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Peer response writing groups support faculty in their development as scholarly writers around the globe. Nevertheless, little is known about feedback provision inside these groups. This work analyses written and oral comments in a faculty writing group to determine how feedback progressed as meetings developed. Results indicate that participants shifted from mainly correcting or giving directions to eliciting clarification, confirmation or information. Similarly, orally retaken comments (oral comments that referred to previous written comments) changed from discussing linguistic accuracy issues to centring on the content and cohesion/coherence of the text, with most of the latter prompting exchanges among participants. With continued participation members moved from mainly offering corrections to establishing a dialogue with authors. In writing groups faculty safely engage in peer feedback practices that enrich texts and writers. KEYWORDS academics, faculty development, oral comments, peer revision, writing circle, writing for publication, written comments, In academia's current culture, researchers increasingly face the pressures associated with writing to publish if they expect to have access to promotions, permanent positions/tenure, and grants or other incentives within [...]

Alzheimer’s disease (AD), the leading cause of dementia in older adults, is a double proteinopathy characterized by amyloid-β (Aβ) and tau pathology. Despite enormous efforts that have been spent in the last decades to find effective therapies, late pharmacological interventions along the course of the disease, inaccurate clinical methodologies in the enrollment of patients, and inadequate biomarkers for evaluating drug efficacy have not allowed the development of an effective therapeutic strategy. The approaches followed so far for developing drugs or antibodies focused solely on targeting Aβ or tau protein. This paper explores the potential therapeutic capacity of an all-D-isomer synthetic peptide limited to the first six amino acids of the N-terminal sequence of the A2V-mutated Aβ, Aβ1-6A2V(D), that was developed following the observation of a clinical case that provided the background for its development. We first performed an in-depth biochemical characterization documenting the capacity of Aβ1-6A2V(D) to interfere with the aggregation and stability of tau protein. To tackle Aβ1-6A2V(D) in vivo effects against a neurological decline in genetically predisposed or acquired high AD risk mice, we tested its effects in triple transgenic animals harboring human PS1(M146 V), APP(SW), and MAPT(P301L) transgenes and aged wild-type mice exposed to experimental traumatic brain injury (TBI), a recognized risk factor for AD. We found that Aβ1-6A2V(D) treatment in TBI mice improved neurological outcomes and reduced blood markers of axonal damage. Exploiting the C. elegansmodel as a biosensor of amyloidogenic proteins’ toxicity, we observed a rescue of locomotor defects in nematodes exposed to the brain homogenates from TBI mice treated with Aβ1-6A2V(D) compared to TBI controls. By this integrated approach, we demonstrate that Aβ1-6A2V(D) not only impedes tau aggregation but also favors its degradation by tissue proteases, confirming that this peptide interferes with both Aβ and tau aggregation propensity and proteotoxicity.

Craving and impulsivity are addiction components which explain why heroin-dependant individuals (HDI), continue using heroin despite not wanting to do so. Opioid maintenance treatment (OMT), such as slow-release oral morphine (SROM), is the most effective treatment for opioid dependence. However, the impact of SROM on craving and impulsivity remains unclear. In this observational study, 23 HDI receiving SROM, their usual OMT, took part in the experiment. Each of the participants filled in the perceived level of craving with a visual analog scale. Their impulsivity was assessed via three laboratory tasks, the stop-signal reaction time, the Balloon Analogue Risk Task and delay discounting. Each evaluation was performed before and after SROM administration. Craving was significantly reduced after administration of SROM (difference 2.83; P = 0.0010), whereas there were no significant differences in performance in the three laboratory tasks. In the long term, we observed an improvement on delay discounting correlated with the duration and dosage of SROM. The acute impact of SROM appears to significantly reduce craving, without impacting impulsivity. Observation of the correlation between delay discounting and the duration and dosage of OMT is of great interest and should be studied further.

