Biological Utilization Research Articles

Biological Characteristics and Resource Utilization of Tagetes minuta L.

Biological Characteristics and Resource Utilization of Tagetes minuta L.

Development of technology of crackers wuth increased food value to improve the food supply to military servants during a special period

Flour confectionery products have an unstable polyphase structure that needs stabilization. The nutrient composition of these products is characterized by a high content of sugar and saturated fatty acids. The content of protein, dietary fiber, vitamins, and minerals is low. This predetermines the feasibility of using the latest raw materials. This paper has proven the possibility of using flour from extruded sunflower seed kernels (FESSK). FESSK is a unique protein-mineral raw material ingredient that contains essential amino and polyunsaturated fatty acids, as well as biologically active substances. In FESSK, compared to high grade wheat flour (HGWF), the content of protein increases by 3.1–3.3 times; minerals – 13.80–13.82 times; fiber – 98.91–98.93 times; fat – 2.54–2.56 times; the total amount of essential amino acids – by 3.15–3.19 times. One should note the balance of amino acid composition and the usefulness of FESSK proteins (amino acid number (AAN) of essential amino acids approaches 100 %). Compared to HGWF, FESSK has increased biological value index and utilization rate of amino acid composition, by 48.74 % and 39.29 %, respectively. Of the 13 vitamins necessary for the human body, 12 vitamins (92.3 % of the total amount of vitamins) were identified as part of the FESSK composition. In FESSK, compared to HGWF, fat-absorbing capacity increases by 1.50–1.52 times and water retention capacity by 3.62–3.64 times. It was found that the addition of 10.0 % FESSK increases wettability by 6.58–11.19 %; expansion rate by (1,0±0,1) %; ash content – 5.71–13.33 times; fat content by 2,19–6,17 %; protein content by 8.29–21.37 %. The integrated quality indicator increases by 5.1–6.8 %. Alkalinity decreases by 1.04–2.06 %. The expediency of the production of crackers with improved nutritional properties to improve the food supply of servicemen in a special period has been proven.

Modeling Topsoil Phosphorus—From Observation-Based Statistical Approach to Land-Use and Soil-Based High-Resolution Mapping

Phosphorus (P) is a macronutrient that often limits the productivity and growth of terrestrial ecosystems, but it is also one of the main causes of eutrophication in aquatic systems at both local and global levels. P content in soils can vary largely, but usually, only a small fraction is plant-available or in an organic form for biological utilization because it is bound in incompletely weathered mineral particles or adsorbed on mineral surfaces. Furthermore, in agricultural ecosystems, plant-available P content in topsoil is mainly controlled by fertilization and land management. To understand, model, and predict P dynamics at the landscape level, the availability of detailed observation-based P data is extremely valuable. We used more than 388,000 topsoil plant-available P samples from the period 2005 to 2021 to study spatial and temporal variability and land-use effect on soil P. We developed a mapping approach based on existing databases of soil, land-use, and fragmentary soil P measurements by land-use classes to provide spatially explicit high-resolution estimates of topsoil P at the national level. The modeled spatially detailed (1:10,000 scale) GIS dataset of topsoil P is useful for precision farming to optimize nutrient application and to increase productivity; it can also be used as input for biogeochemical models and to assess P load in inland waters and sea.

Biosimilar Use Among 38 ASCO PracticeNET Practices, 2019-2021.

Biosimilars offer increased patient choice and potential cost-savings, compared with originator biologics. We studied 3 years of prescribed biologics among US physician practices to determine the relationship of practice type and payment source to oncology biosimilar use. We acquired biologic utilization data from 38 practices participating in PracticeNET. We focused on six biologics (bevacizumab, epoetin alfa, filgrastim, pegfilgrastim, rituximab, and trastuzumab) for the period from 2019 to 2021. We complemented our quantitative analysis with a survey of PracticeNET participants (prescribers and practice leaders) to reveal potential motivators and barriers to biosimilar use. We implemented logistic regression to evaluate the biosimilar use for each biologic, with covariates including time, practice type, and payment source, and accounted for clusters of practices. Use of biosimilars increased over the 3-year period, reaching between 51% and 80% of administered doses by the fourth quarter of 2021, depending on the biologic. Biosimilar use varied by practice, with independent physician practices having higher use of biosimilars for epoetin alfa, filgrastim, rituximab, and trastuzumab. Compared with commercial health plans, Medicaid plans had lower biosimilar use for four biologics; traditional Medicare had lower use for five biologics. The average cost per dose decreased between 24% and 41%, dependent on the biologic. Biosimilars have, through increased use, lowered the average cost per dose of the studied biologics. Biosimilar use differed by originator biologic, practice type, and payment source. There remains further opportunity for increases in biosimilar use among certain practices and payers.

