Search

Tefillin are Jewish ritual artifacts consisting of leather cases, containing inscribed slips, which are affixed with leather straps to the body of the tefillin practitioner. According to current Jewish ritual law, the tefillin cases and straps are to be colored black. The present study examines seventeen ancient tefillin cases discovered among the Dead Sea Scrolls in caves in the Judean Desert. All seventeen cases display grain surfaces with a very dark, nearly black appearance. We start with a hypothesis that the cases were intentionally colored black in antiquity using either a carbon-based or iron-gall-based paint or dye. The aim of this study is to test this hypothesis by subjecting these tefillin cases to a battery of examinations to assess the presence of carbon and iron used as pigments, and of organic materials which may have been used as binding agents in a paint. The tests deployed are: (1) macroscopic and microscopic analyses; (2) multispectral imaging using infrared wavelengths; (3) Raman spectroscopy; (4) Fourier transform infrared spectroscopy (FTIR); and (5) scanning electron microscope (SEM) and energy dispersive X-ray (EDX) spectroscopy. The results of these tests found no traces of carbon-based or iron-gall-based pigments, nor of organic compounds which may have served as binders in a paint. These results suggest that our posited hypothesis is unlikely. Instead, results of the SEM examination suggest it more likely that the black color on the surfaces of the tefillin cases is the result of natural degradation of the leather through gelatinization. The Judean Desert tefillin likely represent tefillin practices prior to when the rabbinic prescription on blackening tefillin was widely practiced. Our study suggests that the kind of non-blackened tefillin which the later rabbis rejected in their own times may well have been quite common in earlier times. [ABSTRACT FROM AUTHOR]

Purpose Methods Results Conclusions Assess aqueous tear production when measured with the dogs' eyelids open or closed.Thirty healthy dogs (15 Shih Tzus, 15 Labrador retrievers) were recruited. With the order of testing randomized for each dog, two sessions (separated by 30 min) of STT‐1 testing were performed with the dogs' eyelids closed or open. Schirmer strip wetness (every 10 s for 60 s) and number of time(s) the strip dislodged during testing were recorded in each eye. Preferred STT‐1 method was surveyed via a global Listserv of the veterinary ophthalmology community.STT‐1 values were significantly higher in closed versus open eyes in Shih Tzus (18.6 ± 2.7 mm/min vs. 16.3 ± 2.5 mm/min; p = .002) and Labrador retrievers (21.6 ± 2.9 mm/min vs. 17.8 ± 3.2 mm/min, p < .001), findings that were also significant at times <60 s for either breed (p ≤ .004). Schirmer strips dislodged from six dogs with open eyelids and no dogs with closed eyelids. Maximal STT‐1 difference with closed versus open eyelids was 13 mm/min in Labrador retrievers and 7 mm/min in Shih Tzus. Survey results from 275 veterinarians showed STT‐1 performed with “closed eyelids” (38.5%), “open eyelids” (26.9%), or “never paid attention, sometimes closed, sometimes open” (34.6%).Eyelids status (closed or open) during STT‐1 testing had a significant impact on aqueous tear secretion in brachycephalic and nonbrachycephalic dogs, highlighting the importance of consistency when repeating STT‐1 in a canine patient. STT‐1 differences are likely due to sustained reflex tearing throughout the test duration when the dogs' eyelids are closed. [ABSTRACT FROM AUTHOR]

Rats are a commonly used animal model for the study of the pathogenesis and novel treatments of glaucoma, which is induced experimentally using invasive, painful procedures. Peribulbar anaesthesia (PBA) is frequently used in people and domestic animals prior to ophthalmic surgeries to provide excellent perioperative analgesia. Our goal was to develop a PBA technique adapted to rat anatomy, improving the welfare of animals used as a model for glaucoma. Eighteen rat cadavers (n = 36 eyes) were used to establish the optimal needle insertion location. Five injection techniques using 0.1 mL/100 g lidocaine 2% and a contrast agent (1:1 volume ratio) were compared via computed tomography (CT). CT images were scored for injectate distribution at four locations: extraconal, intraconal, around the optic nerve and at the orbital fissure (scale 0–8, where 0 = none and 8 = excellent). Median scores using the dorso-medial-75° (5; range 2–6) and medial-canthus (4.5; range 2–8) injection techniques were not different from the dorso-medial-45° (4; range 3–6) technique and were higher (better distribution) compared with mid-ventral (3; range 2–5) and ventro-lateral (2; range 1–3) techniques. The two superior techniques were used in two experimental rats (n = 4 eyes) to determine the volume of bupivacaine 0.5% necessary to affect corneal touch threshold (CTT) and periocular skin sensitivity (PSS). A volume of 0.05 mL/100 g decreased CTT and PSS for several hours, while a larger volume produced excessively long effects. Dorso-medial-75° or medial-canthus PBA using 0.05 mL/100 g bupivacaine are likely to provide ocular and periocular analgesia in rats, with minor transient adverse effects. [ABSTRACT FROM AUTHOR]

The article offers information on the management of early-stage breast cancer, including neoadjuvant systemic therapy and oncoplastic surgical techniques. Topics include the increasing complexity and variability of treatment choices, advances in systemic therapies, and the benefits of extending adjuvant endocrine therapy.

Coral reef ecosystems in Indonesia are under threat due to changes in the environment driven by global climate change, along with local disturbances such as sedimentation and eutrophication. Consequently, comprehensive coral reef monitoring activities have been initiated at numerous locations across Indonesia. In this study, the findings from coral reef health surveys across 14 reef sites (within 40 hectares) in the Bintan area (Riau Archipelago, Indonesia; 100 km southeast of Singapore) revealed a potentially novel epizoic yellow sponge species (Phorbas sp.) that overgrows coral colonies. This species, tentatively classified as a new Phorbas sp. (order Poecilosclerida: family Hymedesmiidae), was identified through a combined approach employing classical taxonomic methods along with DNA barcoding using the cytochrome c oxidase I (COI) gene. At every site, three permanent 20‐m transects were established to annually monitor live coral coverage and species composition between 2014 and 2017. The survey indicated a notable change in the overall coral cover during this period. The abundance of coral diseases was investigated in 2014 and 2017. Additionally, the progress of Phorbas sp., was closely monitored (i.e., every second day for one week) at Bintan Island (site 11) during the dry season in August 2017. This approach aimed to approximate the relative impact of each incident on the coral's condition. The results indicated that the most comprehensive change occurred due to the overgrowth of Phorbas sp., which affected 12 scleractinian coral species across eight genera in almost all sites except one. The abundance of this epizoic sponge infestation was highest at Pulau Beralas Pasir (site 10), constituting 22.9% of all recorded life forms, and lowest at Pulau Pangkil‐Besar (site 13), with only 0.7%. The expansion of the thin yellow sponge tissue was estimated to increase by up to 0.51 ± 0.48 cm2 per day on Porites coral. [ABSTRACT FROM AUTHOR]

Advances in management of early-stage breast cancer include increasing use of neoadjuvant (presurgery) systemic therapy and oncoplastic surgical techniques in selected patients and the availability of new systemic therapies. These include targeted monoclonal antibody therapies, cyclin)dependent kinase 4/6 inhibitors, antibody-drug conjugates and immunotherapies. [ABSTRACT FROM AUTHOR]

The article discusses that breast cancer is the most common cancer affecting women in Australia, with a lifetime risk of one in seven. It highlights the importance of identifying individuals at moderate or high risk for tailored surveillance and risk-reductive interventions, including discussions on genetic mutations, family history, and modifiable risk factors.

