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Background/Objectives: An inhibitor of small Rho GTPase Cdc42, CASIN, has been shown to reduce cancer cell proliferation, migration, and invasion, yet it has several limitations, including rapid drug elimination and low bioavailability, which prevents its systemic administration. In this study, we designed and characterized a nanoparticle-based delivery system for CASIN encapsulated within poly(lactide-co-glycolide)-block-poly(ethylene glycol)-carboxylic acid endcap nanoparticles (PLGA-PEG-COOH NPs) for targeted inhibition of Cdc42 activity in colon cancer. Methods: We applied DLS, TEM, and UV–vis spectroscopy methods to characterize the size, polydispersity index, zeta potential, encapsulation efficiency, loading capacity, and in vitro drug release of the synthesized nanoparticles. The CCK-8 cell viability test was used to study colorectal cancer cell growth in vitro. Results: We showed that CASIN-PLGA-PEG-COOH NPs were smooth, spherical, and had a particle size of 86 ± 1 nm, with an encapsulation efficiency of 66 ± 5% and a drug-loading capacity of 5 ± 1%. CASIN was gradually released from NPs, reaching its peak after 24 h, and could effectively inhibit the proliferation of HT-29 (IC50 = 19.55 µM), SW620 (IC50 = 9.33 µM), and HCT116 (IC50 = 10.45 µM) cells in concentrations ranging between 0.025–0.375 mg/mL. CASIN-PLGA-PEG-COOH NPs demonstrated low hemolytic activity with a hemolytic ratio of less than 1% for all tested concentrations. Conclusion: CASIN-PLGA-PEG-COOH NPs have high encapsulation efficiency, sustained drug release, good hemocompatibility, and antitumor activity in vitro. Our results suggest that PLGA-PEG-COOH nanoparticles loaded with CASIN show potential as a targeted treatment for colorectal cancer and could be recommended for further in vivo evaluation.

Background and Objectives: This study analyzes the issues of position dislocation of the head of the superior poles and lateral points of the outer edge of the middle divisions of each of the thyroid lobes (TL) changes. The purpose was to provide an intravital position study of the clinical anatomy of the middle and superior poles of the thyroid gland (TG). Materials and Methods: We used data on anthropometry obtained during the study and data from MRI of the neck organs and anatomical formations of 100 healthy individuals, comprising 55 (55%) female and 45 (45%) male participants. To evaluate the data obtained in the examined group, the minimum probability value was 0.95 (95% confidence interval or p < 0.05). Results: Maximum flexion of the neck the distance from the center of the jugular notch to the lateral points of the outer edge of the middle parts of the TL decreases in all groups of but mostly in male ectomorphs; the same distance to the superior poles of the TG changes most in ectomorphic males on the right by 38.9% (p value < 0.001) and mesomorphic females on the left by 37.8% (p value < 0.001); in rotation to the left, the maximum was found in male ectomorphs, which decreased by 9.5% on the left (p value < 0.001) and by 7.3% on the right (p value < 0.001). Conclusions: this study provided new information about the intravital anatomy of the TG position, of the superior poles, and the lateral points of the middle part of its lobes.

Our study aimed to clarify the anatomical features of the zygomatic, upper masseteric, lower masseteric and mandibular ligaments and their possible contribution to age-related gravitational ptosis. The study was carried out by the method of layered dissection of fresh cadavers. In several observations, the zygomatic ligament is represented by the fibers originating from the zygomaticus major muscle fibers. It is a true ligament with the fibers inserted directly into the skin. The upper and lower masseteric ligaments originate from the parotideomasseteric fascia and weave into the thickness of the SMAS. The mandibular ligament consists of two connective tissue laminae originating from the parotideomasseteric fascia at the lower edge of the mandible and from the inner surface of this fascia, along the anterior edge of the masseter muscle, skirting the facial vein sheath and the facial artery, traveling toward the platysma and the depressor anguli oris muscle, and merging with their fibers. The zygomatic ligament should be considered an osteo-musculocutaneous ligament, emphasizing the role of the associated zygomaticus major muscle in the mechanism of aging. The upper and lower masseteric and mandibular ligaments are false fascio-SMAS ligaments rather than osteo-cutaneous ones, playing the barrier role and fixing the superficial fascia and the platysma muscle.

