Neural response to emotional salience in schizophrenia.

Neuroimaging probes of brain regions implicated in emotion represent an important research strategy for understanding emotional dysfunction in schizophrenia. Anterior limbic structures, such as the ventral striatum and the amygdala, have been implicated in the pathophysiology of schizophrenia and the generation of emotional responses, although few studies to date have used emotion probes to target these areas in schizophrenia. With this goal in mind, emotionally salient visual images were used in a simple, nondemanding task. In all, 13 medicated, schizophrenic patients, five unmedicated patients, and 10 healthy volunteers viewed complex visual pictures and a nonsalient, blank screen while regional cerebral blood flow was measured with the [O-15] water technique. Pictures consisted of real world scenes with aversive, positive, and nonaversive content. Eye movements were recorded simultaneous with scan acquisition. Positron emission tomography images were analyzed for baseline, tonic activity, in addition to phasic changes ('activation') to salient stimuli. Lateral eye movement measures and on-line ratings showed good behavioral compliance with the task. Patients with schizophrenia showed impaired neural responses to salient stimuli in the right ventral striatum (VS), and they exhibited elevated tonic activity levels in the right VS and bilateral amygdala, inversely correlated with overall symptom severity. The patients also showed reduced modulation of visual cortex by salient stimuli. The results show that patients with schizophrenia exhibit impaired neural responses to emotionally salient stimuli in the VS, supporting a role for this structure in the pathophysiology of the illness. Reduced modulation of visual cortex by emotionally salient stimuli also suggests a failure to organize cerebral activity at a global level.     

Emergence of genetically linked vaccine-originated poliovirus type 2 in the absence of oral polio vaccine,Jerusalem, April to July 2022

We report an emergence and increase in poliovirus type 2 detection via routine wastewater surveillance in three non-overlapping regions in the Jerusalem region, Israel, between April and July 2022. Sequencing showed genetic linkage among isolates and accumulation of mutations over time, with two isolates defined as vaccine-derived polioviruses (VDPV). This demonstrates the emergence and potential circulation of type 2 VDPV in a high-income country with high vaccine coverage and underscores the importance of routine wastewater surveillance during the polio eradication.     

Case of benralizumab‐induced exacerbations of chronic spontaneous urticaria

The role of IL‐5 in chronic spontaneous urticarial (CSU) is unclear. It may be that benralizumab is an important bidirectional modifier of CSU; that is, blocking IL‐5 may improve CSU in some patients, but it is possible that it may worsen CSU in others.     

Phase II study of bevacizumab and pemetrexed for recurrent or persistent epithelial ovarian,fallopian tube or primary peritoneal cancer

Objective

We aimed to evaluate the efficacy and safety of combination bevacizumab/pemetrexed for the treatment of recurrent epithelial ovarian cancer (EOC).

Methods

Platinum-sensitive or -resistant patients with recurrent or persistent EOC were eligible if they had received up to 2 prior chemotherapy regimens, including a platinum/taxane regimen without prior bevacizumab. Pemetrexed 500 mg/m² IV and bevacizumab 15 mg/kg IV were administered every 3 weeks. The primary endpoint was 6-month progression-free survival (PFS); other endpoints included toxicities, PFS and overall survival (OS).

Results

Thirty-four patients received a median of 7 treatment cycles (range, 2–26). Median follow-up was 25.7 months (range, 3.0–47.2). Six month progression-free survival (PFS) was 56% (95% CI: 38–71). The following response rates were documented (%; 95% CI): 0 complete response, 14 partial responses (41%; 25–59), 18 stable disease (53%; 35–70) and 2 progressive disease (6%; 1–20). Median PFS was 7.9 months (95% CI, 4.6–10.9), with a median OS of 25.7 months (95% CI, 15.4–29.8). Twenty-two patients (64.7%) had a platinum-free interval (PFI) of > 6 months prior to enrollment. Grade 3–4 hematologic toxicities included neutropenia (50%), leukopenia (26%), thrombocytopenia (12%) and anemia (9%). Non-hematologic grade 3–4 toxicities included metabolic (29%), constitutional (18%), pain (18%) and gastrointestinal (15%). Two patients developed hematologic malignancies within one year of treatment.

