied gradually from hydrophilic to hydrophobic.


Effects of Parenteral Vitamin D3 Supplementation on Hematological Parameters of Healthy Holstein Bulls.
Vitamin D has been shown to play physiological functions beyond calcium and phosphorus homeostasis and control bone metabolism in the body since its cellular receptors are present in numerous tissues. A total of 20 healthy bulls were divided into four groups to evaluate the effect of different doses of vitamin D3 on the number of bovine blood cells. Groups A, B, C, and D received 11,000, 22,000, 33,000, and 44,000 units/kg of vitamin D3, respectively. The control group was injected with 10 ml of physiological saline intramuscularly. Blood samples were taken before the injection, as well as 2, 4, and 6 days after the injection; furthermore, the white blood cell counts (including granulocytes and lymphocytes), hematocrit, haemoglobin, and platelets were examined by a cell counter. The results showed that vitamin D could cause leukopenia (e.g., neutropenia and lymphopenia), thrombocytopenia, as well as an increase in hematocrit and hemoglobin levels in the blood. Although the mentioned increase or decrease is largely dose- and time-dependent, the first and best group to indicate this is group B. To find the second group, the investigation of the long-term effects of injections, especially in high doses, and evaluation of different tests are required with larger groups over a longer period.


Effects of hydrophobicity and electrostatic charge on complement activation by amino groups.
Some studies have demonstrated that amino groups, acting as nucleophiles, are potent activators of the complement system, but others not. To clarify these contradictory results, we examined complement activation on two series of NH(2)/CH(3) and NH(2)/COOH mixed self-assembled monolayers (SAMs). NH(2)/CH(3) mixed SAMs were not potent activators of the complement system regardless of the ratio of NH(2)/CH(3) in mixed SAMs. Numerous serum proteins, such as albumin, were adsorbed onto those SAMs and formed a protein layer which inhibited access of C3b to amino groups. In contrast, much C3b and/or C3bBb were deposited on NH(2)/COOH mixed SAMs with approximately 50-60% NH(2) density on the surface and SC5b-9 was found in serum exposed to this SAM, indicating activation of the complement system. These results suggest that C3b can easily access nucleophilic NH(2) groups because of the decrease in electrostatic interaction between negatively charged proteins and the NH(2) SAM surface.


Preparation of a Sepia Melanin and Poly(ethylene-alt-maleic Anhydride) Hybrid Material as an Adsorbent for Water Purification.
Meeting the increasing demand of clean water requires the development of novel efficient adsorbent materials for the removal of organic pollutants. In this context the use of natural, renewable sources is of special relevance and sepia melanin, thanks to its ability to bind a variety of organic and inorganic species, has already attracted interest for water purification. Here we describe the synthesis of a material obtained by the combination of sepia melanin and poly(ethylene-alt-maleic anhydride) (P(E-alt-MA)). Compared to sepia melanin, the resulting hybrid displays a high and fast adsorption efficiency towards methylene blue (a common industrial dye) for a wide pH range (from pH 2 to 12) and under high ionic strength conditions. It is easily recovered after use and can be reused up to three times. Given the wide availability of sepia melanin and P(E-alt-MA), the synthesis of our hybrid is simple and affordable, making it suitable for industrial water purification purposes.


Clinical characteristics and surgical outcomes of solitary spinal epidural cavernous angiomas.
The majority of spinal cavernous angiomas (CAs) originate from the vertebral bodies with or without epidural space extension. Solitary epidural CAs are rare. In the present study, we retrospectively reviewed the records of 12 patients who underwent microsurgery for solitary spinal epidural CAs. All patients had performed pre- and postoperative magnetic resonance imaging. The patients were 7 females and 5 males with the mean age of 52.1 years. Two tumors were located in the cervicothoracic spine, nine in the thoracic spine and one in the lumbar spine, respectively. Solitary epidural CAs generally exhibited isointensity on T1-weighted images and hyperintesity on T2-weighted images. Contrast-enhanced T1-weighted images showed homogeneous markedly enhancement. Gross total resection (GTR) was achieved in 11 cases, and subtotal resection (STR) was achieved in 1 case. During an average follow up of 35.9 months, neurological function was improved in 11 patients and in one patient, preoperative status was maintained. No patient experienced tumor recurrence. These findings suggest that CAs should be considered in the differential diagnosis of spinal epidural lesions. Early surgery is advocated to prevent irreversible neurological deficits. When aggravated by a large amount of acute hemorrhage, neurological deterioration is usually acute and prompt surgical decompression is the optimal choice. Because of the excessive vascularity of CAs, en bloc resection is recommended. In addition, a good clinical outcome after GTR can be expected, and the risk of long-term recurrence is low.


Bio-synthetic materials for immunomodulation of islet transplants.
Clinical islet transplantation is an effective therapy in restoring physiological glycemic control in type 1 diabetics. However, allogeneic islets derived from cadaveric sources elicit immune responses that result in acute and chronic islet destruction. To prevent immune destruction of islets, transplant recipients require lifelong delivery of immunosuppressive drugs, which are associated with debilitating side effects. Biomaterial-based strategies to eliminate the need for immunosuppressive drugs are an emerging therapy for improving islet transplantation. In this context, two main approaches have been used: 1) encapsulation of islets to prevent infiltration and contact of immune cells, and 2) local release of immunomodulatory molecules from biomaterial systems that suppress local immunity. Synthetic biomaterials provide excellent control over material properties, molecule presentation, and therapeutic release, and thus, are an emerging platform for immunomodulation to facilitate islet transplantation. This review highlights various synthetic biomaterial-based strategies for preventing immune rejection of islet allografts.


Topographic Evaluation of Unilateral Keratoconus Patients
To compare data obtained by Scheimpflug camera (Pentacam) from both eyes of unilateral keratoconus patients and normal controls. This study was performed by retrospective chart review of 919 keratoconus patients. From these patients, 31 keratoconus eyes of 31 patients with unilateral keratoconus (Group 1), 31 normal fellow eyes of these patients (Group 2), and 30 right eyes of 30 normal controls (Group 3) were included in the study. Detailed ophthalmologic examination and Pentacam parameters at initial examination were analyzed and relationships between Groups 1, 2, and 3 were statistically evaluated. ROC curve analysis was also performed to determine the sensitivity and specificity of parameters that could be used to differentiate Group 2 from Groups 1 and 3. The mean age was 30.07±11.00 (15-60) in Group 1-2 patients and 32.33±9.30 (18-45) in Group 3 patients (p=0.392). In comparison of Pentacam data, there were statistically significant differences between Groups 1 and 2 in all parameters except corneal volume (p<0.05). Group 1 and Group 3 were significantly different in all evaluated parameters (p<0.05). Steep keratometry, flat keratometry, mean keratometry, and posterior elevation (PE) were statistically similar between Groups 2 and 3 (p>0.05), while the other evaluated parameters differed significantly (p<0.05). ROC curve analysis showed that the difference in corneal thickness between the apex and thinnest point, PI, index of surface variance, index of height asymmetry and inferior-superior had the highest sensitivity and specificity in differentiating Group 2 from Group 3, while CCTapex, CCTmin, PE, and Rmin had the highest sensitivity and specificity in differentiating Group 2 from Group 1. In patients with unilateral keratoconus, fellow eyes appear to not be completely normal. Thus, it is recommended that fellow eyes also be evaluated in every examination of unilateral keratoconus patients.


The course of culture of human keratinocytes: increase of heat-labile fraction of glucose-6-phosphate dehydrogenase.
Human epidermal keratinocytes in cell culture are unique in reorganizing the formation of a stratified cellular sheet and performing terminal differentiation. The course of keratinocytes in culture was delineated over 50 days in the primary culture. The rapid increase in total DNA content commencing 2 weeks after plating corresponded to the appearance of small polygonal keratinocytes in groups. The DNA content reached its maximum after 25 days of cultivation, decreasing gradually thereafter. The protein content increase slowly until 16 to 18 days of cultivation, and then increased rapidly, though slightly behind the rapid increase in DNA. The maximum value of protein content was reached at 32 days, after which the value decreased when the keratinized cells of the uppermost layer began to detach. The heat-labile fraction of glucose-6-phosphate dehydrogenase was increased in 33- and 43-day cultures, when the DNA content was decreasing.


