Atypical chemokine receptor 4 shapes activated B cell fate

Activated B cells can initially differentiate into three functionally distinct fates-early plasmablasts (PBs), germinal center (GC) B cells, or early memory B cells-by mechanisms that remain poorly understood. Here, we identify atypical chemokine receptor 4 (ACKR4), a decoy receptor that binds and degrades CCR7 ligands CCL19/CCL21, as a regulator of early activated B cell differentiation. By restricting initial access to splenic interfollicular zones (IFZs), ACKR4 limits the early proliferation of activated B cells, reducing the numbers available for subsequent differentiation. Consequently, ACKR4 deficiency enhanced early PB and GC B cell responses in a CCL19/CCL21-dependent and B cell-intrinsic manner. Conversely, aberrant localization of ACKR4-deficient activated B cells to the IFZ was associated with their preferential commitment to the early PB linage. Our results reveal a regulatory mechanism of B cell trafficking via an atypical chemokine receptor that shapes activated B cell fate

Diagonalization of multicomponent wave equations with a Born-Oppenheimer example

A general method to decouple multicomponent linear wave equations is presented. First, the Weyl calculus is used to transform operator relations into relations between c-number valued matrices. Then it is shown that the symbol representing the wave operator can be diagonalized systematically up to arbitrary order in an appropriate expansion parameter. After transforming the symbols back to operators, the original problem is reduced to solving a set of linear uncoupled scalar wave equations. The procedure is exemplified for a particle with a Born-Oppenheimer-type Hamiltonian valid through second order in h. The resulting effective scalar Hamiltonians are seen to contain an additional velocity-dependent potential. This contribution has not been reported in recent studies investigating the adiabatic motion of a neutral particle moving in an inhomogeneous magnetic field. Finally, the relation of the general method to standard quantum-mechanical perturbation theory is discussed

Adiabatic motion of a neutral spinning particle in an inhomogeneous magnetic field

The motion of a neutral particle with a magnetic moment in an inhomogeneous magnetic field is considered. This situation, occurring, for example, in a Stern-Gerlach experiment, is investigated from classical and semiclassical points of view. It is assumed that the magnetic field is strong or slowly varying in space, i.e., that adiabatic conditions hold. To the classical model, a systematic Lie-transform perturbation technique is applied up to second order in the adiabatic-expansion parameter. The averaged classical Hamiltonian contains not only terms representing fictitious electric and magnetic fields but also an additional velocity-dependent potential. The Hamiltonian of the quantum-mechanical system is diagonalized by means of a systematic WKB analysis for coupled wave equations up to second order in the adiabaticity parameter, which is coupled to Planck’s constant. An exact term-by-term correspondence with the averaged classical Hamiltonian is established, thus confirming the relevance of the additional velocity-dependent second-order contribution

Short Communications Proton MR Spectroscopy Correlates Diffuse Axonal Abnormalities with Post-Concussive Symptoms in Mild Traumatic Brain Injury

Abstract There are no established biomarkers for mild traumatic brain injury (mTBI), in part because post-concussive symptoms (PCS) are subjective and conventional imaging is typically unremarkable. To test whether diffuse axonal abnormalities quantified with three-dimensional (3D) proton magnetic resonance spectroscopic imaging ( 1 H-MRSI) correlated with patients' PCS, we retrospectively studied 26 mTBI patients (mean Glasgow Coma Scale [GCS] score of 14.7), 18-to 56-year-olds and 13 controls three to 55 days post-injury. All were scanned at 3 Tesla with T1-and T2-weighted MRI and 3D 1 H-MRSI (480 voxels over 360 cm 3 , *30% of the brain). On scan day, patients completed a symptom questionnaire, and those who indicated at least one of the most common subacute mTBI symptoms (headache, dizziness, sleep disturbance, memory deficits, blurred vision) were grouped as PCS-positive. Global gray matter and white matter (GM/WM) absolute concentrations of N-acetylaspartate (NAA), choline (Cho), creatine (Cr) and myo-inositol (mI) in PCS-positive and PCS-negative patients were compared to age-and gender-matched controls using two-way analysis of variance. The results showed that the PCS-negative group (n = 11) and controls (n = 8) did not differ in any GM or WM metabolite level. The PCS-positive patients (n = 15) had lower WM NAA than the controls (n = 12; 7.0 -0.6 versus 7.9 -0.5mM; p = 0.0007). Global WM NAA, therefore, showed sensitivity to the TBI sequelae associated with common PCS in patients with mostly normal neuroimaging, as well as GCS scores. This suggests a potential biomarker role in a patient population in which objective measures of injury and symptomatology are currently lacking

Epidemiology of Kaposi’s sarcoma in sub-Saharan Africa

Kaposi’s sarcoma (KS) has become a common AIDS-defining cancer in sub-Saharan Africa. Kaposi’s sarcoma-associated human herpesvirus strongly modulated by HIV-related immune suppression are the principal causes of this cancer. No other risk factors have been identified as playing a strong role. HIV prevention programs and good coverage of antiretroviral therapy (ART) in developed countries resulted in a remarkable decline in HIV-KS incidence and better KS prognosis. By contrast, in sub-Saharan Africa, population ART rollout has lagged, but clinical studies have shown positive results in reduction of KS incidence and better KS prognosis. However, the effect of ART rollout in relation to population KS incidence is unclear. We describe the incidence of KS in sub-Saharan Africa, in four time-periods, (1) before 1980 (before HIV/AIDS era); (2) 1981–2000 (early HIV/AIDS era, limited or no ART coverage); (3) 2001–2010 (early ART coverage period); and (4) 2011–2016 (fair to good ART coverage period). We used KS incidence data available from WHO-International Agency for Research on Cancer (IARC) publications and the Africa Cancer Registry Network. National HIV prevalence and ART coverage data were derived from UNAIDS/WHO. A rapid increase in KS incidence was observed throughout sub-Saharan Africa as the HIV epidemic progressed, reaching peak incidences in Period 2 (pre-ART rollout) of 50.8 in males and 20.3 per 100 000 in females (Zimbabwe, Harare). The overall unweighted average decline in KS incidence between 2000 and 2010 and 2011–2016 was 27%, but this decline was not statistically significant across the region. ART rollout coincides with a decline in KS incidence across several regions in sub-Saharan Africa. The importance of other risk factors such as reductions in HIV incidence could not be ascertained