Purpose: The study aims to explore and explain the affordances and constraints of two-mode virtual collaboration as experienced by a newly forming international research team. Design/methodology/approach: This is self-reflective and action-oriented research on the affordances and constraints of two-mode virtual collaboration. In the spirit of professional development, the authors (nine researchers at different career stages and from various counties) engaged in a joint endeavour to evaluate the affordances and constraints of virtual collaborations in light of the recent literature while also researching the authors' own virtual collaboration during this evaluative task (mid-January–April 2021). The authors used two modes: synchronous (Zoom) and asynchronous (emails) to communicate on the literature exploration and recorded reactions and emotional responses towards existing affordances and constraints through a collective journal. Findings: The results suggest both affordances in terms of communication being negotiable and evolving and constraints, particularly in forming new relations given tools that may not be equally accessible to all. Journaling during collaborations could be a valuable tool, especially for virtual collective work, because it can be used to structure the team supported negotiation and discussion processes, especially often hidden processes. It is evident that the role of a leader can contribute to an alignment in the assumptions and experiences of trust and consequently foster greater mutual understanding of the circumstances for productive team collaborations. Originality/value: The findings of this study can inform academics and practitioners on how to create and facilitate better opportunities for collaboration in virtual teams as a rapidly emerging form of technology-supported working.

•Reduced cholesterol biosynthesis in the brain is an early dysfunction in Huntington's disease.•Liquid chromatography-mass spectrometry is a powerful technique for cholesterol metabolites quantitation in biological samples.•Validation of analytical methods regarding sample preparation and instrumental analysis is critical for metabolic studies.•Identifying reproducible and reliable changes in cholesterol metabolism in Huntington's disease has important implications for developing new biomarkers and new therapies.

Alzheimer’s disease (AD) is an irreversible neurodegenerative disorder that affects millions of people worldwide. AD pathogenesis is intricate. It primarily involves two main molecular players—amyloid-β (Aβ) and tau—which actually have an intrinsic trend to generate molecular assemblies that are toxic to neurons. Incomplete knowledge of the molecular mechanisms inducing the onset and sustaining the progression of the disease, as well as the lack of valid models to fully recapitulate the pathogenesis of human disease, have until now hampered the development of a successful therapy for AD. The overall experience with clinical trials with a number of potential drugs—including the recent outcomes of studies with monoclonal antibodies against Aβ—seems to indicate that Aβ-targeting is not effective if it is not accompanied by an efficient challenge of Aβ neurotoxic properties. We took advantage from the discovery of a naturally-occurring variant of Aβ (AβA2V) that has anti-amyloidogenic properties, and designed a novel bio-inspiredstrategy for AD based on the intranasal delivery of a six-mer peptide (Aβ1-6A2V) retaining the anti-amyloidogenic abilities of the full-length AβA2Vvariant. This approach turned out to be effective in preventing the aggregation of wild type Aβ and averting the synaptic damage associated with amyloidogenesis in a mouse model of AD. The results of our preclinical studies inspired by a protective model already existing in nature, that is the human heterozygous AβA2Vcarriers which seem to be protected from AD, open the way to an unprecedented and promising approach for the prevention of the disease in humans.

BackgroundTo evaluate the safety and tolerability of ranibizumab 0.5 mg in patients with uni/bilateral neovascular age-related macular degeneration (nAMD) and best-corrected visual acuity (BCVA)<2/10 and/or second eye affected, regardless of BCVA.MethodsIn this 12-month, prospective, multicentre, open-label, single arm, pragmatic interventional study, patients (N=941) aged ≥ 50 years were to receive ranibizumab as per approved label, monthly until maximum stable visual acuity (VA) was achieved (initially, three or more injections may be required). Thereafter, patients were to be monitored monthly for VA and treatment was to be resumed if VA was reduced due to disease activity.ResultsOf the 936 patients treated with ranibizumab at least once during the study, 823/113 were unilaterally/bilaterally (not simultaneously) treated . The mean (SD) number of ranibizumab injections during the study was 5.4 (2.9)/10.6 (5.0) injections in uni/bilaterally treated patients. Three systemic drug-related adverse events (AEs) (all serious, all in unilaterally treated patients) and 18 systemic AE of special interest (AESIs) (11 serious, 16/2 in unilaterally/bilaterally treated patients) occurred during the study. The annual incidence rate (AIR) (events/1000 person-years) for systemic drug-related AEs, considering a 15-day/30-day risk period, 11.0/8.5 for unilaterally treated patients. Considering the same risk period, the AIR (events/1000 person-years) for systemic AESIs for unilaterally treated patients was 22.1/19.9. Considering a 30-day risk period, the AIR (events/1000 treated eye-years) of ocular drug-related AEs was 23 and AESIs was 11.5.ConclusionsThe low incidence of AEs and AESIs demonstrated the good safety and tolerability of ranibizumab in unilaterally/bilaterally treated patients with nAMD in this real-world setting.