Regional nodal status is one of the most powerful prognosticators in breast cancer. The sentinel lymph node biopsy (SLNB) evaluates the first node in the axillary lymphatic basin theorised to drain the anatomical region of breast cancer. Recent literature has appropriately raised the query of the need for SLNB for breast cancer in older patients (BCOP). Though some early-stage older patients may safely have SLNB omitted, we are potentially missing the under-represented aggressive cancers. No sentinel lymph node metastases nomogram has been developed solely from BCOP data to date. This study aimed to identify older patients with breast cancer at risk for nodal involvement using a nomogram developed from their data alone. A retrospective analysis of prospectively collected data on BCOP (aged ≥70 years) was performed using the Breast Surgery Quality Audit (BQA). Inclusion criteria were T1-2 invasive breast cancer patients that underwent a SLNB from 1st January 2001 to 31st December 2019. The primary outcome was nodal involvement. Data obtained from the dataset included: age, tumour type, tumour size in millimeters, histological grade, lymphovascular invasion, oestrogen receptor status, progesterone receptor status, HER2 status and referral source. Binary logistic regression was used to develop a nomogram. The model was internally validated by splitting the data set (80% for training and 20% for testing). A receiver operating characteristic curve was developed, with the area under the curve (AUC) and a calibration plot. There were 22,313 patients of which 14,856 (66.6%) were symptomatic presentations and 7457 (33.4%) were screen-detected. Invasive tumour type, tumour size, tumour grade, lymphovascular invasion, oestrogen receptors, and referral source indicated a statistically significant effect on predicting a nodal positivity event (Table 1). The AUC was 0.782 (95% CI 0.776–0.789) (Fig. 1a) and demonstrated good calibration (Fig. 1b). The negative predictive value established was 85%. We have developed an Australian sentinel lymph node metastasis nomogram for BCOP using routine histopathological data obtained pre-operatively (Fig. 2). This is the first Australian nomogram, as well as the first nomogram developed solely for BCOP – and maintains a superior AUC compared to other well-established nomograms. • There are many variables impacting nodal positivity for breast cancer in older patients • An AUC is not the defining characteristic of a nomogram • This Australian nomogram has been designed solely for breast cancer in older patients [ABSTRACT FROM AUTHOR]

Breast cancer is the most common non-skin cancer in Australia, affecting 1 in 7 women by the age of 85 years. Current management of early breast cancer is becoming increasingly variable and complex. The typical range of treatments include some combination of surgery, chemotherapy and targeted therapy, immunotherapy, radiotherapy, and endocrine therapy. Neoadjuvant chemotherapy (NACT) in carefully selected patients can facilitate increased rates of breast conservation therapy, and when successful, offers improved cosmesis due to less extensive resection of tissue. A neoadjuvant approach also provides biological insight into a patient's tumour, prognostication based on a patient's response to therapy, as well as enabling their treating oncologist to personalise adjuvant strategies based on the presence or absence of residual cancer at surgery. Neoadjuvant chemotherapy has become an integral element in the provision of breast conserving surgery to selected early-stage breast cancer patients. Appreciating the indications and understanding the likely outcomes from NACT in select situations, can result in significant improvements in patient tailored care. • Neoadjuvant chemotherapy has significantly influenced surgical management. • There are multiple indications for NACT, however weaknesses do exist. • An understanding of NACT can provide best oncological and cosmetic outcomes for patients. [ABSTRACT FROM AUTHOR]

Background: The gut microbiota in patients with inflammatory bowel disease are perturbed in both composition and function. The vaginal microbiome and its role in the reproductive health of women with inflammatory bowel disease is less well described. Objective: We aim to compare the vaginal microbiota of women with inflammatory bowel disease to healthy controls. Methods: Women with inflammatory bowel disease enrolled in a longitudinal cohort study provided self-collected vaginal swabs. Healthy controls underwent provider-collected vaginal swabs at routine gynecologic exams. All participants completed surveys on health history, vulvovaginal symptoms and gastrointestinal symptoms, if applicable. Microbiota were characterized by sequencing the V4 region of the 16S rRNA gene. Associations between patient characteristics and microbial community composition were evaluated by PERMANOVA and Principal Components Analysis. Lactobacillus dominance of the microbial community was compared between groups using chi-square and Poisson regression. Results: The cohort included 54 women with inflammatory bowel disease (25 Ulcerative colitis, 25 Crohn's Disease) and 26 controls. A majority, 72 (90%) were White; 17 (31%) with inflammatory bowel disease and 7 (27%) controls were postmenopausal. The composition of the vaginal microbiota did not vary significantly by diagnosis or severity of inflammatory bowel disease but did vary by menopausal status (p = 0.042). There were no significant differences in Shannon Diversity Index between healthy controls and women with IBD in premenopausal participants. There was no difference in proportion of Lactobacillus dominance according to diagnosis in premenopausal participants. A subgroup of postmenopausal women with Ulcerative colitis showed a significant higher alpha diversity and a lack of Lactobacillus dominance in the vaginal microbiome. Conclusions: Menopausal status had a larger impact on vaginal microbial communities than inflammatory bowel disease diagnosis or severity. [ABSTRACT FROM AUTHOR]

Objective: Assess the accuracy of abstracts in published veterinary ophthalmology articles. Procedures: Abstracts and contents of 204 original research articles in veterinary ophthalmology published in seven peer‐reviewed journals between 2016–2020 were reviewed. Abstracts were considered inconsistent if they contained data that were either missing from or inconsistent with corresponding data in the article's body. Each abstract was graded between 0 (inaccurate) to 3 (accurate), and each inconsistency was subjectively classified as minor or major. The influence of selected variables was assessed: journal, impact factor, year of publication, number of words in abstract, study type (prospective/retrospective), and characteristics of the corresponding author [institution (academia/private practice), country of domicile (native/non‐native English), number of publications]. Results: Most abstracts were accurate, with 1%, 4%, 9% and 86% receiving a score of 0, 1, 2 and 3, respectively. When detected, most inconsistencies were considered minor (77%). Although not statistically significant (p ≥.130), the proportion of articles with a perfect score (=3) was higher in prospective (88%) vs. retrospective (81%) studies, academia (88%) vs. private practice (78%), and studies from corresponding authors domiciled in English (89%) vs. non‐English (83%) speaking countries. A significant but very weak (r = −0.15 to −0.19; p ≤.034) negative correlation was found between accuracy score and number of words, as well as 1‐year and 5‐year impact factors. Conclusions: Although relatively uncommon, data in abstracts that are inconsistent or missing from the article's body do occur in veterinary ophthalmology articles, and could adversely influence a reader's interpretation of study findings. [ABSTRACT FROM AUTHOR]

The ribosome is one of the largest complexes in the cell. Adding to its complexity are more than 200 RNA modification sites present on ribosomal RNAs (rRNAs) in a single human ribosome. These modifications occur in functionally important regions of the rRNA molecule, and they are vital for ribosome function and proper gene expression. Until recent technological advancements, the study of rRNA modifications and their profiles has been extremely laborious, leaving many questions unanswered. Small nucleolar RNAs (snoRNAs) are non-coding RNAs that facilitate and dictate the specificity of rRNA modification deposition, making them an attractive target for ribosome modulation. Here, we propose that through the mapping of rRNA modification profiles, we can identify cell-specific modifications with high therapeutic potential. We also describe the challenges of achieving the targeting specificity needed to implement snoRNAs as therapeutic targets in cancers. [ABSTRACT FROM AUTHOR]

Background: Tirzepatide, a once-weekly glucose-dependent insulinotropic polypeptide/ glucagon-like peptide-1 receptor agonist, is approved in the United States, Europe and Japan for the treatment of type 2 diabetes. Across the SURPASS-1 to -5 clinical studies, tirzepatide 5, 10 and 15 mg demonstrated significant improvements in glycated haemoglobin A1c (HbA1c) (− 1.9 to − 2.6%), body weight (− 6.6 to − 13.9%) and systolic blood pressure (SBP) (− 2.8 to − 12.6 mmHg) at the end of study treatment. Methods: Post-hoc mediation analyses were conducted to evaluate weight-loss dependent and weight-loss independent effects of tirzepatide on SBP reductions across the 5 SURPASS studies. The safety population (all randomized patients who took at least 1 dose of study drug) of each study was analyzed. Additional analyses were conducted at individual study level or pooled across 5 SURPASS trials. Results: The difference in mean SBP change from baseline at 40 weeks (total effect) between the tirzepatide and comparator groups was − 1.3 to − 5.1 mmHg (tirzepatide 5 mg), − 1.7 to − 6.5 mmHg (tirzepatide 10 mg) and − 3.1 to − 11.5 mmHg (tirzepatide 15 mg). These SBP reductions were primarily mediated through weight loss, with different degrees of contributions from weight-loss independent effects across the different trials. In the SURPASS-4 study, which enrolled patients with established cardiovascular disease, weight-loss independent effects explained 33% to 57% of difference in SBP change between tirzepatide and insulin glargine groups. In a pooled analysis of the SURPASS-1 to -5 studies, there was a significant (p < 0.001) but weak correlation (r = 0.18 to 0.22) between change in body weight and SBP. Reductions in SBP with tirzepatide were not dependent on concomitant antihypertensive medications at baseline as similar reductions were observed whether participants were receiving them or not (interaction p = 0.77). The largest SBP reductions were observed in the highest baseline category (> 140 mmHg), while those in the first quartile of baseline SBP category (< 122 mmHg) observed no further decrease in SBP. Conclusions: Tirzepatide-induced SBP reduction was primarily mediated through weight loss, with different degrees of contributions from weight-loss independent effects across the different trials. SBP reduction was not dependent on antihypertensive medication use but dependent on baseline SBP value, alleviating theoretical concerns of hypotension. [ABSTRACT FROM AUTHOR]