Conclusions

Combination bevacizumab/pemetrexed is an active option for both platinum-sensitive and -resistant recurrent EOC. Further investigation of cost and novel toxicities associated with this regimen may be warranted.     

Heparanase expression increases throughout the endometrial hyperplasia-cancer sequence.

OBJECTIVE: To assess the expression of heparanase in the different stages leading to endometrial cancer. METHODS: The 38 examined specimens included adenocarcinoma, hyperplasia, and normal endometrium specimens. Heparanase, estrogen, and progesterone receptor expressions were analyzed immunohistochemically and the intensity was scored. RESULTS: Secretory normal endometrium and simple hyperplasia specimens expressed the lowest mean values of expression (1.00 and 0.63, respectively); the complex hyperplasia specimens and G2 endometrioid adenocarcinoma showed the highest values of expression (2.33 and 2.71, respectively). A linear trend (P=0.005) of heparanase expression was observed when comparing the normal endometrium and simple hyperplasia group with the complex hyperplasia+G1 carcinoma group and the G2+G3 carcinoma group. Evaluation of atrophic and inactive endometrium compared with papillary serous carcinomas yielded no significant differences. We found no significant correlation between heparanase expression and estrogen receptor or progesterone receptor expression. CONCLUSION: Heparanase expression was tightly regulated in endometrial tumorigenesis.     

Pulmonary pattern in systemic vasculitis: granulomatosis,lung cancer or both?

As clinical manifestations of systemic vasculitides share many common features with other conditions, the rate of diagnostic errors and delayed diagnoses is high. Hence we performed an analysis of the available data regarding misdiagnosis of vasculitis as lung cancer and vice versa, as well as coexistence of vasculitis and lung cancer. The present case-based review highlights the diagnostic challenges encountered when granulomatosis with polyangiitis (GPA) mimics lung cancer. The importance of a multidisciplinary team approach to patients with pulmonary involvement and multisystem manifestations is essential for appropriate planning of further diagnostic steps and for minimizing the delay in correct diagnosis and treatment. In the present case, although computed tomography raised suspicion for lung cancer, further biopsies and laboratory screening for systemic vasculitides rejected malignancy and confirmed the diagnosis of GPA.     

Corrosion Behavior of Al Modified with Zn in Chloride Solution

Aluminum-based alloys have been considered candidate materials for cathodic protection anodes. However, the Al-based alloys can form a layer of alumina, which is a drawback in a sacrificial anode. The anodes must exhibit uniform corrosion to achieve better performance. Aluminum can be alloyed with Zn to improve their performance. In this sense, in the present research, the electrochemical corrosion performance of Al-xZn alloys (x = 1.5, 3.5, and 5 at.% Zn) exposed to 3.5 wt.% NaCl for 24 h was evaluated. Polarization curves, linear polarization resistance (LPR), and electrochemical impedance spectroscopy (EIS) were used to identify the electrochemical behavior. The microstructure of the samples before the corrosion assessment was characterized by means of X-ray diffraction analyses (XRD) and scanning electron microscopy (SEM). In addition, microstructures of the corroded surfaces were characterized using X-ray mappings via SEM. Polarization curves indicated that Zn additions changed the pseudo-passivation behavior from what pure Al exhibited in a uniform dissolution regime. Furthermore, the addition of Zn shifted the corrosion potential to the active side and increased the corrosion rate. This behavior was consistent with the proportional decrease in polarization resistance (R_p) and charge transfer resistance (R_ct) in the EIS. The analysis of EIS was done using a mathematical model related to an adsorption electrochemical mechanism. The adsorption of chloride at the Al-Zn alloy surface formed aluminum chloride intermediates, which controlled the rate of the process. The rate constants of the reactions of a proposed chemical mechanism were evaluated.     

