Expediting treatments in the 21st century: orphan drugs and accelerated approvals.

Background: In response to activated patient communities' catalyzation, two significant efforts by the FDA to expedite treatments have now been in place for multiple decades. In 1983, the United States Congress passed the Orphan Drug Act to provide financial incentives for development of drugs for rare diseases. In 1992, partly in response to the HIV epidemic, the FDA implemented Accelerated Approval (AA) to expedite access to promising new therapies to treat serious conditions with unmet medical need based on surrogate marker efficacy while additional clinical data is confirmed.

Center of mass mechanics during locomotion in the arboreal squirrel monkey (Saimiri sciureus) as a function of speed and substrate.

It is thought that the magnitude of center of mass (COM) oscillations can affect stability and locomotor costs in arboreal animals. Previous studies have suggested that minimizing collisional losses and maximizing pendular energy exchange are effective mechanisms to reduce muscular input and energy expenditure during terrestrial locomotion. However, few studies have explored whether these mechanisms are used in an arboreal context, where stability and efficiency often act as trade-offs.

Genome sequence of multi-drug-resistant isolated from a clinical sample collected in Maroua, Cameroon.

is a major pathogen of public health concern due to its implications in pathologies and its increasing antimicrobial resistance. Here, we present the draft genome of a 2.7-Mbp isolate obtained from a pus swab sampled in Cameroon.

A coati conundrum: how variation in levels of arboreality influences gait mechanics among three musteloid species.

The gait characteristics associated with arboreal locomotion have been frequently discussed in the context of primate evolution, wherein they present as a trio of distinctive features: a diagonal-sequence, diagonal-couplet gait pattern; a protracted arm at forelimb touchdown; and a hindlimb-biased weight support pattern. The same locomotor characteristics have been found in the woolly opossum, a fine-branch arborealist similar in ecology to some small-bodied primates. To further our understanding of the functional link between arboreality and primate-like locomotion, we present comparative data collected in the laboratory for three musteloid taxa.

Electrostatic microfiltration (EM) enriches and recovers viable microorganisms at low-abundance in large-volume samples and enhances downstream detection.

Rapid and sensitive detection of pathogens in various samples is crucial for disease diagnosis, environmental surveillance, as well as food and water safety monitoring. However, the low abundance of pathogens (<10 CFU) in large volume (1 mL-1 L) samples containing vast backgrounds critically limits the sensitivity of even the most advanced techniques, such as digital PCR. Therefore, there is a critical need for sample preparation that can enrich low-abundance pathogens from complex and large-volume samples.

Multidose transient transfection of human embryonic kidney 293 cells modulates recombinant adeno-associated virus2/5 Rep protein expression and influences the enrichment fraction of filled capsids.

Recombinant adeno-associated virus (rAAV) is a commonly used in vivo gene therapy vector because of its nonpathogenicity, long-term transgene expression, broad tropism, and ability to transduce both dividing and nondividing cells. However, rAAV vector production via transient transfection of mammalian cells typically yields a low fraction of filled-to-total capsids (~1%-30% of total capsids produced). Analysis of our previously developed mechanistic model for rAAV2/5 production attributed these low fill fractions to a poorly coordinated timeline between capsid synthesis and viral DNA replication and the repression of later phase capsid formation by Rep proteins.

The state of technological advancement to address challenges in the manufacture of rAAV gene therapies.

Current processes for the production of recombinant adeno-associated virus (rAAV) are inadequate to meet the surging demand for rAAV-based gene therapies. This article reviews recent advances that hold the potential to address current limitations in rAAV manufacturing. A multidisciplinary perspective on technological progress in rAAV production is presented, underscoring the necessity to move beyond incremental refinements and adopt a holistic strategy to address existing challenges.

A GCaMP reporter mouse with chondrocyte specific expression of a green fluorescent calcium indicator.

One of the major processes occurring during the healing of a fractured long bone is chondrogenesis, leading to the formation of the soft callus, which subsequently undergoes endochondral ossification and ultimately bridges the fracture site. Thus, understanding the molecular mechanisms of chondrogenesis can enhance our knowledge of the fracture repair process. One such molecular process is calciun (Ca) signaling, which is known to play a critical role in the development and regeneration of multiple tissues, including bone, in response to external stimuli.

Students with prior anatomy experience start out stronger in medical school gross anatomy.

Gross anatomy is a crucial course in medical school; it sets the foundation for future coursework and is highly valued by clinicians. While both medical students and faculty recognize the importance of pre-medical school anatomy experience, few medical schools require it as a prerequisite. Consequently, medical school gross anatomy courses have a diverse range of prior anatomy experience among students.

Quantitative evaluation of water, sanitation, and hygiene measures on COVID-19 pandemic peak reduction in the Philippines.

New cases of coronavirus disease 2019 (COVID-19) are continually being recorded worldwide, despite global efforts in implementing non-pharmaceutical interventions and establishing vaccination programs. This trend highlights the need to identify the factors associated with the continued spread of COVID-19. The World Health Organization recommends hand washing as a cost-effective intervention for preventing COVID-19, indicating that water, sanitation, and hygiene (WaSH) are central to the prevention of the disease.

