Porphyrin nanoemulsion for antimicrobial photodynamic therapy: effective delivery to inactivate biofilm-related infections.

The management of biofilm-related infections is a challenge in healthcare, and antimicrobial photodynamic therapy (aPDT) is a powerful tool that has demonstrated a broad-spectrum activity. Nanotechnology has been used to increase the aPDT effectiveness by improving the photosensitizer's delivery properties. NewPS is a simple, versatile, and safe surfactant-free nanoemulsion with a porphyrin salt shell encapsulating a food-grade oil core with promising photodynamic action. This study evaluated the use of NewPS for aPDT against microorganisms in planktonic, biofilm, and in vivo models of infected wounds. First, the potential of NewPS-mediated aPDT to inactivate Streptococcus pneumoniae and Staphylococcus aureus suspensions was evaluated. Then, a series of protocols were assessed against S. aureus biofilms by means of cell viability and confocal microscopy. Finally, the best biofilm protocol was used for the treatment of S. aureus in a murine-infected wound model. A high NewPS-bacteria cell interaction was achieved since 0.5 nM and 30 J/cm2 was able to kill S. pneumoniae suspension. In the S. aureus biofilm, enhanced efficacy of NewPS-aPDT was achieved when 100 µM of NewPS was applied with longer periods of incubation at the light dose of 60 J/cm2. The best single and double-session protocol reduced 5.56 logs and 6.03 logs, respectively, homogeneous NewPS distribution, resulting in a high number of dead cells after aPDT. The in vivo model showed that one aPDT session enabled a reduction of 6 logs and faster tissue healing than the other groups. In conclusion, NewPS-aPDT may be considered a safe and effective anti-biofilm antimicrobial photosensitizer.

Cutin-derived oligomers induce hallmark plant immune responses.

The cuticle constitutes the outermost defensive barrier of most land plants. It comprises a polymeric matrix-cutin, surrounded by soluble waxes. Moreover, the cuticle constitutes the first line of defense against pathogen invasion, while also protecting the plant from many abiotic stresses. Aliphatic monomers in cutin have been suggested to act as immune elicitors in plants. This study analyses the potential of cutin oligomers to activate rapid signaling outputs reminiscent of pattern-triggered immunity in the model plant Arabidopsis. Cutin oligomeric mixtures led to Ca2+ influx and mitogen-activated protein kinase activation. Comparable responses were measured for cutin, which was also able to induce a reactive oxygen species burst. Furthermore, cutin oligomer treatment resulted in a unique transcriptional reprogramming profile, having many archetypal features of pattern-triggered immunity. Targeted spectroscopic and spectrometric analyses of the cutin oligomers suggest that the elicitor compounds consist mostly of two up to three 10,16-dihydroxyhexadecanoic acid monomers linked together through ester bonds. This study demonstrates that cutin breakdown products can act as inducers of early plant immune responses. Further investigation is needed to understand how cutin breakdowns are perceived and to explore their potential use in agriculture.

Appendicular invagination as a rare manifestation of endometriosis.

Appendicular invagination is a rare situation, with an incidence of 0.01 %. The clinical presentation can be variable from acute appendicitis to chronic abdominal pain, intestinal obstruction by intussusception or simply appear as a radiologic or intraoperative finding. Endometriosis is the underlying cause of appendicular invagination in one-third of cases but the possibility of neoplastic pathology should always be considered in these cases.

Efficacy of vitamin D in the treatment of depression: a systematic review and meta-analysis.

Vitamin D is a fat-soluble vitamin that performs multiple functions in the body. In addition to regulating calcium and phosphate levels in the body and contributing to bone mineralization, it participates in various brain and neurocognitive processes. In fact, the deficiency of this vitamin has also been linked to various psychiatric disorders, including depression.

Challenges in COVID-19 medical response: a nephrology perspective.

The new coronavirus disease, named by World Health Organization (WHO) as COVID-19 brought great challenges to patients with end-stage renal disease (ESRD). In general, ESRD patients have higher number of comorbidities and are at age-risk for severe pulmonary presentation of this disease. Another important issue is that hemodialysis (HD) clinics are usually not located in small towns, and these frail patients often travel to their dialysis center in groups and also cannot keep the 6-feet safe distance during their HD session.1.

