Current Candidates Research Articles

High transparency of PbO–BaO–Fe2O3–SrO–B2O3 glasses with improved radiation shielding properties

This study investigated the role of PbO and BaO on the optical and radiation shielding properties of PbO–Fe2O3–SrO–B2O3–BaO glass systems. Optical studies indicate that the prepared glass samples are transparent within the visible spectrum; the transparency increases marginally with increasing PbO/BaO concentrations. Furthermore, by increasing the PbO/BaO ratio, the BO4 units increase (BO3 units decrease), and the density values increase. In addition, the optical band gaps widen, and linear and nonlinear refractive indices decrease. The reductions in nonbridging oxygen were responsible for the increased band gaps and decreased refractive index behavior. Moreover, the ionizing radiation shielding studies showed improved behavior with additional PbO additives. Also, the HVL values of the present glass samples are comparatively lower than the HVL of some standard ionizing radiation shielding materials. Finally, the combination of effective radiation shielding properties and high transparency makes the current glass samples good candidates in the ionizing radiation shielding field.

Host Responses to Respiratory Syncytial Virus Infection.

Respiratory syncytial virus (RSV) infections are a constant public health problem, especially in infants and older adults. Virtually all children will have been infected with RSV by the age of two, and reinfections are common throughout life. Since antigenic variation, which is frequently observed among other respiratory viruses such as SARS-CoV-2 or influenza viruses, can only be observed for RSV to a limited extent, reinfections may result from short-term or incomplete immunity. After decades of research, two RSV vaccines were approved to prevent lower respiratory tract infections in older adults. Recently, the FDA approved a vaccine for active vaccination of pregnant women to prevent severe RSV disease in infants during their first RSV season. This review focuses on the host response to RSV infections mediated by epithelial cells as the first physical barrier, followed by responses of the innate and adaptive immune systems. We address possible RSV-mediated immunomodulatory and pathogenic mechanisms during infections and discuss the current vaccine candidates and alternative treatment options.

Whole-genome surveillance identifies markers of Plasmodium falciparum drug resistance and novel genomic regions under selection in Mozambique.

Malaria is a devastating disease caused by Plasmodium parasites. The evolution of parasite drug resistance continues to hamper progress toward malaria elimination, and despite extensive efforts to control malaria, it remains a leading cause of death in Mozambique and other countries in the region. The development of successful vaccines and identification of molecular markers to track drug efficacy are essential for managing the disease burden. We present an analysis of the parasite genome in Mozambique, a country with one of the highest malaria burdens globally and limited available genomic data, revealing current selection pressure. We contribute additional evidence to limited prior studies supporting the effectiveness of SWGA in producing reliable genomic data from complex clinical samples. Our results provide the identity of genomic loci that may be associated with current antimalarial drug use, including artemisinin and lumefantrine, and reveal selection pressure predicted to compromise the efficacy of current vaccine candidates.

Query-based selection of optimal candidates under the Mallows model

We study the secretary problem in which rank-ordered lists are generated by the Mallows model and the goal is to identify the highest ranked candidate through a sequential interview process which does not allow rejected candidates to be revisited. The main difference between our formulation and existing models is that, during the selection process, we are given a fixed number of opportunities to query an infallible expert whether the current candidate is the highest-ranked or not. If the response is positive, the selection process terminates, otherwise, the search continues until a new potentially optimal candidate is identified. Our optimal interview strategy, as well as the expected number of candidates interviewed and expected number of queries used can be determined through the evaluation of well-defined recurrence relations. Specifically, if we are allowed to query s−1 times and to make a final selection without querying (thus, making s selections in total) then the optimum scheme is characterized by s thresholds that depend on the parameter θ of the Mallows distribution but are independent on the maximum number of queries.

Criteria for central respiratory chemoreceptors: experimental evidence supporting current candidate cell groups.