Injuries to humans caused by wild animals, particularly bears, are rarely mentioned in the literature. Such injuries are frequent in Siberia, which is a territory surrounded by dense forests inhabited by brown bears. In the last 4 months alone (September–December 2023), four bear attacks on humans were registered in Khakassia, Russia. This article presents a clinical case of rehabilitating a patient after a bear attack, who suffered multiple fragmentary fractures of the facial skeleton with displaced bone fragments, subcutaneous emphysema of the soft tissues of the face, damage to the parietal and right occipital regions and paranasal sinus hemorrhage on the left side. The nature of the injuries was enhanced by trauma to the upper extremity caused by the patient defending himself against the animal. In addition to the damage to his face, the bear tried to open his cranium, as evidenced by four furrows caused by its canines, including two each on the frontal and occipital bones of the skull. The patient’s complex treatment included both maxillofacial and reconstructive surgeries, and outpatient treatment involved the formation of normotrophic scars using a neodymium laser and injections of a heterogeneous composition consisting of microparticles of “crosslinked” collagen of animal origin placed in a gel identical to the natural extracellular matrix.

We have developed Convacell®—a COVID-19 vaccine based on the recombinant nucleocapsid (N) protein of SARS-CoV-2. This paper details Convacell’s® combined phase I/II and IIb randomized, double-blind, interventional clinical trials. The primary endpoints were the frequency of adverse effects (AEs) and the titers of specific anti-N IgGs induced by the vaccination; secondary endpoints included the nature of the immune response. Convacell® demonstrated high safety in phase I with no severe AEs detected, 100% seroconversion by day 42 and high and sustained for 350 days anti-N IgG levels in phase II. Convacell® also demonstrated a fused cellular and humoral immune response. Phase IIb results showed significant post-vaccination increases in circulating anti-N IgG and N protein-specific IFNγ+-producing PBMC quantities among 438 volunteers. Convacell® showed same level of immunological efficacy for single and double dose vaccination regimens, including for elderly patients. The clinical studies indicate that Convacell® is safe and highly immunogenic.

The prevalence of periodontal diseases is increasing, tends to increase with age and is considered as one of the main causes of tooth loss. To assess the effectiveness of new methods of treatment of periodontal diseases, studies on laboratory animals can be promising. The aim of the study: to develop a new method of accelerated modeling of experimental periodontitis on laboratory animals. Material and methods. The study was carried out on 22 female rats. A wire ligature was applied to the cervical area of the incisors of the animals in an eight-shaped manner. Plaque obtained from a patient with periodontitis was placed under the wire, and nicotine and ethyl alcohol solutions were injected under the gingival mucosa. A complex index has been proposed to assess inflammation. At the end of the experiment the animals were euthanized, their jaws were dissected into dentoalveolar blocks and further descriptive histologic analysis was performed. Results. On the second day the gingiva of the rats acquired a cyanotic-pink color, on the fourth day the consistency of the gingiva became friable, mobility appeared in the lower incisors. Complex index of inflammation in animals of the main group: before the study—9, on the 7th day—195. Gingival preparations showed signs of exudative inflammation. In alveolar processes—irreversible resorption of bone structures. The difference of indicators in animals before and after the experiment was statistically significant (p < 0.05). Conclusion. The new experimental model of periodontitis is reproduced in a short period of time, provides intensive development of inflammation, leads to disruption of the integrity of epithelial and connective tissue attachment, destruction of alveolar bone.

We studied the risk factors, etiology, clinical manifestations, and treatment outcomes of COVID-19-associated invasive candidiasis (COVID-IC) in adult patients admitted to six medical facilities in St. Petersburg. (November 2020–December 2022). In this retrospective study, we included 72 patients with COVID-IC with a median age of 61 years (range 29–96), 51% of whom were women. The predisposing factors for COVID-IC were a central venous catheter (CVC) for more than 10 days (the odds ratio (OR) = 70 [15–309]), abdominal surgical treatment performed in the previous 2 weeks (OR = 8.8 [1.9–40.3]), bacteremia (OR = 10.6 [4.8–23.3]), pulmonary ventilation (OR = 12.9 [5.9–28.4]), and hemodialysis (OR = 11.5 [2.5–50.8]). The signs and symptoms of COVID-IC were non-specific: fever (59%), renal failure (33%), liver failure (23%), and cardiovascular failure (10%). Candida albicans (41%) predominated among the pathogens of the candidemia. The multidrug-resistant Candida species C. auris (23%) and C. glabrata (5%) were also identified. Empirical therapy was used in 21% of COVID-IC patients: azole-93%, echinocandin–7%. The majority of COVID-IC patients (79%) received, after laboratory confirmation of the diagnosis of IC, fluconazole (47%), voriconazole (25%), echinocandin (26%), and amphotericin B (2)%. The 30 days overall survival rate was 45%. The prognosis worsened concomitant bacteremia, hemodialysis, and long-term therapy by systemic glucocorticosteroids (SGCs), bronchial colonization with Candida spp. The survival prognosis was improved by the early change/replacement of CVC (within 24 h), the initiation of empirical therapy, and the use of echinocandin. Conclusions: We highlighted the risk factors that predispose COVID-19 patients to candidiasis and worsen the survival prognosis. Their individual effects in patients with COVID-19 must be well understood to prevent the development of opportunistic co-infections that drastically lower chances of survival.