Determinants of Severity in Acute Pancreatitis: A Nation-wide Multicenter Prospective Cohort Study.

OBJECTIVE: The aim of this study was to compare and validate the different classifications of severity in acute pancreatitis (AP) and to investigate which characteristics of the disease are associated with worse outcomes. SUMMARY OF BACKGROUND DATA: AP is a heterogeneous disease, ranging from uneventful cases to patients with considerable morbidity and high mortality rates. Severity classifications based on legitimate determinants of severity are important to correctly describe the course of disease. METHODS: A prospective multicenter cohort study involving patients with AP from 23 hospitals in Spain. The Atlanta Classification (AC), Revised Atlanta Classification (RAC), and Determinant-based Classification (DBC) were compared. Binary logistic multivariate analysis was performed to investigate independent determinants of severity. RESULTS: A total of 1655 patients were included; 70 patients (4.2%) died. RAC and DBC were equally superior to AC for describing the clinical course of AP. Although any kind of organ failure was associated with increased morbidity and mortality, persistent organ failure (POF) was the most significant determinant of severity. All local complications were associated with worse outcomes. Infected pancreatic necrosis correlated with high morbidity, but in the presence of POF, it was not associated to higher mortality when compared with sterile necrotizing pancreatitis. Exacerbation of previous comorbidity was associated with increased morbidity and mortality. CONCLUSION: The RAC and DBC both signify an advance in the description and differentiation of AP patients. Herein, we describe the complications of the disease independently associated to morbidity and mortality. Our findings are valuable not only when designing future studies on AP but also for the improvement of current classifications.

Does a review of urban resilience allow for the support of an evolutionary concept?

Over the last five decades, resilience has received ever greater interest from academics and practitioners and has been applied in different scientific areas, such as engineering, environmental science or medicine. In particular, resilience has become a fundamental concept in contemporary urban development, planning and management (UDPM). Despite the various reviews that have recently been made of this subject, an updated analysis of the concept is required so that commonly held views about resilience can be matched against empirical evidence while, at the same time, clarifying the use of its main formulations and connecting its embryonic development to its application in urban-centric research. This paper therefore reviews the concept of resilience (considering its primary formulations, its historical evolution and its conceptual underpinnings), establishing how it has been applied and developed in the UDPM context. Based on this review, this paper reiterates the idea of a three-dimensional framework for exploring the concept of resilience ([1] 'engineering' vs. [2] 'ecological' vs. [3] 'evolutionary resilience'). The search for urban resilience can potentially adopt an integrative approach, assuming an evolutionary perspective that can be adapted to different situations and stakeholders, thus offering a better adjusted and more dynamic urban planning and management.

Urban-centric resilience in search of theoretical stabilisation? A phased thematic and conceptual review.

Over the last decades 'resilience' has particularly arisen as an attractive perspective with respect to cities. As cities continue to expand, their susceptibility to uncertainties and new challenges, such as climate change, has increased, rendering 'urban resilience' an increasingly favoured concept in the realm of Urban Development, Planning and Management (UDPM). Despite recent reviews, an updated analysis of the concept is required to understand whether there is in fact scientific evidence to support the expansion and favouring of 'urban resilience' in UDPM. The need to understand how the concept evolved is further emphasised by the need to perceive how the distinct sciences have contributed to its development, and which were the focuses and conceptual underpinnings of such evolution. Thus, the objective of this paper is to provide a broader review of the multidimensional concept of 'urban resilience', while understanding how distinct research fields have contributed to its inception and expansion, and how distinct conceptualisations of resilience have influenced its evolution. Supported by a bibliometric analysis of urban-centric publications, this paper highlights the recent extensive growth and expanding application of 'urban resilience' to distinct research fields, as well as an apparent theoretical stabilisation of the concept, which reemphasises the idea of a three-dimensional conceptual resilience perspective in scientific literature: (1) 'engineering', (2) 'ecological', and (3) 'social-ecological resilience'. Consequently, this research emphasises that, if the related conceptual underpinnings are clear, 'urban resilience' can potentially serve as an 'integrative metaphor', adapted by diverse stakeholders, to reinforce UDPM initiatives.

