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Adjuvants and antigen delivery kinetics can profoundly influence B cell responses and should be critically considered in rational vaccine design, particularly for difficult neutralizing antibody targets such as human immunodeficiency virus (HIV). Antigen kinetics can change depending on the delivery method. To promote extended immunogen bioavailability and to present antigen in a multivalent form, native-HIV Env trimers are modified with short phosphoserine peptide linkers that promote tight binding to aluminum hydroxide (pSer:alum). Here we explore the use of a combined adjuvant approach that incorporates pSer:alum-mediated antigen delivery with potent adjuvants (SMNP, 3M-052) in an extensive head-to-head comparison study with conventional alum to assess germinal center (GC) and humoral immune responses. Priming with pSer:alum plus SMNP induces additive effects that enhance the magnitude and persistence of GCs, which correlate with better GC-T FH cell help. Autologous HIV-neutralizing antibody titers are improved in SMNP-immunized animals after two immunizations. Over 9 months after priming immunization of pSer:alum with either SMNP or 3M-052, robust Env-specific bone marrow plasma cells (BM B PC ) are observed. Furthermore, pSer-modification of Env trimer reduce targeting towards immunodominant non-neutralizing epitopes. The study shows that a combined adjuvant approach can augment humoral immunity by modulating immunodominance and shows promise for clinical translation. Protein antigens, such as HIV envelope protein, require adjuvants for high immunogenicity. Here the authors show that a combined adjuvant approach with slow antigen delivery and potent ISCOMs adjuvant primes robust germinal center activity and humoral immunity in non-human primates. pSer-modified antigen shifts immunodominance to allow subdominant epitope-targeting of rare B cells.

Vaccination strategies aimed at maturing broadly neutralizing antibodies (bnAbs) from naïve precursors are hindered by unusual features that characterize these Abs, including insertions and deletions (indels). Longitudinal studies of natural HIV infection cases shed light on the complex processes underlying bnAb development and have suggested a role for superinfection as a potential enhancer of neutralization breadth. Here we describe the development of a potent bnAb lineage that was elicited by two founder viruses to inform vaccine design. The V3-glycan targeting bnAb lineage (PC39-1) was isolated from subtype C-infected IAVI Protocol C elite neutralizer, donor PC39, and is defined by the presence of multiple independent insertions in CDRH1 that range from 1-11 amino acids in length. Memory B cell members of this lineage are predominantly atypical in phenotype yet also span the class-switched and antibody-secreting cell compartments. Development of neutralization breadth occurred concomitantly with extensive recombination between founder viruses before each virus separated into two distinct population “arms” that evolved independently to escape the PC39-1 lineage. Ab crystal structures show an extended CDRH1 that can help stabilize the CDRH3. Overall, these findings suggest that early exposure of the humoral system to multiple related Env molecules could promote the induction of bnAbs by focusing Ab responses to conserved epitopes.

This study aimed to explore experiences of women with anal incontinence following a childbirth injury, and to identify areas of missed opportunities within care they received. This is a qualitative study involving semi-structured interviews. Participants were recruited via five hospitals in the UK, and via social media adverts and communication from charity organisations. Women who have experienced anal incontinence following a childbirth injury, either within 7 years of sustaining the injury, or if they identified new, or worsening symptoms of AI at the time of menopause. Main outcomes are experiences of women with anal incontinence following childbirth injury, and missed opportunities within the care they received. The following main themes were identified: opportunities for diagnosis missed, missed opportunities for information sharing and continuity and timeliness of care. Anal Incontinence following a childbirth injury has a profound impact on women. Lack of information and awareness both amongst women and healthcare professionals contributes to delays in accurate diagnosis and appropriate treatment.

Control of wire-borne underactuated brachiating robots requires a robust feedback control design that can deal with dynamic uncertainties, actuator constraints and unmeasurable states. In this paper, we develop a robust feedback control for brachiating on flexible cables, building on previous work on optimal trajectory generation and time-varying LQR controller design. We propose a novel simplified model for approximation of the flexible cable dynamics, which enables inclusion of parametric model uncertainties in the system. We then use semidefinite programming (SDP) and sum-of-squares (SOS) optimization to synthesize a time-varying feedback control with formal robustness guarantees to account for model uncertainties and unmeasurable states in the system. Through simulation, hardware experiments and comparison with a time-varying LQR controller, it is shown that the proposed robust controller results in relatively large robust backward reachable sets and is able to reliably track a pre-generated optimal trajectory and achieve the desired brachiating motion in the presence of parametric model uncertainties, actuator limits, and unobservable states.

In an attempt to isolate cells that could survive with total replacement of thymidine by bromodeoxyuridine in nuclear DNA, cells of a bromodeoxyuridine-dependent Syrian hamster line were cultured in medium containing aminopterin and bromodeoxyuridine but no thymidine. A line of cells, called HAB, was isolated. The HAB cells have been maintained in continuous cultivation for over nine months and have undergone more than 125 population doublings. Direct base analysis showed that the level of substitution of bromodeoxyuridine for thymidine in nuclear DNA was at least 99.8%, and possibly 100%. The existence of such cells raises many questions. The expected high frequency of bromodeoxyuridine-induced base transitions, including errors in both replication and transcription, would seem to be incompatible with the apparently stable transmission and expression of the genetic information in these cells.

When cells of a Syrian hamster melanoma were grown in increasing concentrations of bromodeoxyuridine (BrdU), lines of mutant cells able to grow well at high concentrations of BrdU were isolated. The mutant cells were characterized by BrdU dependence. In the absence of BrdU, the cells grew very poorly. The requirement for BrdU was specific for both the bromine and the deoxy sugar. The mutant cells incorporated BrdU into the DNA, replacing about 50% of the thymine residues with bromouracil. The reason for the BrdU dependence is not known.

Previous work has shown the complement of leucyl transfer RNA (tRNALeu) isoaccepting species present in soybean cotyledons to change during cotyledon senescence. Of the six tRNALeuspecies resolved by Freoncolumn chromatography, the capacity of species 1-4 to accept leucine is decreased between 5 and 21 days of age. Parallel changes in tRNALeusynthetase activity are reported here during the same time period. There is a reduction in the capacity of the synthetase from 21-day-old cotyledons to aminoacylate tRNALeu1-4, while the capacity to charge tRNALeu5-6 remains high. When tRNALeuderived from 5-day-old cotyledons is maximally charged with the 21-day synthetase, the subsequent addition of synthetase from 5-day-old cotyledons promotes additional charging, primarily of species 1-4. These results suggest the presence of tRNALeu``subspecies'' within the individual peaks resolved on a Freon column, differing in synthetase specificity.

Mammalian cell DNA that exhibited anomalous sedimentation in alkaline sucrose gradients was examined directly by electron microscopy. Its appearance was that of duplex DNA. In addition, some duplex DNA was observed under conditions in which the sedimentation anomaly was no longer apparent. Persistence of double-stranded DNA under denaturing conditions suggests caution in the interpretation of changes in the molecular weight or conformation of DNA based solely on analysis of sedimentation profiles.