In this research, for a given time interval, which is the general period of melanoma treatment, a bilinear control model is considered, given by a system of differential equations, which describes the interaction between drug-sensitive and drug-resistant cancer cells both during drug therapy and in the absence of it. This model also contains a control function responsible for the transition from the stage of such therapy to the stage of its absence and vice versa. To find the optimal moments of switching between these stages, the problem of minimizing the cancer cells load both during the entire period of melanoma treatment and at its final moment is stated. Such a minimization problem has a nonconvex control set, which can lead to the absence of an optimal solution to the stated minimization problem in the classes of admissible modes traditional for applications. To avoid this problem, the control set is imposed to be convex. As a result, a relaxed minimization problem arises, in which the optimal solution exists. An analytical study of this minimization problem is carried out using the Pontryagin maximum principle. The corresponding optimal solution is found in the form of synthesis and may contain a singular arc. It shows that there are values of the parameters of the bilinear control model, its initial conditions, and the time interval for which the original minimization problem does not have an optimal solution, because it has a sliding mode. Then for such values it is possible to find an approximate optimal solution to the original minimization problem in the class of piecewise constant controls with a predetermined number of switchings. This research presents the results of the analysis of the connection between such an approximate solution of the original minimization problem and the optimal solution of the relaxed minimization problem based on numerical calculations performed in the Maple environment for the specific values of the parameters of the bilinear control model, its initial conditions, and the time interval.

The vast majority of SARS-CoV-2 vaccines which are licensed or under development focus on the spike (S) protein and its receptor binding domain (RBD). However, the S protein shows considerable sequence variations among variants of concern. The aim of this study was to develop and characterize a SARS-CoV-2 vaccine targeting the highly conserved nucleocapsid (N) protein. Recombinant N protein was expressed in Escherichia coli, purified to homogeneity by chromatography and characterized by SDS-PAGE, immunoblotting, mass spectrometry, dynamic light scattering and differential scanning calorimetry. The vaccine, formulated as a squalane-based emulsion, was used to immunize Balb/c mice and NOD SCID gamma (NSG) mice engrafted with human PBMCs, rabbits and marmoset monkeys. Safety and immunogenicity of the vaccine was assessed via ELISA, cytokine titer assays and CFSE dilution assays. The protective effect of the vaccine was studied in SARS-CoV-2-infected Syrian hamsters. Immunization induced sustainable N-specific IgG responses and an N-specific mixed Th1/Th2 cytokine response. In marmoset monkeys, an N-specific CD4+/CD8+ T cell response was observed. Vaccinated Syrian hamsters showed reduced lung histopathology, lower virus proliferation, lower lung weight relative to the body, and faster body weight recovery. Convacell® thus is shown to be effective and may augment the existing armamentarium of vaccines against COVID-19.

In surgical dentistry, suture material is the only foreign body that remains in the tissues after surgery, and it can lead to several negative reactions, for example, infection of the wound. The purpose of this study was to compare the mechanical properties and microbiological resistance of mono- and polyfilament suture materials used in tooth extraction operations. The study of elongation and knot force was carried out on an Instron 5969 Dual Column Testing System device. The capillarity of the materials was studied on a setup assembled by the authors manually by immersing the ends of the filaments in a colored manganese solution. A microbiological study was carried out on the threads taken for the experiment immediately after wound suturing, and on day 7, at which time they were removed. The comparison was made according to Rothia mucilaginosa, Streptococcus sanguinis, Staphylococcus epidermidis. Results: monofilament suture materials (Prolene and Glycolon), after calculating the Kruskal–Wallis and Mann–Whitney indices, showed better performance in all experiments compared to polyfilament sutures (Vicryl and PGA). In capillarity comparison, there was a significant difference between groups (p = 0.00018). According to the sum of the results of three microbiological studies on day 7, monofilament suture materials absorbed less of the studied bacteria on their surface compared to the polyfilament ones (p < 0.05). Conclusions: Of the studied suture materials, Prolene had the best microbiological resistance and good mechanical properties.