Mode of replicon fusion mediated by the duplicated insertion sequence IS21 in Escherichia coli.
The insertion sequence IS21 (2.1 kb) originating from the broad-host-range IncP plasmid R68 transposes infrequently; by contrast, the IS21 tandem repeat found on the derivative R68.45 is highly active in transpositional mobilization of other replicons in a variety of Gram-negative bacteria. The mobilized plasmids are joined to R68.45 by single IS21 copies in direct orientation. The formation of IS21 tandem duplications was observed in cointegrates between R68.45 and pBR325::IS21 and also in an RP1::IS21 plasmid derivative in which a segment located between two directly repeated copies of IS21 was deleted spontaneously. We speculate that IS21 tandem repeats can arise when the termini of two IS21 elements are specifically joined in a transposition or deletion event. A resistance gene flanked by two IS21 elements in direct orientation did not behave as a transposon. The omega fragment carrying transcription and translation stop signals was inserted into various sites of the IS21 tandem repeat; in this way it could be shown that the left IS21 element (which is next to the kanamycin resistance gene in R68.45) was 100 times more active in cointegrate formation than was the right-hand element. Cointegrates between the conjugative plasmid R751 and pBR325 derivatives carrying IS21 and IS21::omega in tandem contained a single IS21 at one replicon junction and a single IS21::omega at the other. In the IS21 duplications the inner IS21 ends were preferentially recognized (presumably by IS21 transposase), whereas the outer termini were not required for cointegrate formation. Based on these findings a conservative (simple) pathway of transposition is proposed for R68.45 and other plasmids with an IS21 tandem repeat.(ABSTRACT TRUNCATED AT 250 WORDS)


Angle-resolved UV photoelectron spectra (UPS) of thin films of perylene-3,4,9,10-tetracarboxylic dianhydride on MoS(2).
Angle-resolved UV photoelectron spectra (ARUPS) were measured for thin films of perylene-3,4,9,10-tetracarboxylic dianhydride (PTCDA) deposited on cleaved MoS(2) surfaces. The take-off angle (theta) dependence of the photoelectron intensity of the highest pi band showed a sharp maximum at theta = 32-34 degrees. A spectral feature of the binding energy at approximately 8.9 eV, which is believed to originate from a pi state, showed a remarkably different theta dependence from that of the pi band. A quantitative analysis of the observed theta dependencies clearly indicates that (a) the feature at approximately 8.9 eV originates from the oxygen 2p non-bonding states and (b) the molecules lie flat on the substrate surface.


Laparoscopic adrenalectomy: comparison of outcomes between posterior retroperitoneoscopic and transperitoneal adrenalectomy with 10 years' experience.
Laparoscopic adrenalectomy is widely used for treating various adrenal tumors. Posterior retroperitoneoscopic adrenalectomy was introduced after transperitoneal laparoscopic adrenalectomy. The comparability and superiority of posterior retroperitoneoscopic adrenalectomy have been widely investigated. We aimed to compare the outcomes of posterior retroperitoneoscopic adrenalectomy and transperitoneal laparoscopic adrenalectomy using 10 years' data. The changes in outcomes over time were also analyzed. This was a retrospective observational study. A total of 505 patients who underwent laparoscopic adrenalectomy between 2009 and 2018 were included. The patients were divided into two groups: transperitoneal (n=114) and retroperitoneal (n=391) groups. Patients who underwent posterior retroperitoneoscopic adrenalectomy were further classified into sub-groups (sub-group 1: 2009-2012; sub-group 2: 2013-2015; and sub-group 3: 2016-2018) based on time periods. Clinicopathological factors and postoperative outcomes were retrospectively reviewed and analyzed. The retroperitoneal group showed significantly shorter operation time, diet initiation time, and hospital stay compared to the transperitoneal group (P=0.000, 0.000 and 0.000, respectively). Analgesics were used less frequently in the retroperitoneal group than in the transperitoneal group (P=0.048). In the retroperitoneal group, the time to postoperative diet initiation shortened over time (P=0.000). Posterior retroperitoneoscopic adrenalectomy is a favorable surgical method that results in patient outcomes that are comparable to those of conventional transperitoneal laparoscopic adrenalectomy, without compromising patient safety.


Reductive biotransformations of organic compounds by saccharomyces cerevisiae: study of oxidoreductases involved using electrophoretic zymograms.
The role of oxidoreductases in reduction of carbonyl compounds was investigated by application of zymogram techniques. Eight bands were observed using ethanol with nicotinamide adenine dinucleotide (NAD) as coenzyme. Bands observed with lactic acid and (R)-(-)-phenyl-1,2-ethanediol with nicotinamide adenine dinucleotide phosphate (NADP) had similar R(m) values. 2-Hydroxyvalerate and malate manifested bands having similar R(m) values and were active with both NAD and NADP. Based on their structural similarity and identical R(m) values, oxidation of 1,4-cyclooctanediol (band #2) and cis-1,5-cyclooctanediol may be due to a common enzyme. The PAGE-zymogram technique may be used on a preparative scale to facilitate purification and full characterization on the observed stained bands.


EFFECTIVE POPULATION SIZE IN A CONTINUOUSLY DISTRIBUTED POPULATION.
An individual-based simulation model was created to examine genetic variability, time until fixation and spatial genetic structure in a continuously distributed population. Previous mathematical models for continuously distributed populations have the difficulty that the assumption of independent reproduction and independent dispersal of offspring cause clumped spatial distribution and thus violate an assumption of random spatial distribution. In this study, this problem is avoided by considering the dispersal behavior of offspring. The simulation results showed that the inbreeding effective population size estimated by the rate of decrease of heterozygosity during the first 15 generations corresponds to the neighborhood size calculated by the standard deviation of the dispersal distance (σT ). This inbreeding effective population size does not greatly change with the area of simulation when the densities and σT are the same. However, the inbreeding effective population size estimated by heterozygosity using the first 500 generations is larger than the neighborhood size calculated by the dispersal distance and increases with the area of simulation with the same densities. The variance effective population size, estimated by time until fixation of alleles, increases with dispersal distance (σT ) and with the area of simulation given the same densities. The inbreeding effective population size and variance effective population size were smaller than the actual population size unless σT is sufficiently large (2 σT > approximate L/2, where L is a side of the simulation square).


Quantitative risk assessment of lung cancer in U.S. uranium miners.
The National Institute for Occupational Safety and Health (NIOSH) has recently updated the vital status of the U.S. cohort of U miners through the end of 1982. This represents 69 additional lung cancer deaths since the last published follow-up through 1977. This more recent data was used to generate quantitative risk estimates of lung cancer after exposure to Rn daughters. Relative risks were estimated through use of the Cox proportional hazards model with an internal referent group. Results indicated that the exposure-response relationship was a slightly convex curve, predicting excess relative risks between 0.9 and 1.4 per 100 working level months (WLM) in the lower cumulative exposure range. Other findings of interest include a significant exposure-rate effect with low exposure rates more harmful per unit of cumulative exposure (WLM). Two temporal effects which modify relative risk estimates were also found. Relative risk increased with age at initial exposure to underground U mining. However, relative risk of lung cancer fell dramatically in the years following cessation of exposure.


Monofunctional polymer nanoparticles prepared through intramolecularly cross-linking the polymer chains sparsely grafted on the surface of sacrificial silica spheres.
Herein we report preparation of polymeric monofunctional nanoparticles (PMNs) through intramolecularly cross-linking the polymer chains sparsely grafted on the surface of sacrificial silica spheres, and a one-to-one coupling reaction between PMNs and linear polymer chains and that between two PMNs.


