Redesigning therapies for pantothenate kinase-associated neurodegeneration.

Pantothenate kinase-associated neurodegeneration (PKAN) is an incurable rare genetic disorder of children and young adults caused by mutations in the PANK2 gene, which encodes an enzyme critical for the biosynthesis of coenzyme A. Although PKAN affects only a small number of patients, it shares several hallmarks of more common neurodegenerative diseases of older adults such as Alzheimer's disease and Parkinson's disease. Advances in etiological understanding and treatment of PKAN could therefore have implications for our understanding of more common diseases and may shed new lights on the physiological importance of coenzyme A, a cofactor critical for the operation of various cellular metabolic processes. The large body of knowledge that accumulated over the years around PKAN pathology, including but not limited to studies of various PKAN models and therapies, has contributed not only to progress in our understanding of the disease but also, importantly, to the crystallization of key questions that guide future investigations of the disease. In this review, we will summarize this knowledge and demonstrate how it forms the backdrop to new avenues of research.

Vitamin B5 metabolism is essential for vacuolar and mitochondrial functions and drug detoxification in fungi.

Fungal infections, a leading cause of mortality among eukaryotic pathogens, pose a growing global health threat due to the rise of drug-resistant strains. New therapeutic strategies are urgently needed to combat this challenge. The PCA pathway for biosynthesis of Co-enzyme A (CoA) and Acetyl-CoA (AcCoA) from vitamin B5 (pantothenic acid) has been validated as an excellent target for the development of new antimicrobials against fungi and protozoa. The pathway regulates key cellular processes including metabolism of fatty acids, amino acids, sterols, and heme. In this study, we provide genetic evidence that disruption of the PCA pathway in Saccharomyces cerevisiae results in a significant alteration in the susceptibility of fungi to a wide range of xenobiotics, including clinically approved antifungal drugs through alteration of vacuolar morphology and drug detoxification. The drug potentiation mediated by genetic regulation of genes in the PCA pathway could be recapitulated using the pantazine analog PZ-2891 as well as the celecoxib derivative, AR-12 through inhibition of fungal AcCoA synthase activity. Collectively, the data validate the PCA pathway as a suitable target for enhancing the efficacy and safety of current antifungal therapies.

Enhancing post-training evaluation of annual performance agreement training: A fusion of fsQCA and artificial neural network approach.

This study aims to enhance the post-training evaluation of the annual performance agreement (APA) training organized by the Bangladesh Public Administration Training Centre (BPATC), the apex training institute for civil servants. Utilizing fuzzy-set qualitative comparative analysis (fsQCA) and artificial neural network (ANN) techniques within Kirkpatrick's four-stage model framework, data were collected from a self-administered questionnaire survey of 71 in-service civil servants who participated in the APA training program. This study employs an asymmetric, non-linear model analyzed through a configurational approach and ANN to explore interrelationships among the four Kirkpatrick levels namely, reaction, learning, behavior, and results. Findings indicate that trainees were satisfied across all levels, identifying a non-linear relationship among these levels in post-training evaluation process. The research highlights that "learning skills" are most significant in the APA post-training evaluation, followed by behavior, results, and reaction. Theoretically, this research advances Kirkpatrick's model and adds to the literature on public service post-training evaluation. Practically, it recommends prioritizing strategies that address cognitive barriers to enhance training effectiveness. This study's innovative approach lies in its concurrent use of fsQCA and ANN methods to analyze the success or failure of APA-related trainees, offering alternative pathways to desired outcomes and contrasting traditional quantitative methods that provide a single solution. The findings have practical implications for public service training institutions and bureaucratic policymakers involved in capacity development, guiding the creation of more effective in-service training courses for public officials. The methodology and analysis can be applied in other contexts, allowing bureaucratic policymakers to replicate these findings in their learning institutes to identify unique configurations that lead to successful or unsuccessful training outcomes, adopt effective strategies, and avoid detrimental ones.

Extending the theory of planned behavior to envisage social distancing behavior in containing the COVID-19 outbreak.

The study investigates the antecedents that influence social distancing behavior during the COVID-19 outbreak and develops a hypothetical model integrating additional pertinent variables into the classic theory of planned behavior (TPB) to grasp the social distancing behavior accurately. The extended model was investigated employing structural equation modeling using the data collected through Snowball Technology from 331 respondents. The results unearth significant influences of all the predictor variables on their outcome variables. Surprisingly, the supportive government strategy has no crucial impact on perceived behavioral control toward social distancing. Furthermore, the study reports no trivial difference between young and old and high-low income groups on the intention-actual social distancing. The study outlines policy interventions to prevent mass transmission of the COVID-19 catastrophe. Lastly, limitations are specified to open up novel insights for future researchers.

Babesia duncani multi-omics identifies virulence factors and drug targets.