An interoceptive homeostatic system monitors levels of CO2/H+ and provides a proportionate drive to respiratory control networks that adjust lung ventilation to maintain physiologically appropriate levels of CO2 and rapidly regulate tissue acid-base balance. It has long been suspected that the sensory cells responsible for the major CNS contribution to this so-called respiratory CO2/H+ chemoreception are located in the brainstem-but there is still substantial debate in the field as to which specific cells subserve the sensory function. Indeed, at the present time, several cell types have been championed as potential respiratory chemoreceptors, including neurons and astrocytes. In this review, we advance a set of criteria that are necessary and sufficient for definitive acceptance of any cell type as a respiratory chemoreceptor. We examine the extant evidence supporting consideration of the different putative chemoreceptor candidate cell types in the context of these criteria and also note for each where the criteria have not yet been fulfilled. By enumerating these specific criteria we hope to provide a useful heuristic that can be employed both to evaluate the various existing respiratory chemoreceptor candidates, and also to focus effort on specific experimental tests that can satisfy the remaining requirements for definitive acceptance.

Partial response continuous phase modulation with a prolate spheroidal wave function for compass system in the S-band

Continuous phase modulation (CPM) has the characteristics of high power efficiency, spectral efficiency, and less out-of-band radiation, which is very suitable for the Compass S-band (2483.5–2500 MHz) with limited power and bandwidth. However, as more and more navigation systems share the S-band, the mutual interference between different systems is gradually increasing, and the compatibility of CPM signals with rectangular or raised cosine pulses needs to be further improved. To enhance the navigation performance and compatibility of current CPM candidate signals, we propose to apply continuous phase modulation with prolate spheroidal wave function (CPM-PSWF) to S-band navigation. The proposed modulation scheme selects PSWF with excellent time-frequency energy aggregation and flexible time-bandwidth product as the frequency pulse function of CPM. Then, the influence of key modulation parameters such as M, L, h, and C on CPM-PSWF power spectral density is analyzed, and a specific partial-response CPM-PSWF signal is proposed as the S-band candidate navigation signal. Finally, the navigation performance evaluation criteria are derived, and the proposed signal scheme and existing candidate schemes are comprehensively evaluated. Theoretical analysis and simulation results indicate that compared with CPM with BM2RC(8), cos-phase binary offset carrier (BOCc(4,4)), sin-phase binary offset carrier (BOCs(4,4)), minimum shift keying-BOCs (MSK-BOCs(4,4)) and binary offset carrier (BPSK(8)), the proposed signal scheme not only delivers exceptional spectral performance but also exhibits superior performance in code tracking accuracy and multipath suppression. In addition, in the acquisition and tracking phase, compared with other candidate signals except for BOCc(4,4), the mutual interference between the proposed signal scheme and most S-band signals is the lowest, which is easier to realize the compatibility of the Compass system with IRNSS, Galileo, and Globalstar systems.

Capturing geometric structure change through deformation aware correlation

Capturing the inner structure change of the target is crucial for a siamese tracker confronted with severe deformation or occlusion. The conventional siamese tracker utilizes a strict grid-to-grid correlation to pass the template information towards the current candidate, which may suffer severe mismatch compared to the initial frame caused by undesirable conditions such as rotation and deformation. Thus such mismatch would lead to insufficient information passed from the template and eventually end with a poor performance in classification and regression branches. The inherent CNN structure with the restricted grid-to-grid matching mechanism during correlation is not able to capture the corresponding change of the target structure. Motivated by DCNv2, we propose a novel deformation aware correlation to replace the widely-used depthwise-correlation. An offset-prediction module is proposed based on the similarity matrix to compensate for the mismatch of the grid assignment between template and candidate. Then we utilize an importance bilinear sampling algorithm to assess the similarity of the matching pair, alleviating the occlusion drift problem. Finally, a modulated deformable correlation is fed into the aforementioned input and realizes a better information modulation. We replace the correlation operator on SiamRPN++ with our deformation aware correlation operator and obtain our tracker, SiamDAC. Massive experiments on OTB100, UAV123, VOT2019, LaSOT and DTB70 validate the effectiveness of our proposed operator, especially confronted with severe deformation or occlusion.