Rapid and Automated Method for Detecting and Quantifying Adulterations in High-Quality Honey Using Vis-NIRs in Combination with Machine Learning.
Honey is one of the most adulterated foods, usually through the addition of sweeteners or low-cost honeys. This study presents a method based on visible near infrared spectroscopy (Vis-NIRs), in combination with machine learning (ML) algorithms, for the correct identification and quantification of adulterants in honey. Honey samples from two botanical origins (orange blossom and sunflower) were evaluated and adulterated with low-cost honey in different percentages (5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, and 50%). The results of the exploratory analysis showed a tendency to group the samples according to botanical origin, as well as the presence of adulteration. A supervised analysis was performed to detect the presence of adulterations. The best performance with 100% accuracy was achieved by support vector machines (SVM) and random forests (RF). A regression study was also carried out to quantify the percentage of adulteration. The best result was obtained by support vector regression (SVR) with a coefficient of determination (R2) of 0.991 and a root mean squared error (RMSE) of 1.894. These results demonstrate the potential of combining ML with spectroscopic data as a method for the automated quality control of honey.


Nanoscale X-ray Imaging of Composition and Ferroelastic Domains in Heterostructured Perovskite Nanowires: Implications for Optoelectronic Devices.
Metal halide perovskites (MHPs) have garnered significant interest as promising candidates for nanoscale optoelectronic applications due to their excellent optical properties. Axially heterostructured CsPbBr3-CsPb(Br(1-x)Clx)3 nanowires can be produced by localized anion exchange of pregrown CsPbBr3 nanowires. However, characterizing such heterostructures with sufficient strain and real space resolution is challenging. Here, we use nanofocused scanning X-ray diffraction (XRD) and X-ray fluorescence (XRF) with a 60 nm beam to investigate a heterostructured MHP nanowire as well as a reference CsPbBr3 nanowire. The nano-XRD approach gives spatially resolved maps of composition, lattice spacing, and lattice tilt. Both the reference and exchanged nanowire show signs of diverse types of ferroelastic domains, as revealed by the tilt maps. The chlorinated segment shows an average Cl composition of x = 66 and x = 70% as measured by XRD and XRF, respectively. The XRD measurements give a much more consistent result than the XRF ones. These findings are consistent with photoluminescence measurements, showing x = 73%. The nominally unexchanged segment also has a small concentration of Cl, as observed with all three methods, which we attribute to diffusion after processing. These results highlight the need to prevent such unwanted processes in order to fabricate optoelectronic devices based on MHP heterostructures.


[HIV (human immunodeficiency virus) and HIV-associated diseases].
The discovery of the Human Immunodeficiency Virus (HIV), the characterization of its molecular biology and the development of serologic methods for detecting antibodies have led to a better understanding of HIV-associated clinical syndromes. Recently, the Centre of Disease Control has proposed a classification of HIV-related conditions. This classification forms the basis for this review. It is completed by remarks on antiviral and immunomodulating drugs and its effects on HIV. Difficulties in development of vaccines are discussed.


Pathological examination of a ruptured fusiform aneurysm of the middle cerebral artery.
Little is known about the pathogenesis and clinical course of fusiform compared with saccular aneurysms. The case of a ruptured fusiform aneurysm accompanied by dissection at the M2 portion of the middle cerebral artery (MCA) is reported, along with pathological findings. A 41-year-old female presenting with subarachnoid hemorrhage was revealed to have a ruptured fusiform aneurysm at the M2 portion of the right MCA on angiography. She was treated with superficial temporal artery-MCA anastomosis and trapping of the aneurysm. The aneurysm consisted of a whitish fusiform dilatation with a thickened wall of the MCA and two red protrusions on it. Pathological examinations revealed disruption and fragmentation of the internal elastic lamina and intimal thickening in the fusiform lesion. There were two aneurysmal protrusions on the main fusiform dilatation. In one protruded lesion, a dissection of the intima was observed. We propose that a dissection and saccular aneurysm additionally developed on the wall of a preexisting segmental ectasia of the MCA in our case. In this report, we discuss the etiology of fusiform aneurysms of the MCA.


[Acute aortic regurgitation by spontaneous rupture of a fibrous strand in fenestrated aortic valve; report of a case].
Although fenestration of the aortic valve cusps is a common anatomic finding, it rarely causes aortic regurgitation. We describe acute aortic regurgitation by spontaneous rupture of a fibrous strand in fenestrated aortic valve. A 65-year-old man was referred with sudden onset of dyspnea and cough. He diagnosed acute heart failure due to severe aortic valve regurgitation. After medical therapy, the aortic valve replacement was performed. Operative findings reviewed that a fibrous strand in the fenestrated non-coronary cusp was ruptured, which caused severe aortic regurgitation. Pathological examination showed the myxomatous degeneration. The postoperative course was uneventful, and the patient was discharged on postoperative day 11 with good health.


Medical Imaging for the Tracking of Micromotors.
Micro/nanomotors are useful tools for several biomedical applications, including targeted drug delivery and minimally invasive microsurgeries. However, major challenges such as in vivo imaging need to be addressed before they can be safely applied on a living body. Here, we show that positron emission tomography (PET), a molecular imaging technique widely used in medical imaging, can also be used to track a large population of tubular Au/PEDOT/Pt micromotors. Chemisorption of an iodine isotope onto the micromotor's Au surface rendered them detectable by PET, and we could track their movements in a tubular phantom over time frames of up to 15 min. In a second set of experiments, micromotors and the bubbles released during self-propulsion were optically tracked by video imaging and bright-field microscopy. The results from direct optical tracking agreed with those from PET tracking, demonstrating that PET is a suitable technique for the imaging of large populations of active micromotors in opaque environments, thus opening opportunities for the use of this mature imaging technology for the in vivo localization of artificial swimmers.


Naturally induced biphasic phytoplankton spring bloom reveals rapid and distinct substrate and bacterial community dynamics.
Phytoplankton spring blooms are typical features in coastal seas and provide heterotrophic bacteria with a rich blend of dissolved substrates. However, they are difficult to study in coastal seas in-situ. Here, we induced a phytoplankton spring bloom and followed its fate for 37 days in four 600 L-mesocosms. To specifically investigate the significance of phytoplankton-born dissolved organic carbon (DOC) we used artificial seawater with low DOC background and inoculated it with a 100 µm-prefiltered plankton community from the North Sea. A biphasic bloom developed, dominated by diatoms and Phaeocystis globosa respectively. In between, bacterial numbers peaked, followed by a peak in virus-like particles, implying that virus infection caused the collapse. Concentrations of dissolved free amino acids exhibited rapid changes, in particular during the diatom bloom and until the peak in bacterial abundance. Dissolved combined amino acids and neutral monosaccharides accumulated continuously, accounting for 22% of DOC as a mean and reaching levels as high as 44%. Bacterial communities were largely dominated by Bacteroidetes, especially the NS3a marine group (family Flavobacteriaceae), but Rhodobacteraceae and Gammaproteobacteria were also prominent members. Our study shows rapid organic matter and community composition dynamics that are hard to trace in natural coastal ecosystems.


[Delusional ectoparasitic infestation in multiple system atrophy].
Multiple system atrophy (MSA) is a neurodegenerative disease of unclear etiology and pathogenesis. Clinically, there are combinations of extrapyramidal, cerebellar, pyramidal and autonomic dysfunctions. Diagnosis is sorted into different categories according to criteria. The appearance of hallucinations unrelated to medication is considered to be a criterion of exclusion for the diagnosis of MSA. A case is described in which delusional parasitosis occurred as a possible initial syndrome of MSA. The simultaneous appearance of MSA and a psychotic disease is possible and has been described repeatedly. Therefore, this criterion of exclusion is discussed. Delusional parasitosis is an unspecific syndrome of multifactorial genesis. Partial remission of the monothematic symptomatology of delusion shows that a continuous and consequent therapy with neuroleptics seems to be promising. In the case presented, the good efficacy of olanzapine in low dosage over an extended period of time is described.