The spore differentiation pathway in the enteric pathogen Clostridium difficile.

Endosporulation is an ancient bacterial developmental program that culminates with the differentiation of a highly resistant endospore. In the model organism Bacillus subtilis, gene expression in the forespore and in the mother cell, the two cells that participate in endospore development, is governed by cell type-specific RNA polymerase sigma subunits. σ(F) in the forespore, and σ(E) in the mother cell control early stages of development and are replaced, at later stages, by σ(G) and σ(K), respectively. Starting with σ(F), the activation of the sigma factors is sequential, requires the preceding factor, and involves cell-cell signaling pathways that operate at key morphological stages. Here, we have studied the function and regulation of the sporulation sigma factors in the intestinal pathogen Clostridium difficile, an obligate anaerobe in which the endospores are central to the infectious cycle. The morphological characterization of mutants for the sporulation sigma factors, in parallel with use of a fluorescence reporter for single cell analysis of gene expression, unraveled important deviations from the B. subtilis paradigm. While the main periods of activity of the sigma factors are conserved, we show that the activity of σ(E) is partially independent of σ(F), that σ(G) activity is not dependent on σ(E), and that the activity of σ(K) does not require σ(G). We also show that σ(K) is not strictly required for heat resistant spore formation. In all, our results indicate reduced temporal segregation between the activities of the early and late sigma factors, and reduced requirement for the σ(F)-to-σ(E), σ(E)-to-σ(G), and σ(G)-to-σ(K) cell-cell signaling pathways. Nevertheless, our results support the view that the top level of the endosporulation network is conserved in evolution, with the sigma factors acting as the key regulators of the pathway, established some 2.5 billion years ago upon its emergence at the base of the Firmicutes Phylum.

Cognitive bio-radar: The natural evolution of bio-signals measurement.

In this article we discuss a novel approach to Bio-Radar, contactless measurement of bio-signals, called Cognitive Bio-Radar. This new approach implements the Bio-Radar in a Software Defined Radio (SDR) platform in order to obtain awareness of the environment where it operates. Due to this, the Cognitive Bio-Radar can adapt to its surroundings in order to have an intelligent usage of the radio frequency spectrum to improve its performance. In order to study the feasibility of such implementation, a SDR based Bio-Radar testbench was developed and evaluated. The prototype is shown to be able to acquire the heartbeat activity and the respiratory effort. The acquired data is compared with the acquisitions from a Biopac research data acquisition system, showing coherent results for both heartbeat and breathing rate.

Protein gels and emulsions from mixtures of Cape hake and pea proteins.

BACKGROUND: Portioning of frozen fish generates by-products such as fish 'sawdust' and cut-offs which can be further processed into protein concentrates and isolates. The objective of the present work was to produce gels and emulsions using recovered Cape hake protein powder (HPP). In previous works, the structures of the gels produced by HPP were found to be strong, with a high rubbery character. In this work, the addition of commercial pea proteins (PPC) to HPP gels and emulsions was studied. RESULTS: Physical properties of gels and emulsions prepared with different proportions of mixtures of PPC and HPP were evaluated. In general, gels and emulsions showed high values for whiteness and, as expected, the higher content of HPP in the protein mixtures led to higher firmness values of the gels. The gel network was rapidly formed upon heating due to the fish protein macromolecules and further reinforced by the pea protein macromolecules when cooled to 5 °C. Both visco-elastic parameters, storage and loss moduli, of the produced gels increased with the HPP proportion in the protein mixtures, corresponding to more structured systems. For the emulsions, two different pH environments were studied: 3.8 and 7.0. At neutral pH a synergy was found between the vegetable and fish protein, which is not so strong when pH is lowered to 3.8, near the isoelectric point of pea proteins (pI = 4.5). This evidence was supported by the results from the texture measurements, viscosity and visco-elastic parameters. CONCLUSIONS: Gels made from Cape hake proteins showed a softer texture and were less rubbery with the addition of pea proteins. Emulsions stabilised by these mixtures showed slightly different behaviour when produced at pH 7.0 or pH 3.8.

Crystal structure of a poxvirus-like zalpha domain from cyprinid herpesvirus 3.