Drug Candidates for the Treatment of Alzheimer’s Disease: New Findings from 2021 and 2022

Alzheimer’s disease (AD), an ongoing neurodegenerative disorder among the elderly, is signalized by amnesia, progressive deficiency in cognitive roles, and behavioral deformity. Over the last ten years, its pathogenesis still remains unclear despite several efforts from various researchers across the globe. There are certain factors that seem to be involved in the progression of the disease such as the accumulation of β-amyloid, oxidative stress, the hyperphosphorylation of tau protein, and a deficit of acetylcholine (ACh). Ongoing therapeutics are mainly based on the cholinergic hypothesis, which suggests that the decrease in the ACh levels leads to the loss of memory. Therefore, increasing the cholinergic function seems to be beneficial. Acetylcholinesterase inhibitors (AChEIs) inhibit the enzyme by avoiding the cleavage of acetylcholine (ACh) and increasing the neurotransmitter acetylcholine (ACh) levels in the brain areas. Thus, the cholinergic deficit is the root cause of Alzheimer’s disease (AD). Currently, drugs such as tacrine, donepezil, rivastigmine, and galantamine have been launched on the market for a cholinergic approach to AD to increase neurotransmission at cholinergic synapses in the brain and to improve cognition. These commercialized medicines only provide supportive care, and there is a loss of medicinal strength over time. Therefore, there is a demand for investigating a novel molecule that overcomes the drawbacks of commercially available drugs. Therefore, butyrylcholinesterase (BChE), amyloid-β (Aβ), β-secretase-1 (BACE), metals Cu(II), Zn(II), or Fe(II), antioxidant properties, and the free radical scavenging capacity have been primarily targeted in the preceding five years along with targeting the AChE enzyme. A desired, well-established pharmacological profile with a number of hybrid molecules incorporating substructures within a single scaffold has been investigated. From distinct chemical categories such as acridine, quinoline, carbamate, huperzine, and other heterocyclic analogs, the main substructures used in developing these molecules are derived. The optimization of activity through structural modifications of the prototype molecules has been followed to develop the Structure Activity Relationship (SAR), which in turn facilitates the development of novel molecules with expected AChE inhibitory activity together with many more pharmacological properties. The present review outlines the current drug candidates in the advancement of these AChEIs in the last two years.

Improvements to CPCES

This paper introduces three improvements to the conformant planner CPCES, which continuously searches candidate plans and counter-examples against the current candidate plan until a valid plan (no counter-example exists) is found. First, we identify and merge equivalent PDDL facts to accelerate candidate plan generation. Second, we warm-start CPCES by generating multiple carefully selected counter-examples at the beginning of the procedure, which reduces the number of calls to the classical planner. Third, we investigate the use Fast Downward (FD) as the candidate plan generator; in particular, we propose an incremental procedure to generate the SAS+ file used by FD. Our experimental results show significant improvements for each technique.

Elucidating the effect of La2O3–B2O3 exchange on structure, optical and radiation shielding improvements of Na2O–NiO–B2O3 glass

In this work, borate glass systems containing lanthanum oxide (La2O3), nickel oxide (NiO), and sodium oxide (Na2O) were prepared using the melt quenching technique by changing the La2O3/B2O3 contents. Furthermore, the structural, optical, and radiation shielding characteristics of these glasses were investigated. Optical transmittance was measured to show that all glass samples have good transparency in the visible range. Structurally, with increasing La2O3/B2O3 contents, the density increases (from 2.226 to 3.184 g.cm−3), the molar volume decreases, and the average bond density increases. Furthermore, with increasing La2O3/B2O3 contents, the refractive index and optical basicity shift toward higher values while the electronegativity decreases. On the other hand, the radiation shielding properties, such as mass attenuation coefficient and half value layer, show enhanced behaviors with further La2O3 additions. Further, we found that the HVL of the highest La2O3-containing glass samples is smaller than all commonly used radiation shielding materials. Finally, the combination of enhanced radiation shielding properties and good transparency makes the current glasses good candidates in the radiation shielding field.

Resident Selection Criteria in Veterinary Medicine.