Efficacy of endoscopic variceal ligation for bleeding esophageal varices in patients with tumor thrombus of the portal vein trunk (Vp3) associated with hepatocellular carcinoma.
We studied the efficacy of endoscopic variceal ligation (EVL) in 16 patients with tumor thrombus of the portal vein trunk (Vp3) associated with hepatocellular carcinoma. The average (+/-SD) number of O rings used was 9.0 +/- 5.0 for the esophageal varices (n = 7) and 16.4 +/- 4.5 for the esophagogastric varices (n = 9). The variceal size was quickly reduced in 11 of the 13 cases whose therapeutic outcome was able to be assessed by endoscopy. The red color sign improved in 10 of the 13 cases, but the therapeutic end point (F0, RC-) was achieved in only two patients, who were also treated by endoscopic injection sclerotherapy. Emergency EVL achieved only short-term survival (17.14 +/- 6.64 days) and transient hemostasis. Elective EVL was associated with a survival duration of 90.0 +/- 64.25 days. The difference in the survival rate between emergency and elective cases was significant (P < .05). With regard to the timing of its application, EVL, being a less-invasive treatment, should be performed electively before variceal rebleeding for those patients with Vp3 hepatocellular carcinoma whose liver function is preserved.


Combined Training Improves the Expression Profile of Inflammation-associated Antimicrobial Peptides, MicroRNAs, and TLR-4 in Patients with Multiple Sclerosis.
Some antimicrobial peptides (AMPs), microRNAs (miRs), and Toll-like receptor 4 (TLR-4) are involved in autoimmune diseases, which may be affected by exercise training. The purpose of this study was to investigate the effect of an eight-week combined exercise training (aerobic and resistance) on the expression of inflammatory factors, including, human beta-defensin-2 (hBD-2), cathelicidin (LL-37), TLR-4, miR-23b, miR-155, and miR-326 in women with relapsing and remitting multiple sclerosis (RRMS), which has not been investigated yet. Twenty-three women (20-40 years) with RRMS were randomized into the combined training (CT) and control (CON) groups. The CT group subjects completed eight weeks of supervised CT using a treadmill and stationary bicycle for aerobic exercise and weight machines for resistance exercise. The expression levels of hBD-2, LL-37, TLR-4, miR-23b, miR-155, and miR-326 were measured by real-time polymerase chain reaction (RT-PCR) at the baseline and end of the study. Although the expression of hBD-2 and miR-23b decreased in both CT and CON groups, the reduction was lower in the CT group than in the CON group (p=0.001). The expression of LL-37 in the CT group remained unchanged, but that of the CON group increased; thus, the between-group difference was significant. Although the TLR-4, miR-155, and miR-326 expression increased in both groups compared to the baseline, the increase in the CT group was lower than the CON group. Our results showed that the combined training might improve inflammatory symptoms by affecting the expression of some AMPs, miRs, and TLR-4 in patients with relapsing and remitting multiple sclerosis.


Interprofessional case conference: impact on learner outcomes.
Transition to interprofessional team-based care is a quickly progressing healthcare model and requires changes in medical training approaches. The Department of Veteran Affairs (VA) has taken a lead role in creating such training experiences, one of which is the establishment of multiple Centers of Excellence in Primary Care Education (CoEPCE). These sites are tasked with developing teaching innovations to better facilitate interprofessional team-based care. The patient-aligned care team interprofessional care update (PACT-ICU) is an interprofessional workplace learning activity with the goals of simultaneously addressing educational and patient care needs. Participants of the PACT-ICU included trainees and faculty of a variety of medical disciplines (e.g., internal medicine, psychology, and pharmacy) involved in a training primary care clinic. Two medically complex patients were presented at each PACT-ICU conference with the purpose of creating a plan of care that maintained an interprofessional team-based approach. Following implementation of the PACT-ICU conference intervention, two primary outcomes were assessed. First, self-assessment of PACT-ICU attendee learner outcomes was measured using a brief questionnaire surveying knowledge gain as it related to increase in knowledge of other professions' capabilities, roles, and responsibilities. Secondly, trainee provider behavior change was evaluated by measuring number of "within PACT" consults before and after participating in PACT-ICU. There was a significant positive change in self-assessed knowledge along with an indication of trainee behavioral change, as measured by electronic medical record consult patterns. This study demonstrates that interprofessional case conferences involving trainees and staff from multiple professions can increase awareness of other professions roles in patient care as well as facilitate interprofessional collaboration.


Employees with hearing impairment. A qualitative study exploring managers' experiences.
Purpose: Explore managers' experiences regarding employees with hearing impairments.Materials and methods: Individual interviews with ten managers having employees with hearing impairment. The interviews were analyzed using Systematic text condensation.Results: The managers felt great responsibility for their employees' functioning, but hearing loss issues were easily forgotten. They found access to information as imperative to secure workplace adjustments, and temporary needs, rather than permanent ones, were easily met. Despite their challenging nature, meetings were not accommodated to meet hearing loss needs. Support in accommodation processes at the workplace was not requested since minor adjustments were perceived as sufficient.Conclusion: The results show that there are barriers towards developing less strenuous working conditions for employees with hearing impairments. The implications of hearing loss should be recognized as risk factors for fatigue and treated accordingly. Appropriate services are necessary to support the stakeholders at the workplace and utilize the room for manoeuver in the accommodation process. Further studies should identify how such services can accommodate both the employees, and managers' needs.IMPLICATIONS FOR REHABILITATIONHearing loss as a risk factor for fatigue needs to be addressed by rehabilitation professionals.Vocational rehabilitation professionals are needed to support employees with hearing loss and their employers in making adjustments at the work place.Occupational rehabilitation professionals and professionals targeting hearing impairments are both needed in the process.


Serum keratin-18 detects hepatic inflammation and predicts progression in compensated alcohol-associated liver disease.
Alcohol-associated liver fibrosis accumulates over decades, driven by hepatic inflammation and cell death. We investigated the diagnostic accuracy of keratin-18 degradation, measured using serum M30 and M65 levels, and the ActiTest for hepatic inflammatory activity in patients with compensated alcohol-associated liver disease (ALD). Furthermore, we evaluated the prognostic accuracy of markers for liver-related events and all-cause mortality. All findings were compared with routine liver function tests: Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma-glutamyltransferase. Our prospective, biopsy-controlled, single-center study included 265 patients with ongoing or prior excessive alcohol intake, representing the full spectrum of compensated ALD. We defined hepatic inflammatory activity as a combined score of lobular inflammation and ballooning. For severe hepatic inflammatory activity (n = 40), we found excellent diagnostic accuracy for M30 (area under the receiver operating characteristics curve [AUROC] = 0.90), M65 (AUROC = 0.86), and AST (AUROC = 0.86). Elevated M30 (M30 > 240 U/L) had the highest positive predictive value (PPV) and specificity, significantly higher than M65, ActiTest and ALT, but not AST (M30: sensitivity = 83%, specificity = 82%, positive predictive value = 45%, negative predictive value = 95%). Patients were followed up for 1445 patient-years. All markers, except for ALT, significantly predicted liver-related events and all-cause mortality. After adjusting for advanced fibrosis, drinking behavior and body mass index, M30 and M65 remained significant predictors of liver-related events, whereas M30 and AST were significant predictors of all-cause mortality. Conclusion: M30 and AST accurately detect severe hepatic inflammatory activity in patients with compensated ALD. M30 was the only significant predictor of both liver-related events and all-cause mortality after adjusting for advanced fibrosis, body mass index, and drinking behavior at inclusion.


Meiotic viral attenuation through an ancestral apoptotic pathway.
The programmed release of apoptogenic proteins from mitochondria is a core event of apoptosis, although ancestral roles of this phenomenon are not known. In mammals, one such apoptogenic protein is Endonuclease G (EndoG), a conserved mitochondrial nuclease that fragments the DNA of dying cells. In this work, we show that budding yeast executes meiotically programmed mitochondrial release of an EndoG homolog, Nuc1, during sporulation. In contrast to EndoG's ostensible pro-death function during apoptosis, Nuc1 mitochondrial release is pro-survival, attenuating the cytosolic L-A and Killer double-stranded RNA mycoviruses and protecting meiotic progeny from the catastrophic consequences of their derepression. The protective viral attenuation role of this pathway illuminates a primordial role for mitochondrial release of EndoG, and perhaps of apoptosis itself.