Neurodegenerative disorders such as Parkinson’s disease (PD) have no effective therapies. However, many promising drugs are precluded from clinical trials because of their poor brain availability. The chaperone protein Hsp70 has been reported to be effective in PD models, but its brain targeting is challenging. We developed a novel brain Hsp70 delivery system using injectable, biocompatible, and biodegradable semi-interpenetrating polymer networks of collagen (COLL) and low-molecular-weight hyaluronic acid (LMW HA) structured with gelatin particles. We produced human recombinant Hsp70-1A fused with the cell-penetrating peptide Tat (Tat-Hsp70) that was neuroprotective in vitro against the dopaminergic toxin 6-hydroxydopamine (6-OHDA). We assessed Tat-Hsp70 release from the selected COLL-LMW HA composites in vitro, observing a 95% release of loaded protein after 96 h. The release kinetics FITTED the Korsmeyer-Peppas model (regression coefficient 0.98) and the released Tat-Hsp70 remained neuroprotective for SH-SY5Y cells. Magnetic resonance imaging revealed that COLL-LMW HA composites lasted at least 96 h at the brain level, and in vivo Tat-Hsp70 release studies indicated that hydrogel presence is pivotal for a spatially focused neuroprotective effect. In an in vivo model of dopaminergic degeneration, Tat-Hsp70-loaded composites conveyed neuroprotection at both the behavioral and dopaminergic neuronal levels against the striatal injection of 6-OHDA. After the injection of Tat-Hsp70-loaded composites, mice showed a transient inflammatory response, with a decrease in GFAP and CD11b immunostaining after 7 days. Our delivery system enabled the effective brain release of Tat-Hsp70 and is ready for further improvements. An injectable, biocompatible and biodegradable system for delivering drugs to the brain, developed by researchers in Italy, could help in the treatment of neurodegenerative disorders. Parkinson’s disease (PD) is characterized by the misfolding of specific proteins in the brain, which then aggregate and become toxic. Heat shock protein 70 (Hsp70) is known to prevent misfolding and aggregation. This makes Hsp70 a potential therapeutic strategy in PD but its delivery to brain cells is challenging because of its low cell membrane permeability. Carmen Giordano, Diego Albani and co-workers fused Hsp70 with a cell-penetrating peptide and embedded in a network of collagen and hyaluronic acid. Experiments also in a mouse model of PD showed that within 96 h more than 95% of the Hsp70 had been released to the dopaminergic neurons affected in PD. We produced a human recombinant Hsp70-1A fused with the cell-penetrating peptide Tat (Tat-Hsp70-1A), that was neuroprotective in vitro against the dopaminergic toxin 6-hydroxydopamine (6-OHDA). We developed and characterized a Tat-Hsp70-1A delivery system by exploiting an injectable, biocompatible, biodegradable semi-interpenetrating polymer network composed of collagen (COLL) and low-molecular-weight hyaluronic acid (LMW HA), structured with gelatin particles. Tat-Hsp70-1A diffused from the selected COLL-LMW HA composites in an active form and protected dopaminergic cells and neurons in Parkinson’s disease (PD) models. Furthermore, Tat-Hsp70-loaded composites conveyed neuroprotection both at behavioral and dopaminergic neuronal level against striatal injection of 6-OHDA.