A proposed unified interphase nucleus chromosome structure: Preliminary preponderance of evidence

Cryoelectron tomography of the cell nucleus using scanning transmission electron microscopy and deconvolution processing technology has highlighted a large-scale, 100- to 300-nm interphase chromosome structure, which is present throughout the nucleus. This study further documents and analyzes these chromosome structures. The paper is divided into four parts: 1) evidence (preliminary) for a unified interphase chromosome structure; 2) a proposed unified interphase chromosome architecture; 3) organization as chromosome territories (e.g., fitting the 46 human chromosomes into a 10-μm-diameter nucleus); and 4) structure unification into a polytene chromosome architecture and lampbrush chromosomes. Finally, the paper concludes with a living light microscopy cell study showing that the G1 nucleus contains very similar structures throughout. The main finding is that this chromosome structure appears to coil the 11-nm nucleosome fiber into a defined hollow structure, analogous to a Slinky helical spring [https://en.wikipedia.org/wiki/Slinky; motif used in Bowerman et al., eLife 10, e65587 (2021)]. This Slinky architecture can be used to build chromosome territories, extended to the polytene chromosome structure, as well as to the structure of lampbrush chromosomes.

A recent publication introduced iterative deconvolution for scanning transmission electron microscopy (TEM) tomograms of cryopreserved cellular structures (ref. 1 and references therein). Micron-thick areas of the vitrified cells were accessible without prior cryosectioning or lamella preparation. The deconvolution computation simplified interpretation of the tomograms by substantially filling the missing wedges of information that result from incomplete tilts. The effect was a substantial improvement in resolution along the depth (Z) direction. This technology made it possible to assess a tomogram from an area of the nucleus intact, in which large-scale interphase chromosome structures were noted (1).Here, the chromosome structures observed in these nuclear tomograms are further documented and analyzed. This paper is divided into four parts. The first part presents the evidence, preliminary but compelling, for a unified interphase chromosome structure. The second part presents the proposed unified interphase chromosome architecture. The third part shows that this interphase chromosome structure could be further organized as chromosome territories: for example, by fitting the 46 human chromosomes into a 10-μm-diameter nucleus. The fourth part unifies this structure into a polytene chromosome architecture and lampbrush chromosomes. The paper concludes with a living light microscopy cell study showing that the G1 nucleus has very similar structures throughout this organelle.The interphase nucleus encloses the genomic DNA, as well as the machinery for regulation of gene expression, RNA synthesis, and DNA replication (2). DNA is packaged into chromatin, the in vivo structure of which remains unclear. While mitotic chromosomes are highly condensed, interphase chromosomes decondense but remain in distinct territories with little overlap. Interphase chromatin is organized in a number of ways, including immutable gene-rich and -poor domains in the primary sequence and expression-promoting or -suppressing regions that may vary during the cell cycle or reflect cell differentiation (2). A classic distinction is drawn between euchromatin and heterochromatin, with the former more “open” and prone to expression, while the latter is more “closed” and prone to silencing (but see ref. 3). However, different methods, such as fluorescence and electron microscopy (EM), or posttranslational histone modifications, are sensitive to different parameters and do not necessarily agree in their identification.The predominant model to describe the path of the DNA strand in the interphase nucleus is the constrained random walk (4) or fractal globule (5, 6). At prophase, the dispersed polymers must recondense without entangling. During mitosis, the space-filling interphase chromatin condenses into a compact micrometer-sized structure. The degree of order in these structures remains undefined.The double-stranded DNA polymer itself, which in isolation appears as a semiflexible, right-hand helix 2 nm in diameter, winds tightly around core histones to form nucleosomes. Each nucleosome has a DNA footprint of 146 base pairs and a geometric diameter of ∼11 nm (7–9). Nucleosomes appear as beads on a string, but the density and spacing of nucleosomes along the DNA sequence may be highly variable (10). In the next stage, the nucleosomes are supposed to coil up into a 30-nm filament, possibly as a tight solenoid or alternatively with a zig-zag structure (11, 12). Today, the 30-nm filament is largely considered an artifact (13, 14). It has been observed in vitro, in isolated or ruptured nuclei, and in cases of deliberate manipulation of divalent cation concentration, but not in intact nuclei (13–15).Current insights into chromatin structure arise primarily from methods based on sequencing. With a number of