Zalpha domains are a subfamily of the winged helix-turn-helix domains sharing the unique ability to recognize CpG repeats in the left-handed Z-DNA conformation. In vertebrates, domains of this family are found exclusively in proteins that detect foreign nucleic acids and activate components of the antiviral interferon response. Moreover, poxviruses encode the Zalpha domain-containing protein E3L, a well-studied and potent inhibitor of interferon response. Here we describe a herpesvirus Zalpha-domain-containing protein (ORF112) from cyprinid herpesvirus 3. We demonstrate that ORF112 also binds CpG repeats in the left-handed conformation, and moreover, its structure at 1.75 Å reveals the Zalpha fold found in ADAR1, DAI, PKZ, and E3L. Unlike other Zalpha domains, however, ORF112 forms a dimer through a unique domain-swapping mechanism. Thus, ORF112 may be considered a new member of the Z-domain family having DNA binding properties similar to those of the poxvirus E3L inhibitor of interferon response.

Bringing up to date the toolkit for the catabolism of aromatic compounds in fungi: The unexpected 1,2,3,5-tetrahydroxybenzene central pathway.

Saprophytic fungi are able to catabolize many plant-derived aromatics, including, for example, gallate. The catabolism of gallate in fungi is assumed to depend on the five main central pathways, i.e., of the central intermediates' catechol, protocatechuate, hydroxyquinol, homogentisate and gentisate, but a definitive demonstration is lacking. To shed light on this process, we analysed the transcriptional reprogramming of the growth of Aspergillus terreus on gallate compared with acetate as the control condition. Surprisingly, the results revealed that the five main central pathways did not exhibit significant positive regulation. Instead, an in-depth analysis identified four highly expressed and upregulated genes that are part of a conserved gene cluster found in numerous species of fungi, though not in Aspergilli. The cluster comprises a monooxygenase gene and a fumarylacetoacetate hydrolase-like gene, which are recognized as key components of catabolic pathways responsible for aromatic compound degradation. The other two genes encode proteins with no reported enzymatic activities. Through functional analyses of gene deletion mutants in Aspergillus nidulans, the conserved short protein with no known domains could be linked to the conversion of the novel metabolite 5-hydroxydienelatone, whereas the DUF3500 gene likely encodes a ring-cleavage enzyme for 1,2,3,5-tetrahydroxybenzene. These significant findings establish the existence of a new 1,2,3,5-tetrahydroxybenzene central pathway for the catabolism of gallate and related compounds (e.g. 2,4,6-trihydroxybenzoate) in numerous fungi where this catabolic gene cluster was observed.

Practical management of disease-related manifestations and drug toxicities in patients with multiple myeloma.

Multiple myeloma (MM) is a very heterogeneous disease with multiple symptoms and clinical manifestations. MM affects mainly elderly patients and is difficult to manage in the presence of comorbidities, polypharmacy, frailty and adverse events of disease-targeted drugs. The rapid changes in MM treatment resulting from constant innovations in this area, together with the introduction of numerous new drugs with distinct mechanisms of action and toxicity profiles, have led to an increased complexity in the therapeutic decision-making and patient management processes. The prolonged exposure to novel agents, sometimes in combination with conventional therapies, makes this management even more challenging. A careful balance between treatment efficacy and its tolerability should be considered for every patient. During treatment, a close monitoring of comorbidities, disease-related manifestations and treatment side effects is recommended, as well as a proactive approach, with reinforcement of information and patient awareness for the early recognition of adverse events, allowing prompt therapeutic adjustments. In this review, we discuss various issues that must be considered in the treatment of MM patients, while giving practical guidance for monitoring, prevention and management of myeloma-related manifestations and treatment-related toxicities.

SMIM1 absence is associated with reduced energy expenditure and excess weight.