With the continued rise of interest and need for veterinary specialists, information regarding optimal selection criteria for successful residency candidates has been lacking in veterinary medicine. A 28-question online survey was developed to determine prioritized resident selection criteria, the importance of formal interviews, and residency supervisor satisfaction with the current selection process. This survey was sent to all programs listed by the Veterinary Internship and Residency Matching Program (VIRMP) for the 2019-2020 program year. Overall, the most important aspects of the residency application process were (1) letters of recommendation, (2) performance during the interview, (3) personal contact/recommendation from a colleague, (4) personal statement, and (5) demonstrated interest in the residency specialty. While measures of academic performance including GPA and veterinary class rank may play a role in sorting of candidates in more competitive specialties, this does not necessarily exclude them from the ranking process. This information should be helpful to candidates and program directors alike in understanding the success of the current residency candidate selection process.

An updated review on the genetics of arteriovenous malformations.

Arteriovenous malformations (AVM) are congenital malformations of the cerebral vasculature resulting in pathological shunting of blood through dilated arteries and veins. The most common clinical manifestations of AVM are intracerebral hemorrhage, due to rupture of these lesions as they continue to expand, which can have devastating neurological consequences and residual deficits. The genetic underpinnings of AVM have been explored for their role in the angiogenesis of these lesions in both its sporadic and inherited forms. In recent times, our understanding of the genetic variation involved in the pathogenesis AVM has advanced in both the preclinical and clinical realms. The current review highlights in detail these advancements, namely, the genetic underpinnings of diagnostic testing and profiling of AVM, and the preclinical epigenetic and genetic data on AVM pathogenesis and growth. In addition, we review the current candidate genes implicated in AVM pathogenesis in the literature. Finally, we provide a discussion on the genetic conditions associated with AVM and the advancements in treatment paradigms influenced by the genetic profiles of these lesions.

The views and experiences of candidates and graduates from a South African emergency medicine doctoral programme.

With the emergency medicine speciality in its nascency in Africa, EM doctoral programmes will need to be developed to facilitate the establishment of an evidence base that is responsive to the African populace. This study aimed to understand the thoughts, experiences, and opinions of current and past candidates of a South African EM PhD programme. Descriptive, qualitative, semi-structured interviews were used to gather data on PhD EM candidates and graduates. Four candidates, and four graduates were interviewed. Four categories emerged from the data 1) interviewees had various motivations for starting a PhD in EM, 2) candidate expectations and learning needs were not always aligned with reality, and the challenges and opportunities for success in the PhD programme are related both 3) intrinsically (candidate) and 4) extrinsically (system). Many of the barriers noted by the participants can be related to the nascency of the EM in Africa. Participants felt underprepared for their doctorate in terms of their baseline research literacy and skill. Candidates did not receive the level of student-supervisor engagement they desired. Candidates who are also clinicians faced both academic challenges and a resource-limited healthcare system. Pre-doctoral training may upskill prospective candidates in research literacy before they officially register. Distance-learning can be sub-optimal in terms of social interaction and collaboration. A well-curriculated, competency-based programme with clear outcomes, structured teaching-learning opportunities, intentional academic support throughout the programme, can mitigate the above. Protected academic time, promotion criteria which acknowledges academic contributions, financial incentives and more joint positions between universities and clinical services are potential solutions for clinician researcher challenges. An African PhD EM programme should produce graduates who are independent researchers, skilled in academic supervision and who are impactful to African needs when contributing to the African EM knowledge economy.

Stressed stability and protective efficacy of lead lyophilized formulations of ID93+GLA-SE tuberculosis vaccine