The v-abl tyrosine kinase negatively regulates NF-kappa B/Rel factors and blocks kappa gene transcription in pre-B lymphocytes.
Transformation of B-lineage precursors by the Abelson murine leukemia virus appears to arrest development at the pre-B stage. Abelson-transformed pre-B cell lines generally retain transcriptionally inactive, unrearranged immunoglobulin kappa alleles. We demonstrate that nontransformed pre-B cells expanded from the mouse bone marrow efficiently transcribe unrearranged kappa alleles. In addition, they contain activated complexes of the NF-kappa B/Rel transcription factor family, in contrast with their Abelson-transformed counterparts. Using conditionally transformed pre-B cell lines, we show that the v-abl viral transforming protein, a tyrosine kinase, blocks germ-line kappa gene transcription and negatively regulates NF-kappa B/Rel activity. An active v-abl kinase specifically inhibits the NF-kappa B/Rel-dependent kappa intron enhancer, which is implicated in promoting both transcription and rearrangement of the kappa locus. v-abl inhibits the activated state of NF-kappa B/Rel complexes in a pre-B cell via a post-translational mechanism that results in increased stability of the inhibitory subunit I kappa B alpha. This analysis suggests a molecular pathway by which v-abl inhibits kappa locus transcription and rearrangement.


Liposomes in tissue engineering and regenerative medicine.
Liposomes are vesicular structures made of lipids that are formed in aqueous solutions. Structurally, they resemble the lipid membrane of living cells. Therefore, they have been widely investigated, since the 1960s, as models to study the cell membrane, and as carriers for protection and/or delivery of bioactive agents. They have been used in different areas of research including vaccines, imaging, applications in cosmetics and tissue engineering. Tissue engineering is defined as a strategy for promoting the regeneration of tissues for the human body. This strategy may involve the coordinated application of defined cell types with structured biomaterial scaffolds to produce living structures. To create a new tissue, based on this strategy, a controlled stimulation of cultured cells is needed, through a systematic combination of bioactive agents and mechanical signals. In this review, we highlight the potential role of liposomes as a platform for the sustained and local delivery of bioactive agents for tissue engineering and regenerative medicine approaches.


Statistical procedures in clinical pharmacology: decision-theorectic foundations.
The function of statistical analysis is to reach optimal decisions in situations of principal uncertainty. The foundations of statistical procedures are experiments X, whose distributions PX are characterised by random samples. Within given classes of distributions (distribution hypothesis) mathematical statistics make optimal procedures available, which allow conclusions on the real properties of PX. The use of optimal procedures minimises the risk of incorrect decisions made on the basis of random samples (principle of greatest chance). Statistics, however, refrain from any statement on the quality of the decision to which a procedure in a certain situation leads. Against a decision-theoretic background of statistical decisions the growing complexity of clinical-pharmacological test models leads to the necessity of using descriptive-statistical methods on an even larger scale. The aim should be to reduce the number of individual parameters to a few important factors, so that the relation between the number of trial subjects on the one hand and the number of parameters on the other remains valid for meaningful statistical statements.


[Preoperative chemotherapy for advanced gastric cancer].
In the present study, we evaluated the outcome of preoperative treatment with S-1 and CDDP for the treatment of advanced gastric cancer. Fifty-five cases of advanced gastric cancer received pre-operative treatment with S-1 and CDDP. The tumor control rate( PR and CR according to RECIST criteria) was 55%. The clinical response and histological response to the treatment and curative resection were closely related to favorable postoperative survival. We noted that patients who demonstrated CR or PR received S-1 as postoperative treatment, whereas those with SD or PD were more likely to receive paclitaxel as postoperative treatment. Preoperative treatment with S-1 and CDDP was not only an effective initial treatment, but also demonstrated favorable results in a S-1 in vivo sensitivity test.


Inhibition of TMV multiplication by siRNA constructs against TOM1 and TOM3 genes of Capsicum annuum.
The host proteins TOM1 and TOM3 associated with tonoplast membrane are shown to be required for efficient multiplication of Tobamoviruses. In this study, homologous of TOM1 and TOM3 genes were identified in pepper (Capsicum annuum) using specific primers. Their gene sequences have similarity to Nicotiana tabacum NtTOM1 and NtTOM3. Sequence alignment showed that CaTOM1 and CaTOM3 are closely related to TOM1 and TOM3 of N. tabacum and Solanum lycopersicum with 90% and 70% nucleotide sequence identities, respectively. RNA interference approach was used to suppress the TOM1 and TOM3 gene expression which in turn prevented Tobacco mosaic virus replication in tobacco. Nicotiana plants agro-infiltrated with siRNA constructs of TOM1 or TOM3 showed no mosaic or necrotic infection symptoms upon inoculation with TMV. The results indicated that silencing of TOM1 and TOM3 of pepper using the siRNA constructs is an efficient method for generating TMV-resistant plants.


Cytomorphology of tumoral calcinosis: a case report.
This paper describes the clinical, radiological and cytomorphological findings of tumoral calcinosis in a twelve-year old boy with normal serum calcium levels and simultaneous involvement of the right shoulder and the left hip. The aim of presentation is to highlights the fact that clinicoradiological correlation and correct interpretation of cytologic findings can alleviate patients' anxiety and avoid unnecessary mutilating surgery in this uncommon but completely benign condition.


Resveratrol, sirtuins, and viruses.
Resveratrol is a natural phenolic product found in some plants in response to stress and has been linked to the many health benefits of red wine. Over the past several decades, a great deal of research has identified diverse biological roles associated with resveratrol, including anti-oxidant, anti-proliferation, anti-inflammation, anti-cancer, anti-fungal, and antiviral activities. Such biological activities of resveratrol are likely mediated through multiple cellular targets or pathways, such as sirtuins, a family of NAD(+)-dependent deacetylases. In this treatise, the literatures focusing on the roles of resveratrol and sirtuins in modulating infections by a broad-spectrum of viruses are reviewed, with an emphasis on its potential antiviral mechanisms. A working model about the effects of resveratrol on virus infection is proposed to stimulate further researches on this exciting topic.


A Survey on Patient and Clinician Satisfaction With a Rapidly Implemented Telephone Consultation Service During the COVID-19 Pandemic.
The novel coronavirus pandemic presented unique challenges to healthcare organisations on an unprecedented scale. Due to the cessation of routine care, the Humberside Oral and Maxillofacial Surgery department implemented a telephone review service to maintain access to care. This survey study was conducted to gain feedback from patients and staff regarding the recently implemented remote telephone consultation service within the Humberside Oral and Maxillofacial Surgery unit. A paper questionnaire comprising 16 questions was posted to 199 patients who underwent telephone review. A further questionnaire was sent via SurveyMonkey (Momentive Inc., San Mateo) to the clinicians involved. From 199 patients, 93 surveys returned were suitable for inclusion; 7 out of 12 staff replied to the survey. The results showed a high level of satisfaction with the service from both groups. There were also suggestions for future additions to the service, including use for new patient consultations, addition of webcam facilities and further streamlining of suitable cases for remote consultation. Our study demonstrated high patient and staff satisfaction with telephone consultations. It showed that over one third (37%) of patients were able to be discharged via telephone consultation, helping to maintain access, free up clinical resources and reduce the need for face-to-face clinical attendance, which has been vital throughout the coronavirus disease 2019 (COVID-19) pandemic. We now have suggestions for how this service can be implemented in the longer term within our department, including developing clearer guidelines for inclusion in the service and the possible benefit of video consultation.


Enhancing vaccine safety capacity globally: A lifecycle perspective.
Major vaccine safety controversies have arisen in several countries beginning in the last decades of 20th century. Such periodic vaccine safety controversies are unlikely to go away in the near future as more national immunization programs mature with near elimination of target vaccine-preventable diseases that result in relative greater prominence of adverse events following immunizations, both true reactions and temporally coincidental events. There are several ways in which vaccine safety capacity can be improved to potentially mitigate the impact of future vaccine safety controversies. This paper aims to take a "lifecycle" approach, examining some potential pre- and post-licensure opportunities to improve vaccine safety, in both developed (specifically U.S. and Europe) and low- and middle-income countries.