Vitamin D deficiency has been linked with adverse events in various liver diseases. The present study aimed to recognize the association between severe vitamin D deficiency and disease progression, hepatobiliary malignancies, liver-related mortality, and the need for liver transplantation in primary sclerosing cholangitis (PSC). Patients with a diagnosis of PSC (n = 354), followed by the autoimmune liver disease clinic at the University of Alberta, were included. Patients with vitamin D levels < 25 nmol/L were defined as severely deficient. Univariate and multivariate analyses were conducted using the Cox proportional hazards regression models. The mean vitamin D level was 59 ± 2 nmol/L, and 63 patients (18%) had a severe vitamin D deficiency. Patients with a severe vitamin D deficiency were 2.5 times more likely to experience hepatobiliary malignancies (HR 2.55, 95% CI, 1.02–6.40, p = 0.046). A severe vitamin D deficiency at diagnosis (HR 1.82, 95% CI, 1.05–3.15, p = 0.03) and persistent deficiencies over time (HR 2.26, 95% CI, 1.17–4.37, p = 0.02) were independently associated with a higher risk of poor clinical liver outcomes. A severe vitamin D deficiency at diagnosis and persistent deficiency at longitudinal assessments were associated with liver-related mortality or the need for liver transplantation.

FLASH radiotherapy, or the delivery of a dose at an ultra-high dose rate (>40 Gy/s), has recently emerged as a promising tool to enhance the therapeutic index in cancer treatment. The remarkable sparing of normal tissues and equivalent tumor control by FLASH irradiation compared to conventional dose rate irradiation—the FLASH effect—has already been demonstrated in several preclinical models and even in a first patient with T-cell cutaneous lymphoma. However, the biological mechanisms responsible for the differential effect produced by FLASH irradiation in normal and cancer cells remain to be elucidated. This is of great importance because a good understanding of the underlying radiobiological mechanisms and characterization of the specific beam parameters is required for a successful clinical translation of FLASH radiotherapy. In this review, we summarize the FLASH investigations performed so far and critically evaluate the current hypotheses explaining the FLASH effect, including oxygen depletion, the production of reactive oxygen species, and an altered immune response. We also propose a new theory that assumes an important role of mitochondria in mediating the normal tissue and tumor response to FLASH dose rates.

Cryogels are a unique macroporous material for tissue engineering. In this work, we study the effect of hyaluronic acid on the physicochemical properties of cryogel as well as on the proliferation of a 3D model of mesenchymal stem cells. The functional groups of the synthesized cryogels were identified using Fourier transform infrared spectroscopy. With an increase in the content of hyaluronic acid in the composition of the cryogel, an increase in porosity, gel content and swelling behavior was observed. As the hyaluronic acid content increased, the average pore size increased and more open pores were formed. Degradation studies have shown that all cryogels were resistant to PBS solution for 8 weeks. Cytotoxicity assays demonstrated no toxic effect on viability of rat adipose-derived mesenchymal stem cells (ADMSCs) cultured on cryogels. ADMSC spheroids were proliferated on scaffolds and showed the ability of the cryogels to orient cell differentiation into chondrogenic lineage even in the absence of inductive agents. Thus, our results demonstrate an effective resemblance to extracellular matrix structures specific to cartilage-like microenvironments by cryogels and their further perspective application as potential biomaterials.