Lifestyle factors associated with sex differences in Kaposi sarcoma incidence among adult black South Africans : A case-control study

Kaposi Sarcoma (KS) is endemic in several countries in Southern and Eastern Africa, relatively rare worldwide but a leading cancer among people living with HIV. KS has always been more common in adult males than females. We assessed the prevalence of known cancer modifying factors (parity, hormonal contraceptive use in females, sex-partners, smoking and alcohol consumption in both sexes), and their relationship to KS, and whether any of these could account for the unequal KS sex ratios. We calculated logistic regression case-control adjusted odds ratios (ORadj), and 95% confidence intervals (95%CI), between KS and each of the modifying factors, using appropriate comparison controls. Controls were cancer types that had no known relationship to exposures of interest (infection or alcohol or smoking or contraceptive use). The majority of the 1275 KS cases were HIV positive (97%), vs. 15.7% in 10,309 controls. The risk of KS among those with HIV was high in males (ORadj=116.70;95%CI=71.35-190.88) and females (ORadj=93.91;95%CI=54.22-162.40). Among controls, the prevalence of smoking and alcohol consumption was five and three times higher in males vs. females. We found a positive association between KS and heavy vs. non-drinking (ORadj=1.31;95%CI=1.03-1.67), and in current heavy vs. never smokers (ORadj=1.82;95%CI=1.07-3.10). These associations remained positive for alcohol consumption (but with wider CIs) after stratification by sex, and restriction to HIV positive participants. We found no evidence of interactions of smoking and alcohol by sex. Smoking and alcohol consumption may provide a possible explanation for the KS sex differences, given both exposures are more common in men, but confounding and bias cannot be fully ruled out. The role smoking and alcohol play in relation to viral loads of HIV/KSHV, differences in immunological responses or other genetic differences between males and females warrant further studies

Kaposi sarcoma-associated herpesvirus, HIV-1 and Kaposi sarcoma risk in black South Africans diagnosed with cancer during antiretroviral treatment rollout

Abstract Kaposi sarcoma-associated herpesvirus (KSHV) causes Kaposi sarcoma (KS). The risk of KS is amplified in HIV-immunosuppressed individuals and antiretroviral therapy (ART) reduces KS incidence. Reliable data on the relationship between these factors are lacking in Africa. We used questionnaires and serum from 7886 black South Africans (18-74 years) with incident cancer, recruited between 1995 and 2016. ART rollout started in 2004. We measured associations between KS, HIV-1 and KSHV before and after ART rollout. We measured seropositivity to HIV-1, KSHV latency-associated nuclear antigen (LANA) and glycoprotein (K8.1) and calculated case-control-adjusted odds ratios (ORadj) and 95CI) in relation to KS and KSHV infection, before (1995-2004), early (2005-2009) and late (2010-2016) ART rollout periods. KSHV seropositivity among 1237 KS cases was 98649 controls, KSHV seropositivity was higher in males (ORadj = 1.4 [95.23-1.52]), in persons with HIV, (ORadj = 4.2 [95.74-4.73]) and lower in high school leavers (ORadj = 0.7 [95.59-0.83]). KSHV seropositivity declined over the three ART rollout periods (37 288 Ptren

HPV types 16/18 L1 E6 and E7 proteins seropositivity and cervical cancer risk in HIV-positive and HIV-negative black South African women

BACKGROUND: In populations with high rates of human immunodeficiency virus (HIV)-coinfection, the nature of the relationship between human papillomavirus (HPV)-16 and -18 (L1, E6 and E7) antibodies and cervical cancer is still uncertain. We measured the association between seropositivity to HPV (L1, E6 and E7) proteins and cervical cancer among black South African women with and without HIV co-infection. METHODS: We used questionnaire data and serum collected from consecutively recruited patients with a newly diagnosed cancer from the Johannesburg Cancer Study from 1346 cervical cancer cases and 2532 controls (diagnosed with other non-infection related cancers). Seropositivity to HPV proteins was measured using a multiplex serological assay based on recombinant glutathione S-transferase (GST) fusion proteins. We measured associations between their presence and cervical cancer using unconditional logistic regression models and evaluated the sensitivity and specificity of these HPV biomarkers. RESULTS: Among controls, HIV-negative women from rural areas compared to urban had significantly higher HPV seroprevalence, HPV16 E7 (8.6% vs 3.7%) and HPV18 E7 (7.9% vs 2.0%). HPV16 E6 and E7 antibodies were positively associated with cervical cancer in HIV-positive (Adjusted Odds Ratio (AOR) = 33; 95% CI 10-107) and HIV-negative women (AOR = 97; 95% CI 46-203). In HIV-positive women, HPV E6/E7 antibodies had low sensitivity (43.0%) and high specificity (90.6%) for cervical cancer detection. In HIV-negative women, HPV E6/E7 antibodies sensitivity was 70.6% and specificity was 89.7%. CONCLUSIONS: Our data show that HPV (L1, especially E6 and E7) antibody positivity is associated with cervical cancer in both HIV-positive and HIV-negative women. Nonetheless, being HIV-positive plays an important role in the development of cervical cancer