Immune responses of a native and an invasive bird to Buggy Creek Virus (Togaviridae: Alphavirus) and its arthropod vector, the swallow bug (Oeciacus vicarius).
Invasive species often display different patterns of parasite burden and virulence compared to their native counterparts. These differences may be the result of variability in host-parasite co-evolutionary relationships, the occurrence of novel host-parasite encounters, or possibly innate differences in physiological responses to infection between invasive and native hosts. Here we examine the adaptive, humoral immune responses of a resistant, native bird and a susceptible, invasive bird to an arbovirus (Buggy Creek virus; Togaviridae: Alphavirus) and its ectoparasitic arthropod vector (the swallow bug; Oeciacus vicarius). Swallow bugs parasitize the native, colonially nesting cliff swallow (Petrochelidon pyrrhonota) and the introduced house sparrow (Passer domesticus) that occupies nests in cliff swallow colonies. We measured levels of BCRV-specific and swallow bug-specific IgY levels before nesting (prior to swallow bug exposure) and after nesting (after swallow bug exposure) in house sparrows and cliff swallows in western Nebraska. Levels of BCRV-specific IgY increased significantly following nesting in the house sparrow but not in the cliff swallow. Additionally, house sparrows displayed consistently higher levels of swallow bug-specific antibodies both before and after nesting compared to cliff swallows. The higher levels of BCRV and swallow bug specific antibodies detected in house sparrows may be reflective of significant differences in both antiviral and anti-ectoparasite immune responses that exist between these two avian species. To our knowledge, this is the first study to compare the macro- and microparasite-specific immune responses of an invasive and a native avian host exposed to the same parasites.


Effect of neonatal thyroid deficiency on the catecholamine, substance P, and thyrotropin-releasing hormone contents of discrete rat brain nuclei.
The effects of neonatal thyroidectomy and thyroid hormone replacement therapy on the development of catecholamine-, TRH-, and substance P-containing neurons in discrete rat brain nuclei were studied. Newborn male rats were rendered hypothyroid by the injection of 125 muCi 131I and, after 45 days, were compared with normal littermate controls and 131I-injected animals subsequently maintained on T4 injections. The peptide or catecholamine content of discrete brain nuclei removed by punches of frozen brain slices was measured by RIA or radioenzymatic assay, respectively. The success of the thyroidectomy was verified by criteria of weight, length, plasma T4, and pituitary GH content. Animals receiving T4 replacement therapy were indistinguishable from normal littermates. Substance P was measured in 32 different brain nuclei and was significantly increased in 19 of these areas in hypothyroid animals. No changes in norepinephrine were detected, and the dopamine content of all but 3 brain nuclei was increased by thyroidectomy. The TRH concentration was drastically reduced in the median eminence of hypothyroid animals and also changed in 3 other extrahypothalamic areas. All of the changes seen in catecholamine, TRH, and substance P distribution in hypothyroid animals were completely reversed by T4 replacement therapy. These results demonstrate changes in brain peptide neurotransmitters during the hypothyroid state and open new vistas for comprehension of biochemical mechanisms underlying central nervous system malfunction.


In vivo development of an acetyldinaline resistant subline of the BN rat acute myelocytic leukemia (BNML).
The cytostatic drug acetyldinaline [ACD, CI-994, 4-acetylamine-N-(2-aminophenyl)-benzamide] shows an extreme antileukemic effect in the Brown Norway (BN) rate model for acute myelocytic leukemia (BNML) with only minor toxicity for normal pluripotent hemopoietic stem cells. So far, the mode of action is unknown. A resistant subline (BNML/ACD-R) was developed in vivo in the BNML model. Leukemic rats received repeated oral administrations of ACD. When the leukemia relapsed after initial remission-induction with ACD, the cells were transferred to new recipients which were again treated. In total, the animals received 247 oral administrations of ACD (33 x 2 mg/kg per day and 214 x 5 mg/kg per day) before full resistance was reached. The cell line was transferred 17 times in total. Treatment of the final resistant cell line with therapeutically highly active doses of 23.7 mg/kg per day and 11.85 mg/kg per day ACD for 5 days, that resulted in an increase of life span (ILS) of 57 and 18 days, respectively, when applied to the sensitive parent BNML line (BNML/S), resulted in only 10 and 3 days ILS, respectively. These results indicate that a significant degree of resistance has been achieved, which can be overcome partially by increasing the dose of ACD. Whether the development of a resistant subpopulation of the BNML is a result of acquired resistance or whether a naturally resistant subpopulation has been selected out after prolonged treatment with ACD remains to be established. The currently available resistant subline BNML/ACD-R now offers the possibility for further studies on the mechanism of action of ACD.


Effects of mir-128a on the invasion and proliferation of glioma U251 cells.
Effects of mir-128a on the proliferation and migration of human glioma U251 cells were explored. The constructed mir-128a-shRNA lentivirus vector (infection group) and scramble shRNA (interference group) were transfected into glioma U251 cells, and uninfected U251 cells as control group. The expression level of mir-128a, the ability of proliferation, invasion, apoptosis and migration of cells in each group were detected by RT-qPCR, MTT assay, Transwell migration in vitro, cell wound scratch assay and TUNEL cell apoptosis assay. The expression level of mir-128a in U251 cells of infection group was significantly higher than that in U251 cells of interference group (P<0.05). Τhe expression level of mir-128a in U251 cells of control group was significantly lower than that in U251 cells of infection group (P<0.05). The OD values of infection and control group were lower than that of interference group at 6, 12, 24, 48 and 72 h, and the OD values of infection were lower than that of control group at 6, 12, 24, 48 and 72 h (P<0.05). Compared with infection and control group, the number of membrane-penetrating cells in U251 cells of interference group increased significantly (P<0.05). The apoptosis rate of U251 cells of infection and control group was significantly higher than that of interference group, and the apoptosis rate of infection was significantly higher than that of control group (P<0.05). The migration distance of U251 cells of infection and interference group was significantly larger than that of control group (P<0.05). Τhe migration distance of U251 cells of interference group was significantly larger than that of infection group (P<0.05). mir-128a may play a role similar to anti-oncogene in glioma, inhibiting the ability of proliferation, invasion and migration of glioma cells, and promoting the apoptosis of glioma cells.


Thermodynamic and structural characterization of an EBV infected B-cell lymphoma transcriptome.
Epstein-Barr virus (EBV) is a widely prevalent human herpes virus infecting over 95% of all adults and is associated with a variety of B-cell cancers and induction of multiple sclerosis. EBV accomplishes this in part by expression of coding and noncoding RNAs and alteration of the host cell transcriptome. To better understand the structures which are forming in the viral and host transcriptomes of infected cells, the RNA structure probing technique Structure-seq2 was applied to the BJAB-B1 cell line (an EBV infected B-cell lymphoma). This resulted in reactivity profiles and secondary structural analyses for over 10000 human mRNAs and lncRNAs, along with 19 lytic and latent EBV transcripts. We report in-depth structural analyses for the human MYC mRNA and the human lncRNA CYTOR. Additionally, we provide a new model for the EBV noncoding RNA EBER2 and provide the first reported model for the EBV tandem terminal repeat RNA. In-depth thermodynamic and structural analyses were carried out with the motif discovery tool ScanFold and RNAfold prediction tool; subsequent covariation analyses were performed on resulting models finding various levels of support. ScanFold results for all analyzed transcripts are made available for viewing and download on the user-friendly RNAStructuromeDB.


Proteolytic activity in erythrocyte precursors.
Thalassemia is characterized by unequal rates of synthesis of the alpha and beta globin chains that are part of the hemoglobin tetramer. In the type of thalassemia due to a defect in beta-chain synthesis (beta-thalassemia), this imbalance results in a relative exoess of alpha-chains. We have studied the susceptibility of excess free alpha-chains to proteolysis. Incubation of isotopically labeled peripheral blood lysates from individuals with beta-thalassemia trait in the presence of bone marrow or normoblast lysates from thalassemic or hematologically normal individuals resulted in a decrease in the alpha/beta ratio and a loss of free alpha-chain radioactivity. Neither contamination with leukocytes nor higher ATP contents in young erythrocytes appeared to be responsible for this activity in normoblasts and bone marrow. We propose that erythroid precursor cells possess proteolytic activity that is markedly diminished in mature cells. This activity serves an important control function in the regulation of hemoglobin synthesis. It accounts at least in part for the more balanced synthesis of alpha- and beta-chains observed in bone marrow than in peripheral blood in heterozygous beta-thalassemia. It also plays a fine-tuning role in maintaining balanced synthesis in non-thalassemic erythrocytes.