Babesiosis is a malaria-like disease in humans and animals that is caused by Babesia species, which are tick-transmitted apicomplexan pathogens. Babesia duncani causes severe to lethal infection in humans, but despite the risk that this parasite poses as an emerging pathogen, little is known about its biology, metabolic requirements or pathogenesis. Unlike other apicomplexan parasites that infect red blood cells, B. duncani can be continuously cultured in vitro in human erythrocytes and can infect mice resulting in fulminant babesiosis and death. We report comprehensive, detailed molecular, genomic, transcriptomic and epigenetic analyses to gain insights into the biology of B. duncani. We completed the assembly, 3D structure and annotation of its nuclear genome, and analysed its transcriptomic and epigenetics profiles during its asexual life cycle stages in human erythrocytes. We used RNA-seq data to produce an atlas of parasite metabolism during its intraerythrocytic life cycle. Characterization of the B. duncani genome, epigenome and transcriptome identified classes of candidate virulence factors, antigens for diagnosis of active infection and several attractive drug targets. Furthermore, metabolic reconstitutions from genome annotation and in vitro efficacy studies identified antifolates, pyrimethamine and WR-99210 as potent inhibitors of B. duncani to establish a pipeline of small molecules that could be developed as effective therapies for the treatment of human babesiosis.

Strengthening the Trialability for the Intention to Use of mHealth Apps Amidst Pandemic: A Cross-Sectional Study.

Recent advancements in mHealth apps and services have played a vital role in strengthening healthcare services and enabling their accessibility to marginalized people. With the alarming rise in COVID-19 infection rates around the world, there appears to be an urgent call to modernize traditional medical practices to combat the pandemic. This study aims to investigate the key factors influencing the trialability of mHealth apps/services and behavioral intention to adopt mobile health applications. The study also examines the moderating effects of self-discipline motivation, knowledge, and attitude on the relationship between trialability and behavioral intention to use. The deductive reasoning approach was followed in a positivism paradigm. The study used convenience sampling and collected responses from 280 Generation Y participants in Bangladesh. Partial least square-based structural equation modeling was employed. The results revealed that relative advantage (ß = 0.229, p < 0.05), compatibility (ß = 0.232, p < 0.05), complexity (ß = −0.411, p < 0.05), and observability (ß = 0.235, p < 0.05) of mHealth apps influence the trialability of mHealth apps and services among users. Trialability compatibility (ß = 0.425, p < 0.05) of mHealth was positively related to the behavioral intention to use these mobile apps. The study found no moderating effects of attitude (ß = 0.043, p > 0.05) or self-discipline motivation (ß = −0.007, p > 0.05) on the hypothesized relationships. The empirical findings of this study may facilitate the development, design process, and implementation of mHealth applications with improved features that can lead to high user acceptance among Generation Y during future health crises.

Evidence for SARS-CoV-2 Spike Protein in the Urine of COVID-19 Patients.

Background: SARS-CoV-2 infection has, as of April 2021, affected >133 million people worldwide, causing >2.5 million deaths. Because the large majority of individuals infected with SARS-CoV-2 are asymptomatic, major concerns have been raised about possible long-term consequences of the infection. Methods: Wedeveloped an antigen capture assay to detect SARS-CoV-2 spike protein in urine samples from patients with COVID-19whose diagnosis was confirmed by positive PCR results from nasopharyngeal swabs (NP-PCR+) forSARS-CoV-2. We used a collection of 233 urine samples from 132 participants from Yale New Haven Hospital and the Children's Hospital of Philadelphia that were obtained during the pandemic (106 NP-PCR+ and 26 NP-PCR-), and a collection of 20 urine samples from 20 individuals collected before the pandemic. Results: Our analysis identified 23 out of 91 (25%) NP-PCR+ adult participants with SARS-CoV-2 spike S1 protein in urine (Ur-S+). Interestingly, although all NP-PCR+ children were Ur-S-, one child who was NP-PCR- was found to be positive for spike protein in their urine. Of the 23 adults who were Ur-S+, only one individual showed detectable viral RNA in urine. Our analysis further showed that 24% and 21% of adults who were NP-PCR+ had high levels of albumin and cystatin C, respectively, in their urine. Among individuals with albuminuria (>0.3 mg/mg of creatinine), statistical correlation could be found between albumin and spike protein in urine. Conclusions: Together, our data showed that one of four individuals infected with SARS-CoV-2 develop renal abnormalities, such as albuminuria. Awareness about the long-term effect of these findings is warranted.

MR imaging, MR arthrography, and specimen correlation of the posterolateral corner of the knee: an anatomic study.