Simple Summary: Although progress has been made in the treatment and survival of patients with a range of malignancies, the prognosis for patients harboring metastatic osteosarcoma (bone cancer) remains dismal due to the limited therapeutic options available. Endothelial progenitor cells (EPCs) mediate the angiogenic (blood vessel formation) switch in several cancers. Spatial proximity between EPCs and osteosarcoma in the bone led to the hypothesis that EPCs-osteosarcoma interactions may possibly promote osteosarcoma (OS) progression and aggressiveness. In the current paper, we demonstrate the non-physical role that EPCs play in OS migration and invasion, along with deciphering a potential underlying molecular mechanism. Our findings may pave the way toward the development of new EPCs-targeted therapies to inhibit OS metastasis and hence enhance the therapeutic efficacy of this devastating bone cancer. Background: Osteosarcoma (OS) mortality is attributed to lung metastases. Endothelial progenitor cells (EPCs) mediate the angiogenic switch in several cancers. The spatial proximity between EPCs and OS in the bone led to the hypothesis that EPCs-osteosarcoma interactions may possibly promote OS progression and aggressiveness. Methods: A PI3K inhibitor, Bevacizumab (an anti-VEGF-A antibody), and an anti-FGF2 antibody were added to the EPCs' conditioned medium (EPC-CM), and their impacts on OS cell (U2-OS and 143B) proliferation, migration, invasion, MMP9 expression, and AKT phosphorylation were determined. The autocrine role of VEGF-A was assessed using Bevacizumab treatment and VEGF-A silencing in OS cells. Toward this end, an orthotopic mouse OS model was established. Mouse and human tumors were immunolabeled with antibodies to the abovementioned factors. Results: EPC-CM enhanced osteosarcoma MMP9 expression, invasiveness, and migration via the PI3K/AKT pathway. The addition of Bevacizumab and an anti-FGF2 antibody to the EPC-CM diminished OS cell migration. The autocrine role of VEGF-A was assessed using Bevacizumab and VEGF-A silencing in OS cells, resulting in decreased AKT phosphorylation and, consequently, diminished invasiveness and migration. Consistently, OS xenografts in mice displayed high VEGF-A and FGF2 levels. Remarkably, lung metastasis specimens derived from OS patients exhibited marked immunolabeling of CD31, VEGF-A, and FGF2. Conclusions: EPCs promote OS progression not only by physically incorporating into blood vessels, but also by secreting cytokines, which act via paracrine signaling. EPCs induced in vitro MMP9 overexpression, invasion, and migration. Additional animal studies are warranted to further expand these results. These findings may pave the way toward the development of novel EPCs-targeted therapeutics aimed at blocking OS metastasis. [ABSTRACT FROM AUTHOR]

Aminoacyl tRNA synthetases (aaRSs) are a well-studied family of enzymes with a canonical role in charging tRNAs with a specific amino acid. These proteins appear to also have non-canonical roles, including post-transcriptional regulation of mRNA expression. Many aaRSs were found to bind mRNAs and regulate their translation into proteins. However, the mRNA targets, mechanism of interaction, and regulatory consequences of this binding are not fully resolved. Here, we focused on yeast cytosolic threonine tRNA synthetase (ThrRS) to decipher its impact on mRNA binding. Affinity purification of ThrRS with its associated mRNAs followed by transcriptome analysis revealed a preference for mRNAs encoding RNA polymerase subunits. An mRNA that was significantly bound compared to all others was the mRNA encoding RPC10, a small subunit of RNA polymerase III. Structural modeling suggested that this mRNA includes a stem-loop element that is similar to the anti-codon stem loop (ASL) structure of ThrRS cognate tRNA (tRNAThr). We introduced random mutations within this element and found that almost every change from the normal sequence leads to reduced binding by ThrRS. Furthermore, point mutations at six key positions that abolish the predicted ASL-like structure showed a significant decrease in ThrRS binding with a decrease in RPC10 protein levels. Concomitantly, tRNAThr levels were reduced in the mutated strain. These data suggest a novel regulatory mechanism in which cellular tRNA levels are regulated through a mimicking element within an RNA polymerase III subunit in a manner that involves the tRNA cognate aaRS. [ABSTRACT FROM AUTHOR]

Previous studies demonstrated that dysfunctional yeast proteasomes accumulate in the insoluble protein deposit (IPOD), described as the final deposition site for amyloidogenic insoluble proteins and that this compartment also mediates proteasome ubiquitination, a prerequisite for their targeted autophagy (proteaphagy). Here, we examined the solubility state of proteasomes subjected to autophagy as a result of their inactivation, or under nutrient starvation. In both cases, only soluble proteasomes could serve as a substrate to autophagy, suggesting a modified model whereby substrates for proteaphagy are dysfunctional proteasomes in their near-native soluble state, and not as previously believed, those sequestered at the IPOD. Furthermore, the insoluble fraction accumulating in the IPOD represents an alternative pathway, enabling the removal of inactive proteasomes that escaped proteaphagy when the system became saturated. Altogether, we suggest that the relocalization of proteasomes to soluble aggregates represents a general stage of proteasome recycling through autophagy. [ABSTRACT FROM AUTHOR]

Background: As well known to any photographer, controlling the "field of view" offers an extremely powerful mechanism by which to adjust target acquisition. Only a few natural sensory systems can actively control their field of view (e.g., dolphins, whales, and bats). Bats are known for their active sensing abilities and modify their echolocation signals by actively controlling their spectral and temporal characteristics. Less is known about bats' ability to actively modify their bio-sonar field of view. Results: We show that Pipistrellus kuhlii bats rapidly narrow their sensory field of view (i.e., their bio-sonar beam) when scanning a target. On-target vertical sonar beams were twofold narrower than off-target beams. Continuous measurements of the mouth gape of free-flying bats revealed that they control their bio-sonar beam by a ~3.6 mm widening of their mouth gape: namely, bats open their mouth to narrow the beam and vice versa. Conclusions: Bats actively and rapidly control their echolocation vertical beam width by modifying their mouth gape. We hypothesize that narrowing their vertical beam narrows the zone of ensonification when estimating the elevation of a target. In other words, bats open their mouth to improve sensory localization. [ABSTRACT FROM AUTHOR]

Ubiquitination is a critical type of post-translational modification in eukaryotic cells. It is involved in regulating nearly all cellular processes in the cytosol and nucleus. Mitochondria, known as the metabolism heart of the cell, are organelles that evolved from bacteria. Using the subcellular compartment-dependent α-complementation, we detect multiple components of ubiquitination machinery as being eclipsed distributed to yeast mitochondria. Ubiquitin conjugates and mono-ubiquitin can be detected in lysates of isolated mitochondria from cells expressing HA-Ub and treated with trypsin. By expressing MTS (mitochondrial targeting sequence) targeted HA-tagged ubiquitin, we demonstrate that certain ubiquitination events specifically occur in yeast mitochondria and are independent of proteasome activity. Importantly, we show that the E2 Rad6 affects the pattern of protein ubiquitination in mitochondria and provides an in vivo assay for its activity in the matrix of the organelle. This study shows that ubiquitination occurs in the mitochondrial matrix by eclipsed targeted components of the ubiquitin machinery, providing a new perspective on mitochondrial and ubiquitination research. [ABSTRACT FROM AUTHOR]