HIV-associated neurocognitive disorder in HIV patients substantially reduces their quality of life. We previously showed that the HIV matrix protein, p17 could stimulate lymph-angiogenesis in vitro potentially contributing to lymphoma tumour growth and in addition is associated with vascular activation in neuro-degenerating brain tissue; here, therefore, we have investigated the detailed molecular mechanisms of this action. We performed in vitro cell culture, angiogenesis experiments, phospho-protein microarrays and Western blotting to identify cellular signalling induced by p17 within human brain endothelial cells (HbMEC), and inhibitor studies to block p17-induced vascular growth. We also characterised the effects of hippocampal CA1 injection of p17 on epidermal growth factor receptor-1 (EGFR1) expression linked to our murine model of dementia. p17 strongly induced angiogenesis of HbMEC (migration, tube formation and spheroid growth). p17 concomitantly increased phosphorylation of EGFR1 as well as down-stream intermediates ERK1/2, FAK, PLC-γ and PKC-β whilst an inhibitor peptide of EGFR, blocked cell signalling and angiogenesis. Finally, Mice that showed reduced cognitive function and behavioural deficiencies after p17 injection, demonstrated that p17 localised in cortical microvessels and also neurones many of which stained positive for p-EGFR1 by histology/IHC. This work provides strong support that p17 may be involved in initiating and/or perpetuating vascular tissue pathophysiology associated with comorbidity in HIV patients.

Bacillus cereusis a gram positive microorganism commonly involved in gastrointestinal infection but capable of causing severe infections and bacteremia. We describe here a case of bacteremia caused by B. cereusin a previously healthy young woman admitted to the intensive care unit following emergency surgery due to a penetrating abdominal stab wound and subsequent hepatic lesion. She developed fever during admission and cultures were taken. B. cereuswas isolated in blood and hepatic fluid collection cultures. Treatment was adjusted according to the isolate, with good clinical results. It is important to highlight the pathogenic potential of this microorganism and not underestimate it as a contaminant when it is isolated from blood samples.

Scedosporiumes un hongo de distribución mundial que se encuentra en el suelo y en aguas contaminadas. Raramente afecta tejido óseo y puede hacerlo por inoculación directa a través de traumatismos. Se presenta el caso clínico de un paciente de 54 años con antecedente de accidente acuático y fractura expuesta de tibia-peroné de ambos miembros inferiores, con diagnóstico de osteomielitis crónica bacteriana tratada con antibióticos de amplio espectro por 120 días. Luego de ocho meses iniciado el cuadro, se aísla Scedosporiumspp. en colección de miembro afectado; por tal motivo, el paciente recibe terapia con voriconazol asociado a terbinafina.

ABSTRACTA recent study by Zimmerman et al. (2023) reported non-significant higher relative vaccine effectiveness of recombinant (RIV4) over the standard-dose influenza vaccines (SDIV) against outpatient illness during the 2018–19 and 2019–20 vaccination seasons. We agree with the authors’ conclusions and would like to emphasize minimal difference between RIV4 and SDIV using Number Needed to Vaccinate (NNV). The NNV analysis showed 8.9 for the RIV4 and 10 for the SDIV in the 50–64 age group. In the 65+ age group, the NNV was 10.6 for the RIV4 and 11.4 for the SDIV. This indicates a minimal difference between both vaccines and hence they both can be used in immunization programs to improve vaccine coverage.