Toxicity evaluation of some plants used in ethnofishery in Arunachal Pradesh, India

Plant-based natural products have shaped traditional knowledge systems due to their numerous biological and pharmacological utility. However, in addition to their extensive utilization, some of these plants are also known for their toxicological properties. Since the foundation of human civilization, these toxic plants were used for fishing, hunting and safeguarding against enemies. In this study, a total of five plant species used in ethnofishery were considered for the toxicological study. The toxicities of these plants were evaluated using Brine Shrimp Lethality Assay (BSLA) and LC50 values were estimated. All the plants have displayed the toxic effect and have been graded to be highly toxic (i.e., LC50 of 0–100 μg/ml or LC50 < 1000 μg/ml). Furthermore, with the lowest LC50 (0.14 in 12 h of incubation), the plant species D. scandens was reported to be the most toxic. The toxic plants have an important role in rural livelihood; however, if the concentration of these compounds from poisonous plants reaches a high concentration in the vulnerable biological system, it could bring a devastating health-related issue for the frequent consumers.

De novo design of modular peptide-binding proteins by superhelical matching

General approaches for designing sequence-specific peptide-binding proteins would have wide utility in proteomics and synthetic biology. However, designing peptide-binding proteins is challenging, as most peptides do not have defined structures in isolation, and hydrogen bonds must be made to the buried polar groups in the peptide backbone1–3. Here, inspired by natural and re-engineered protein–peptide systems4–11, we set out to design proteins made out of repeating units that bind peptides with repeating sequences, with a one-to-one correspondence between the repeat units of the protein and those of the peptide. We use geometric hashing to identify protein backbones and peptide-docking arrangements that are compatible with bidentate hydrogen bonds between the side chains of the protein and the peptide backbone12. The remainder of the protein sequence is then optimized for folding and peptide binding. We design repeat proteins to bind to six different tripeptide-repeat sequences in polyproline II conformations. The proteins are hyperstable and bind to four to six tandem repeats of their tripeptide targets with nanomolar to picomolar affinities in vitro and in living cells. Crystal structures reveal repeating interactions between protein and peptide interactions as designed, including ladders of hydrogen bonds from protein side chains to peptide backbones. By redesigning the binding interfaces of individual repeat units, specificity can be achieved for non-repeating peptide sequences and for disordered regions of native proteins.

Abstract 2661: Engineered Toxin Bodies (ETBs): Clinical stage immunotoxins with a safer and differentiated profile