A Phyllodes Tumour (PT) is an uncommon fibroepithelial lesion, with three histological grades - benign, borderline and malignant. PTs cause significant challenges in diagnosis, management and prognostication. Recent publications have clarified the definitions and prognostication of PTs. Contemporary data currently challenge international guidelines on PT management. We performed an in-depth literature review to develop a best-practice management algorithm for PTs. Diagnostic recommendations are that neither current imaging techniques, nor fine-needle biopsies, can reliably diagnose a PT. Core needle biopsy is the optimal diagnostic technique. Indeterminate or suspicious lesions are recommended to undergo an excisional biopsy due to the inherently heterogeneous nature of PTs. Management guidelines are that benign PTs should be completely excised, although an involved margin is acceptable in select situations. Borderline PTs should have a clear margin on excision due to their higher risk of recurrence, as well as the potential for a recurrence to progress to a malignant PT. In malignant PTs, a margin of 3 mm is acceptable as there is no reduction in recurrence risk if margins are >3 mm. Routine axillary surgery is not indicated in PTs, with axillary surgery only indicated in a histologically-confirmed positive axilla. Adjuvant treatment recommendations are that borderline and malignant PTs should be discussed at MDT, with radiotherapy considered in both. Chemotherapy should be discussed in malignant PT patients. In summary, we have developed an up-to-date simple algorithm to guide the surgeon's management of patients diagnosed with PTs and reduce excessive surgery. [ABSTRACT FROM AUTHOR]

Objective: In patients with moderate to severe albuminuric kidney disease, sodium-glucose cotransporter 2 inhibitors reduce the risk of kidney disease progression. These post hoc analyses assess the effects of dapagliflozin on kidney function decline in patients with type 2 diabetes (T2D), focusing on populations with low kidney risk.Research Design and Methods: In the Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58 (DECLARE-TIMI 58) trial, patients with T2D at high cardiovascular risk were randomly assigned to dapagliflozin versus placebo. Outcomes were analyzed by treatment arms, overall, and by Kidney Disease: Improving Global Outcomes (KDIGO) risk categories. The prespecified kidney-specific composite outcome was a sustained decline ≥40% in the estimated glomerular filtration rate (eGFR) to <60 mL/min/1.73 m2, end-stage kidney disease, and kidney-related death. Other outcomes included incidence of categorical eGFR decline of different thresholds and chronic (6 month to 4 year) or total (baseline to 4 year) eGFR slopes.Results: Most participants were in the low-moderate KDIGO risk categories (n = 15,201 [90.3%]). The hazard for the kidney-specific composite outcome was lower with dapagliflozin across all KDIGO risk categories (P-interaction = 0.97), including those at low risk (hazard ratio [HR] 0.54, 95% CI 0.38-0.77). Risks for categorical eGFR reductions (≥57% [in those with baseline eGFR ≥60 mL/min/1.73 m2], ≥50%, ≥40%, and ≥30%) were lower with dapagliflozin (HRs 0.52, 0.57, 0.55, and 0.70, respectively; P < 0.05). Slopes of eGFR decline favored dapagliflozin across KDIGO risk categories, including the low KDIGO risk (between-arm differences of 0.87 [chronic] and 0.55 [total] mL/min/1.73 m2/year; P < 0.0001).Conclusions: Dapagliflozin mitigated kidney function decline in patients with T2D at high cardiovascular risk, including those with low KDIGO risk, suggesting a role of dapagliflozin in the early prevention of diabetic kidney disease. [ABSTRACT FROM AUTHOR]

Background: Exploratory analysis to determine the effect of semaglutide versus comparators on high-sensitivity C-reactive protein (hsCRP) in subjects with type 2 diabetes. Methods: Trials of once-weekly subcutaneous (SUSTAIN 3) and once-daily oral (PIONEER 1, 2, 5) semaglutide with hsCRP data were analyzed. Subjects with type 2 diabetes (N = 2482) received semaglutide (n = 1328) or comparators (placebo, n = 339; exenatide extended-release, n = 405; empagliflozin, n = 410). hsCRP ratio to baseline at end-of-treatment was analyzed overall, by clinical cutoff (< 1.0, ≥ 1.0 to ≤ 3.0, or > 3.0 mg/L), by tertile, and by estimated glomerular filtration rate in PIONEER 5 (a trial which was conducted in a population with type 2 diabetes and chronic kidney disease [CKD]). Mediation analyses assessed the effect of change in glycated hemoglobin (HbA1c) and/or change in body weight (BW) on hsCRP reductions. Results: Geometric mean baseline hsCRP was similar across trials (range 2.7–3.0 mg/L). Semaglutide reduced hsCRP levels by clinical cutoffs and tertiles from baseline to end-of-treatment in all trials versus comparators (estimated treatment ratios [ETRs] versus comparators: 0.70–0.76; p < 0.01) except versus placebo in PIONEER 5 (ETR [95% CI]: 0.83 [0.67–1.03]; p > 0.05). The effect of semaglutide on hsCRP was partially mediated (20.6–61.8%) by change in HbA1c and BW. Conclusions: Semaglutide reduced hsCRP ratios-to-baseline versus comparators in subjects with type 2 diabetes (not significant with CKD). This effect was partially mediated via reductions in HbA1c and BW and potentially by a direct effect of semaglutide. Semaglutide appears to have an anti-inflammatory effect, which is being further investigated in ongoing trials. Trial registrations: ClinicalTrials.gov identifiers: NCT01885208 (first registered June 2013), NCT02906930 (first registered September 2016), NCT02863328 (first registered August 2016), NCT02827708 (first registered July 2016). [ABSTRACT FROM AUTHOR]

Purpose: Tuberous sclerosis complex (TSC) is an inherited neurocutaneous disorder. Fifty percent of patients with TSC will develop retinal astrocytic hamartoma (RAH). The mammalian target of rapamycin (mTOR) inhibitors interferes with the pathological mechanisms of TSC. Treatment of RAH with mTOR inhibitors has been described in only a few isolated case reports. The purpose of this study was to assess the effect of mTOR inhibitors on RAH in a small cohort of patients. Methods: The medical records of all consecutive patients with ocular manifestations of TSC that were treated with mTOR inhibitors at the Sheba Medical Center from January 2014 to December 2018 were retrospectively reviewed. Data collection included demographics, medical history, ocular presentation, ocular treatment, and treatment outcome. Tumor size was assessed by a masked observer, before and after treatment. Lesion measurements were made with Heidelberg SD-OCT (HRA + OCT SPECTRALIS), and fundus photos were taken with RetCam3® (Natus, USA) and analyzed by "ImageJ" software. Results: Eleven patients with tuberous sclerosis and astrocytic hamartoma were treated with mTOR inhibitors in the study period. Of them, 6 children (11 eyes, 20 tumors) had proper imaging of tumor size before and after treatment. The analysis included these 11 eyes. All six patients had non-ocular manifestations of TSC, including dermatologic (n = 5), neurologic (n = 5), and renal (n = 3) involvement. Ocular involvement included in five eyes (45%) tumors near the optic disc and in four eyes (37%) foveal tumors. The mean follow-up duration was 2.15 ± 1.4 years (range 10 months to 4.5 years). The average tumor base reduction in the treated group was 17.8% ± 15.9. The average maximal thickness at baseline was 414 ± 174 μm (range 152–686 μm). There was a 14% ± 7.1 reduction after treatment. None of the tumors showed evidence of growth at the final follow-up. Conclusion: The findings of this study suggest that mTOR inhibitors can reduce tumor size and that they can be considered as an optional treatment in certain conditions. This preliminary report is the first to quantitatively assess pre- and posttreatment tumor size, in young patients. [ABSTRACT FROM AUTHOR]