Glioblastoma leads to a fatal course within two years in more than two thirds of patients. An essential cornerstone of therapy is chemotherapy with temozolomide (TMZ). The effect of TMZ is counteracted by the cellular repair enzyme O6-methylguanine-DNA methyltransferase (MGMT). The MGMT promoter methylation, the main regulator of MGMT expression, can change from primary tumor to recurrence, and TMZ may play a significant role in this process. To identify the potential mechanisms involved, three primary stem-like cell lines (one astrocytoma with the mutation of the isocitrate dehydrogenase (IDH), CNS WHO grade 4 (HGA)), and two glioblastoma (IDH-wildtype, CNS WHO grade 4) were treated with TMZ. The MGMT promoter methylation, migration, proliferation, and TMZ-response of the tumor cells were examined at different time points. The strong effects of TMZ treatment on the MGMT methylated cells were observed. Furthermore, TMZ led to a loss of the MGMT promoter hypermethylation and induced migratory rather than proliferative behavior. Cells with the unmethylated MGMT promoter showed more aggressive behavior after treatment, while HGA cells reacted heterogenously. Our study provides further evidence to consider the potential adverse effects of TMZ chemotherapy and a rationale for investigating potential relationships between TMZ treatment and change in the MGMT promoter methylation during relapse.

Vitamin D (VD) deficiency has been associated with clinical outcomes in patients with chronic liver disease. This study aims to identify the prevalence of VD deficiency in patients with primary biliary cholangitis (PBC) and its association with treatment response to ursodeoxycholic acid (UDCA), cirrhosis development, and liver-related events (mortality and liver transplantation). Two hundred and fifty-five patients with PBC diagnosis were evaluated. Patients with VD levels below 50 nmol/L were defined as deficient. Treatment response to UDCA was defined according to the Toronto criteria. Independent risk factors were identified using binary logistic and Cox regression analysis. The mean level of serum VD was 77 ± 39 nmol/L, and 64 patients (25%) were VD deficient. Incomplete response to UDCA was more prevalent in VD-deficient patients compared to their counterparts (45% vs. 22%; p < 0.001). The risk of cirrhosis development (hazard ratio (HR) 1.93; 95% confidence interval (CI) 1.17–3.19, p = 0.01) and liver-related mortality or need for liver transplantation (HR 3.33, 95% CI, 1.57–7.07, p = 0.002) was higher in VD-deficient patients after adjusting for confounders. Vitamin D deficiency is frequent in patients with PBC and is associated with incomplete response to UDCA, cirrhosis development, and liver-related mortality or need for liver transplantation.

We studied the risk factors, etiology, clinical features and the effectiveness of therapy of COVID-19-associated pulmonary aspergillosis (CAPA) in adult patients. In this retrospective study, we included 45 patients with proven (7%) and probable (93%) CAPA. The ECMM/ISHAM, 2020 criteria were used to diagnose CAPA. A case-control study was conducted to study the risk factors of CAPA; the control group included 90 adult COVID-19 patients without IA. In CAPA patients, the main underlying diseases were diabetes mellitus (33%), and hematological and oncological diseases (31%). The probability of CAPA developing significantly increased with lymphocytopenia >10 days (OR = 8.156 (3.056–21.771), p = 0.001), decompensated diabetes mellitus (29% vs. 7%, (OR = 5.688 (1.991–16.246), p = 0.001)), use of glucocorticosteroids (GCS) in prednisolone-equivalent dose > 60 mg/day (OR = 4.493 (1.896–10.647), p = 0.001) and monoclonal antibodies to IL-1ß and IL-6 (OR = 2.880 (1.272–6.518), p = 0.01). The main area of localization of CAPA was the lungs (100%). The clinical features of CAPA were fever (98% vs. 85%, p = 0.007), cough (89% vs. 72%, p = 0.002) and hemoptysis (36% vs. 3%, p = 0.0001). Overall, 71% of patients were in intensive care units (ICU) (median—15.5 (5–60) days), mechanical ventilation was used in 52% of cases, and acute respiratory distress syndrome (ARDS) occurred at a rate of 31%. The lung CT scan features of CAPA were bilateral (93%) lung tissue consolidation (89% vs. 59%, p = 0.004) and destruction (47% vs. 1%, p = 0.00001), and hydrothorax (26% vs. 11%, p = 0.03). The main pathogens were A. fumigatus (44%) and A. niger (31%). The overall survival rate after 12 weeks was 47.2%.