Abstract Immunotoxins (the fusion of a bacterial cytotoxic protein with a targeting moiety) have been explored since the 1970s but have been limited in their therapeutic utility because of the propensity to drive a host innate immune response resulting in potentially fatal cytokine elevations and capillary leak syndrome (CLS). Engineered Toxin Bodies (ETBs) represent an important evolution in immunotoxins, overcoming the issues with innate immunity and adding biologic utility not previously seen. ETBs use an antibody-based targeting domain genetically fused to a de-immunized form of the Shiga-like toxin A subunit (SLTA). Like previous immunotoxins, ETBs bind and induce cell-death in a target-specific manner but have additional biology not inherent to other immunotoxins. ETBs can induce their own internalization, allowing for the targeting of poorly/non internalizing receptors. ETBs can deliver other payloads like viral class I antigen or small molecules in addition to SLTA, allowing for multiple MOAs. And, most importantly, we have de-immunized SLTA through genetic engineering to create ETBs devoid of innate immune effects/CLS seen with previous immunotoxins. Three ETBs (MT-0169, MT-5111, and MT-6402) are currently in clinical studies across different targets (CD38, HER2, PD-L1) and across hematologic malignancies, solid tumor, and immuno-oncology indications. To date, no clinical manifestations of CLS have been observed in 80+ patients; in contrast, the rate of CLS for approved immunotoxins ranges for 33% to &amp;gt;50%. In general, all three ETBs have shown good tolerability with little off-target toxicity and all three ETBs have shown monotherapy clinical benefit in heavily pre-treated patients. MT-6402, an ETB targeting PD-L1, is the first ETB to carry the additional mechanism of antigen seeding. Along with its ability to destroy ribosome in a PD-L1-targeted fashion, MT-6402 can deliver a class I antigen derived from human cytomegalovirus (CMV) to the ER, allowing for presentation of the antigen in complex with MHC class I on the cell surface of a tumor cell. Early clinical data demonstrate antigen seeding with MT-6402 can result in T-cells specific to the seeded CMV antigen mounting an immune response to the tumor. ETBs represent a unique and wholly distinct scaffold for drug development in oncology. ETBs allow for the targeting of non-internalizing receptors that are not amenable to ADCs. ETBs have a mechanism of cell-kill (enzymatic and irreversible ribosomal destruction) that is distinct from any approved agent in oncology. ETBs can also deliver additional payloads to drive unique biology like the alteration of tumor immunophenotype. Here we describe three active clinical stage programs with encouraging safety and efficacy data that represent a transformation of the immunotoxin landscape into a more viable therapeutic approach to target validated as well as typically intractable clinical cancer targets. Citation Format: Chris Moore, Lee Robinson, Garrett Cornelison, Joseph Dekker, Roger Waltzman, John Majercak, Joseph Phillips, Jay Zhao, Jason Kim, Eric Poma. Engineered Toxin Bodies (ETBs): Clinical stage immunotoxins with a safer and differentiated profile [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2661.

Discovery of Potent and Highly Selective Interleukin-2-Inducible T-Cell Kinase Degraders with In Vivo Activity.

Interleukin-2-inducible T-cell kinase (ITK) is a promising therapeutic target for human autoimmune diseases and T-cell malignant lymphomas. This paper reports the development of a series of cereblon-recruiting ITK proteolysis targeting chimeras based on a structure-based design strategy. The representative compounds 23 and 28 exhibited potent ITK degradation and IL-2 inhibition activities in Jurkat cells. Global proteomic profiling assays indicated that compounds 23 and 28 are highly selective ITK degraders. Moreover, compound 28 showed good plasma exposure levels and elicited efficient, rapid, and prolonged ITK degradation in Balb/c mice. Furthermore, it significantly suppressed IL-2 secretion stimulated by anti-CD3 antibody. Compound 28 represents the first effective and highly selective ITK degrader. Thus, 28 is a valuable tool compound for further in vitro and in vivo studies exploring the underlying biological effects and potential therapeutic utility of ITK degradation in human diseases.

SLiM 4: Multispecies Eco-Evolutionary Modeling.

AbstractThe SLiM software framework for genetically explicit forward simulation has been widely used in population genetics. However, it has been largely restricted to modeling only a single species, which has limited its broader utility in evolutionary biology. Indeed, to our knowledge no general-purpose, flexible modeling framework exists that provides support for simulating multiple species while also providing other key features, such as explicit genetics and continuous space. The lack of such software has limited our ability to model higher biological levels such as communities, ecosystems, coevolutionary and eco-evolutionary processes, and biodiversity, which is crucial for many purposes, from extending our basic understanding of evolutionary ecology to informing conservation and management decisions. We here announce the release of SLiM 4, which fills this important gap by adding support for multiple species, including ecological interactions between species such as predation, parasitism, and mutualism, and illustrate its new features with examples.