OBJECTIVE: We sought to evaluate the anatomy of the posterolateral aspect of the knee with anatomic dissection, MR imaging, MR arthrography, and sectional anatomy. MATERIALS AND METHODS: We assessed the posterolateral corner of the knee during dissection of one gross anatomic specimen. MR imaging and MR arthrography were performed in seven additional knee specimens. T1-weighted spin-echo MR images were obtained in the standard imaging planes as well as in the coronal oblique plane. The specimens underwent T1-weighted spin-echo MR imaging after administration of intraarticular contrast material and were sectioned into planes corresponding to those of the MR images. RESULTS: At anatomic dissection, the following posterolateral structures were identified: the arcuate ligament (medial and lateral limbs), fabellofibular ligament, popliteofibular ligament, popliteus tendon and its two posterior attachments to the lateral meniscus, fibular collateral ligament, direct and anterior arms of the tendon of the long head of the biceps femoris muscle, and direct and anterior arms of the tendon of the short head of the biceps femoris muscle. Correlation of MR imaging and anatomic findings showed that the popliteofibular ligament and oblique popliteal ligament were found in 57% and 100% of specimens, respectively. At least one of the two limbs of the arcuate ligament was identified in 71% of specimens. The fabellofibular ligament was not identified on MR images in any of the specimens. The anteroinferior and posterosuperior popliteomeniscal fascicles were identified in all specimens. CONCLUSION: The posterolateral corner of the knee comprises complex and variable anatomic structures. Recognition of these variations is important in the assessment of MR images of the knee.

Anterior bundle of ulnar collateral ligament: evaluation of anatomic relationships by using MR imaging, MR arthrography, and gross anatomic and histologic analysis.

PURPOSE: To evaluate the gross and microscopic anatomy and the magnetic resonance (MR) imaging and MR arthrographic appearance of the anterior bundle of the ulnar collateral ligament (UCL) of the elbow. MATERIALS AND METHODS: The origin and insertion of the anterior bundle of the UCL, the bundle's relationship to the overlying flexor tendons, and the presence of a layered configuration were assessed through inspection and dissection of an elbow specimen. T1-weighted spin-echo MR imaging and MR arthrography in standard imaging planes and a coronal oblique plane were performed in eight other elbow specimens. Additional MR arthrography was performed in four specimens by using the coronal plane with the elbow in 20 degrees of flexion. The specimens were then cut in planes corresponding to those of the MR images. Histologic analysis of two specimens was performed. RESULTS: The anterior bundle of the UCL appeared as a low-signal-intensity structure on T1-weighted spin-echo MR and MR arthrographic images. It consisted of a uniform layer of parallel collagen fibers attaching proximally to the base of the medial epicondyle of the humerus and distally to the medial aspect of the coronoid process of the ulna (sublime tubercle). A layer of synovium separated the anterior bundle from the more superficial tendon of the flexor digitorum superficialis muscle. MR imaging-anatomic comparison in four (50%) specimens revealed separation between the anterior bundle of the UCL and the sublime tubercle. Results of histologic analysis of two of these specimens confirmed insertion of the anterior bundle of the UCL 3 and 4 mm distal to the articular margin. Ligamentous degeneration was detected in only one of these specimens. CONCLUSION: There is variability in the distal insertion of the anterior bundle, and this suggests that caution should be exercised in the diagnosis of its partial detachment from the sublime tubercle of the ulna.

Avulsion fracture of the head of the fibula (the "arcuate" sign): MR imaging findings predictive of injuries to the posterolateral ligaments and posterior cruciate ligament.

OBJECTIVE: The purpose of this study was to describe the significance of an avulsion fracture of the head of the fibula ("arcuate" sign) and its association with injuries of the knee on MR imaging. MATERIALS AND METHODS: We conducted a retrospective search of 2318 patients who underwent conventional radiography and MR imaging after an episode of knee trauma. Patients were included in this study if they had an avulsion fracture of the head of the fibula revealed on conventional radiography and underwent arthroscopy. Thirteen patients, all of whom were men, satisfied the inclusion criteria. Ten patients underwent further explorative surgery. The clinical, radiographic, MR imaging, and surgical findings were then reviewed. RESULTS: The avulsion fracture of the styloid process of the fibular head was apparently related to injuries of the arcuate complex in all 13 patients. Radiographically, the bony fragment was horizontally oriented and similar in size in most patients, ranging from 8 to 10 mm in length and from 2 to 5 mm in width. On MR imaging, the fibular avulsion was identified in 11 of the 13 patients. The other two patients had marrow edema in the fibular styloid process, although the avulsion fracture was not evident. All patients had injuries of the posterior cruciate ligament (six tibial avulsions, seven midsubstance tears). No patient had a tear of the anterior cruciate ligament. Disruption of the lateral collateral ligament was evident in seven patients, and one patient had a tear of the popliteal tendon. During surgery, six patients had disruption of the arcuate complex, but this disruption could not be identified on the MR images. CONCLUSION: An avulsion fracture of the fibular head generally involves the styloid process and causes injury of some of the major stabilizers in the posterolateral corner. Avulsion fractures are strongly associated with disruption of the posterior cruciate ligament.