BACKGROUND: Obesity rates have nearly tripled in the past 50 years, and by 2030 more than 1 billion individuals worldwide are projected to be obese. This creates a significant economic strain due to the associated non-communicable diseases. The root cause is an energy expenditure imbalance, owing to an interplay of lifestyle, environmental, and genetic factors. Obesity has a polygenic genetic architecture; however, single genetic variants with large effect size are etiological in a minority of cases. These variants allowed the discovery of novel genes and biology relevant to weight regulation and ultimately led to the development of novel specific treatments. METHODS: We used a case-control approach to determine metabolic differences between individuals homozygous for a loss-of-function genetic variant in the small integral membrane protein 1 (SMIM1) and the general population, leveraging data from five cohorts. Metabolic characterization of SMIM1-/- individuals was performed using plasma biochemistry, calorimetric chamber, and DXA scan. FINDINGS: We found that individuals homozygous for a loss-of-function genetic variant in SMIM1 gene, underlying the blood group Vel, display excess body weight, dyslipidemia, altered leptin to adiponectin ratio, increased liver enzymes, and lower thyroid hormone levels. This was accompanied by a reduction in resting energy expenditure. CONCLUSION: This research identified a novel genetic predisposition to being overweight or obese. It highlights the need to investigate the genetic causes of obesity to select the most appropriate treatment given the large cost disparity between them. FUNDING: This work was funded by the National Institute of Health Research, British Heart Foundation, and NHS Blood and Transplant.

Interstitial Ectopic Pregnancy: A Rare Diagnosis.

An ectopic pregnancy is located outside the uterus, mostly found in the fallopian tubes. The main predisposing factors are usually related to anatomical and/or functional disturbances of the fallopian tubes. Typically, an ectopic pregnancy presents with vaginal bleeding or abdominal pain in the first trimester of pregnancy, although it may be asymptomatic. The diagnosis of ectopic pregnancy, which is based on transvaginal ultrasound associated with the serum beta fraction of human chorionic gonadotropin values, is of the highest relevance due to the mortality risk involved. We report the case of a 26-year-old woman who presented with a four-week history of amenorrhea and abdominal pain. Initially, the diagnostic hypothesis was a pelvic inflammatory disease, as the patient complained of pain during deep palpation of the lower quadrants of the abdomen, and gynecological observation detected malodorous discharge and cervical tenderness. Antibiotic treatment was initiated. The patient was later diagnosed with ectopic pregnancy, which was discovered during a routine pregnancy ultrasound. She was submitted to urgent laparotomy with intraoperative confirmation of the interstitial location of the gestational sac.

Breast Phyllodes Tumor: A Tumor With Unpredictable Clinical Behavior.

Phyllodes tumors are uncommon biphasic breast tumors with a wide range of clinical behaviors. The distinction between a phyllodes tumor and a fibroadenoma can be difficult. The diagnosis of phyllodes tumor should be suspected in all women who present with a rapidly growing breast lump. Based on the histological characteristics, the World Health Organization (WHO) classifies phyllodes tumors as benign, borderline, or malignant. The risk of recurrence and metastatic potential varies based on histological features. Wide excision or mastectomy is the standard of care ensuring histologically clear margins. Despite the grading criteria defined by the WHO, the management of phyllodes tumors continues to be a challenge. We report the case of a 48-year-old woman who presented to the emergency department with a large and ulcerated phyllodes tumor of the left breast. The tumor size did not allow conservative surgery. The final diagnosis of a borderline phyllodes tumor was made, and, in this case, the patient did not undergo adjuvant treatment.

A Metastatic Invasive Mole in a Perimenopausal Woman: A Rare Case.

Gestational trophoblastic neoplasia (GTN) represents a heterogeneous group of pregnancy-related tumors that usually develop from the malignant transformation of trophoblastic tissue after molar evacuation. The first presentation as an invasive mole is particularly rare. GTN is considered the most curable gynecological malignancy as most cases are treated successfully with chemotherapy agents. Although extremes of reproductive age are an established risk factor for complete moles, GTN is extremely rare in perimenopausal women. GTN should be considered in the differential diagnosis of patients with abnormal uterine bleeding. Delays in the diagnosis and treatment can worsen the prognosis of patients with GTN. Here, we describe the case of a 54-year-old woman who presented to the emergency department with abdominal pain and heavy vaginal bleeding. She reported pregnancy-related symptoms that had developed over two months but was apprehensive to search for medical care. The final diagnosis was an invasive mole that had a catastrophic clinical course. Arterial embolization should be considered in patients with uncontrollable vaginal bleeding and hemodynamic instability.