Design, Synthesis, and Application of a Water‐soluble Photocage for Aqueous Cyclopentadiene‐based Diels‐Alder Photoclick Chemistry in Hydrogels

AbstractSpatiotemporally functionalized hydrogels have exciting applications in tissue engineering, but their preparation often relies on radical‐based strategies that can be deleterious in biological settings. Herein, the computationally guided design, synthesis, and application of a water‐soluble cyclopentadienone‐norbornadiene (CPD‐NBD) adduct is disclosed as a diene photocage for radical‐free Diels‐Alder photopatterning. We show that this scalable CPD‐NBD derivative is readily incorporated into hydrogel formulations, providing gels that can be patterned with dienophiles upon 365 nm uncaging of cyclopentadiene. Patterning is first visualized through conjugation of cyanine dyes, then biological utility is highlighted by patterning peptides to direct cellular adhesion. Finally, the ease of use and versatility of this CPD‐NBD derivative is demonstrated by direct incorporation into a commercial 3D printing resin to enable the photopatterning of structurally complex, printed hydrogels.

A dual-reaction-site and dual-channel fluorescent-on probe for selectively monitoring mitochondrial glutathione

Glutathione (GSH) is the most abundant endogenous antioxidant and serves critical cellular functions in living system. As a results, it is of great significant to disclose GSH-specific fluorescent probe to deeply understand its biological functions. In this study, we developed a dual-reaction-site and dual-channel turn-on fluorescent probe Cyan-S-Nap for GSH by installing the sensing groups of thiophenol and sulfonamide moieties into the dyes of heptamethine cyanine and naphthalimide, respectively. The probe displayed selective response to GSH by the two independent fluorescent channels in visible (λem = 492 nm) and near-infrared (λem = 810 nm) regions. The dual emissions feature endows the probe with the ability to precisely detect the concentration fluctuation of GSH. In addition, the biological utilities of Cyan-S-Nap suggested that the probe was capable of imaging mitochondrial GSH in dual channels in a synchronous and independent manner, as well as monitoring the changes of GSH levels modulated by exogenous/endogenous reactive oxygen species in living cells and zebrafish.

Caseins: Versatility of Their Micellar Organization in Relation to the Functional and Nutritional Properties of Milk.

The milk of mammals is a complex fluid mixture of various proteins, minerals, lipids, and other micronutrients that play a critical role in providing nutrition and immunity to newborns. Casein proteins together with calcium phosphate form large colloidal particles, called casein micelles. Caseins and their micelles have received great scientific interest, but their versatility and role in the functional and nutritional properties of milk from different animal species are not fully understood. Caseins belong to a class of proteins that exhibit open and flexible conformations. Here, we discuss the key features that maintain the structures of the protein sequences in four selected animal species: cow, camel, human, and African elephant. The primary sequences of these proteins and their posttranslational modifications (phosphorylation and glycosylation) that determine their secondary structures have distinctively evolved in these different animal species, leading to differences in their structural, functional, and nutritional properties. The variability in the structures of milk caseins influence the properties of their dairy products, such as cheese and yogurt, as well as their digestibility and allergic properties. Such differences are beneficial to the development of different functionally improved casein molecules with variable biological and industrial utilities.

Efficiency and Mechanism of O3-SBBR Combined Process for Advanced Treatment of Biochemical Effluent from Printing and Dyeing Industrial Park

With the aim of addressing the difficult problem of biodegradable organic nitrogen in biochemical effluent of a printing and dyeing industrial park, the combined ozonation-sequencing batch biofilm reactor (O3-SBBR) process was used for advanced treatment. The influencing factors and degradation kinetics were analyzed; quenching experiments were carried out; and the types of free radicals, succinate dehydrogenase activity, and denitrification function genes were determined. The results showed that the suitable ozonation condition was pH 8.0-8.5, O3 concentration was approximately 35.0 mg·L-1, O3 dosage was approximately 100.0 mg·L-1, and reaction time was 90.0-120.0 min. Organic nitrogen in the biochemical effluent by ozonation conformed to the pseudo first-order kinetic model, and the maximum rate constant k was 0.01035 min-1 (experimental conditions:pH 8.0, ozone dosage 150.0 mg·L-1, and ozone concentration 35.0 mg·L-1). Ozonation significantly improved the denitrification performance of the sequencing biofilm batch reactor (SBBR), and the denitrification efficiency increased from 19.8% (SBBR) to 32.9% (O3-SBBR). Ozonation could convert organic nitrogen and organic substances with strong toxicity and difficult biological utilization into small molecular substances with low toxicity and biodegradability. The abundance of functional genes (nirS, nirK, and nor) in the O3-SBBR combined process was significantly higher than that in the single SBBR, which further confirmed that ozonation could improve the nitrogen removal performance of SBBR. The operation cost of the combined process was 0.74-1.07 yuan·m-3, with good technical economy. This study provided a basis for the application of the O3-SBBR combined process in the advanced treatment of biochemical effluent in printing and dyeing industrial parks.