The application of biopolymers in tissue engineering is of a great interest due to of their inherent properties such as cell adhesion, biodegradation, bioavailability, and viscoelasticity. In this study, we synthesized cryogels based on biopolymers of gelatin, chitosan, and chondroitin sulfate by cryopolymerization and studied the effect of chondroitin sulfate on changing the physicochemical properties of cryogels such as pore size, pore volume, density, gel fraction, and biodegradation. A macroporous surface of the synthesized polymers has been investigated by SEM. The glass transition temperatures of the crosslinked cryogels, determined by the DSC method, were higher compared to that of the non-crosslinked cryogel used as a reference. The results of the MTT test showed that aqueous extracts of the prepared cryogels had no toxic effect on rat adipose-derived mesenchymal stem cells. The research in this area is of great importance and provides new insights into novel, effective methods for obtaining biopolymers that can be used as carriers of cells.

Optimal control theory is a modern extension of the classical calculus of variations [...]

Incorporation of heavy metal ions in cement hydrates is of great interest for the storage and immobilization of toxic, hazardous, and radioactive wastes using cementitious matrix. Magnesium silicate hydrate (M-S-H) is a low pH alternative cementitious binder to commonly used Portland cement. Low pH cements have been considered as promising matrix for municipal and nuclear waste immobilization in the last decades. It is however crucial to assure that the incorporation of secondary ions is not detrimental for the formation of the hydration products. Herein, we investigate the early stages of formation of M-S-H from electrolyte solutions in presence of a wide range of metal cations (LiI, BaII, CsI, CrIII, FeIII, CoII, NiII, CuI, ZnII, PbII, AlIII). The final solid products obtained after 24 h have been characterized via powder X-ray diffraction (PXRD), attenuated total reflectance-Fourier transformed infrared spectroscopy (FTIR-ATR), elemental analysis via energy-dispersive X-ray spectroscopy (EDX), scanning electron microscopy (SEM), and high-resolution transmission electron microscopy (HR-TEM). In all the experiments, the main precipitated phase after 24 h was confirmed to be M-S-H with a ratio (total metal/Si) close to one. The obtained M-S-H products showed strong immobilization capacity for the secondary metal cations and can incorporate up to 30% of the total metal content at the early stages of M-S-H formation without significantly delaying the nucleation of the M-S-H. It has been observed that presence of Cr, Co, and Fe in the solution is prolonging the growth period of M-S-H. This is related to a higher average secondary metal/total metal ratio in the precipitated material. Secondary phases that co-precipitate in some of the experiments (Fe, Pb, Ni, and Zn) were also effectively trapped within in the M-S-H matrix. Barium was the only element in which the formation of a secondary carbonate phase isolated from the M-S-H precipitates was detected.

Despite the high regenerative capacity of bone tissue, there are some cases where bone repair is insufficient for a complete functional and structural recovery after damage. Current surgical techniques utilize natural and synthetic bone grafts for bone healing, as well as collagen sponges loaded with drugs. However, there are certain disadvantages associated with these techniques in clinical usage. To improve the therapeutic efficacy of bone tissue regeneration, a number of drug delivery systems based on biodegradable natural and synthetic polymers were developed and examined in in vitro and in vivo studies. Recent studies have demonstrated that biodegradable polymers play a key role in the development of innovative drug delivery systems and tissue engineered constructs, which improve the treatment and regeneration of damaged bone tissue. In this review, we discuss the most recent advances in the field of polymer-based drug delivery systems for the promotion of bone tissue regeneration and the physical-chemical modifications of polymers for controlled and sustained release of one or more drugs. In addition, special attention is given to recent developments on polymer nano- and microparticle-based drug delivery systems for bone regeneration.

CAR T-cell immunotherapy is a new development in the treatment of leukemia, promising a new era in oncology. Although so far, this procedure only helps 50–90% of patients and, like other cancer treatments, has serious side effects. In this work, we have proposed a controlled model for leukemia treatment to explore possible ways to improve immunotherapy methodology. Our model is described by four nonlinear differential equations with two bounded controls, which are responsible for the rate of injection of chimeric cells, as well as for the dosage of the drug that suppresses the so-called “cytokine storm”. The optimal control problem of minimizing the cancer cells and the activity of the cytokine is stated and solved using the Pontryagin maximum principle. The five possible optimal control scenarios are predicted analytically using investigation of the behavior of the switching functions. The optimal solutions, obtained numerically using BOCOP-2.2.0, confirmed our analytical findings. Interesting results, explaining, why therapies with rest intervals (for example, stopping injections in the middle of the treatment interval) are more effective (within the model), rather than with continuous injections, are presented. Possible improvements to the mathematical model and method of immunotherapy are discussed.