significant variations, chromatin is cross-linked, cleaved, captured, and sequenced in order to determine which sequences lie in close proximity (5, 16). These methods have revealed a genetic structure of chromosome territories at the largest scale, active and inactive compartments at the multimega base level, followed by topologically associated domains (also known as TADs) whose regulation is controlled concomitantly even if they appear to be distant in sequence (16, 17). An overall, three-dimensional (3D) spatial map of the genome can be generated from the proximity constraints. Extension of the methods to analysis of individual cells revealed a strong heterogeneity, however, making it difficult to connect proximity data to local structure.Microscopy offers the most direct observations of structure, but specimen preparation may be disruptive. Classic EM requires fixation, followed by solvent-based dehydration and impregnation with a hardening polymer. Heavy metal salts are added to generate image contrast based on electron scattering; the indirect nature makes it difficult to interpret apparent density in terms of molecular composition (18). This limitation was circumvented by electron spectroscopic imaging, which distinguishes protein from nucleic acid on the basis of nitrogen and phosphorus concentrations (19). A recent advance used a DNA-binding dye to induce a localized polymerization of diaminobenzidine, which in turn binds an osmium stain (15). A modest density difference between euchromatin and heterochromatin was found, but no evidence was seen for long-range order (15). Fluorescence microscopy has made great advances with the introduction of superresolution methods. The combination with in situ hybridization permits even a degree of sequencing in situ. Still, long exposures and biochemical manipulations require strong cross-linking, which necessarily influences local structure. Cryoelectron tomography offers the most direct and pristine view of cellular structure, including chromatin, but conventional TEM requires thin sectioning or lamella fabrication using the focused ion beam microscope.Cryoscanning transmission electron tomography is a new addition to the toolkit of cellular imaging techniques. The most obvious advantages in relation to conventional defocus phase-contrast TEM are the ability to accommodate thicker specimens and the quantitative contrast based on electron scattering cross-sections. As implemented for cellular tomography, it provides: 1) a unipolar optical transfer function with the specimen in focus, 2) a long depth of field, and most importantly, 3) strong contrast for low spatial frequencies (20). We have recently demonstrated the application of cryoscanning transmission electron tomography in combination with 3D iterative deconvolution processing to whole-cell tomography and obtained a view of the cell nucleus that revealed unexpected large-scale structures (1).Data Considerations and Their Complexity.The primary data for this paper have considerably different attributes, such as the close-spaced 3D pixels with subtle gray level differences and textures, requiring new ways to display its details and architecture. This is a common problem for various imaging technologies (e.g., cellular cryoelectron tomography and MRI). The usual methods to visualize 3D data, such as moving up and down in the Z-dimension through two-dimensional (2D) slices, do not adequately show 3D relationships. Therefore, we propose the extensive use of stereo with extensions to circumvent this problem. Evidence for the chromosome structure is presented primarily in 3D stereo movies of various kinds (Movie S1 and rocking angular stereo pairs A to C′ presented in Movies S2–S8). Visualization guidance and challenges for the stereo movies are also discussed in depth in SI Appendix.     

National Scale Real-Time Surveillance of SARS-CoV-2 Variants Dynamics by Wastewater Monitoring in Israel

In this report, we describe a national-scale monitoring of the SARS-CoV-2 (SC-2) variant dynamics in Israel, using multiple-time sampling of 13 wastewater treatment plants. We used a combination of inclusive and selective quantitative PCR assays that specifically identify variants A19/A20 or B.1.1.7 and tested each sample for the presence and relative viral RNA load of each variant. We show that between December 2020 and March 2021, a complete shift in the SC-2 variant circulation was observed, where the B.1.1.7 replaced the A19 in all examined test points. We further show that the normalized viral load (NVL) values and the average new cases per week reached a peak in January 2021 and then decreased gradually in almost all test points, in parallel with the progression of the national vaccination campaign, during February–March 2021. This study demonstrates the importance of monitoring SC-2 variant by using a combination of inclusive and selective PCR tests on a national scale through wastewater sampling, which is far more amendable for high-throughput monitoring compared with sequencing. This approach may be useful for real-time dynamics surveillance of current and future variants, such as the Omicron (BA.1, BA.2) and other variants.