Prion diseases are transmissible neurodegenerative disorders of humans and animals for which no effective treatment is available. Conformationally altered, proteaseresistant forms of the prion protein (PrP), termed PrPsc, are critical for disease transmissibility and pathogenesis, thus representing a primary target for therapeutic strategies. Different approaches affecting the clearance of PrPsc, inhibiting or preventing its conformation change are currently under investigation. Some compounds antagonize prion propagation in cellular and / or animal models of the disease. These molecules include polyanions, polyene antibiotics, tetrapyrroles, branched polyamines and compounds termed 'beta-sheet breakers' whose direct target its the abnormal conformational change for PrPsc. The suitability of these compounds for therapy is limited, primarily because they cannot cross the blood-brain barrier (BBB) and / or show severe toxicity. A variety of drugs already used for treatment of unrelated human diseases and known to penetrate the BBB have now been screened. The tricyclic derivatives of acridine and phenothiazine inhibit PrPsc formation in scrapie-infected neuroblastoma cells, confirming earlier reports on anti-prion activity of these compounds. In addition, activation of the immune system has been proposed to increase the clearance of PrPsc and reduce the prion infectivity and antibodies can exert antiaggregation activity. We showed that tetracyclines reverse abnormal physicochemical properties and abolish the neurotoxicity of PrP peptides in vitro. These compounds interact with PrPsc from brain tissue of BSE-affected cattle and patients with new-variant Creutzfeldt-Jakob disease (vCJD). Syrian hamsters injected with tetracycline-treated inoculum showed a significant delay in the onset of clinical signs of disease and prolonged survival time. When tetracycline was pre-incubated with a high dilution of the scrapie-infected inoculum, one third of the hamsters did not develop disease. These conformation-based approaches appear to hold the most promise for prion diseases and for the neurodegenerative disorders associated with protein misfolding. Although several classes of compounds offer anti-prion action their use in clinical practice is limited by the fact they have little or no efficacy at the onset of the disease. Thus, the discovery of more efficient drugs must run in parallel with the development of diagnostic tests to identify TSE earlier.

Elucidation of structure and biological properties of the prion protein scrapie (PrP(Sc)) is fundamental to an understanding of the mechanism of conformational transition of cellular (PrP(C)) into disease-specific isoforms and the pathogenesis of prion diseases. Unfortunately, the insolubility and heterogeneity of PrP(Sc) have limited these studies. The observation that a construct of 106 amino acids (termed PrP106 or miniprion), derived from mouse PrP and containing two deletions (Delta 23-88, Delta 141-176), becomes protease-resistant when expressed in scrapie-infected neuroblastoma cells and sustains prion replication when expressed in PrP(0/0) mice prompted us to generate a corresponding synthetic peptide (sPrP106) to be used for biochemical and cell culture studies. sPrP106 was obtained successfully with a straightforward procedure, which combines classical stepwise solid phase synthesis with a purification strategy based on transient labeling with a lipophilic chromatographic probe. sPrP106 readily adopted a beta-sheet structure, aggregated into branched filamentous structures without ultrastructural and tinctorial properties of amyloid, exhibited a proteinase K-resistant domain spanning residues 134-217, was highly toxic to primary neuronal cultures, and induced a remarkable increase in membrane microviscosity. These features are central properties of PrP(Sc) and make sPrP106 an excellent tool for investigating the molecular basis of the conformational conversion of PrP(C) into PrP(Sc) and prion disease pathogenesis.

Cerebral deposition of β‐amyloid is a major neuropathological feature in Alzheimer's disease. Here we show that tetracyclines, tetracycline and doxycycline, classical antibiotics, exhibit anti‐amyloidogenic activity. This capacity was determined by the exposure of β 1‐42 amyloid peptide to the drugs followed by the electron microscopy examination of the amyloid fibrils spontaneously formed and quantified with thioflavine T binding assay. The drugs reduced also the resistance of β 1‐42 amyloid fibrils to trypsin digestion. Tetracyclines not only inhibited the β‐amyloid aggregates formation but also disassembled the pre‐formed fibrils. The results indicate that drugs with a well‐known clinical profile, including activity in the central nervous system, are potentially useful for Alzheimer's therapy.