A SEIR control model describing the Ebola epidemic in a population of a constant size is considered over a given time interval. It contains two intervention control functions reflecting efforts to protect susceptible individuals from infected and exposed individuals. For this model, the problem of minimizing the weighted sum of total fractions of infected and exposed individuals and total costs of intervention control constraints at a given time interval is stated. For the analysis of the corresponding optimal controls, the Pontryagin maximum principle is used. According to it, these controls are bang-bang, and are determined using the same switching function. A linear non-autonomous system of differential equations, to which this function satisfies together with its corresponding auxiliary functions, is found. In order to estimate the number of zeroes of the switching function, the matrix of the linear non-autonomous system is transformed to an upper triangular form on the entire time interval and the generalized Rolle’s theorem is applied to the converted system of differential equations. It is found that the optimal controls of the original problem have at most two switchings. This fact allows the reduction of the original complex optimal control problem to the solution of a much simpler problem of conditional minimization of a function of two variables. Results of the numerical solution to this problem and their detailed analysis are provided.

Drought has been a major limiting factor for rice production. Drought yield QTLs (qDTYs; QTLs = quantitative trait loci) were pyramided into MRQ74 and MR219 to produce drought tolerant lines. In this study, new drought tolerant MRQ74 and MR219 pyramided lines (PLs) were evaluated under drought stress (RS) and non-stress (NS) conditions to evaluate the effects of different qDTYs combinations on morphological and agronomical traits. MRQ74 PLs having qDTY12.1 possessed the best root length (RL) under both RS and NS but the effect was only significant for MR219 PLs under RS. Some qDTYs combinations also found to have consistent effect on the same trait of both populations. PLs with only qDTY12.1 showed the highest grain yield (GY) under RS in both populations which means qDTY12.1 controlled RL and caused higher GY under drought condition. The interaction of major-effect qDTY12.1 with qDTY2.2 also shows significant effect on leaf rolling (LR) of both PL populations. These qDTYs proved to be beneficial in improving traits related to drought tolerance. Selected PLs with qDTY12.1 combinations also found to have better RL and root weight (RW) under RS. Improvement of morphological and agronomical traits led to higher GY of PLs. Therefore, qDTY12.1 either is present singly or in combination with other qDTYs was the best qDTY due to its consistent effect on morphological and agronomical traits and GY across populations under RS and NS.

Within a given time interval we consider a nonlinear system of differential equations describing psoriasis treatment. Its phase variables define the concentrations of T-lymphocytes, keratinocytes and dendritic cells. Two scalar bounded controls are introduced into this system to reflect medication dosages aimed at suppressing interactions between T-lymphocytes and keratinocytes, and between T-lymphocytes and dendritic cells. For such a controlled system, a minimization problem of the concentration of keratinocytes at the terminal time is considered. For its analysis, the Pontryagin maximum principle is applied. As a result of this analysis, the properties of the optimal controls and their possible types are established. It is shown that each of these controls is either a bang-bang type on the entire time interval or (in addition to bang-bang type) contains a singular arc. The obtained analytical results are confirmed by numerical calculations using the software “BOCOP-2.0.5”. Their detailed analysis and the corresponding conclusions are presented.

Leishmaniasis is a neglected tropical vector-borne epidemic disease, and its transmission is a complex process. Zoonotic transmission to humans or animals occurs through the bites of female Phlebotominae sand flies. Here, reservoir is considered as a major source of endemic pathogen pool for disease outbreak, and the role of more than one reservoir animal becomes indispensable. To study the role of the reservoir animals on disease dynamics, a mathematical model was constructed consisting of susceptible and infected populations of humans and two types of reservoir (animal) and vector populations, respectively. Our aim is to prevent the disease by applying a control theoretic approach, when more than one type of reservoir animal exists in the region. We use drugs like sodium stibogluconate and meglumine antimoniate to control the disease for humans and spray insecticide to control the sand fly population. Similarly, drugs are applied for infected reservoir animals of Types A and B. We calculated the cost-effectiveness of all possible combinations of the intervention and control policies. One of our findings is that the most cost-effective case for Leishmania control is the spray of insecticides for infected sand fly vector. Alternate strategic cases were compared to address the critical shortcomings of single strategic cases, and a range of control strategies were estimated for effective control and economical benefit of the overall control strategy. Our findings provide the most innovative techniques available for application to the successful eradication of cutaneous leishmaniasis in the future.