One of the most difficult sensorimotor behaviors exhibited by flying animals is the ability to track another flying animal based on its sound emissions. From insects to mammals, animals display this ability in order to localize and track conspecifics, mate or prey. The pursuing individual must overcome multiple non-trivial challenges including the detection of the sounds emitted by the target, matching the input received by its (mostly) two sensors, localizing the direction of the sound target in real time and then pursuing it. All this has to be done rapidly as the target is constantly moving. In this project, we set to mimic this ability using a physical bio-mimetic autonomous drone. We equipped a miniature commercial drone with our in-house 2D sound localization electronic circuit which uses two microphones (mimicking biological ears) to localize sound signals in real-time and steer the drone in the horizontal plane accordingly. We focus on bat signals because bats are known to eavesdrop on conspecifics and follow them, but our approach could be generalized to other biological signals and other man-made signals. Using two different experiments, we show that our fully autonomous aviator can track the position of a moving sound emitting target and pursue it in real-time. Building an actual robotic-agent, forced us to deal with real-life difficulties which also challenge animals. We thus discuss the similarities and differences between our and the biological approach. Author summary: Animals solve problems that are considered very difficult for human engineers. In this study, we aimed to mimic animals' ability to localize and track a moving sound source in real time. We do so using a bio-inspired approach by developing a miniature electronic circuit with two ear-like microphones and a micro-processor that is placed on a miniature drone. The circuit detects ultrasonic signals that are typical for echolocating bats and it uses its two 'ears' to estimate the azimuth of the sound source and to steer the drone accordingly. The system is completely autonomous without external human intervention. We focus on bat signals as a proof of concept, but we can alter the electronics to suit other biological signals. Future research will include groups of multiple drones moving together based on acoustic signals as bats and some birds can do in nature. [ABSTRACT FROM AUTHOR]

Attachment personality theory provides an interpersonal and relational perspective of human functioning. The current research examines the role of attachment diversity within the theoretical framework of the categorization‐elaboration model (CEM). We hypothesized that teams comprised of diverse attachment orientations would be beneficial to team performance. Specifically, diverse anxiety teams may have members who would be more vigilant to team threats, whereas diverse avoidance teams could comprise individuals who may be more goal‐oriented. Also, we examined whether perceived organizational support (POS) moderates the association between attachment diversity and team performance. The study was conducted at a large private communications company. Data were obtained for 44 sales teams (N = 404). Supplementing this data, the company's administrative systems provided team performance ratings derived from team achievements. Findings indicated that the relationship between anxiety diversity and performance were stronger under lower POS levels than under higher POS levels. Interpersonal avoidance strategies seem to be less productive in avoidance diversity teams under lower levels of POS. However, higher POS levels buffered the negative impact of avoidance diversity on team performance. [ABSTRACT FROM AUTHOR]

Recent studies underscore RNA modifications as a novel mechanism to coordinate expression and function of different genes. While modifications on the sugar or base moieties of tRNA are well known, their roles in mRNA regulation are only starting to emerge. Interestingly, some modifications are present in both tRNA and mRNA, and here we discuss the functional significance of these common features. We describe key modifications that are present in both RNA types, elaborate on proteins that interact with them, and indicate recent works that identify roles in communicating tRNA processes and mRNA regulation. We propose that as tools are developed, the shortlist of features that are common between types of RNA will greatly expand and proteins that interact with them will be identified. In conclusion, the presence of the same modification in both RNA types provides an intersect between tRNA processes and mRNA regulation and implies a novel mechanism for connecting diverse cellular processes. [ABSTRACT FROM AUTHOR]

Objective: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) improve albuminuria in patients with high cardiorenal risk. We report albuminuria change in the Dapagliflozin Effect on Cardiovascular Events (DECLARE-TIMI 58) cardiovascular outcome trial, which included populations with lower cardiorenal risk.Research Design and Methods: DECLARE-TIMI 58 randomized 17,160 patients with type 2 diabetes, creatinine clearance >60 mL/min, and either atherosclerotic cardiovascular disease (CVD; 40.6%) or risk-factors for CVD (59.4%) to dapagliflozin or placebo. Urinary albumin-to-creatinine ratio (UACR) was tested at baseline, 6 months, 12 months, and yearly thereafter. The change in UACR over time was measured as a continuous and categorical variable (≤15, >15 to <30, ≥30 to ≤300, and >300 mg/g) by treatment arm. The composite cardiorenal outcome was a ≥40% sustained decline in the estimated glomerular filtration rate (eGFR) to <60 mL/min/1.73 m2, end-stage kidney disease, and cardiovascular or renal death; specific renal outcome included all except cardiovascular death.Results: Baseline UACR was available for 16,843 (98.15%) participants: 9,067 (53.83%) with ≤15 mg/g, 2,577 (15.30%) with >15 to <30 mg/g, 4,030 (23.93%) with 30-300 mg/g, and 1,169 (6.94%) with >300 mg/g. Measured as a continuous variable, UACR improved from baseline to 4.0 years with dapagliflozin, compared with placebo, across all UACR and eGFR categories (all P < 0.0001). Sustained confirmed ≥1 category improvement in UACR was more common in dapagliflozin versus placebo (hazard ratio 1.45 [95% CI 1.35-1.56], P < 0.0001). Cardiorenal outcome was reduced with dapagliflozin for subgroups of UACR ≥30 mg/g (P < 0.0125, Pinteraction = 0.033), and the renal-specific outcome was reduced for all UACR subgroups (P < 0.05, Pinteraction = 0.480).Conclusions: In DECLARE-TIMI 58, dapagliflozin demonstrated a favorable effect on UACR and renal-specific outcome across baseline UACR categories, including patients with normal albumin excretion. The results suggest a role for SGLT2i also in the primary prevention of diabetic kidney disease. [ABSTRACT FROM AUTHOR]

Objective: Amongst the many intricacies engendered by the COVID-19 pandemic was the posed risk of exposure to SARS-COV2 infections among workers and the need to evaluate fitness for work (FFW) of individuals in high exposure groups or those with background morbidity. A designated task force of the Israeli Association of Occupational Medicine has evaluated the relevant literature and published guidelines concerning medical work restrictions for employees in high-risk occupations during the epidemic of novel COVID-19. Methods: The study depicts a case series of 17 FFW evaluations performed in Maccabi Health Services occupational clinics using the guidelines formulated by the Israeli Occupational Medicine Association. Results: 17 patients, mainly healthcare workers, whose major health hazards were immunodeficiency, respiratory diseases and pregnancy, were assessed in this case series. We present the essential parameters of these FFW evaluations and discuss decision-making in selected cases. Conclusions: Applying guidelines in various work settings and health risk levels during the SARS-CoV-2 pandemic allows for both patients' health preservation and efficient workforce deployment. [ABSTRACT FROM AUTHOR]

Background: There is a paucity of global data on cardiovascular disease (CVD) prevalence in people with type 2 diabetes (T2D). The primary objective of the CAPTURE study was to estimate the prevalence of established CVD and its management in adults with T2D across 13 countries from five continents. Additional objectives were to further characterize the study sample regarding demographics, clinical parameters and medication usage, with particular reference to blood glucose-lowering agents (GLAs: glucagon-like peptide-1 receptor agonists and sodium-glucose co-transporter-2 inhibitors) with demonstrated cardiovascular benefit in randomized intervention trials. Methods: Data were collected from adults with T2D managed in primary or specialist care in Australia, China, Japan, Czech Republic, France, Hungary, Italy, Argentina, Brazil, Mexico, Israel, Kingdom of Saudi Arabia, and Turkey in 2019, using standardized methodology. CVD prevalence, weighted by diabetes prevalence in each country, was estimated for the overall CAPTURE sample and participating countries. Country-specific odds ratios for CVD prevalence were further adjusted for relevant demographic and clinical parameters. Results: The overall CAPTURE sample included 9823 adults with T2D (n = 4502 from primary care; n = 5321 from specialist care). The overall CAPTURE sample had median (interquartile range) diabetes duration 10.7 years (5.6–17.9 years) and glycated hemoglobin 7.3% (6.6–8.4%) [56 mmol/mol (49–68 mmol/mol)]. Overall weighted CVD and atherosclerotic CVD prevalence estimates were 34.8% (95% confidence interval [CI] 32.7–36.8) and 31.8% (95% CI 29.7–33.8%), respectively. Age, gender, and clinical parameters accounted for some of the between-country variation in CVD prevalence. GLAs with demonstrated cardiovascular benefit were used by 21.9% of participants, which was similar in participants with and without CVD: 21.5% and 22.2%, respectively. Conclusions: In 2019, approximately one in three adults with T2D in CAPTURE had diagnosed CVD. The low use of GLAs with demonstrated cardiovascular benefit even in participants with established CVD suggested that most were not managed according to contemporary diabetes and cardiology guidelines. Study registration NCT03786406 (registered on December 20, 2018), NCT03811288 (registered on January 18, 2019). [ABSTRACT FROM AUTHOR]