DOP61 Ethnic disparities in the management of Inflammatory Bowel Disease in Israel and impact on outcomes

Abstract Background In this nationwide study, we aimed to explore health services utilization, medical management, and disease outcomes of inflammatory bowel diseases (IBD) between Jews and Arabs, the two major ethnic groups in Israel. Methods We utilized a cohort including all patients diagnosed with IBD in Israel since 2005. The primary outcome was steroid-dependency, with secondary outcomes including use of biologics, time to surgery, and IBD-related admissions. Outcomes were controlled for possible inherent differences in disease course and phenotype. Results Of the 32,491 included patients, 18,252 (56%) had Crohn’s disease (CD) and 14,239 (44%) had ulcerative colitis (UC); 10% were Arabs and 90% were Jews. Jewish ethnicity was associated with lower rates of steroid-dependency compared to Arab ethnicity in both CD )HR=0.7 [95%CI 0.6-0.8]) and UC (HR=0.7 [95%CI 0.6-0.8]). In addition, Jewish ethnicity was associated with increased use of biologics during the first year from diagnosis in patients with CD (HR=1.3 [95%CI 1.1-1.6]) but not with UC. The risk of IBD-related surgery in CD at 3 and 5 years was higher in the Arab group at all time points (13% vs 10%, 16% vs 14%, respectively, p=0.005). Arabs had higher number of IBD-related hospitalizations than Jews (19% vs. 28% with two or more IBD-related hospitalizations at 5 years, p&amp;lt;0.001). Conclusion Arab ethnicity is associated with higher rate of hospitalizations, steroid-dependency and surgeries on one hand, and lower utilization of biologics on the other. The results should be considered by policy makers to improve access to medical care across all populations.

TREATMENT PATTERNS OF PEDIATRIC AND ADULT PATIENTS WITH ULCERATIVE COLITIS

Abstract OBJECTIVE Ulcerative Colitis (UC) is a chronic disease characterized by continuous inflammation of the colonic and rectal mucosa. Children with UC are more likely to present with extensive disease and have more rapid clinical progression than adults.1 This study compared treatment patterns between pediatric and adult patients with UC. METHODS This retrospective, claims-based, cohort study used data from the Merative L.P Marketscan® Research Database to identify newly diagnosed patients with a confirmed UC diagnosis from January 1, 2014 through December 31, 2021. Pediatric (≤ 17 years) and adult (≥ 18 years) patients with continuous enrollment for 12 months before and 12 months following the first UC diagnosis (index date) who also received at least 1 medication related to inflammatory bowel disease (aminosalicylates, corticosteroids, immunomodulators, or biologics) after the first diagnosis date, were included. Descriptive statistics described treatment patterns for both cohorts. RESULTS This analysis included 1343 pediatric and 37,617 adult patients with UC. The mean (SD) ages (years) for pediatric and adult patients were 13.7 (3.3) and 48.8 (15.3) years, respectively (Table 1). The time from diagnosis to initiation of corticosteroids was numerically shorter in children in contrast to adults (median days between index date and corticosteroids initiation: 15 vs 56). Among all UC patients, aminosalicylates (74.0% adults vs 72.5% children) were the most prescribed monotherapy, followed by corticosteroids (16.6% adults vs 15.3% children) and immunomodulators (5.1% adults vs. 7.4% children). Additionally, children were started on combination therapies numerically more often than adults (32.3% vs 16.7%). The most used combination therapies for both cohorts were aminosalicylates plus corticosteroids (63.0% adults vs 62.4% children), followed by aminosalicylates and immunomodulators (15.3% adults vs 8.3% children). Children had numerically higher utilization of biologics than adults (22.6% vs 10.8%). The persistence rates of all drug therapies within 6 months following initiation in both cohorts were similar (Table 2). Notably, a small proportion of pediatric patients were on ustekinumab, vedolizumab, or tofacitinib as add-on therapy (0.2%, 2.0%, and 0.2%, respectively), despite those medications not being currently approved in this population. CONCLUSION More children with newly diagnosed UC receive combination therapies and have higher utilization of biologics compared to adults. This may reflect greater disease progression and complications in children. REFERENCE 1. Ruemmele, F., Turner, D. Differences in the management of pediatric and adult-onset ulcerative colitis – lessons from the joint ECCO and ESPGHAN consensus guidelines for the management of pediatric ulcerative colitis. Journal of Crohn’s and Colitis, 8(1), January 2014, pages 1-4.