With the recent exception of coronavirus disease 2019 (COVID-19), tuberculosis (TB) causes more deaths globally than any other infectious disease, and approximately 1/3 of the world's population is infected with Mycobacterium tuberculosis (Mtb). However, encouraging progress in TB vaccine development has been reported, with approximately 50% efficacy achieved in Phase 2b clinical testing of an adjuvanted subunit TB vaccine candidate. Nevertheless, current lead vaccine candidates require cold-chain transportation and storage. In addition to temperature stress, vaccines may be subject to several other stresses during storage and transport, including mechanical, photochemical, and oxidative stresses. Optimal formulations should enable vaccine configurations with enhanced stability and decreased sensitivity to physical and chemical stresses, thus reducing reliance on the cold chain and facilitating easier worldwide distribution. In this report, we describe the physicochemical stability performance of three lead thermostable formulations of the ID93 + GLA-SE TB vaccine candidate under various stress conditions. Moreover, we evaluate the impact of thermal stress on the protective efficacy of the vaccine formulations. We find that formulation composition impacts stressed stability performance, and our comprehensive evaluation enables selection of a lead single-vial lyophilized candidate containing the excipient trehalose and Tris buffer for advanced development.

Structure-guided discovery of adenosine triphosphate-competitive casein kinase 2 inhibitors.

Casein kinase 2 (CK2) is a ubiquitous, highly pleiotropic serine-threonine kinase. CK2 has been identified as a potential drug target for the treatment of cancer and related disorders. Several adenosine triphosphate-competitive CK2 inhibitors have been identified and have progressed at different levels of clinical trials. This review presents details of CK2 protein, structural insights into adenosine triphosphate binding pocket, current clinical trial candidates and their analogues. Further, it includes the emerging structure-based drug design approaches, chemistry, structure-activity relationship and biological screening of potent and selective CK2 inhibitors. The authors tabulated the details of CK2 co-crystal structures because these co-crystal structures facilitated the structure-guided discovery of CK2 inhibitors. The narrow hinge pocket compared with related kinases provides useful insights into the discovery of CK2 inhibitors.

FFCSA - Finite Field Constructions, Search, and Algorithms

In this work we present the new GAP package FFCSA - Finite Field Constructions, Search, and Algorithms. It was designed to enable Design Space Exploration for hardware implementations of cryptographic algorithms defined over finite fields. FFCSA constructions and searches are used to produce the design space, and FFCSA algorithms, parameterized for the current candidate field, are used to generate expressions needed for implementation in hardware.

Compositional dependence of transparency, linear and non-linear optical parameters, and radiation shielding properties in lanthanum, iron and calcium borate glasses

In this paper, we synthesized a novel lanthanum, iron, and calcium borate glasses system by changing lanthanum oxide (La2O3)/boron oxide (B2O3) contents and investigated their structure, optical parameters, and radiation shielding characteristics. Optical absorbance and transmittance were measured, while the optical band gap values were obtained by investigating the fundamental absorption edges via Tauc's plot. Our analyses show that all glass samples show good transparency in the visible range; further, the transparency increases from 64% to 72.5% (at 600 nm) with increasing La2O3/B2O3 contents. Moreover, with increasing La2O3/B2O3 contents, the fourfold coordinated boron units (BO4) increase, the density increases, and the trigonal boron units (BO3) decrease. Furthermore, with increasing La2O3/B2O3 contents, the fundamental absorption edges shift toward higher wavelengths, and the optical band gaps decrease. Also, with increasing La2O3/B2O3 contents, the linear and non-linear refractive indices increase. These behaviors were justified by the decreased electronegativity and increased electronic polarizability values. On the other hand, the radiation shielding properties, such as the mass attenuation coefficient and half value layer, show enhanced behaviors with further La2O3 additions. The combination of enhanced radiation shielding properties and enhanced transparency makes the current glasses good candidates in the radiation shielding field.

Intervention reducing malaria parasite load in vector mosquitoes: No impact on Plasmodium falciparum extrinsic incubation period and the survival of Anopheles gambiae.