Purpose: Review octopus ocular anatomy and describe the histopathologic findings in three octopuses diagnosed with phakitis and retinitis. Animals: Two common octopuses (Octopus vulgaris) and one giant Pacific octopus (Enteroctopus dofleini) with a history of ophthalmic disease. Methods: A literature search was performed for the ocular anatomy section. Both eyes from all three octopuses, and two control eyes, were submitted for histopathologic evaluation. Hematoxylin and eosin stain was used for standard histopathologic evaluation; GMS stain was used to screen for fungi, gram stain for bacteria; and Fite's acid fast stain for acid fast bacteria. Results: Anatomically, the anterior chamber of the octopus has direct contact with ambient water due to an opening in the dorsal aspect of a pseudocornea. The octopus lens is divided into anterior and posterior segments. The anterior half is exposed to the environment through the opening into the anterior chamber. Neither part of the lens has a lens capsule. The retina is everted, unlike the inverted vertebrate retina, and consists of just two layers. Histopathology revealed inflammatory phakitis and retinitis of varying severity in all six eyes of the study animals. No intraocular infectious organisms were recognized but one common octopus eye had clusters of coccidian parasites, identified as Aggregata sp., in extraocular tissues and blood vessels. Conclusion: We describe inflammatory phakitis and retinitis in two species of octopuses. The underlying cause for the severe intraocular response may be direct intraocular infection, water quality, an ocular manifestation of a systemic disease, or natural senescence. [ABSTRACT FROM AUTHOR]

Background: Recent years have seen significant exploration into the potential link between allergic contact dermatitis and atopic dermatitis, yielding contradictory findings. Methods: A retrospective cohort analysis of children aged 2 to 18 who underwent patch testing at the pediatric dermatology clinic at a tertiary medical center in Israel was conducted. Results: Overall, 367 patients were included in the study, 31.6% of whom were diagnosed with atopic dermatitis. 160 children (43.6%) exhibited a positive reaction to at least one compound in the European baseline series. There was no statistically significant difference in reactivity between children with atopic dermatitis and those without (P = 0.848). Sub‐analyses based on ethnicity, gender, and age did not reveal significant differences in overall European baseline series reactivity (P = 0.612, P = 0.446, P = 0.488, respectively). Sensitivity was notably higher when patch readings were conducted 72 h after application compared to 48 h [0.95 (CI: 0.91–0.97) vs. 0.60 (CI: 0.55–0.66)]. Conclusions: Patch testing is imperative for suspected cases of allergic contact dermatitis in all children, regardless of their atopic background. Further research is warranted to potentially replace the traditional 48‐h reading with a single 72‐h reading in future guidelines, contributing to enhanced efficiency and cost‐effectiveness in clinical practice. [ABSTRACT FROM AUTHOR]

During the last decade we experienced a surge in the number of glucose lowering agents that can be used to treat patients with type 2 diabetes. Especially important are the discoveries that sodium glucose co-transporter type 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA) improve patients' cardiovascular and renal outcomes. Accordingly, various medical associations have updated their guidelines for the treatment of diabetes in this new era. Though not agreeing on every issue, these position-statements generally share a detailed and often complex workflow that may be too complicated for the busy and overworked primary care setting, where the majority of patients with type 2 diabetes are managed in many countries. Other guidelines, generally those from the cardiology associations focus primarily on the population of patients with high risk for or pre-existing cardiovascular disease, which represent only the minority of patients with type 2 diabetes. We believe that we should re-define SGLT2i and GLP-1 RA as diabetes/disease modifying drugs (DMDs) given the recent evidence of their cardiovascular and renal benefits. Based on this definition we have designed a SIMPLE approach in order to assist primary care teams in selecting the most appropriate therapy for their patients. We believe that most subjects newly diagnosed with type 2 diabetes should initiate early combination therapy with metformin and a prognosis changing DMD. The decision whether to use GLP-1 RA or SGLT2i should be made based on specific patient's risk factors and preferences. Importantly, DMDs are known to have a generally safe side-effect profile, with lower risk for hypoglycemia and weight gain, further promoting their wider usage. Early combination therapy with DMDs may improve the multiple pathophysiological abnormalities responsible for type 2 diabetes and its complications, thus resulting in the greatest long term benefits. [ABSTRACT FROM AUTHOR]

The opportunistic human pathogen Bacillus cereus controls the expression of key infection-promoting phenotypes using bacterial quorum sensing (QS). QS signal transduction within the species is controlled by an autoinducing peptide, PapR 7 , and its cognate receptor, PlcR, indicating that the PlcR:PapR interface is a prime target for QS inhibitor development. The C-terminal region of the peptide (PapR 7 ; ADLPFEF) has been successfully employed as a scaffold to develop potent QS modulators. Despite the noted importance of the C-terminal carboxylate and amide protons in crystallographic data, their role in QS activity has yet to be explored. In this study, an N-methyl scan of PapR 7 was conducted in conjunction with a C-terminal modification of previously identified B. cereus QS inhibitors. The results indicate that the amide proton at Glu6 and the C-terminal carboxylate are important for effective QS inhibition of the PlcR regulon. Through β-galactosidase and hemolysis assays, a series of QS inhibitors were discovered, including several capable of inhibiting QS with nanomolar potency. These inhibitors, along with the structure–activity data reported, will serve as valuable tools for disrupting the B. cereus QS pathway towards developing novel anti-infective strategies. [ABSTRACT FROM AUTHOR]

Our ability to compare sensory stimuli is a fundamental cognitive function, which is known to be affected by two biases: choice bias, which reflects a preference for a given response, and contraction bias, which reflects a tendency to perceive stimuli as similar to previous ones. To test whether both reflect supervised processes, we designed feedback protocols aimed to modify them and tested them in human participants. Choice bias was readily modifiable. However, contraction bias was not. To compare these results to those predicted from an optimal supervised process, we studied a noise-matched optimal linear discriminator (Perceptron). In this model, both biases were substantially modified, indicating that the “resilience” of contraction bias to feedback does not maximize performance. These results suggest that perceptual discrimination is a hierarchical, two-stage process. In the first, stimulus statistics are learned and integrated with representations in an unsupervised process that is impenetrable to external feedback. In the second, a binary judgment, learned in a supervised way, is applied to the combined percept. [ABSTRACT FROM AUTHOR]

Objective: To compare short-term fertility rates after medical and surgical management of early miscarriage.Design: Observational cohort study.Setting: Academic tertiary-care medical center.Patient(s): A total of 203 patients were enrolled between June 2017 and May 2018, comprising 106 surgical evacuations and 97 medical evacuations.Intervention(s): Either surgical or medical evacuation of the uterine cavity.Main Outcome Measure(s): Conception rates 6 months after miscarriage.Result(s): Conception rates 6 months after miscarriage among women who had attempted to become pregnant were similar between the medically and surgically evacuated groups (68.0% vs. 65.1%). There were no significant differences in background characteristics between the groups, apart from younger age and earlier gestational age among the medically treated group. There was no difference in the proportion of women using assisted reproductive technologies between the medically and surgically managed groups (15.5% vs. 12.6%, respectively). The median time-to-conception was 4 ± 2 months in both groups. Cumulative pregnancy rate 12 months after pregnancy loss, live birth rate, and repeat miscarriage rate also were similar between groups.Conclusion(s): Modality of uterine evacuation after early miscarriage does not affect short-term fertility outcomes. [ABSTRACT FROM AUTHOR]