Factors to Consider in Prescribing Asthma Biologic Therapies to Children

The increasing availability of biologics, both by expanding age indications and by development of new therapies, provides additional options to treat children and adolescents with severe asthma. However, the evidence for these biologics in these populations is limited compared with that for adult studies. As such, before initiation of therapy, possible alternative therapies that can also provide asthma control, confirmation of the diagnosis of asthma, management of comorbidities, and assessment of adherence should be explored. The choice of a biologic should be a shared decision-making process between providers and families, balancing biologic efficacy, goals of care, administration, and ability to treat multiple conditions. Response to treatment should be periodically evaluated not only to ensure an ineffective treatment is not continued but also to consider when to potentially discontinue therapy should it be beneficial. The utilization of biologics in children and adolescents with severe asthma also leads to unanswered questions on their role in disease remission and long-term outcomes.

The geochemistry of zinc and copper stable isotopes in marine hydrothermal brine pools: Perspectives from metalliferous sediments of the Atlantis II Deep, Red Sea

This study provides a zinc and copper stable isotope characterization (δ66Zn, δ68Zn, and δ65Cu) of metalliferous seafloor sediments from the Atlantis II Deep, a hydrothermally influenced brine basin in the Red Sea. Samples collected from box cores that capture the entire stratigraphy in the Deep have δ66Zn and δ65Cu values of −0.31 to 0.34 ‰ (0.02 ‰ median) and − 1.81 to 1.02 ‰ (−0.34 ‰ median) relative to the JMC-Lyon and NIST SRM 976 standards, respectively. These results suggest enrichments of light stable isotopes in sediments compared to the hydrothermal inputs to the basin, which likely overlap the mantle-like isotopic signatures of basalts beneath the Deep. Such shifts to lower δ66Zn and δ65Cu values are consistent with widespread metal sulfide deposition from the brines because sulfide anions preferentially consume the light stable isotopes of zinc and copper. However, this interpretation contrasts with observations in the open ocean, where the fractionation of zinc and copper stable isotopes is strongly influenced by biological utilization and organic matter. Previous studies proposed that metal deposition in the Atlantis II Deep is also driven by adsorption onto iron oxides/hydroxides and their weakly crystalline (Si-)Fe-OOH precursor phases within the brines. However, because this process should accumulate heavy zinc and copper stable isotopes, its influence on isotopic fractionation is likely limited. Controls by metal sulfide precipitation are also indicated by spatial covariations between δ66Zn and concentrations of zinc and copper, that is, δ66Zn values increase whereas metal contents decrease with distance away from hydrothermal venting. Comparable trends are lacking for copper isotopes, perhaps because of additional influence by redox processes or, compared to zinc, a much stronger influence by adsorption onto (Si-)Fe-OOH phases, particularly in areas distal to hydrothermal venting where reduced sulfur could be scarce. Collectively, our results from the Atlantis II Deep indicate that zinc and copper stable isotopes could provide information about base and precious metals deposits from similar paleoenvironments. Firstly, zinc and copper stable isotopes shed light on metal sourcing and accumulation processes. Secondly, mineral precipitation in hydrothermally influenced brine pools produces zinc stable isotope patterns that, at least theoretically, could be of interest in mineral exploration at sub-basin and deposit scales.

AuNP-Modulated qPCR: An Optimized System for Detecting MIR Biophotons Released in DNA Replication.