Prion diseases are characterized by the accumulation of altered forms of the prion protein (termed PrPSc) in the brain. Unlike the normal protein, PrPScisoforms have a high content of β-sheet secondary structure, are protease-resistant, and form insoluble aggregates and amyloid fibrils. Evidence indicates that they are responsible for neuropathological changes (i.e. nerve cell degeneration and glial cell activation) and transmissibility of the disease process. Here, we show that the antibiotic tetracycline: (i) binds to amyloid fibrils generated by synthetic peptides corresponding to residues 106–126 and 82–146 of human PrP; (ii) hinders assembly of these peptides into amyloid fibrils; (iii) reverts the protease resistance of PrP peptide aggregates and PrPScextracted from brain tissue of patients with Creutzfeldt-Jakob disease; (iv) prevents neuronal death and astrocyte proliferation induced by PrP peptides in vitro. NMR spectroscopy revealed several through-space interactions between aromatic protons of tetracycline and side-chain protons of Ala117–119, Val121–122and Leu125of PrP 106–126. These properties make tetracycline a prototype of compounds with the potential of inactivating the pathogenic forms of PrP.

Since the metabolic activity of the colonic flora plays a definite role in colon cancer and an increased incidence of this disease is reported after cholecystectomy, we studied the metabolic activity of the colonic flora in a group of postcholecystectomy patients and matched controls by measuring, as representative end products of the bacterial metabolism, their fecal bile acids (BA), fecal 3-methylindole (SK) and indole (IN), and respiratory methane and hydrogen. Patients had significantly higher SK and lower IN, and, among BA, higher lithocholic (LCA) and chenodeoxycholic acid concentrations and LCA/deoxycholic acid ratio in the stools than controls. Similar differences from controls were reported for colon cancer. Comparable bacterial metabolic activities are thus operative in the large bowel of postcholecystectomized and colon cancer patients. This supports the biological plausibility of the association of cholecystectomy and colon cancer.

Alterations of the connective tissue in the varicose vein wall have been noted by several investigators; however, the cause of the vein dilatation has still not been established. The aim of this study was to find a biochemical explanation to the development of varices by evaluating sensitive biochemical markers of collagen and elastin in the varicose vein wall. 4-L-Hydroxyproline (HYP), as a marker of collagen content, and desmosine (DES) and isodesmosine (IDES), as markers of elastin, were measured in 47 macroscopically dilated and 32 nondilated segments of 20 varicose saphenous veins collected from 20 patients with varices. The same measurements were made in 24 fragments of normal saphenous veins collected from 14 patients in whom the vein was removed to be used for graft procedures. HYP (collagen) and DES and IDES (elastin) were determined with a colorimetric method and HPLC, respectively. ANOVA test was used to compare mean values (±SD). HYP and collagen content were similar in varicose and normal veins. There was a significant reduction of both DES and IDES in dilated segments of varicose veins (P< 0.05 vs normal veins and nondilated segments); the ratio of elastin to collagen was lower in varicose than normal veins (P< 0.05), and this reduction was most significant in the dilated segments (P< 0.01 vs normal veins). These results suggest that dilatation of the varicose vein wall may be related to some defect of elastin metabolism. Further studies on the metabolic activity of vein muscle cells are required.

The aim of this study was to investigate the biochemical basis of biomechanical and morphological alterations of upper esophageal sphincter, which have been reported in patients with Zenker's diverticulum. 4-l-Hydroxyproline (4-Hyp) (collagen), isodesmosine (Ides), and desmosine (Des) (elastin) contents were measured in samples of cricopharyngeal muscle (CPM) and muscularis propria of the esophagus below the CPM. The specimens were collected from seven patients operated for Zenker's diverticulum and eight cadavers, without esophageal and connective tissue disease. 4-Hyp was assayed colorimetrically, Ides and Des by high-performance liquid chromatography. Mean (±SEM) values were compared by Mann–WhitneyUtest. In patients, collagen content was significantly increased, both in CPM and in the muscularis propria of the esophagus below the CPM (P< 0.05). In CPM, Ides to Des and collagen to elastin ratios were significantly higher in patients than in controls (P< 0.05). Both the CPM and the upper muscular cuff of the esophagus appear to be involved in the pathogenesis of Zenker's diverticulum. This finding supports the extension of the myotomy to the muscularis propria of the esophagus below the CPM. The alterated Ides to Des ratio suggests a primary disease of CPM as a cause of Zenker's diverticulum.

A small library of novel cis‐glycofused benzopyrans (VI) is synthesized.