Aim: To assess cardiorenal outcomes by baseline urinary albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) in the contemporary LEADER cohort. Materials and methods: LEADER was a multinational, double-blind trial. Patients with type 2 diabetes and high cardiovascular (CV) risk were randomized 1:1 to the glucagon-like peptide-1 analogue liraglutide (≤1.8 mg daily; n = 4668) or placebo (n = 4672) plus standard care and followed for 3.5 to 5 years. Primary composite outcomes were time to first non-fatal myocardial infarction, non-fatal stroke or CV death. Post hoc Cox regression analyses of outcomes by baseline UACR and eGFR subgroups were conducted with adjustment for baseline variables. Results: In the LEADER population, 1598 (17.5%), 2917 (31.9%), 1200 (13.1%), 1611 (17.6%), 845 (9.2%) and 966 (10.6%) had UACR = 0, >0 to <15, 15 to <30, 30 to <100, 100 to <300 and ≥300 mg/g, respectively. Increasing UACR and decreasing eGFR were linked with higher risks of the primary outcome, heart failure hospitalization, a composite renal outcome and death (P-values for the Cochran-Armitage test for trends were all <.0001). Across UACR and eGFR subgroups, risks of cardiorenal events and death were generally lower or similar with liraglutide versus placebo. Conclusions: In a contemporary type 2 diabetes population, increasing baseline UACR and declining eGFR were linked with higher risks of cardiorenal events and death. [ABSTRACT FROM AUTHOR]

Objectives: In a previous rat model, MRONJ occurrence was 50%. Our aim was to investigate the potential of endothelial progenitor cells (EPCs) to improve fibroblasts function and prevent MRONJ. Methods: Human gingival fibroblasts were cultured with EPC‐conditioned media (EPC‐CM); endothelial growth media (EGM‐2) or DMEM followed by incubation with 10 µM zoledronic (ZOL) and dexamethasone (DEX). Cell proliferation and migration were assessed by XTT and scratch wound healing assays. In vivo, ten Lewis rats were treated weekly with ZOL and DEX for 11 weeks. After a week, EPCs or EGM‐2 were injected to the gingiva around the molars. At 3 weeks, bilateral molars were extracted. After 8 weeks, wound healing was assessed, and serum VEGF and blood vessels were quantified. Results: ZOL/DEX significantly reduced fibroblasts proliferation and wound healing. Treatment with EPC‐CM before ZOL/DEX improved cell proliferation, and scratch healing (p =.007, p =.023). In vivo, local EPC injection before tooth extraction increased serum VEGF (p =.01) and soft tissue vascularization (p =.05). Normal healing was similar (80%) in EPCs and EGM‐2 groups. Conclusion: EPC rescued fibroblasts from the cytotoxic effect of ZOL/DEX and elevated serum VEGF and vessel density that might reduce MRONJ occurrence to 20% compared to 50% in a similar model. [ABSTRACT FROM AUTHOR]

Background: Several secreted factors have been identified as drivers of cerebral vasculature development and inducers of blood–brain barrier (BBB) differentiation. Vascular endothelial growth factor A (VEGF-A) is central for driving cerebral angiogenesis and Wnt family factors (Wnt7a, Wnt7b and norrin) are central for induction and maintenance of barrier properties. Expressed by developing neural tissue (neuron and glia progenitors), they influence the formation of central nervous system (CNS) vascular networks. Another type of factors are tissue-specific paracrine factors produced by endothelial cells (ECs), also known as 'angiocrine' factors, that provide instructive signals to regulate homeostatic and regenerative processes. Very little is known about CNS angiocrine factors and their role in BBB development. Angiomodulin (AGM) was reported to be expressed by developing vasculature and by pathological tumor vasculature. Here we investigated AGM in the developing CNS and its function as a potential BBB inducer. Methods: We analyzed microarray data to identify potential angiocrine factors specifically expressed at early stages of barrier formation. We then tested AGM expression with immunofluorescence and real-time PCR in various organs during development, post-natal and in adults. Permeability induction with recombinant proteins (Miles assay) was used to test potential interaction of AGM with VEGF-A. Results: Several angiocrine factors are differentially expressed by CNS ECs and AGM is a prominent CNS-specific angiocrine candidate. Contrary to previous reports, we found that AGM protein expression is specific to developing CNS endothelium and not to highly angiogenic developing vasculature in general. In skin vasculature we found that AGM antagonizes VEGF-A-induced vascular hyperpermeability. Finally, CNS AGM expression is not specific to BBB vasculature and AGM is highly expressed in non-BBB choroid-plexus vasculature. Conclusions: We propose AGM as a developmental CNS vascular-specific marker. AGM is not a pan-endothelial marker, nor a general marker for developing angiogenic vasculature. Thus, AGM induction in the developing CNS might be distinct from its induction in pathology. While AGM is able to antagonize VEGF-A-induced vascular hyperpermeability in the skin, its high expression levels in non-BBB CNS vasculature does not support its potential role as a BBB inducer. Further investigation including loss-of-function approaches might elucidate AGM function in the developing CNS. [ABSTRACT FROM AUTHOR]

The yeast S. cerevisiae serves as a model organism for many decades. Numerous molecular tools have been developed throughout the years to engineer its genome. Specifically, homologous recombination protocols allowed gene deletion, replacement and tagging of almost every S. cerevisiae gene, thus enabling mechanistic understanding of various cellular processes. Recently, CRISPR/Cas9-based approaches have been adapted to the yeast system, simplifying the protocols to manipulate this organism. In CRISPR/Cas9 systems, guide-RNA directs a site-specific double-strand DNA cleavage by the Cas9 nuclease. The directed cleavage enhances homologous recombination events, thereby facilitating changes to desired genomic loci. The use of a single vector to express both guide-RNA and Cas9 enzyme may simplify genomic manipulations and was used to introduce double-strand breaks at artificial sites (Anand et al. in Nature 544(7650):377–380, 2017. https://doi.org/10.1038/nature22046) or within selection markers (Ryan et al. in Cold Spring Harbor Protoc, 2014. https://doi.org/10.1101/pdb.prot086827). Here, we generalize this approach to demonstrate its utility in modifying natural genomic loci. We devise vectors to perform common genetic manipulations in S. cerevisiae, including gene deletion, single-base mutations, introduction of site-specific polymorphism and tag insertion. Notably, a vector that efficiently cleaves within GFP was generated, allowing replacing a GFP tag with other sequences. This vector may be of utility for replacing any gene tagged with GFP by a sequence of choice. Importantly, we demonstrate the efficiency of chemically synthesized 80-mer homologous DNA as a substrate for recombination, alleviating the need for PCR steps in the procedure. In all presented applications, high efficiency of the expected gene alteration and no other change in the genomic loci were obtained. Overall, this work expands the repertoire of single-plasmid CRISPR/cas9 approaches and provides a facile alternative to manipulate the yeast genome. [ABSTRACT FROM AUTHOR]

The article discusses the Hebraist political rhetoric of the German national movement in the first two decades of the nineteenth century, focusing on the cult of the 'national god' [Nationalgott] – an extreme manifestation of the national shift in German Christianity. During the first decades of the nineteenth century, preachers and propagandists active in the German principalities adopted a distinctive biblical rhetoric. In the period approaching Napoleon's defeat, a new Christian political rhetoric took shape in Prussia that combined Old Testament ideas of chosenness, New Testament sacrifice mysticism, and the political components of patriotism and nationalism. By examining religious sermons, political tracts and patriotic hymns, I demonstrate how Ernst Moritz Arndt (1769–1860) and others created a novel theological terminology during the Anti-Napoleonic wars – a synthesis between Old Testament images of the fighting God, Gospel-like metaphors of sacrifice, and nationalist political rhetoric. [ABSTRACT FROM AUTHOR]