Living systems can utilize energy with a high efficiency. Biophotons are proposed to modulate biological functions with such efficiency; however, the underlying mechanism remains unexplored, especially due to the challenge of ultraweak mid-infrared (MIR) light detection and the theoretical perturbation from spontaneous MIR emission. Here, we proposed an optimized system to detect MIR biophotons generated in the hydrolysis of deoxynucleotide triphosphates (dNTPs, energy-storing molecules similar to ATP). The system used a quantitative polymerase chain reaction (qPCR) that was modulated by gold nanoparticle (AuNP) concentration and thus by the inter-AuNP distance, which depends on the concentration above. The measurements indicate that 33- and 84-THz photons are released by dNTP hydrolysis, which can drive DNA replication. Our findings provide a novel chain-reaction-based method for detecting MIR photons in solution, and pave a way for photon-based insights to understand the highly efficient energy utilization of biology.

An exploration of biosimilar TNF-alpha inhibitors uptake determinants in hospital environments in Italy, Portugal, and Spain.

The availability of biosimilar medicines in Southern European markets has allowed purchasing biologics at a lower cost for healthcare systems. However, the capacity to seize this cost-reduction opportunity in the long run depends on fostering a sustainable competitive environment for all the market players involved. Diverse policies and information campaigns have been launched in Italy, Portugal and Spain to support uptake of "best-value" biologics (BVB). Despite these measures, the utilization of lower-cost biologics in certain regions is low, especially when it comes to the treatment of chronic conditions. We aim to identify biosimilar uptake determinants in hospital environments in Italy, Portugal and Spain, using the class of TNF-alpha inhibitors as an example. This is a mixed-methods study based on (1) the quantitative analysis of regional uptake data for TNF-alpha inhibitor biosimilars and (2) the qualitative processing of semi-structured interviews capturing experts' views on uptake determinants for biosimilars. The organization of multi-stakeholder information campaigns supporting TNF-alpha inhibitor biosimilars use in Italy, Portugal and Spain has resulted in an increased familiarity of healthcare professionals and patients with the prescription/use of these products. However, barriers persist that impede high biosimilars uptake, especially in chronic patient populations eligible for a switch. These are: (1) the late publication of position statements on biosimilars interchangeability by regulatory health authorities; (2) the vague positioning of (national/regional) health authorities on best switching practices (including multiple biosimilar-to-biosimilar switches); (3) the existence of policy frameworks that do not necessarily support the initiation of switching protocols; (4) the establishment of sometimes inefficient purchasing procedures that limit biosimilars potential to compete for market shares. Diverse approaches taken regionally to address these barriers have contributed to heterogeneous TNF-alpha inhibitor biosimilars uptake across Southern Europe. Our research signaled the limited reach of biosimilar policies implemented locally, if not supported by a national policy framework. This study highlights the need for the coordinated implementation of policy measures fostering biosimilars use at the regional and national level in Italy, Portugal and Spain. These measures should account for the particularities of off-patent biologic and biosimilar markets and should jointly address supply- and demand-side challenges.

A benchtop brain injury model using resected donor tissue from patients with Chiari malformation.

The use of live animal models for testing new therapies for brain and spinal cord repair is a controversial area. Live animal models have associated ethical issues and scientific concerns regarding the predictability of human responses. Alternative models that replicate the 3D architecture of the central nervous system have prompted the development of organotypic neural injury models. However, the lack of reliable means to access normal human neural tissue has driven reliance on pathological or post-mortem tissue which limits their biological utility. We have established a protocol to use donor cerebellar tonsillar tissue surgically resected from patients with Chiari malformation (cerebellar herniation towards the foramen magnum, with ectopic rather than diseased tissue) to develop an in vitro organotypic model of traumatic brain injury. Viable tissue was maintained for approximately 2 weeks with all the major neural cell types detected. Traumatic injuries could be introduced into the slices with some cardinal features of post-injury pathology evident. Biomaterial placement was also feasible within the in vitro lesions. Accordingly, this 'proof-of-concept' study demonstrates that the model offers potential as an alternative to the use of animal tissue for preclinical testing in neural tissue engineering. To our knowledge, this is the first demonstration that donor tissue from patients with Chiari malformation can be used to develop a benchtop model of traumatic brain injury. However, significant challenges in relation to the clinical availability of tissue were encountered, and we discuss logistical issues that must be considered for model scale-up.