Upskilling the cell therapy manufacturing workforce: design, implementation, and evaluation of a massive open online course.

Cell therapies have gained prominence as a promising therapeutic modality for treating a range of diseases. Despite the recent clinical successes of cell therapy products, very few formal training programs exist for cell therapy manufacturing. To meet the demand for a well-trained workforce, we assembled a team of university researchers and industry professionals to develop an online course on the principles and practice of cell therapy manufacturing.

Mechanical Constraints during Vertical Climbing Reveals Limited Deviation from Theoretical Minima.

Center of mass (COM) mechanics, often used as an energetic proxy during locomotion, has primarily focused on level movement and hardly explores climbing scenarios. This study examines three-dimensional COM movements across five phylogenetically distinct species to test theoretical expectations of climbing costs, explore how interspecific variation (i.e.

MSLN induced EMT, cancer stem cell traits and chemotherapy resistance of pancreatic cancer cells.

Chemoresistance is one of the main reasons for poor prognosis of pancreatic cancer. The effects of mesothelin (MSLN) on chemoresistance in pancreatic cancer are still unclear. We aim to investigate potential roles of MSLN in chemoresistance and its relationship with proliferation, epithelial-mesenchymal transition (EMT) and cancer stemness of pancreatic cancer cells.

Center of mass position does not drive energetic costs during climbing.

Climbing animals theoretically should optimize the energetic costs of vertical climbing while also maintaining stability. Many modifications to climbing behaviors have been proposed as methods of satisfying these criteria, focusing on controlling the center of mass (COM) during ascent. However, the link between COM movements and metabolic energy costs has yet to be evaluated empirically.

Comparative kinetics of humans and non-human primates during vertical climbing.

Climbing represents a critical behavior in the context of primate evolution. However, anatomically modern human populations are considered ill-suited for climbing. This adaptation can be attributed to the evolution of striding bipedalism, redirecting anatomical traits away from efficient climbing.

Beakiation: how a novel parrot gait expands the locomotor repertoire of living birds.

Occupation of arboreal habitats poses myriad locomotor challenges, driving both anatomical and behavioural innovations across various tetrapod lineages. Here, we report and biomechanically assess a novel, beak-driven locomotor mode-'beakiation'-by which parrots advance along the underside of narrow arboreal substrates. Using high-speed videography and kinetic analyses, we describe the limb loading patterns and pendular mechanics of beakiation, and compare the biomechanical characteristics of this gait with other suspensory behaviours (namely, forelimb-driven brachiation and inverted quadrupedal walking).

ablation in skeletal muscle results in functional alterations.

, a gene expressed exclusively in the musculoskeletal system, was shown in previous in vitro studies to be a key regulator of myogenic differentiation and myofusion. Other studies also showed expression associated with skeletal muscle development and hypertrophy. However, its specific role in skeletal muscle function remains unclear.

Ecological correlates of three-dimensional muscle architecture within the dietarily diverse Strepsirrhini.

Analysis of muscle architecture, traditionally conducted via gross dissection, has been used to evaluate adaptive relationships between anatomical form and behavioral function. However, gross dissection cannot preserve three-dimensional relationships between myological structures for analysis. To analyze such data, we employ diffusible, iodine-based contrast-enhanced computed tomography (DiceCT) to explore the relationships between feeding ecology and masticatory muscle microanatomy in eight dietarily diverse strepsirrhines: allowing, for the first time, preservation of three-dimensional fascicle orientation and tortuosity across a functional comparative sample.

The dual function of prokinesis in the feeding and locomotor systems of parrots.

Prokinesis, a mode of avian cranial kinesis involving motion between the neurocranium and upper beak, has long been investigated in biomechanical analyses of avian feeding and drinking. However, the modern avian beak is also used for non-feeding functions. Here, we investigate the dual function of prokinesis in the feeding and locomotor systems of the rosy-faced lovebird (Agapornis roseicollis).

Development and Application of a Data-Driven Signal Detection Method for Surveillance of Adverse Event Variability Across Manufacturing Lots of Biologics.

Introduction: Postmarketing drug safety surveillance research has focused on the product-patient interaction as the primary source of variability in clinical outcomes. However, the inherent complexity of pharmaceutical manufacturing and distribution, especially of biologic drugs, also underscores the importance of risks related to variability in manufacturing and supply chain conditions that could potentially impact clinical outcomes. We propose a data-driven signal detection method called HMMScan to monitor for manufacturing lot-dependent changes in adverse event (AE) rates, and herein apply it to a biologic drug.

Mechanistic modeling explains the production dynamics of recombinant adeno-associated virus with the baculovirus expression vector system.

Current manufacturing processes for recombinant adeno-associated viruses (rAAVs) have less-than-desired yields and produce significant amounts of empty capsids. The increasing demand and the high cost of goods for rAAV-based gene therapies motivate development of more efficient manufacturing processes. Recently, the US Food and Drug Administration (FDA) approved the first rAAV-based gene therapy product manufactured in the baculovirus expression vector system (BEVS), a technology that demonstrated production of high titers of full capsids.