Meteorological benefits from atmospheric nuclear tests.
The presence in the atmosphere of radioactive debris from nuclear tests provided a unique opportunity to study atmospheric motions and transfers of trace substances. Measurements of the concentrations in air of radionuclides were used to verify trajectories derived solely from weather data. The profiles of radioactive concentration along the aircraft tracks were non-Gaussian. High-flying aircraft and balloons collected air and particulate samples to approximately 30,000 m from Alaska to South America. The measurements from these samples were used in verifying stratospheric motions on a hemispheric and global scale. Other benefits to the atmospheric sciences gained during the nuclear testing era are briefly described.


[Effect of diphosphonates on bone tissue of the rat during hypokinesia].
The diphosphonate effect on bones was studied in Wistar male rats weighing about 200 g. The rats were kept for 60 days in small-size cages where their motor activity was diminished. Every day the rats were given per os 0.3% solution of 1-hydroxy-ethylene-1,1-diphosphonate (HEDP) containing 9 mg/kg phosphorus. In the course of hypokinetic exposure the rats developed generalized osteoporosis. Histomorphometric measurements demonstrated that the drug did not prevent mineral losses from the tubular bones (humerus, femur). However, the drug led to a complete bone mass recovery in the pelvic and a partial recovery in the sternum. The drug also produced a preventive effect on the population of cells-precursors of osteogenesis the number of which decreases significantly during hypokinesia.


Moderate phosphorus additions consistently affect community composition of arbuscular mycorrhizal fungi in tropical montane forests in southern Ecuador.
Anthropogenic atmospheric deposition can increase nutrient supply in the most remote ecosystems, potentially affecting soil biodiversity. Arbuscular mycorrhizal fungal (AMF) communities rapidly respond to simulated soil eutrophication in tropical forests. Yet the limited spatio-temporal extent of such manipulations, together with the often unrealistically high fertilization rates employed, impedes generalization of such responses. We sequenced mixed root AMF communities within a seven year-long fully factorial nitrogen (N) and phosphorus (P) addition experiment, replicated at three tropical montane forests in southern Ecuador with differing environmental characteristics. We hypothesized: strong shifts in community composition and species richness after long-term fertilization, site- and clade-specific responses to N vs P additions depending on local soil fertility and clade life history traits respectively. Fertilization consistently shifted AMF community composition across sites, but only reduced richness of Glomeraceae. Compositional changes were mainly driven by increases in P supply while richness reductions were observed only after combined N and P additions. We conclude that moderate increases of N and P exert a mild but consistent effect on tropical AMF communities. To predict the consequences of these shifts, current results need to be supplemented with experiments that characterize local species-specific AMF functionality.


Proteins of bacteriophage phi6.
We investigated the protein composition of the lipid-containing bacteriophage phi 6. We also studied the synthesis of phage-specific proteins in the host bacterium Pseudomonas phaseolicola HB10Y. The virion was found to contain 10 proteins of the following molecular weights: P1, 93,000; P2, 88,000; P3, 84,000; P4, 36,800; P5, 24,000; P6, 21,000; P7, 19,900; P8, 10,500; P9, 8,700; and P10, less than 6,000. Proteins P3, P9, and P10 were completely extracted from the virion with 1% Triton X-100. Protein P6 was partially extracted. Proteins P8 and P9 were purified by column chromatography. The amino acid composition of P9 was determined and was found to lack methionine. Labeling of viral proteins with [35S]methionine in infected cells indicated that proteins P5, P9, P10, and P11 lacked methionine. Treatment of host cells with UV light before infection allowed the synthesis of P1, P2, P4, and P7; however, the extent of viral protein synthesis fell off exponentially with increasing delay time between irradiation and infection. Treatment of host cells with rifampin during infection allowed preferential synthesis of viral proteins, but the extent of synthesis also fell off exponentially with increasing delay time between the addition of rifampin and the addition of radioactive amino acids. All of the virion proteins were seen in gels prepared from rifampin-treated infected cells. In addition, two proteins, P11 and P12, were observed; their molecular weights were 25,200 and 20,100, respectively. Proteins P1, P2, P4, and P7 were synthesized early, whereas the rest began to increase at 45 min post-infection.


Methodological Issues in Antifungal Susceptibility Testing of Malassezia pachydermatis.
Reference methods for antifungal susceptibility testing of yeasts have been developed by the Clinical and Laboratory Standards Institute (CLSI) and the European Committee on Antibiotic Susceptibility Testing (EUCAST). These methods are intended to test the main pathogenic yeasts that cause invasive infections, namely Candida spp. and Cryptococcusneoformans, while testing other yeast species introduces several additional problems in standardization not addressed by these reference procedures. As a consequence, a number of procedures have been employed in the literature to test the antifungal susceptibility of Malassezia pachydermatis. This has resulted in conflicting results. The aim of the present study is to review the procedures and the technical parameters (growth media, inoculum preparation, temperature and length of incubation, method of reading) employed for susceptibility testing of M. pachydermatis, and when possible, to propose recommendations for or against their use. Such information may be useful for the future development of a reference assay.


Grandparents providing childcare in Italy.
Research on the choices of childcare arrangements in Italy shows the fundamental role of grandparents in providing informal childcare. Therefore, it is important to understand how grandparents provide different types of childcare, especially in terms of differences in their socio-economic, demographic and physical status, jointly with the characteristics of their grandchildren. Grandparents aged 50 and over with at least one non-co-resident grandchild aged 13 years or less were selected from the 2009 Italian household survey. Multilevel multinomial logistic regression models for grandmothers and grandfathers were used to identify the determinants of the probability of providing childcare intensively, occasionally or during school holidays rather than never. The probability of a grandparent providing intensive childcare is significantly reduced by being: male, unmarried, in bad health and with inadequate economic resources. Nevertheless, when analysing the probability of providing childcare occasionally or during holidays, the individual characteristics of grandparents and grandchildren are less significant compared to intensive childcare, meaning that grandparents provide non-intensive care regardless of their individual characteristics, and this is particularly true for grandmothers. Results confirm the fundamental importance of grandparents in providing informal childcare in Italy, and they offer useful information to understand the individual characteristics associated with different types of grandparental childcare.


Expression profile of CADM1 and CADM4 in triple negative breast cancer with primary systemic therapy.
Triple negative breast cancer (TNBC) is defined by a lack of ER, PgR, and HER2 expression, and to date there have been no significant advances in treatment by targeted therapies against those molecules. Therefore, primary systemic therapy (PST) followed by surgery is the standard therapy for patients with advanced TNBC. According to gene expression analysis, TNBC has a distinct profile when compared with non-TNBC, suggesting that a unique gene affects the treatment efficacy of PST. Cell adhesion molecule (CADM) genes encode an immunoglobulin superfamily molecule involved in cell-to-cell adhesion in a variety of human epithelial cells. While it has been reported that inactivation of CADM1 and CADM4 serves a pivotal role in the progression of breast cancer, a full analysis has not been completed for TNBC. Previous studies have reported that CADM1 and CADM4 expression is less likely to be decreased in TNBC than in non-TNBC. In the present study, CADM1 and CADM4 expression was evaluated in patients with TNBC who had received PST. The present study revealed that loss or weak expression of CADM1 was frequently observed in non-pathological complete response patients. Furthermore, while the majority of TNBC cases exhibited high CADM1 expression, a small number of cases exhibited low CADM1 expression and low therapeutic response of PST for TNBC. These results suggest that CADM1 has a pivotal role in anti-PST efficacy in patients with TNBC.


Drug-Resistant Salmonella typhi in Pakistan.
Enteric fever (formerly typhoid fever) is a bacterial illness caused by fecal-oral transmission of Salmonella typhi or paratyphi. In early 2018, an outbreak of Salmonella typhi resistant to third-generation cephalosporins, ampicillin, ciprofloxacin, trimethroprim-sulfamethoxazole, and chloramphenicol was reported in Pakistan. This strain, termed "extensively resistant typhi," has infected more than 5000 patients in endemic areas of South Asia, as well as travelers to and from these areas, including 5 cases in the United States. We present the case of one such child who developed extensively resistant enteric fever during a recent visit to Pakistan and required broader antimicrobial treatment than typically required. Clinicians should be aware that incoming cases of enteric fever may be nonsusceptible to commonly recommended antibiotics and that extensively resistant typhi requires treatment with carbapenems such as meropenem or azithromycin.