In the fight against malaria, transmission blocking interventions (TBIs) such as transmission blocking vaccines or drugs, are promising approaches to complement conventional tools. They aim to prevent the infection of vectors and thereby reduce the subsequent exposure of a human population to infectious mosquitoes. The effectiveness of these approaches has been shown to depend on the initial intensity of infection in mosquitoes, often measured as the mean number of oocysts resulting from an infectious blood meal in absence of intervention. In mosquitoes exposed to a high intensity of infection, current TBI candidates are expected to be ineffective at completely blocking infection but will decrease parasite load and therefore, potentially also affect key parameters of vector transmission. The present study investigated the consequences of changes in oocyst intensity on subsequent parasite development and mosquito survival. To address this, we experimentally produced different intensities of infection for Anopheles gambiae females from Burkina Faso by diluting gametocytes from three natural Plasmodium falciparum local isolates and used a newly developed non-destructive method based on the exploitation of mosquito sugar feeding to track parasite and mosquito life history traits throughout sporogonic development. Our results indicate the extrinsic incubation period (EIP) of P. falciparum and mosquito survival did not vary with parasite density but differed significantly between parasite isolates with estimated EIP50 of 16 (95% CI: 15-18), 14 (95% CI: 12-16) and 12 (95% CI: 12-13) days and median longevity of 25 (95% CI: 22-29), 15 (95% CI: 13-15) and 18 (95% CI: 17-19) days for the three isolates respectively. Our results here do not identify unintended consequences of the decrease of parasite loads in mosquitoes on the parasite incubation period or on mosquito survival, two key parameters of vectorial capacity, and hence support the use of transmission blocking strategies to control malaria.

ERK1/2 inhibitors act as monovalent degraders inducing ubiquitylation and proteasome-dependent turnover of ERK2, but not ERK1.

Innate or acquired resistance to small molecule BRAF or MEK1/2 inhibitors (BRAFi or MEKi) typically arises through mechanisms that sustain or reinstate ERK1/2 activation. This has led to the development of a range of ERK1/2 inhibitors (ERKi) that either inhibit kinase catalytic activity (catERKi) or additionally prevent the activating pT-E-pY dual phosphorylation of ERK1/2 by MEK1/2 (dual-mechanism or dmERKi). Here, we show that eight different ERKi (both catERKi or dmERKi) drive the turnover of ERK2, the most abundant ERK isoform, with little or no effect on ERK1. Thermal stability assays show that ERKi do not destabilise ERK2 (or ERK1) in vitro, suggesting that ERK2 turnover is a cellular consequence of ERKi binding. ERK2 turnover is not observed upon treatment with MEKi alone, suggesting it is ERKi binding to ERK2 that drives ERK2 turnover. However, MEKi pre-treatment, which blocks ERK2 pT-E-pY phosphorylation and dissociation from MEK1/2, prevents ERK2 turnover. ERKi treatment of cells drives the poly-ubiquitylation and proteasome-dependent turnover of ERK2 and pharmacological or genetic inhibition of Cullin-RING E3 ligases prevents this. Our results suggest that ERKi, including current clinical candidates, act as 'kinase degraders', driving the proteasome-dependent turnover of their major target, ERK2. This may be relevant to the suggestion of kinase-independent effects of ERK1/2 and the therapeutic use of ERKi.

Asteroseismology of evolved stars to constrain the internal transport of angular momentum

Context. Asteroseismic measurements of the internal rotation rate in evolved stars pointed to a lack of angular momentum (AM) transport in stellar evolution models. Several physical processes in addition to hydrodynamical ones were proposed as candidates for the missing mechanism. Nonetheless, no current candidate can satisfy all the constraints provided by asteroseismology. Aims. We revisit the role of a candidate process whose efficiency scales with the contrast between the rotation rate of the core and the surface. This process was proposed in previous works to be related to the azimuthal magneto-rotational instability. Methods. We computed stellar evolution models of low- and intermediate-mass stars with the parametric formulation of AM transport proposed in previous works for this instability until the end of the core-helium burning for low- and intermediate-mass stars, and compare our results to the latest asteroseismic constraints available in the post-main sequence phase. Results. Both hydrogen-shell-burning stars in the red-giant branch and core-helium-burning stars of low- and intermediate-mass in the mass range 1 M⊙ ≲ M ≲ 2.5 M⊙ can be simultaneously reproduced by this kind of parametrisation. Conclusions. Given the current constraints from asteroseismology, the core rotation rate of post-main sequence stars seems to be well explained by a process whose efficiency is regulated by the internal degree of differential rotation in radiative zones.