Objective: Data regarding the effects of sodium-glucose cotransporter 2 inhibitors in the elderly (age ≥65 years) and very elderly (age ≥75 years) are limited.Research Design and Methods: The Dapagliflozin Effect on Cardiovascular Events (DECLARE)-TIMI 58 assessed cardiac and renal outcomes of dapagliflozin versus placebo in patients with type 2 diabetes. Efficacy and safety outcomes were studied within age subgroups for treatment effect and age-based treatment interaction.Results: Of the 17,160 patients, 9,253 were <65 years of age, 6,811 ≥65 to <75 years, and 1,096 ≥75 years. Dapagliflozin reduced the composite of cardiovascular death or hospitalization for heart failure consistently, with a hazard ratio (HR) of 0.88 (95% CI 0.72, 1.07), 0.77 (0.63, 0.94), and 0.94 (0.65, 1.36) in age-groups <65, ≥65 to <75, and ≥75 years, respectively (interaction P value 0.5277). Overall, dapagliflozin did not significantly decrease the rates of major adverse cardiovascular events, with HR 0.93 (95% CI 0.81, 1.08), 0.97 (0.83, 1.13), and 0.84 (0.61, 1.15) in age-groups <65, ≥65 to <75, and ≥75 years, respectively (interaction P value 0.7352). The relative risk reduction for the secondary prespecified cardiorenal composite outcome ranged from 18% to 28% in the different age-groups with no heterogeneity. Major hypoglycemia was less frequent with dapagliflozin versus placebo, with HR 0.97 (95% CI 0.58, 1.64), 0.50 (0.29, 0.84), and 0.68 (0.29, 1.57) in age-groups <65, ≥65 to <75, and ≥75 years, respectively (interaction P value 0.2107). Safety outcomes, including fractures, volume depletion, cancer, urinary tract infections, and amputations were balanced with dapagliflozin versus placebo, and acute kidney injury was reduced, all regardless of age. Genital infections that were serious or led to discontinuation of the study drug and diabetic ketoacidosis were uncommon, yet more frequent with dapagliflozin versus placebo, without heterogeneity (interaction P values 0.1058 and 0.8433, respectively).Conclusions: The overall efficacy and safety of dapagliflozin are consistent regardless of age. [ABSTRACT FROM AUTHOR]

Objective: Our aim was to generate baseline optical coherence tomography (OCT) measurements of retinal thickness in female Beagles and to determine how these are affected by meridian, eccentricity, and age. Methods: Twenty‐three female Beagles, including six puppies (<6 months old), six mature (1.8‐8.2 years old), and 11 elderly dogs (>11 years old) were studied. Both retinas of each dog were scanned (in 4 principal meridians) using the Heidelberg Spectralis following ophthalmic examination, refraction, and sedation. In each eye and each meridian, total retinal, outer retinal, and nerve fiber layer (NFL) thickness were measured from the disc rim up to 6 mm peripherally. Results: The canine retina is thickest dorsally and thinnest ventrally. Total retinal, outer retinal, and NFL thickness decrease progressively and significantly as a function of eccentricity. The greatest eccentricity‐dependent thinning occurs dorsally. This thinning is due mostly to NFL tapering, while the eccentricity‐dependent change in outer retinal thickness is more moderate, especially in the lateral meridian, possibly due to the presence of the visual streak. The retina is thickest in puppies, but there were no significant differences between mature and elderly dogs. Conclusions: Our results provide normative values for total, outer, and inner retinal thickness in female dogs and may facilitate OCT use in the diagnosis of canine glaucoma and inherited retinopathies. [ABSTRACT FROM AUTHOR]

Brain-training, aimed at advancing and improving cognitive and perceptual abilities, is vastly studied because of its immense promise. Yet, there are major controversies regarding its main claim that intensive weeks' training on a single challenging task could improve performance in related untrained tasks. Ample training studies showing transfer were criticized for flawed design. We now explored the impact of perceptual training (auditory frequency discrimination), applying a carefully controlled intensive training experiment. First, we administered a battery of perceptual, linguistic, and cognitive tasks to a large population to determine "near" to "far" tasks according to (pretraining) correlations in performance. This assessment revealed significant correlations between simple pitch discrimination and complex linguistic tasks, including reading and syntactic reasoning. Second, we administered a broad test battery before (and after) training, which included several tasks assessing pitch discrimination, and the linguistic tasks that showed pretraining correlation with auditory frequency discrimination. The test group trained with 2 tone frequency discrimination for 40 sessions. An active control group trained with a working memory (n-back) task for the same duration, and a passive control group was only tested before and after training. Pretraining performance levels were similar in the three groups. Our results were straightforward. No transfer was found to untrained tasks that rely on pith discrimination, or to linguistic tasks that showed pretraining correlation. Mild to marginal transfer was found only to pitch discrimination tasks using almost exactly the trained protocol. [ABSTRACT FROM AUTHOR]

Introduction Methods Results Conclusions The growing presence of allergens in materials and scarce data on allergic contact dermatitis in children has increased our need to refine its diagnosis in this population. We aimed to analyze children's specific responsivity to highly reactive subcomponents of Fragrance mix I, Fragrance mix II, and Textile dye mix from the European baseline series.We retrospectively analyzed patch test records of children aged 2 to 18 who underwent patch testing with the European baseline series between 2014 and 2022 in Israel.A total of 367 children were included in the study. In all, 160 children had positive results; 43 patients reacted to one of the mixes, and 20 performed further testing. Eleven of them completed the extended series at the exact same times as the regular European series, which benefited children. Farnesol was the most reactive compound (30.8%).Performing the extended European series provides a more accurate and time‐efficient allergic contact dermatitis diagnosis. Farnesol reactivity appears prominent in children and may justify tighter product regulations. [ABSTRACT FROM AUTHOR]

Aminoacyl-tRNA synthetases (aaRSs) are well studied for their role in binding and charging tRNAs with cognate amino acids. Recent RNA interactome studies had suggested that these enzymes can also bind polyadenylated RNAs. Here, we explored the mRNA repertoire bound by several yeast aaRSs. RNA immunoprecipitation (RIP) followed by deep sequencing revealed unique sets of mRNAs bound by each aaRS. Interestingly, for every tested aaRSs, a preferential association with its own mRNA was observed, suggesting an autoregulatory process. Self-association of histidyl-tRNA synthetase (HisRS) was found to be mediated primarily through binding to a region predicted to fold into a tRNAHis anticodon-like structure. Introducing point mutations that are expected to disassemble this putative anticodon mimic alleviated self-association, concomitant with increased synthesis of the protein. Finally, we found that increased cellular levels of uncharged tRNAHis lead to reduced self-association and increased HisRS translation, in a manner that depends on the anticodon-like element. Together, these results reveal a novel post-transcriptional autoregulatory mechanism that exploits binding mimicry to control mRNA translation according to tRNA demands. [ABSTRACT FROM AUTHOR]

Aims: To assess the cardiovascular (CV) safety of oral semaglutide, the first tablet formulation of a glucagon‐like peptide‐1 receptor agonist. Materials and methods: PIONEER 6 is a multinational, randomized, placebo‐controlled, double‐blind trial in patients with type 2 diabetes at high risk of CV events (defined as being aged ≥50 years and having established CV disease [CVD] or moderate [stage 3] chronic kidney disease [CKD], or being aged ≥60 years with ≥1 other CV risk factor). Patients were randomized to once‐daily oral semaglutide (up to 14 mg) or placebo added to standard of care. The primary composite endpoint is time to first occurrence of CV death or non‐fatal myocardial infarction or non‐fatal stroke. The primary hypothesis was to exclude an excess in CV risk with oral semaglutide by assessing non‐inferiority versus placebo for the primary endpoint (non‐inferiority margin of 1.8 for the upper boundary of the 95% confidence interval of the hazard ratio). PIONEER 6 is event‐driven, with follow‐up continuing until accrual of at least 122 primary outcome events. There is no pre‐defined minimal duration. Results: Overall, 3183 patients have been enrolled (mean age 66.1 years, 31.6% females) in 214 sites across 21 countries. At baseline, the mean duration of diabetes was 14.9 years, mean glycated haemoglobin concentration was 66 mmol/mol (8.2%), and 84.6% of patients had established CVD/moderate CKD. Conclusions: PIONEER 6 will provide evidence regarding the CV safety of oral semaglutide in patients with type 2 diabetes and high CV risk. [ABSTRACT FROM AUTHOR]