Molecular determinants of cross-reactivity and potency by VH3-33 antibodies against the Plasmodium falciparum circumsporozoite protein.

IGHV3-33-encoded antibodies are prevalent in the human humoral response against the Plasmodium falciparum circumsporozoite protein (PfCSP). Among VH3-33 antibodies, cross-reactivity between PfCSP major repeat (NANP), minor (NVDP), and junctional (NPDP) motifs is associated with high affinity and potent parasite inhibition. However, the molecular basis of antibody cross-reactivity and the relationship with efficacy remain unresolved. Here, we perform an extensive structure-function characterization of 12 VH3-33 anti-PfCSP monoclonal antibodies (mAbs) with varying degrees of cross-reactivity induced by immunization of mice expressing a human immunoglobulin gene repertoire. We identify residues in the antibody paratope that mediate cross-reactive binding and delineate four distinct epitope conformations induced by antibody binding, with one consistently associated with high protective efficacy and another that confers comparably potent inhibition of parasite liver invasion. Our data show a link between molecular features of cross-reactive VH3-33 mAb binding to PfCSP and mAb potency, relevant for the development of antibody-based interventions against malaria.

Increased PrEP uptake and PrEP-RN coincide with decreased HIV diagnoses in men who have sex with men in Ottawa, Canada.

Background: We sought to evaluate if increased uptake of HIV pre-exposure prophylaxis (PrEP) correlated to population-level changes in human immunodeficiency virus (HIV) epidemiology, in a setting with an integrated PrEP delivery system centred on a public health nurse-led PrEP clinic and referral process. Methods: This study was conducted in Ottawa, Canada, where all positive HIV test results are reported to the public health units. Risk factor information is also collected by nurses and subsequently entered into a provincial database. We extracted these data for Ottawa from 2017 to 2021 and restricted our analyses to first-time diagnoses. Results: We identified 154 persons with a new HIV diagnosis. Over this period, the number of new diagnoses among men who have sex with men, the group most targeted for PrEP, decreased by 50%-60%. We did not identify changes in the number of new diagnoses based on race, intravenous drug use or among women. Conclusion: Increasing PrEP uptake in Ottawa in 2017 to 2021 coincided with a significant decrease in new HIV diagnoses among men who have sex with men. PrEP uptake in Ottawa, particularly by those most at risk, is likely supported by an integrated approach via PrEP-RN, a nurse-led public health program where individuals diagnosed with syphilis or rectal gonorrhea or chlamydia receive an automatic offer of PrEP. While these findings cannot causally link PrEP-RN or PrEP with this reduction in new HIV diagnoses, these changes in HIV epidemiology in Ottawa occurred exclusively among the group targeted for PrEP. These data highlight the efficacy and importance of PrEP.

Intracellular localization of the proteasome in response to stress conditions.

The ubiquitin-proteasome system fulfills an essential role in regulating protein homeostasis by spatially and temporally controlling proteolysis in an ATP- and ubiquitin-dependent manner. However, the localization of proteasomes is highly variable under diverse cellular conditions. In yeast, newly synthesized proteasomes are primarily localized to the nucleus during cell proliferation. Yeast proteasomes are transported into the nucleus through the nuclear pore either as immature subcomplexes or as mature enzymes via adapter proteins Sts1 and Blm10, while in mammalian cells, postmitotic uptake of proteasomes into the nucleus is mediated by AKIRIN2, an adapter protein essentially required for nuclear protein degradation. Stressful growth conditions and the reversible halt of proliferation, that is quiescence, are associated with a decline in ATP and the reorganization of proteasome localization. Cellular stress leads to proteasome accumulation in membraneless granules either in the nucleus or in the cytoplasm. In quiescence, yeast proteasomes are sequestered in an ubiquitin-dependent manner into motile and reversible proteasome storage granules in the cytoplasm. In cancer cells, upon amino acid deprivation, heat shock, osmotic stress, oxidative stress, or the inhibition of either proteasome activity or nuclear export, reversible proteasome foci containing polyubiquitinated substrates are formed by liquid-liquid phase separation in the nucleus. In this review, we summarize recent literature revealing new links between nuclear transport, ubiquitin signaling, and the intracellular organization of proteasomes during cellular stress conditions.

Sinus arrest during valsalva maneuver after pneumonectomy: A case report / 대한마취과학회지

We report a case of cardiac arrest in a 71 year old male during the Valsalva maneuver that had been performed immediately after completing a pneumonectomy. The patient had a subclinical atrial septal defect (1.08 cm sized) and he previously undergone a left upper lobectomy of the lung without complications 11 months earlier. He underwent a left completion pneumonectomy due to recurrent lung cancer. After surgery a Valsalva maneuver was performed with 35 cmH2O to relocate the mediastinum. During this procedure, the patient experienced a cardiac arrest and was resuscitated with difficulty. It is believed that the cardiac arrest was due to pulmonary hypertension, right ventricular failure and right to left shunt caused by several factors, such as the pneumonectomy, subclinical atrial septal defect (1.08 cm sized), and Valsalva maneuver. In addition, the hypovolemia caused by fluid restriction and the epidural injection of local anesthetics might have contributed to this incident. Although it is a rare complication, it is suggested that subclinical ASD can cause severe hypoxemia, dyspnea even cardiac arrest after pneumonectomy. In order to avoid these complications, ASD should be treated with percutaneous closure or surgical intervention. If these are not possible, care must be taken when anesthetizing the patient, and anything that can increase the pulmonary vascular resistance and right to left shunt should be avoided.

Isolation of Phenolate Type Siderophore from Pseudomonas sp. PY002

Phenolate type siderophore was produced in Pseudomonas sp. PY002 (P. sp. PY002) which cultured in M9 minimal medium supplemented with 0 to 500 uM of dipyridyl. Pyochelin, a kind of siderophore, was detected as a single broad absorption band (280 nm) at pH 12.0, which is a characteristic of phenolate type siderophore. The 280 nm absorption spectrum of pyochelin was changed to 310 nm at pH 1.5. The pyochelin produced was a structurally unique phenolate siderophore, designated 2-[2-(o-hydroxyphenyl)-2-thiazolin-4-yl]-3-methyl-4-thiazolidine car- boxylic acid on the analysis of infrared radiation and 'H and ""C nuclear magnetic resonance spectroscopy. Additionally, purified pyochelin increased the cell growth rate, like as growth fac- tor. All these results suggest that phenolate type siderophore play an important role in cell growth of P. sp. PY002.