The continuous evolution of SARS-CoV-2 generated highly mutated variants, like omicron BA.1 and BA.2, able to escape natural and vaccine-induced primary immunity1,2. The administration of a third dose of mRNA vaccines induces a secondary response with increased protection. We investigated, at single-cell level, the longitudinal evolution of the neutralizing antibody response in four donors after three mRNA doses3. A total of 4,100 spike protein specific memory B cells were single cell sorted and 350 neutralizing antibodies were identified. The third dose increased the antibody neutralization potency and breadth against all SARS-CoV-2 variants of concern as previously observed with hybrid immunity3. However, the B cell repertoire that stands behind the response is dramatically different. The increased neutralizing response was largely due to the expansion of B cell germlines poorly represented after two doses, and the reduction of germlines predominant after primary immunization such as IGHV3-53;IGHJ6-1 and IGHV3-66;IGHJ4-1. Divergently to hybrid immunity, cross-protection after a third dose was mainly guided by Class 1/2 antibodies encoded by IGHV1-58;IGHJ3-1 and IGHV1-69;IGHJ4-1 germlines. The IGHV2-5;IGHJ3-1 germline, which induced broadly cross-reactive Class 3 antibodies after infection or viral vector vaccination, was not induced by a third mRNA dose. Our data show that while neutralizing breadth and potency can be improved by different immunization regimens, each of them has a unique molecular signature which should be considered while designing novel vaccines and immunization strategies.

Controlling posture, i.e., governing the ensemble of involuntary muscular activities that manage body equilibrium, represents a demanding function in which the cerebellum plays a key role. Postural activities are particularly important during gait initiation when passing from quiet standing to locomotion. Indeed, several studies used such motor task for evaluating pathological conditions, including cerebellar disorders. The linkage between cerebellum maturation and the development of postural control has received less attention. Therefore, we evaluated postural control during quiet standing and gait initiation in children affected by a slow progressive generalized cerebellar atrophy (SlowP) or non-progressive vermian hypoplasia (Joubert syndrome, NonP), compared to that of healthy children (H). Despite the similar clinical evaluation of motor impairments in NonP and SlowP, only SlowP showed a less stable quiet standing and a shorter and slower first step than H. Moreover, a descriptive analysis of lower limb and back muscle activities suggested a more severe timing disruption in SlowP. Such differences might stem from the extent of cerebellar damage. However, literature reports that during childhood, neural plasticity of intact brain areas could compensate for cerebellar agenesis. We thus proposed that the difference might stem from disease progression, which contrasts the consolidation of compensatory strategies.

Recent data suggest that the parietal operculum acts as an integration center within a multimodal network, originating from different primary sensory and motor cortices and projecting to frontal, parietal and temporal cortical hubs, which in turn govern cognitive and motor functions. Thus, parietal operculum might also play a crucial role in the integrated control of voluntary movement and posture. As a first step to test this hypothesis, the Anticipatory Postural Adjustments (APAs) stabilizing the arm when the index-finger is briskly flexed were recorded, on the preferred side, in three groups of 10 healthy subjects, before, during and after CATHODAL or ANODAL transcranial Direct Current Stimulation (tDCS, 20 min at 2 mA) applied over the contralateral Parietal Operculum (coPO). Results were compared to those obtained in a SHAM group. In agreement with literature, in the SHAM group the activation of the prime mover Flexor Digitorum Superficialis was preceded by an inhibitory APA in Biceps Brachii and Anterior Deltoid, and almost simultaneous to an excitatory APA in Triceps Brachii. The same pattern was observed in both the CATHODAL and ANODAL groups, with no significant tDCS effects on APAs amplitude and timing. Index-finger kinematics were also unchanged. These negative results suggest that the coPO does not disturb the key network governing APAs in index-finger flexion. Since it has been well documented that such APAs share many features with those observed in trunk and limb muscles when performing several other movements, we suggest that coPO may not be crucial to the general APA control.

Voluntary movements induce postural perturbations which are counteracted by anticipatory postural adjustments (APAs). These actions are known to build up long fixation chains toward available support points (inter-limb APAs), so as to grant whole body equilibrium. Moreover, recent studies highlighted that APAs also build-up short fixation chains, within the same limb where a distal segment is moved (intra-limb APAs), aimed at stabilizing the proximal segments. The neural structures generating intra-limb APAs still need investigations; the present study aims to compare focal movement kinematics and intra-limb APA latencies and pattern between healthy subjects and parkinsonian patients, assuming the latter as a model of basal ganglia dysfunction. Intra-limb APAs that stabilize the arm when the index-finger is briskly flexed were recorded in 13 parkinsonian patients and in 10 age-matched healthy subjects. Index-finger movement was smaller in parkinsonian patients vs. healthy subjects (p = 0.01) and more delayed with respect to the onset of the prime mover flexor digitorum superficialis (FDS, p < 0.0001). In agreement with the literature, in all healthy subjects the FDS activation was preceded by an inhibitory intra-limb APA in biceps brachii (BB) and anterior deltoid (AD), and almost simultaneous to an excitatory intra-limb APA in triceps brachii (TB). In parkinsonian patients, no significant differences were found for TB and AD intra-limb APA timings, however only four patients showed an inhibitory intra-limb APA in BB, while other four did not show any BB intra-limb APAs and five actually developed a BB excitation. The frequency of occurrence of normal sign, lacking, and inverted BB APAs was different in healthy vs. parkinsonian participants (p = 0.0016). The observed alterations in index-finger kinematics and intra-limb APA pattern in parkinsonian patients suggest that basal ganglia, in addition to shaping the focal movement, may also contribute to intra-limb APA control.

This review aims to highlight the important contribution of the cerebellum in the Anticipatory Postural Adjustments (APAs). These are unconscious muscular activities, accompanying every voluntary movement, which are crucial for optimizing motor performance by contrasting any destabilization of the whole body and of each single segment. Moreover, APAs are deeply involved in initiating the displacement of the center of mass in whole-body reaching movements or when starting gait. Here we present literature that illustrates how the peculiar abilities of the cerebellum i) to predict, and contrast in advance, the upcoming mechanical events; ii) to adapt motor outputs to the mechanical context, and iii) to control the temporal relationship between task-relevant events, are all exploited in the APA control. Moreover, recent papers are discussed which underline the key role of cerebellum ontogenesis in the correct maturation of APAs. Finally, on the basis of a survey of animal and human studies about cortical and subcortical compensatory processes that follow brain lesions, we propose a candidate neural network that could compensate for cerebellar deficits and suggest how to verify such a hypothesis.