Localization of intraorbital foreign bodies: an improved photoradiographic method.
A previously described photoradiographic camera used to localize intraocular or intraorbital foreign bodies has been modified to a more versatile unit. One photograph and one radiograph are taken simultaneously, and the pictures are combined, whereby the eye appears as its own indicator on the radiophotograph. More than 50 foreign bodies have been successfully localized with the camera which is easy to handle and can be used in any x-ray film room where an overhead tube is available.


Development of a diagnostic gene expression assay for tuberculosis and its use under field conditions in African buffaloes (Syncerus caffer).
The development of diagnostic tests for tuberculosis (TB) in exotic species is constrained by host biology and the limited availability of suitable assay reagents. As such, we evaluated a gene expression assay (GEA) which is easily modified for novel species and allows for initial sample processing under field conditions. African buffaloes (Syncerus caffer) were categorized using the single comparative intradermal tuberculin test, and blood from test-positive and test-negative animals was incubated for 20 h in "Nil" tubes (containing saline) and "TB Antigen" tubes (containing Mycobacterium tuberculosis complex (MTC)-specific antigens) of a commercial human TB test, the QuantiFERON(®)-TB Gold (In-Tube) (QFT) assay. Blood samples were then stabilized in RNAlater(®) and transported to the laboratory for RNA extraction. A Custom TaqMan GEA was used to calculate the relative abundance of interferon-gamma (IFN-γ) mRNA in the TB Antigen tube compared to that in the Nil tube as a marker of immune activation in response to MTC antigen recognition. The GEA results from the two buffalo groups were compared and a cutoff value of 2.85 was calculated to differentiate between animals from these groups with a sensitivity of 80% (95% C.I.: 56-94%) and a specificity of 95% (95% C.I.: 75-100%). Further optimization of this assay could provide a highly useful tool for the diagnosis of MTC infection in exotic species.


Strongly phosphorescent neutral rhenium(i) isocyanoborato complexes: synthesis, characterization, and photophysical, electrochemical, and computational studies.
A new series of neutral isocyanoborato rhenium(I) diimine complexes [Re(CO)3 (N^N)(CNBR3 )], where N^N=bpy, 4,4'-Me2 bpy, phen, 4,7-Me2 phen, 2,9-Me2 phen, 3,4,7,8-Me4 phen; R=C6 F5 , C6 H5 , Cl, 4-ClC6 H4 , 3,5-(CF3 )2 C6 H3 , with various isocyanoborate and diimine ligands of diverse electronic and steric nature have been synthesized and characterized. The X-ray crystal structures of six complexes have also been determined. These complexes displayed intense bluish green to yellow phosphorescence at room temperature in dichloromethane solution. The photophysical and electrochemical properties of these complexes had been investigated. To elucidate the electronic structures and transitions of these complexes, DFT and TD-DFT calculations have been performed, which revealed that the lowest-energy electronic transition associated with these complexes originates from a mixture of MLCT [dπ(Re)→π*(N^N)] and LLCT [π(CNBR3 )→π*(N^N)] transitions.


Transmission of Bamboo mosaic virus in Bamboos Mediated by Insects in the Order Diptera.
Bamboo mosaic virus (BaMV), a member of the genus Potexvirus, is the major threat to bamboo cultivation. Similar to most potexviruses, the transmission of BaMV by insect vectors has not been documented previously. However, field observations of BaMV disease incidences suggested that insect vectors might be involved. In this study, we aimed to investigate the possibility of insect-mediated transmission of BaMV among bamboo clumps, in order to provide further insights into the infection cycles of BaMV for the development of effective disease management measures. From the major insects collected from infected bamboo plantations, BaMV genomic RNAs were detected inside the bodies of two dipteran insects, Gastrozona fasciventris and Atherigona orientalis, but not in thrips (Scirtothrips dorsalis). Artificial feeding assays using green fluorescent protein-tagged BaMV virions revealed that BaMV could enter the digestive systems and survive in the regurgitant and excretion of the dipterans. BaMV RNA could be retained in the dipterans for up to 4 weeks. Insect-mediated transmission assays indicated that both dipterans could transmit BaMV to bamboo seedlings through artificially created wounds with low infection efficiency (14 - 41%), suggesting that the dipterans may mediate the transmission in a mechanical-like manner. These results demonstrated that dipterans with sponge-like mouthparts may also serve as vectors for at least one potexvirus, BaMV, among bamboo plants. The finding suggested that dipteran insect control should be integrated into the disease management measures against BaMV infections.


BPL3 binds the long non-coding RNA nalncFL7 to suppress FORKED-LIKE7 and modulate HAI1-mediated MPK3/6 dephosphorylation in plant immunity.
RNA-binding proteins (RBPs) participate in a diverse set of biological processes in plants, but their functions and underlying mechanisms in plant-pathogen interactions are largely unknown. We previously showed that Arabidopsis thaliana BPA1-LIKE PROTEIN3 (BPL3) belongs to a conserved plant RBP family and negatively regulates reactive oxygen species (ROS) accumulation and cell death under biotic stress. In this study, we demonstrate that BPL3 suppresses FORKED-LIKE7 (FL7) transcript accumulation and raises levels of the cis-natural antisense long non-coding RNA (lncRNA) of FL7 (nalncFL7). FL7 positively regulated plant immunity to Phytophthora capsici while nalncFL7 negatively regulated resistance. We also showed that BPL3 directly binds to and stabilizes nalncFL7. Moreover, nalncFL7 suppressed accumulation of FL7 transcripts. Furthermore, FL7 interacted with HIGHLY ABA-INDUCED PP2C1 (HAI1), a type 2C protein phosphatase, and inhibited HAI1 phosphatase activity. By suppressing HAI1 activity, FL7 increased the phosphorylation levels of MITOGEN-ACTIVATED PROTEIN KINASE 3 (MPK3) and MPK6, thus enhancing immunity responses. BPL3 and FL7 are conserved in all plant species tested, but the BPL3-nalncFL7-FL7 cascade was specific to the Brassicaceae. Thus, we identified a conserved BPL3-nalncFL7-FL7 cascade that coordinates plant immunity.


Enhanced electrochromic properties of a polypyrrole-indigo carmine-gold nanoparticles nanocomposite.
An indigo carmine doped polypyrrole embedded with gold nanoparticles nanocomposite (PPy-IC-Aunanop) was synthesized by in situ electrochemical polymerization of polypyrrole in the presence of HAuCl4. The nanocomposite was characterized by in situ spectroelectrochemical experiments to study the effect of embedded gold nanoparticles on the electrochromic properties of the material. The results show the formation of a nanocomposite presenting enhanced electrochromic and optical properties, higher electroactivity and 10% lower band-gap energies. The PPy-IC-Aunanop presented a two-fold increase in optical contrast when compared to PPy-IC, in addition to better optical stability.


Application of Metagenomic Analyses in Dentistry as a Novel Strategy Enabling Complex Insight into Microbial Diversity of the Oral Cavity.
The composition of the oral microbiome in healthy individuals is complex and dynamic, and depends on many factors, such as anatomical location in the oral cavity, diet, oral hygiene habits or host immune responses. It is estimated at present that worldwide about 2 billion people suffer from diseases of the oral cavity, mainly periodontal disease and dental caries. Importantly, the oral microflora involved in local infections may spread and cause systemic, even life-threatening infections. In search for etiological agents of infections in dentistry, traditional approaches are not sufficient, as about 50% of oral bacteria are not cultivable. Instead, metagenomic analyses are particularly useful for studies of the complex oral microbiome - both in healthy individuals, and in patients with oral and dental diseases. In this paper we review the current and future applications of metagenomic studies in evaluation of both the composition of the oral microbiome as well as its potential pathogenic role in infections in dentistry.